Melanoma
Özet
Melanoma, melanositlerin malign transformasyonu sonucu oluşan, en sık deri, sonrasında mukozal membranlar, gözün uveal kanalı ve leptomeninkslerde ortaya çıkabilen bir kanser çeşididir. Cilt kanserleri içinde prevalansı %4 iken; cilt kanserleri ilişkili ölümlerin %80’inin nedeni olarak karşımıza çıkmaktadır. Bu nedenle tanı, tedavi ve takip süreçleri oldukça önemlidir. Melanoma, kutanöz melanom, mukozal melanom ve uveal melanom olmak üzere üç ana gruba ayrılmaktadır. Bu alt grupların tümör karsinojenezi, yerleşim yeri, genetik ve moleküler özellikleri farklılıklar göstermekle birlikte tedavi sonrası izlem süreçlerinde en önemli yaklaşım öykü, fizik muayene, semptom ve bulgu takiplerini içeren klinik değerlendirme olmaktadır. Tedavi multimodal yaklaşımla cerrahi, radyoterapi ve sistemik tedavileri içerdiği için takip sürecinin de multidisipliner yaklaşımla yapılması oldukça önem arz etmektedir. Görüntüleme yöntemlerinin uygulanması ile ilgili literatürde ve güncel kılavuzlarda farklı öneriler bulunsa da, özellikle tedavi sonrası ilk 5 yıl için, klinik değerlendirmeye ek olarak, tümör tipi ve yerleşim yerine göre, lokorejyonel nüks ve/veya uzak metastaz riski açısından görüntüleme tetkiklerinin yapılmasının uygun bir yaklaşım olduğu düşünülmektedir. Tedavi sonrası izlem ile hastaların nüks ve metastaz durumlarının erken tespiti, buna bağlı olarak sağkalımlarının artması ve yaşam kalitesini iyileşmesi sağlanabilmektedir. Mevcut sürveyans protokollerine ek olarak, zaman içinde bu izlem önerilerinin geliştirilmesi ve hastalara daha uygun takip süreçlerinin sunulması amaçlanmalıdır.
Melanoma is a type of cancer that occurs as a result of malignant transformation of melanocytes and can occur most frequently in the skin, followed by mucosal membranes, uveal canal of the eye, and leptomeninges. While its prevalence among skin cancers is 4%, it is the cause of 80% of skin cancer-related deaths. Therefore, diagnosis, treatment, and follow-up processes are very important. Melanoma is divided into three main groups: cutaneous melanoma, mucosal melanoma, and uveal melanoma. Although the tumor carcinogenesis, location, genetic, and molecular characteristics of these subgroups differ, the most important approach in the follow-up process after treatment is clinical evaluation, including history, physical examination, symptoms and findings. Since the treatment includes surgery, radiotherapy, and systemic therapies with a multimodal approach, it is very important to perform the follow-up process with a multidisciplinary approach. Although there are different recommendations in the literature and current guidelines regarding the application of imaging methods, it is considered to be an appropriate approach to perform imaging examinations in terms of the risk of locoregional recurrence and/or distant metastasis, especially for the first 5 years after treatment, in addition to clinical evaluation, according to tumor type and location. With post-treatment surveillance, early detection of recurrence and metastasis, increased survival and improved quality of life can be achieved. In addition to the current surveillance protocols, it should be aimed to develop these follow-up recommendations over time and to provide more appropriate follow-up processes to patients.
Referanslar
Giblin AV, Thomas JM. Incidence, mortality and survival in cutaneous melanoma. Journal of Plastic Surgery 2007; 60(1):32-40.
Kibbi N, Kluger H, Choi JN. Melanoma: Clinical Presentations. Cancer Treat Res 2016;167:107-129.
Olsen CM, Green AC, Pandeya N, et al. Trends in melanoma incidence rates in eight susceptible populations through 2015. J Invest Dermatol. 2019;139(6):1392-1395.
Bell KJL, Cust AE. Beyond country-specific incidence and mortality: the global burden of melanoma. Br J Dermatol. 2018;178(2):315-316.
Schadendorf D, van Akkooi ACJ, Berking C, et al. Melanoma. Lancet. 2018 Sep 15;392(10151):971-984.
Siegel RL, Miller KD, Wagle NS, et al. Cancer statistics, 2023. CA Cancer J Clin. 2023 Jan;73(1):17-48.
