Significância prognóstica da expressão de ki-67, receptores de estrógeno e receptores de progesterona em pacientes com melanoma cutâneo / Prognostic significance of ki-67, estrogen receptors and progesterone receptors expression in patients with cutaneous melanoma

Claudia Adriane Kuhn, Cynthia Holzmann Koehler, Lúcia de Noronha, Mário Rodrigues Montemor Netto

Abstract


Introdução: O Melanoma Cutâneo (MC) é a forma mais agressiva de câncer de pele. Pouco se conhece sobre marcadores biológicos que representam uma maior ou menor agressividade desta neoplasia. Estudos indicam uma relação entre os hormônios sexuais e o índice de proliferação celular (Ki-67) com o MC. Objetivo: Analisar o perfil molecular de pacientes com MC invasor, verificando a significância prognóstica dos Receptores de Estrógeno (RE), Receptores de Progesterona (RP) e Ki-67. Métodos: Trata-se de um estudo caso-controle que analisou 179 casos de MC invasor, que ocorreram na região dos Campos Gerais – PR, Brasil, no período de 2002 a 2014. Foi construído um banco de dados com informações anatomopatológicas, clínicas, e imuno-histoquímicas. Posteriormente, os dados foram analisados pelos testes Kolmogorov-Smirnov, Student uni-caudal e exato de Fisher. Resultados: A incidência de metástases foi maior nos casos de Ki-67 alto (p=0,021). Observou-se que a marcação citoplasmática, tanto pelo RE, quanto pelo RP, está associada com pacientes que não possuem metástases (p=0,006; 0,001 respectivamente). Sexo masculino, sítio anatômico, estadiamento clínico, nível de Clark, espessura de Breslow, ulceração e invasão linfática foram os fatores que apresentaram significância estatística como preditores de metástases. Não foi evidenciada correlação entre o Ki- 67 e os outros marcadores. Conclusão: Este estudo foi estatisticamente significante, corroborando as evidências do envolvimento dos hormônios sexuais e do Ki-67 na progressão do MC. Novos estudos devem ser realizados para comprovar os reais papéis do Ki-67 e dos hormônios sexuais, assim como os mecanismos de ação por eles adotados.


Keywords


Imuno-histoquímica; Melanoma: Marcadores biológicos.

References


Mitchell RN. Robbins & Cotran: fundamentos de patologia. 8th. ed. Rio de Janeiro: Elsevier; 2012.

Iranzo CC, Rubia-Ortí JEDL, Castillo SS, Firmino-Canhoto J. Lesões cutâneas malignas e pré-malignas: conhecimentos, hábitos e campanhas de prevenção solar. Acta paul. enferm., São Paulo , v. 28, n. 1, p. 2-6, Feb. 2015.

Moreno M, Conte B, Menegat E. Diferenças Clínico-Epidemiológicas entre Pacientes Masculinos e Femininos com Diagnóstico de Melanoma Cutâneo no Oeste de Santa Catarina. Revista Brasileira de Cancerologia 2015; 61(1): 15-21.

Naser N. Melanoma cutâneo: estudo epidemiológico de 30 anos em cidade do sul do Brasil, de 1980-2009. An. Bras. Dermatol. [online]. 2011; 86(5): 932-941. ISSN 0365-0596.

Longo DL, Kasper DL, Jameson JL, et al. Medicina Interna de Harrison. 18 ed.

New York: The McGraw-Hill; 2011.

Instituto Nacional de Câncer; Ministério da Saúde. Estimativa 2008: incidência do câncer no Brasil. Rio de Janeiro: INCA; 2007. Disponível em: http://www. inca.gov.br/estimativa/2008

Araujo IC, Coelho CMS, Saliba GAM, et al. Melanoma Cutâneo: aspectos clínicos, epidemiológicos e anatomopatológicos de um centro de formação em Belo Horizonte. Rev. Bras. Cir. Plást.2014;29(4):497-503

Thorne C. Grabb and Smith's plastic surgery. 6th ed. Philadelphia: Lippincott Williams & Wilkins; 2007. p.960.

