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6.1. KESIMPULAN

 Tidak terdapat hubungan yang bermakna antara ekspresi protein p16 dengan beberapa faktor prognostik histopatologik melanoma malignum kulit jenis nodular yaitu gambaran ulserasi, dan aktivitas mitosis tinggi, dan metastasis kelenjar getah bening.

 Tidak terdapat hubungan yang bermakna antara ekspresi protein Ki-67 dengan beberapa faktor prognostik histopatologik melanoma malignum kulit jenis nodular yaitu gambaran ulserasi, dan aktivitas mitosis tinggi, dan metastasis kelenjar getah bening.

6.2. SARAN

 Perlu dilakukan penelitian dengan sampel yang lebih besar pada faktor prognostik histopatologik melanoma malignum jenis nodular dan penanda (marker)yang lain.

 Perlu dilakukan penelitian yang menghubungkan dengan angka kesintasan pasien – pasien melanoma malignum nodular.

Universitas Indonesia DAFTAR PUSTAKA.

1. Kanker di Indonesia tahun 2006. Data Histopatologik. Direktorat Jendral Pelayanan Medik Departemen Kesehatan Republik Indonesia. Badan Registrasi Kanker. Perhimpunan Dokter Spesialis Patologi Anatomik. Yayasan Kanker Indonesia.

2. Riker AI, Zea N, Trinh T. The epidemiology, prevention, and detection of melanoma. The Ochner Journal. 2010; 10: 56-65.

3. Tjarta A, Kanoko M, Ueda M, Hamzah M, Cipto H, Ichihashi M, et al. Rare case of melanoma studied for its histopathological features in Indonesia. Med J Indones. 2000;9:93-9.

4. Arisanty R, Tanurahardja B, Kanoko M. Tiga keganasan primer kulit tersering di Departemen Patologi Anatomik Rumah Sakit Cipto Mangunkusumo tahun 2005-2009. [Telaah Retrospektif]. FKUI.;2010. 5. Bandarchi B, Ma L, Navab R, Seth A, Rasty G. From melanocyte to

metastatic malignant melanoma.In : Manga P, Hoek KS, Davids LM, Leachman SA, editors. Dermatology Research and practice. From melanocyte to malignant metastatic melanoma. Hindawi publishing corporation; 2010.

6. Meyskens FLJ, Farmer PJ, Culver HA. Etilogic pathogenesis of melanoma : a unifying hypothesis for the missing atributable risk. Clin Cancer Res. 2004; 10: 2581-3.

7. Carlson JA, Slominski A, Linette GP, Mysliborski J, Hill J, Mihm MC, et al. Malignant melanoma 2003 : predisposition, diagnosis, prognosis and staging. Am J Clin Pathol. 2003; 120 (suppl 1): 101-27.

8. Elder DE, Elenitas R, Murphy FG,Xu X. Bening pigmented lesions and malignant melanoma. In: Elder.DE, editor. Lever’s histopathology of the

skin, 10th ed. Philadelphia: Wolter kluwer-lippincott

williams&wilkins;2009.p. 738-75.

9. Mc Master KM, Edward MJ, Ross MI, Reintgen DS, Martin RC, Urist MM. Ulceration as a predictive marker for response to adjuvan interferon therapy in melanoma. Ann. Surg.2010; 252: 460-6.

10. Homsi J, Sabet MK, Messina JL, Daud A. Cutaneous melanoma : prognostic factors. Cancer control. 2005; 12 (4) : 223-9.

11. Balch CM, Murad TM, Soong SJ, Ingalls AL, Halpern NB, Maddox WA. A multifactorial analysis of melanoma : prognostic histopathological features comparing Clark’s and Breslow’s staging methods. Ann surg. 1978;188(6): 732-42.

12. Attis MG, Vollmer RT. Mitotic rate in melanoma: a reexamination. Am J Clin Pathol. 2007; 127: 380-4.

Universitas Indonesia 13. Elias EG, Hasskamp JH, Sharma BK. Biology of human cutaneous

melanoma.Cancer.2010; 2:165-89.