Australian Institute of Health and Welfare. Cancer in Australia 2021. Canberra: AIHW; 2021. doi:10.25816/ye05-nm50.
Balch CM, Gershenwald JE, Soong SJ, et al. Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol 2009;27:61996206.
Luke JJ, Rutkowski P, Queirolo P, et al. Pembrolizumab versus placebo as adjuvant therapy in completely resected stage IIB or IIC melanoma (KEYNOTE-716): a randomised, double-blind, phase 3 trial. Lancet. 2022 Apr 30;399(10336):1718-1729.
Kirkwood JM, Del Vecchio M, Weber J, et al. Adjuvant nivolumab in resected stage IIB/C melanoma: primary results from the randomized, phase 3 CheckMate 76K trial. Nat Med. 2023 Nov;29(11):2835-2843. doi: 10.1038/s41591-023-02583-2. Epub 2023 Oct 16. Erratum in: Nat Med. 2024 Feb;30(2):607.
Grimaldi AM, Simeone E, Ascierto PA. Vemurafenib plus cobimetinib in the treatment of mutated metastatic melanoma: the CoBRIM trial. Melanoma Manag. 2015 Aug;2(3):209-215.
Dummer R, Brase JC, Garrett J, et al. Adjuvant dabrafenib plus trametinib versus placebo in patients with resected, BRAFV600-mutant, stage III melanoma (COMBI-AD): exploratory biomarker analyses from a randomised, phase 3 trial. Lancet Oncol. 2020 Mar;21(3):358-372.
van Akkooi AC, Hauschild A, Long GV, et al. COLUMBUS-AD: phase III study of adjuvant encorafenib + binimetinib in resected stage IIB/IIC BRAF V600-mutated melanoma. Future Oncol. 2023 Sep;19(30):2017-2027.
Eggermont AMM, Blank CU, Mandala M, et al. Adjuvant Pembrolizumab versus Placebo in Resected Stage III Melanoma. N Engl J Med 2018;378:1789-1801.
Larkin J, Del Vecchio M, Mandalá M, et al. Adjuvant Nivolumab versus Ipilimumab in Resected Stage III/IV Melanoma: 5-Year Efficacy and Biomarker Results from CheckMate 238. Clin Cancer Res. 2023 Sep 1;29(17):3352-3361.
Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015;372(4):320330.
Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2017;377(14):1345-1356.
Long GV, Carlino MS, McNeil C, et al. Pembrolizumab versus ipilimumab for advanced melanoma: 10-year follow-up of the phase III KEYNOTE-006 study. Ann Oncol. 2024;35(12):1191-1199.
Livingstone E, Zimmer L, Hassel JC, et al. Adjuvant nivolumab düşük,plus ipilimumab or nivolumab alone versus placebo in patients with resected stage IV melanoma with no evidence of disease (IMMUNED): f inal results of a randomised, double-blind, phase 2 trial. Lancet. 2022;400(10358):1117-1129.
Tawbi HA, Schadendorf D, Lipson EJ, et al. Relatlimab and nivolumab versus nivolumab in untreated advanced melanoma. N Engl J Med. 2022;386(1):24-34.
Pham JP, Joshua AM, da Silva IP, et al. Chemotherapy in cutaneous melanoma: is there still a role? Curr Oncol Rep. 2023;25(6):609-621.
Goldinger SM, Buder-Bakhaya K, Lo SN, et al. Chemotherapy after immune checkpoint inhibitor failure in metastatic melanoma: a retrospective multicentre analysis. Eur J Cancer. 2022;162:22-33.
National Comprehensive Cancer Network. (2025). Melanoma: Cutaneous (version 1.2025). Retrieved from https://www.nccn.org/professionals/physician_gls/pdf/cutaneous_melanoma.pdf.
Amaral T, Ottaviano M, Arance A, et al. Electronic address: clinicalguidelines@esmo.org. Cutaneous melanoma: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2025 Jan;36(1):10-30.
Mihajlovic M, Vlajkovic S, Jovanovic P, et al. Primary mucosal melanomas: a comprehensive review. Int J Clin Exp Pathol 2012;5:739753.
McLaughlin CC, Wu XC, Jemal A, et al. Incidence of noncutaneous melanomas in the U. S. Cancer. 2005;103:1000–1007.
Dahlgren L, Schedvins K, Kanter-Lewensohn L, et al. Human papilloma virus (HPV) is rarely detected in malignant melanomas of sun sheltered mucosal membranes. Acta Oncol. 2005;44:694–699.