Levi F, randimbison L, la vecchia C, Te VC, et al. Prognostic factors for cutaneous malignant melanoma in Vaud, Switzerland. Int J Cancer, 1998; 78(3):315–9.

Marghoob AA, Koenig K, Bittencourt FV, et al. Breslow thickness and Clark level in melanoma: support for including level in pathology reports and American Joint Committee on Cancer Staging. Cancer, 2000; 88(3): 589–95

Ak I, Stokkel MP, Bergman W, et al. Cutaneous malignant melanoma: clinical aspects, imaging modalities and treatment. Eur J of Nuclear Medicine, 2000; 27(4): 447–58

Kycler W, Grodecka -Gazdecka S, Br?borowicz J, et al. Prognostic value of selected immunohistochemical markers in skin melanoma. Nowotwory, 2002; 52(6): 487–95

Niezabitowski A, Czadecki K, Ry? J, et al. Prognostic evaluation of cutaneus malignant melanoma: a clinicopathologic and immunohistochemical study. J Sur Oncol, 1999; 70: 150–60

Balzi D, Carli P, Giannotti B et al: Skin melanoma in Italy: a population-based study on survival and prognostic factors. Eur J Cancer, 1998; 34(5): 699–704

Massi D, Franchi A, Borgognoni L et al: Thin cutaneous malignant melanomas (< or =1,5mm): identify cation of risk factors indicative of progression. Cancer, 1999; 85(5): 1067–76

Kycler W, Grodecka-Gazdecka S, Br?borowicz J, et al. Prognostic factors in melanoma. Rep Pract Oncol Radiother, 2006; 11(1): 39-48

Miller JG, Mac Neil S. Gender and cutaneous melanoma. Br J Dermatol. 136:657- 665, 1997

Folkerd EJ, Dowsett M. Influence of sex hormones on cancer progression. J Clin Oncol. 2010 Sep 10;28(26):4038-44.

Cocconi G, Bella M, Calabresi F, et al: Treatment of metastatic malignant melanoma with dacarbazine plus tamoxifen. N Engl J Med 327:516-523, 1992.

Smith MA, Fine JA, Barnhill RL, et al: Hormonal and reproductive influences and risk of melanoma in women. Int J Epidemiol 27:751-757, 1998

Henrique R, Azevedo R, Bento MJ, et al. Prognostic value of Ki-67 expression in localized cutaneous malignant melanoma. J Am Acad Dermatol. 2000 Dec;43(6):991-1000.

Vogt T, Zipperer KH, Vogt A, et al. p53 protein and Ki-67 expression are both reliable biomarkers of prognosis in thick stage I nodular melanomas of the skin. Histopathology 1997;30:57-63.

Hernberg M, Turunen JP, Von Boguslawsky K, et al. Prognostic value of biomarkers in malignant melanoma. Melanoma Res 1998;8:283-91.

Nielsen PS, Spaun E, Riber-Hansen R, et al. Automated quantification of MART1- verified Ki-67 indices: useful diagnostic aid in melanocytic lesions. Hum Pathol. 2014 Jun;45(6):1153-61.

Soyer HP. Ki 67 immunostaining in melanocytic skin tumours: correlation with histologic parameters. J Cutan Pathol 1991;18: 264-72.

Karbowniczek M, Chosia M, Domaga?a W. Nuclear morphometry of MIB-1 positive and negative tumor cells in primary and metastatic malignant melanoma of the skin. Pol J Pathol. 1999;50(4):235-41.

Talve LA, Collan YU, Ekfors TO. Nuclear morphometry, immunohistochemical staining with Ki-67 antibody and mitotic index in the assessment of proliferative activity and prognosis of primary malignant melanomas of the skin. J Cutan Pathol. 1996 Aug;23(4):335-43.