14. Gaudi S, Messina JL. Molecular bases of cutaneous and uveal melanomas. In : Manga P, Hoek KS, Davids LM, Leachman SA, editors. Dermatology Research and practice. From melanocyte to malignant metastatic melanoma. Hindawi publishing corporation; 2010.

15. Kuilman T, Michaloglou C, Mooi WJ, Peeper DS. The essence of senescence. Genes dev. 2010; 24: 2463-79.

16. Li N, Mangini J, Bhawan J. New prognostic factors of cutaneous melanoma : a review of literature. J Cutan Pathol. 2002; 29: 324-40.

17. Ladstein RG, Bachmann IM, Staraume O Akslen LA. Ki-67 expression is superior to mitotic count and novel proliferation markers PHH3, MCM4 and mitosis as a prognostic factor in thick cutaneous melanoma. BMC cancer. 2010; 10: 140.

18. Straume O, Sviland L, Akslen LA. Loss of nuclear p16 protein expression correlates with increased tumor cell proliferation (Ki-67) and poor prognosis in patients with vertical growth phase melanoma. Clin Can Res. 2000; 6 : 1845-53.

19. Li W, Sanki A, Karim RZ, Thompson JF, Lee CS,Zhuang L, et al. The role of cell cycle regularory protein in pathogenesis of melanoma. Pathology. 2006; 38 (4): 287-301.

20. Sekulic A, Haluska PJ, Miller AJ, DeLamo JG, Ejadi S, Pulido JS, et al. Malignant melanoma in the 21st century : the emerging molecular landscape.Mayo Clin Proc. 2008; 83(7):825-46.

21. Sadler TW, Langman J. Langman’s Medical Embryology. 9 ed.Lippincott williams & wilkins. Newyork; 2004.p. 427-35

22. Paek SC, Sober AJ, Tsao H, Mihm MCJr, Johnson TM. Cutaneous melanoma. In Wolff K, Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Leffell DJ. Editors. Fitzpatrick’s Dermatology in general medicine, 7th ed. New york:Mc GrawHill Medical; 2008.p. 1134-58.

23. Silver DL, Pavan WJ. The origin and development of neural crest derived melanocyte. In : Hearing VJ, Leong SPL, editors.From melanocytes to melanoma the progression to malignancy. New Jersey : Humana pres inc; 2006.p 3-26.

24. Wasitaatmadja S. Anatomi kulit. In : Djuanda A, Hamzah M, Aisah S, editors. Ilmu penyakit kulit dan kelamin, 3rd ed. Jakarta : FKUI; 1999.p 3-6.

25. Slominski A, Tobin DJ, Shibahara S, Wortsman J. Melanin pigmentation in mammalian skin and its hormonal regulation. Physiol rev. 2004; 84:1155-1228.

26. Stanojevic M, Stanojevic Z, Jovanovic D, Stojiljkovic M. Ultraviolet radiation and melanogenesis. Arch Oncol. 2004; 12(4): 203-5.

Universitas Indonesia 27. Yamaguchi Y, Brenner M, Hearing VJ. The regulation of skin

pigmentation. JBC. 2007; 282 (38): 27557-61.

28. de Vries E, Bray F, Coebergh JW, Cerroni L, Ruiter DJ, Elder DE, et al Melanocytic tumour. In : Leboit PE, Burg G, Weedon D, Sarasin A, editors. Pathology and genetics skin tumours. Lyon: IARC Press; 2006. P 49-75.

29. World health organization. International agency for research on cancer (IARC). Exposure to artificial UV radiation and skin cancer. Lyon.IARC.2005.

30. Wang SQ, Setlow R, Berwick M, Polsky D, Marghoob AA, Kopf AW, et al. Ultraviolet A and melanoma: A review. J Am Acad Dermatol.2001;44(5):837-46.

31. Riker AI, Zea N, Trinh T. The epidemiology, prevention, and detection of melanoma. The Ochsner Journal. 2010; 10(2):56-65.

