EKSPRESI ENDOTELIN-1 PADA BERBAGAI VARIASI HISTOPATOLOGIS KERATOSIS SEBOROIK TESIS Oleh dr. EVITA LOURDES PINEM PROGRAM PENDIDIKAN DOKTER SPESIALIS DEPARTEMEN ILMU KESEHATAN KULIT DAN KELAMIN FAKULTAS KEDOKTERAN UNIVERSITAS SUMATERA UTARA MEDAN 2017
Ekspresi Endotelin-1 pada Berbagai Variasi Histopatologis Keratosis Seboroik Evita Lourdes Pinem, Imam Budi Putra, Nelva Karmila Jusuf Departemen Ilmu Kesehatan Kulit dan Kelamin Fakultas Kedokteran RSUP H. Adam Malik Medan Abstrak: Latar belakang: Keratosis seboroik adalah suatu tumor benigna yang terdiri dari keratinosit epidermis dengan pigmentasi meningkat. Variasi histopatologis keratosis seboroik adalah: akantotik, flat, irritated, stuccokeratosis, pigmented, reticulated, pedunculated, dermatosis papulose nigra, dan klonal. Diduga bahwa melanisasi yang meningkat yang terobservasi pada keratosis seboroik dikaitkan dengan produksi endotelin-1 yang meningkat pada proliferasi keratinosit yang tinggi sehingga menimbulkan neoplasma. Tujuan: Mengetahui ekspresi endotelin-1 pada berbagai variasi histopatologis keratosis seboroik. Metode: Penelitian ini menggunakan studi deskriptif observasional laboratoris dengan rancangan potong lintang yang menggunakan 40 blok parafin yang telah diperiksa secara histopatologis sebagai keratosis seboroik dan telah ditentukan variasi histopatologinya. Hasil: Ekspresi endotelin-1 pada 14 sampel keratosis seboroik varian akantotik didapati kuat 4 sampel (28,57%), sedang 4 sampel (28,57%), dan lemah 6 sampel (42,85%), dan letak endotelin-1 pada stratum basalis 9 sampel (64,28%), 1/3 bawah lapisan epidermis 1 sampel (7,14%), dan seluruh lapisan epidermis 4 sampel (28,57%). Ekspresi endotelin-1 pada 6 sampel keratosis seboroik varian flat didapati kuat 1 sampel (16,67 %), sedang 2 sampel (33,33%), dan lemah 3 sampel (50 %) dan letak endotelin-1 pada stratum basalis 5 sampel (83,33%), dan 1/3 bawah lapisan epidermis 1 sampel (16,66%). Ekspresi endotelin-1 pada1 sampel keratosis seboroik varian irritated didapati lemah 1 sampel (100%) dan letak endotelin-1 pada seluruh lapisan epidermis 1 sampel (100%). Ekspresi endotelin-1 pada 6 sampel keratosis seboroik varian stuccokeratosis didapati kuat pada 2 sampel (33,33 %), sedang 1 sampel (16,67%), dan lemah 3 sampel (50%) dan letak endotelin-1 pada stratum basalis 4 sampel (66,67%), 1/3 bawah lapisan epidermis 1 sampel (16,66%), dan seluruh lapisan epidermis 1 sampel (16,66%). Ekspresi endotelin-1 pada 2 sampel keratosis seboroik varian pigmented didapati kuat pada 2 sampel (100 %) dan letak endotelin-1 pada stratum basalis 1 sampel (50%), dan seluruh lapisan epidermis 1 sampel (50%). Ekspresi endotelin-1 pada 7 sampel keratosis seboroik varian reticulated didapati kuat 1 sampel (14,28%), sedang 4 sampel (57,14%), dan lemah 2 sampel (28,57%) dan letak endotelin-1 pada stratum basalis 7 sampel (100%). Ekspresi endotelin-1 pada 1 sampel keratosis seboroik varian pedunculated didapati sedang 1 sampel (100%) dan letak endotelin-1 pada lapisan stratum basalis 1 sampel (100%). Ekspresi endotelin-1 pada 3 sampel keratosis seboroik varian dermatosis papulose nigra didapati sedang 2 sampel (66,67%), dan lemah 1 sampel (33,33%) dan letak endotelin-1 pada stratum basalis 2 sampel (66,67%), dan seluruh lapisan epidermis 1 sampel (33,33%). Kesimpulan: Dilihat dari ekspresi endotelin-1 pada berbagai variasi histopatologis keratosis seboroik maka didapatkan ekspresi endotelin-1 yang kuat 25% (tipe akantotik 10%, i
stuccokeratosis 5%, pigmented 5%, flat 2,5%, dan reticulated 2,5%), sedang 35% (akantotik 10%, flat 5%, stuccokeratosis 2,5%, reticulated 10%, pedunculated 2,5%, dermatosis papulose nigra 5%), dan lemah 40% (akantotik 15%, flat 7,5%, irritated 2,5%, stuccokeratosis 7,5%, reticulated/ adenoid 5%, dan 1 dermatosis papulose nigra 2,5%). Kata kunci: Keratosis seboroik, ekspresi endotelin-1. ii