MacKie RM, Hauschild A. Eggermont AM: Epidemiology of invasive cutaneous melanoma. Ann Oncol 2009; 20(6):vi1-vi7.

Lee ML, Tomsu K, Von Eschen KB. Duration of survival for disseminated malignant melanoma: results of a meta-analysis. Melanoma Res 2000; 10: 81–92.

Joosse A, Collette S, Suciu S, et al. Superior outcome of women with stage I/II cutaneous melanoma: pooled analysis of four European Organisation for Research and Treatment of Cancer phase III trials. J Clin Oncol 2012;30:2240–7

U.S. Department of Health and Human Services. The Surgeon General’s Call to Action to Prevent Skin Cancer. Washington, DC: U.S. Dept of Health and Human Services, Office of the Surgeon General; 2014.

Fridberg M, Jonsson L, Bergman J, et al. Modifying effect of gender on the prognostic value of clinicopathological factors and Ki67 expression in melanoma: a population-based cohort study. Biol Sex Differ 2012; 3(1):16.

Mervic L: Time Course and Pattern of Metastasis of Cutaneous Melanoma Differ between Men and Women. PLoS One 2012,7(3):e32955.

Balch CM, Thompson JF, Gershenwald JE, et al. Age as a predictor of sentinel node metastasis among patients with localized melanoma: an inverse correlation of melanoma mortality and incidence of sentinel node metastasis among young and old patients. Ann Surg Oncol 2014;21:1075–81.

Fadaki N, Li R, Parrett B, et al. Is head and neck melanoma different from trunk and extremity melanomas with respect to sentinel lymph node status and clinical outcome? Ann Surg Oncol 2013;20:3089–97.

Bartlett EK, Karakousis GC. Current Staging and Prognostic Factors in Melanoma.

Surg Oncol Clin N Am. 2015 Apr;24(2):215-27

National Program of Cancer Registries (NPCR) and Surveillance, Epidemiology, and End Results (SEER) Program. Atlanta, GA: Centers for Disease Control and Prevention and Bethesda, MD: National Cancer Institute. Data from 2007–2011.

Richards TB, Johnson CJ, Tatalovich Z, et al. Association between cutaneous melanoma incidence rates among white U.S. residents and countylevel estimates of solar ultraviolet exposure. J Am Acad Dermatol 2011;65(5 suppl 1):S50.e51- S50.e59.

Tripp MK, Watson M, Balk SJ, et al. State of the science on prevention and screening to reduce melanoma incidence and mortality: The time is now. CA: A Cancer Journal for Clinicians 2016

Australian Institute of Health and Welfare. Cancer in Australia: an overview 2012. Canberra: AIHW; 2012.

Australian Institute of Health and Welfare. Australia’s health 2010. Canberra: AIHW; 2010

Koh HK, Sober AJ., Day CL. Cigarette smoking and malignant melanoma. Cancer. 1984; 53: 2570-3.

Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364(26):2507-2516

Dimatos DC, Duarte FO, Machado RS, et al. Melanoma cutâneo no Brasil.Arquivos Catarinenses de Medicina. 2009; 38(01)

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

Konrad P, Melao S, Fabris MR, Blanco LF. Perfil epidemiológico e histopatológico dos casos de melanoma cutâneo primário diagnosticados em Criciúma no período entre 2005 e 2007. An Bras Dermatol. 2011;86(3):457-61.

Chiba FB, Delfino AC, Schettini AP, Damasceno SA, Chirano CA. Perfil clinicoepidemiológico dos melanomas cutâneos em duas instituições de referência na cidade de Manaus, Brasil. An Bras Dermatol. 2011;86(6):1239-41.

Mays MP, Martin RC, Burton A, et al. Should all patients with melanoma between 1 and 2 mm Breslow thickness undergo sentinel lymph node biopsy? Cancer 2010; 116:1535–44.