32. Demirkan NC, Kesen Z, Akdag B, Larue L, Delmas V. The effect of the sun on expression of β-catenin, p16 and cyclin d1 proteins in melanocytic lesions. Clinical and Experimental Dermatology. 2007; 32: 733-9.

33. Stahl S, Bar-Meir E, Friedman E, Regev E, Orenstein A, Winkler E. Genetics in melanoma. IMAJ. 2004; 6: 774-7.

34. Schafer KA. The cell cycle : a review. Vet pathol. 1998; 35: 461-78. 35. Sherr CJ. The Pezcoller lecture: cancer cell cycles revisited.Cancer

Res.2000;60:3689-95.

36. Palmieri G, Capone M, Ascierto MA, Gentilcore G, Stroncek DF, Casula M, et al. Main road to melanoma. Journal of Translational Medicine.2009; 7: 86.

37. Roussel MF. The INK4 family of cell cycle inhibitors in cancer. Omcogene. 1999; 18: 5311-7.

38. Carlson JA, Slominski A, Linette GP, Mysliborski J, Hill J, Mihm MC, et al. Malignant melanoma 2003. Predisposition, diagnosis, prognosis and staging. Am J Clin Pathol. 2003; 120 (suppl 1): S101-27.

39. Ross W, Hall PA. Ki67: from antibody to molecule to understanding ?. J Clin Pathol. 1995; 48: M113-7

40. Talve LAI, Collan YUI, Ekfors TO. Nuclear morphpmetry, immunohistochemical staining with Ki-67 antibody and mitotic index in the assessment of proliferative activity and prognosis of primary malignant melanmas of the skin. J Cutan Pathol. 1996; 23: 335-43.

41. Takata M, Saida T. Early cancers of the skin : clinical, histopathological, and molecular characteristics. J Clin Oncol. 2005; 10:391-7.

42. Smoller BR. Histologic criteria for diagnosing primary cutaneous malignant melanoma. Mod Pathol. 2006; 19: S34-40

43. Mackie RM. Malignant melanoma: clinical variants and prognostic indicators.Clinical and experimental dermatology. 2000; 25: 471-5.

Universitas Indonesia 44. Ginnotty PA, Van Belle P, Elder DE, Murry T, Montone KT, Xu X, et al.

Biologic and prognostic significance of dermal Ki67 expression, mitoses,and tumorigeicity in thin invasive cutaneous melanoma. J Clin Oncol. 2005; 23: 8048-56.

45. Lasithiotakis K, Leiter U, Meier F, Elgentler T, Metzler G, Moehrie M, et al. Age and gender are significant independent predictors of survival in primary cutaneous melanoma. Cancer. 2008; 112: 1795-804.

46. Talve L, Sauroja I, Collan Y, Punnonen K, Ekfors T. Loss of expression of p16ink4a / CDKN2 gene in cutaneous malignant melanoma correlates with tumor cell proliferation and invasive stage. Int J Cancer (Pred Oncol); 1997: 255-9.

47. Kostov M, Mijovic Z, Mihailovic D, Cerovic S, Stojanovic M, Jelic M. Correlation of cell cycle regularory protein (p53 and p16 ink4a) and bcl-2 oncoprotein with mitotic index and thickness of primary cutaneous malignant melanoma. Bosnian J bas med Scie. 2010; 10: 278-81.

48. Egger ME, Dunki-Jacobs EM, Callender GG, Quillo AR, Scoggins CR, Martin II RCG. Outcomes and prognostic factors in nodular melanoma. Surgery. 2012.

49. Barnhill RL, Katzen J, Spatz A, Fine J,Berwick M. The importance of mitotic rate as a prognostic factor for localized cutaneous melanoma. J.Cutan Pathol.2005; 32:268-73.

50. Mihic-Probst D, Mnich CD, Oberholzer PA, Seifert B, Sasse B, Moch H, et al. P16 expression in primary malignant melanoma is associated with prognosis and lymph node status. Int.J.Cancer.2005;118:2262-8.

51. Henrique R, Azevedo R, Bento MJ, Domingues JC, Silva C, Jeronimo C. Prognostic value of Ki67 expression in localized cutaneous malignant melanoma. J Am Acad Dermatol. 2000;43:6:991-1000.