Endothelin-1 Expressions on Seborrheic Keratosis Histopathology Variants Evita Lourdes Pinem, Imam Budi Putra, Nelva Karmila Jusuf Dermatovenereology Department University of Sumatera Utara Medical Faculty H. Adam Malik Centre General Hospital Medan Abstract Background: Seborrheic keratosis is a benign tumor, composed of keratynocites with increased pigmentation. Seborrheic keratosis histopathological variants are acanthotic, flat, irritated, stuccokeratosis, pigmented, reticulated, pedunculated, dermatosis papulose nigra, and klonal. It suggested that the enhanced pigmentation in seborrheic keratosis is attributable to the upregulated expression of endothelin-1 by highly proliferating basaloid cells. Objective: To describe endothelin-1 expression on seborrheic keratosis histopathological variants. Materials and Methods: This study was descriptive observasional and cross sectional study, used 40 samples of seborrheic keratosis lesions that diagnosed based on histopathological examinations, and the histopathological variants have determined. Result: Endothelin-1 expressions of 14 acanthotic variants were strong 4 samples (28,57%), moderate 4 samples (28,57%), and weak 6 samples (42,85%) and endothelin-1 was located in stratum basale 9 samples (64,28%), one-third lower part of the epidermis 1 sample (7,14%), and epidermis 4 samples (28,57%). Endothelin-1 expressions of 6 flat variants were strong 1 sample (16,67%), moderate 2 samples (33,33%), and weak 3 samples (50%) and endothelin-1 was located in stratum basale 5 samples (83,33%) and one-third lower part of the epidermis 1 sample (16,66%). Endothelin-1 expression of 1 irritated variant was weak 1 sample (100%) and endothelin-1 was located in epidermis 1 sample (100 %). Endothelin-1 expressions of 3 stuccokeratosis variants were strong 2 samples (33,33%), moderate 1 sample (16,67%), and weak 3 samples (50%) and endothelin-1 was located in stratum basale 4 samples (66,67%), one-third lower part of the epidermis 1 sample (16,66%), and epidermis 1 sample (16,66%). Endothelin-1 expressions of 2 pigmented variants were strong 2 (10%) and endothelin-1 was located in stratum basale 1 sample (50%), and epidermis 1 sampel (50%). Endothelin-1 expressions of 7 reticulated variants were strong 1 sampel (14,28%), moderate 4 samples (57,14%), and weak 2 samples (28,57%) and endothelin-1 was located in stratum basale 7 samples(100%). Endothelin-1 expression of 1 pedunculated variant was moderate 1 sample (100%) and endothelin-1 was located in stratum basale 1 sample (100%). Endothelin-1 expressions of 3 dermatosis papulose nigra variants were moderate 2 samples (66,67%) and weak 1 sample (33,33%) and endothelin-1 was located in stratum basale 2 samples (66,67%) and epidermis 1 sample (33,33%). Conclusion: Endothelin-1 expressions of seborrheic keratosis histopathological variants were strong 25% (acanthotic 10 %, stuccokeratosis 5%, pigmented 5%, flat 2,5%, and reticulated 2,5%), moderate 35% (acanthotic 10%, flat 5%, stuccokeratosis 2,5%, reticulated 10%, pedunculated 2,5%, dermatosis papulose nigra 5%), and weak 40% (acanthotic 15%, flat 7,5%, irritated 2,5%, stuccokeratosis 7,5%, reticulated/adenoid 5% and dermatosis papulose nigra 2,5%). Key words: seborrheic keratosis, endothelin-1 expression. iii