Xu X, Chen L, Guerry D, et al. Lymphatic invasion is independently prognostic of metastasis in primary cutaneous melanoma. Clin Cancer Res 2012;18:229–37.

Homsi J1, Kashani-Sabet M, Messina JL, et al. Cutaneous melanoma: prognostic factors. Cancer Control. 2005 Oct;12(4):223-9.

Cintolo JA, Gimotty P, Blair A, et al. Local immune response predicts survival in patients with thick (t4) melanomas. Ann Surg Oncol 2013;20:3610–7.

Karbowniczek M, Chosia M, Domagala W: Nuclear morphometry of MIB-1 positive and negative tumor cells in primary and metastatic malignant melanoma of skin. Pol J Pathol, 1999; 50(4): 235–41

Bardin A, Boulle N, Lazennec G, et al. Loss of ER expression as a common step in estrogen-dependent tumor progression. Endocr Relat Cancer. 2004;11(3):537- 551.

Ruff M, Gangloff M, Wurtz JM, Moras D. Estrogen receptor transcription and transactivation: structure-function relationship in DNA- and ligand-binding domains of estrogen receptors. Breast Cancer Res. 2000; 2(5):353-359.

de Giorgi V, Mavilia C, Massi D, et al. Estrogen receptor expression in cutaneous elanoma: a real-time reverse transcriptase-polymerase chain reaction and immunohistochemical study. Arch Dermatol. 2009 Jan;145(1):30-6.

Schmidt AN, Nanney LB, Boyd AS, et al: Oestrogen receptor-beta expression in melanocytic lesions. Exp Dermatol 15:971-980, 2006

de Giorgi V1, Gori A, Grazzini M, et al. Estrogens, estrogen receptors and melanoma. Expert Rev Anticancer Ther. 2011 May;11(5):739-47.

Walker JM, Beattie CW, Patel MK, et al. Estrogen Receptor in Malignant Melanoma. J lin Oncol 1987; 5:1256-1261.

Mather JP, Sato GH. The growth of mouse melanoma cells in hormone- supplemented, serum-free medium. Exp Cell Res 1979; 120: 191-200.

Pavelic K, Petrusic L, Osmak M, et al. In Vivo and In Vitro effect of progesterone on the growth of some mouse and human tumors. Res Exp Med (Berl) 1983; 183: 183-191.

Kanda N, Watanabe S. 17-b-Estradiol, Progesterone and Dihydrotestosterone suppress the growth of human melanoma by inhibiting Interleukin-8 production. J Invest Dermatol 2001; 117: 274-283.

Ramaraj P, Cox JL. In vitro effect of progesterone on human melanoma (BLM) cell growth. Int J Clin Exp Med 2014;7(11):3941-3953

Leder DC, Brown JR, Ramaraj P. In-vitro rescue and recovery studies of human melanoma (BLM) cell growth, adhesion and migration functions after treatment with progesterone. Int J Clin Exp Med. 2015;8(8):12275-12285

Pache M, Glatz-Krieger K, Sauter G. Peter Meyer Expression of sex hormone receptors and cell cycle proteins in melanocytic lesions of the ocular conjunctiva. Graefes Arch Clin Exp Ophthalmol (2014) 252:359–365

Welsh AW, Lannin DR, Young GS, et al. Cytoplasmic Estrogen Receptor in breast cancer. Clin Cancer Res. 2012 Jan 1; 18(1): 118–126

Li L, Wang Q, Lv X, et al. Expression and localization of estrogen receptor in human breast cancer and its clinical significance. Cell Biochem Biophys. 2015 Jan;71(1):63-8.

Chaudhuri PK, Walker MJ, Briele HA, et al. Incidence of estrogen receptor in benign nevi and human malignant melanoma. JAMA. 1980 Aug 22-29;244(8):791- 3.




DOI: https://doi.org/10.34117/bjdv7n10-361

Refbacks

  • There are currently no refbacks.