52. Frahm SO, Schubert C, Parwaresch R, Rudolph P. High proliferative activity may predict early metastasis of thin melanomas. Hum Pathol. 2001; 32:1376-81.

53. Pearl RA, Pacifico , Richman PJ, Stoll DJ, Wilson GD, Grobbelaar AO. Ki67- expression in melanoma. A potential method of risk assessment for the patient with a positive sentinel node. J Exp Clin Cancer Res.2007;26:109-15.

Lampiran 1.

Hasil uji Fisher’s antara ekspresi p16 dan ulserasi tumor ulserasi * index inti kat Crosstabulation

index inti kat Total loss exp high exp

tumor ulserasi ada Count 10 6 16 Expected Count 10.9 5.1 16.0 % of Total 40.0% 24.0% 64.0% tidak Count 7 2 9 Expected Count 6.1 2.9 9.0 % of Total 28.0% 8.0% 36.0% Total Count 17 8 25 Expected Count 17.0 8.0 25.0 % of Total 68.0% 32.0% 100.0% Chi-Square Tests

Value df Asymp. Sig.

(2-sided) Exact Sig. (2-sided) Exact Sig. (1-sided) Pearson Chi-Square .618a 1 .432 Continuity Correctionb .115 1 .734 Likelihood Ratio .639 1 .424

Fisher's Exact Test .661 .374

Linear-by-Linear

Association .593 1 .441

N of Valid Cases 25

a. 1 cells (25.0%) have expected count less than 5. The minimum expected count is 2.88. b. Computed only for a 2x2 table

Lampiran 2.

Hasil uji Fisher antara ekspresi p16 dan aktivitas mitosis per 1 mm2

mitosis 2 kategorik * index inti kat Crosstabulation

index inti kat Total loss exp high exp

mitosis 2 kategorik low rate Count 4 2 6 Expected Count 4.1 1.9 6.0 % of Total 16.0% 8.0% 24.0% high rate Count 13 6 19 Expected Count 12.9 6.1 19.0 % of Total 52.0% 24.0% 76.0% Total Count 17 8 25 Expected Count 17.0 8.0 25.0 % of Total 68.0% 32.0% 100.0% Chi-Square Tests

Value df Asymp. Sig.

(2-sided) Exact Sig. (2-sided) Exact Sig. (1-sided) Pearson Chi-Square .006a 1 .936 Continuity Correctionb .000 1 1.000 Likelihood Ratio .006 1 .936

Fisher's Exact Test 1.000 .651

Linear-by-Linear

Association .006 1 .937

N of Valid Cases 25

a. 2 cells (50.0%) have expected count less than 5. The minimum expected count is 1.92. b. Computed only for a 2x2 table

Hasil uji Fisher’s antara ekspresi p16 dan metastasis kgb

metastasis kgb * index inti kat Crosstabulation

index inti kat Total loss exp high exp

metastasis kgb ada Count 4 4 8 Expected Count 5.4 2.6 8.0 % of Total 16.0% 16.0% 32.0% tidak Count 13 4 17 Expected Count 11.6 5.4 17.0 % of Total 52.0% 16.0% 68.0% Total Count 17 8 25 Expected Count 17.0 8.0 25.0 % of Total 68.0% 32.0% 100.0% Chi-Square Tests

Value df Asymp. Sig.

(2-sided) Exact Sig. (2-sided) Exact Sig. (1-sided) Pearson Chi-Square 1.752a 1 .186 Continuity Correctionb .746 1 .388 Likelihood Ratio 1.703 1 .192

Fisher's Exact Test .359 .193

Linear-by-Linear

Association 1.682 1 .195

N of Valid Cases 25

a. 1 cells (25.0%) have expected count less than 5. The minimum expected count is 2.56. b. Computed only for a 2x2 table

Lampiran 4.