DAFTAR ISI Halaman ABSTRAK... i ABSTRACT... iii DAFTAR ISI... iv DAFTAR SINGKATAN... vi DAFTAR TABEL... vii DAFTAR GAMBAR... viii DAFTAR LAMPIRAN... ix BAB I PENDAHULUAN... 1 1.1 Latar Belakang... 1 1.2 Rumusan Masalah... 3 1.3 Tujuan Penelitian... 3 1.3.1 Tujuan umum... 3 1.3.2 Tujuan khusus... 3 1.4 Manfaat penelitian... 5 1.4.1. Akademik... 5 1.4.2. Penelitian... 5 BAB II TINJAUAN PUSTAKA... 6 2.1 Keratosis Seboroik... 6 2.1.1. Epidemiologi... 6 2.1.2. Etiopatogenesis... 7 2.1.3. Faktor risiko... 9 2.1.4. Gambaran klinis... 10 2.1.5. Diagnosis banding... 11 2.1.6. Diagnosis... 12 2.1.7 Variasi histopatologis... 12 2.1.8. Penatalaksanaan... 18 2.1.9. Prognosis... 21 2.2 Endotelin-1... 21 2.3 Fungsi Endotelin-1... 21 2.4 Peran Endotelin-1 pada Keratosis Seboroik... 22 2.5 Kerangka Teori... 26 2.6 Kerangka Konsep... 27 BAB III METODE PENELITIAN... 28 3.1 Desain Penelitian... 28 3.2 Waktu dan Tempat Penelitian... 28 3.3 Sampel Penelitian... 28 3.4 Besar Sampel... 29 3.5 Cara Pengambilan Sampel penelitian... 30 3.6 Definisi Operasional... 30 3.7 Alat, Bahan dan Cara Kerja... 32 3.7.1 Alat... 32 3.7.2 Bahan... 32 iv
3.7.3 Cara kerja... 33 3. 8 Kerangka Operasional... 35 3. 9 Ethical Clearance... 35 BAB IV HASIL PENELITIAN DAN PEMBAHASAN... 36 4.1 Variasi Histopatologis... 36 4.2 Hasil Pemeriksaan Imunohistokimia... 37 4.2.1 Ekspresi endotelin-1 berdasarkan variasi histopatologis- nya... 37 4.2.2 Letak endotelin-1... 42 4.2.3 Ekspresi dan letak endotelin-1 berdasarkan variasi... histopatologisnya... 44 BAB V KESIMPULAN DAN SARAN... 47 5.1 Kesimpulan... 47 5.1 Saran... 48 DAFTAR PUSTAKA... 49 v
DAFTAR SINGKATAN Bcl-2 : B-cell lymphoma 2 Bfgf : Basic fibroblast growth factor CGH : Comparative genomic hybridization CO2 : Carbon dioxide DAB : Diaminobenzidine DNA : Deoxyribose nucleic acid DPN : Dermatosis papulosa nigra FGFR3 : Fibroblast growth factor receptor 3 GM-CSF : Granulocyte macrophage colony-stimulating factor receptor HGF : Hepatocyte growth factor HPV-DNA : Human Papilloma Virus- Deoxyribose nucleic acid IL-1 : Interleukin-1 MC1R : The melanocortin 1 receptor PBS : Phosphate buffered saline PCR : Polymerase chain reaction PIK3CA : Phosphatidylinositol-4,5-bisphosphate 3-kinase RSUP : Rumah Sakit Umum Pusat RT-PCR : Real time- polymerase chain reaction SCF : Stem cell factor SMF : Staf medik fungsional TNF-α : Tumour necrosing factor-α Trekavidin-HRP : Trekavidin-Horseradish Peroxidase TRP-1 : Tyronase-related protein 1 UV : Ultraviolet vi
DAFTAR TABEL No. Judul Halaman Tabel 3.1 Tabel tingkatan ekspresi endotelin-1... 32 Tabel 4.1 Tabel distribusi objek penelitian berdasarkan variasi histopatologis...36 Tabel 4.2 Tabel distribusi ekspresi endotelin-1 berdasarkan variasi histopatologis...37 Tabel 4.3 Tabel distribusi tingkatan ekspresi endotelin-1 berdasarkan variasi histopatologis...38 Tabel 4.4 Tabel distribusi objek penelitian berdasarkan letak endotelin-1...42 Tabel 4.5 Tabel distribusi kekuatan ekspresi endotelin-1 berdasarkan letak endotelin-1 pada berbagai variasi histopatologis keratosis seboroik...44 vii
DAFTAR GAMBAR No. Judul Halaman Gambar 2.1. Keratosis seboroik... 11 Gambar 2.2. Gambar histopatologis keratosis seboroik akantotik (umum)... 13 Gambar 2.3. Gambar histopatologis keratosis seboroik reticulated... 14 Gambar 2.4. Gambar histopatologis keratosis seboroik pigmented... 14 Gambar 2.5. Gambar histopatologis keratosis seboroik klonal... 15 Gambar 2.6. Gambar histopatologis keratosis seboroik irritated... 15 Gambar 2.7. Gambar histopatologis keratosis seboroik hiperkeratotik... 16 Gambar 2.8. Gambar histopatologis keratosis seboroik flat...17 Gambar 2.9. Gambar histopatologis dermatosis papulose nigra...18 Gambar 2.10.Gambar model sitokin parakrin hiperpigmentasi epidermal...23 Kerangka teori...26 Kerangka konsep...27 Kerangka operasional...35 viii
DAFTAR LAMPIRAN No. Judul Halaman Lampiran 1. Status penelitian... 55 Lampiran 2. Ethical Clearance... 56 Lampiran 3. Data dasar penelitian... 57 Lampiran 3. Data gambar imunohistokimia... 59 ix