Hasil uji Fisher’s Ekspresi Ki67 dan metastasis kgb Crosstab

ki67 cut off 20% Total <20 >20 metastasis kgb ada Count 3 5 8 Expected Count 3.8 4.2 8.0 % of Total 12.0% 20.0% 32.0% tidak Count 9 8 17 Expected Count 8.2 8.8 17.0 % of Total 36.0% 32.0% 68.0% Total Count 12 13 25 Expected Count 12.0 13.0 25.0 % of Total 48.0% 52.0% 100.0% Chi-Square Tests

Value df Asymp. Sig.

(2-sided) Exact Sig. (2-sided) Exact Sig. (1-sided) Pearson Chi-Square .520a 1 .471 Continuity Correctionb .085 1 .770 Likelihood Ratio .524 1 .469

Fisher's Exact Test .673 .387

Linear-by-Linear

Association .499 1 .480

N of Valid Cases 25

a. 2 cells (50.0%) have expected count less than 5. The minimum expected count is 3.84. b. Computed only for a 2x2 table

Lampiran 5.

Hasil uji Fisher’s ekspresi ki67 dan tumor ulserasi Crosstab

ki67 cut off 20% Total <20 >20 tumor ulserasi ada Count 8 8 16 Expected Count 7.7 8.3 16.0 % of Total 32.0% 32.0% 64.0% tidak Count 4 5 9 Expected Count 4.3 4.7 9.0 % of Total 16.0% 20.0% 36.0% Total Count 12 13 25 Expected Count 12.0 13.0 25.0 % of Total 48.0% 52.0% 100.0% Chi-Square Tests

Value df Asymp. Sig.

(2-sided) Exact Sig. (2-sided) Exact Sig. (1-sided) Pearson Chi-Square .071a 1 .790 Continuity Correctionb .000 1 1.000 Likelihood Ratio .071 1 .789

Fisher's Exact Test 1.000 .560

Linear-by-Linear

Association .068 1 .794

N of Valid Cases 25

a. 2 cells (50.0%) have expected count less than 5. The minimum expected count is 4.32. b. Computed only for a 2x2 table

Lampiran 6.

Hasil uji Fisher’s ekspresi ki67 dan aktivitas mitosis per 1 mm2 Crosstab

ki67 cut off 20% Total <20 >20 mitosis 2 kategorik low rate Count 4 2 6 Expected Count 2.9 3.1 6.0 % of Total 16.0% 8.0% 24.0% high rate Count 8 11 19 Expected Count 9.1 9.9 19.0 % of Total 32.0% 44.0% 76.0% Total Count 12 13 25 Expected Count 12.0 13.0 25.0 % of Total 48.0% 52.0% 100.0% Chi-Square Tests

Value df Asymp. Sig.

(2-sided) Exact Sig. (2-sided) Exact Sig. (1-sided) Pearson Chi-Square 1.102a 1 .294 Continuity Correctionb .338 1 .561 Likelihood Ratio 1.115 1 .291

Fisher's Exact Test .378 .281

Linear-by-Linear

Association 1.058 1 .304

N of Valid Cases 25

a. 2 cells (50.0%) have expected count less than 5. The minimum expected count is 2.88. b. Computed only for a 2x2 table

Lampiran 7.

Hasil uji Mc. Nemar ekspresi p16 pada tumor primer dan sekunder p16 kateg prim * p16 kateg sekunder Crosstabulation

Count

p16 kateg sekunder Total

1.00 2.00

p16 kateg prim 1.00 3 1 4

2.00 0 4 4

Total 3 5 8

Chi-Square Tests

Value Exact Sig. (2-sided)

McNemar Test 1.000a

N of Valid Cases 8

a. Binomial distribution used.

Lampiran 8.

Hasil uji Mc Nemar antara ekspresi ki67 dan tumor primer dan sekunder ki67 primer cutof 20% * ki67 sekunder cutof 20% Crosstabulation

Count

ki67 sekunder cutof 20% Total

1.00 2.00

ki67 primer cutof 20% 1.00 2 1 3

2.00 0 5 5

Total 2 6 8

Chi-Square Tests

Value Exact Sig. (2-sided)

McNemar Test 1.000a

N of Valid Cases 8

a. Binomial distribution used.

2178 57 < 60 1 Lengan bawah ext tidak tidak 3 <5 no staining .00 loss exp .00 .00 .00 Loss exp 75.80 2.00

100847 60 > 60 1 Lengan bawah ext ada tidak 3 <5 strong 51.00 high exp 6.00 7.50 3.00 high exp 2.40 1.00

0305261 I 50 < 60 2 kulit nos others ada ada 0 <5 no staining .00 loss exp .00 .00 .00 Loss exp 68.40 2.00

0605600 III 35 < 60 1 pedis ext tidak tidak 1 <5 weak .00 loss exp .00 56.20 3.00 high exp .00 1.00

703402 25 < 60 2 Lengan atas ext ada tidak 2 <5 no staining .00 loss exp .00 .00 .00 Loss exp .00 1.00

802137 46 < 60 2 pedis ext ada tidak 18 >5 weak .00 loss exp .00 4.20 1.00 Loss exp 10.00 1.00

806505 47 < 60 1 pedis ext ada tidak 23 >5 weak .00 loss exp .00 27.80 2.00 high exp 80.00 2.00

0807814 B2 53 < 60 1 pedis ext tidak tidak 13 >5 no staining .00 loss exp .00 .00 .00 Loss exp .00 1.00

901627 43 < 60 2 hipogastrik others ada tidak 14 >5 moderate 5.80 high exp 2.00 28.00 4.00 high exp 46.40 2.00

1001563 70 > 60 2 digiti manus ext tidak tidak 7 >5 strong 5.00 high exp 3.00 70.00 9.00 high exp 30.00 2.00

1005037 83 > 60 1 mata kaki ext tidak tidak 5 >5 weak .00 loss exp .00 90.00 3.00 high exp 24.40 2.00

1005814 IV 60 > 60 2 plantar pedis ext ada ada 10 >5 moderate .00 loss exp .00 85.60 6.00 high exp 16.00 1.00

1006484 IA 54 < 60 2 kalkaneus ext ada ada 12 >5 weak 10.20 high exp 2.00 54.60 3.00 high exp 69.00 2.00

1006747 74 > 60 2 digiti pedis ext ada tidak 8 >5 weak .00 loss exp .00 14.80 2.00 high exp 16.20 1.00

1006839 89 > 60 2 labium oris inferior others ada tidak 6 >5 no staining .00 loss exp .00 .00 .00 Loss exp 25.20 2.00

1100413 61 > 60 1 telapak kaki ext ada tidak 5 >5 strong 40.00 high exp 6.00 90.00 9.00 high exp 23.00 2.00

1102582 I 48 < 60 1 parietal others tidak ada 10 >5 no staining .00 loss exp .00 .00 .00 Loss exp 5.00 1.00

1104868 IIB 53 < 60 1 pedis ext ada ada 3 <5 moderate 3.40 high exp 2.00 84.40 6.00 high exp 11.20 1.00

1105762 I 54 < 60 1 pedis ext tidak ada 20 >5 weak 16.00 high exp 2.00 46.00 2.00 high exp 68.00 2.00

1106000 I 60 > 60 2 tumit kaki ext tidak ada 30 >5 moderate .00 loss exp .00 80.00 6.00 high exp 53.20 2.00

1107609 I 48 < 60 2 kaki ext ada ada 9 >5 strong 45.20 high exp 6.00 30.60 6.00 high exp 80.00 2.00

1108873 44 < 60 1 femur ext ada tidak 6 >5 no staining .00 loss exp .00 .00 .00 Loss exp 8.00 1.00

1110039 24 < 60 1 anorektal others ada tidak 5 >5 no staining .00 loss exp .00 .00 .00 Loss exp 36.00 2.00

1200526 80 > 60 1 kulit nos others ada tidak 40 >5 no staining .00 loss exp .00 .00 .00 Loss exp .00 1.00

1202671 59 < 60 2 Lengan kiri atas ext tidak tidak 6 >5 no staining .00 loss exp .00 .00 .00 Loss exp 7.00 1.00

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