Lundberg R, Brytting M, Dahlgren L, et al. Human herpes virus DNA is rarely detected in non-UV light-associated primary malignant melanomas of mucous membranes. Anticancer Res. 2006;26:3627–3631.
Giraud G, Ramqvist T, Ragnarsson-Olding B, et al. DNA from BK virus and JC virus and from KI, WU, and MC polyomaviruses as well as from simian virus 40 is not detected in non-UV-light-associated primary malignant melanomas of mucous membranes. J Clin Microbiol. 2008;46:3595–3598.
Thompson LD, Wieneke JA, Miettinen M. Sinonasal tract and nasopharyngeal melanomas: a clinicopathologic study of 115 cases with a proposed staging system. Am J Surg Pathol. 2003;27:594–611.
Axell T, Hedin CA. Epidemiologic study of excessive oral melanin pigmentation with special reference to the influence of tobacco habits. Scand J Dental Res. 1982;90:434–442.
Newell F, Kong Y, Wilmott JS, et al. Whole-genome landscape of mucosal melanoma reveals diverse drivers and therapeutic targets. Nat Commun 2019;10:3163.
Beadling C, Jacobson-Dunlop E, Hodi FS, et al. KIT gene mutations and copy number in melanoma subtypes. Clin Cancer Res. 2008;14:6821–6828.
Cui C, Lian B, Zhou L, et al. Multifactorial analysis of prognostic factors and survival rates among 706 mucosal melanoma patients. Ann Surg Oncol 2018;25:2184-2192.
Thompson LD, Wieneke JA, Miettinen M. Sinonasal tract and nasopharyngeal melanomas: a clinicopathologic study of 115 cases with a proposed staging system. Am J Surg Pathol. 2003;27:594–611.
Moreno MA, Roberts DB, Kupferman ME, et al. Mucosal melanoma of the nose and paranasal sinuses, a contemporary experience from the M. D. Anderson Cancer Center. Cancer. 2010;116:2215–2223.
Clifton N, Harrison L, Bradley PJ, et al. Malignant melanoma of nasal cavity and paranasal sinuses: report of 24 patients and literature review. J Laryngol Otol. 2011;125:479–485.
Hicks MJ, Flaitz CM. Oral mucosal melanoma: epidemiology and pathobiology. Oral Oncol. 2000;36:152–169.
Tanaka N, Amagasa T, Iwaki H, et al. Oral malignant melanoma in Japan. Oral Surg Oral Med Oral Pathol. 1994;78:81–90.
Volpin E, Sauvanet A, Couvelard A, et al. Primary malignant melanoma of the esophagus: a case report and review of the literature. Dis Esophagus. 2002;15:244–249.
Zhou HT, Zhou ZX, Zhang HZ, et al. Wide local excision could be considered as the initial treatment of primary anorectal malignant melanoma. Chin Med J (Engl) 2010;123:585–588.
Che X, Zhao DB, Wu YK, et al. Anorectal malignant melanomas: retrospective experience with surgical management. World J Gastroenterol. 2011;17:534–539.
Grant-Freemantle MC, O’Neill BL, Clover AJP. The effectiveness of radiotherapy in the treatment of head and neck mucosal melanoma: systematic review and meta-analysis. Head Neck 2021;43:323-333.
Caspers CJI, Dronkers EAC, Monserez D, et al. Adjuvant radiotherapy in sinonasal mucosal melanoma: a retrospective analysis. Clin Otolaryngol 2018;43:617-623.
Tchelebi L, Guirguis A, Ashamalla H. Rectal melanoma: epidemiology, prognosis, and role of adjuvant radiation therapy. J Cancer Res Clin Oncol 2016;142:2569-2575.
Kottschade LA, Pond GR, Olszanski AJ, et al. SALVO: single-arm trial of ipilimumab and nivolumab as adjuvant therapy for resected mucosal melanoma. Clin Cancer Res 2023;29:2220-2225.
Jacques SK, McKeown J, Gover P, et al. Outcomes of patients with resected stage III/IV acral or mucosal melanoma, treated with adjuvant anti-PD-1 based therapy. Eur J Cancer 2024;199:113563.
Shoushtari AN, Munhoz RR, Kuk D, et al. The efficacy of anti-PD-1 agents in acral and mucosal melanoma. Cancer 2016;122:3354-3362.
Yan X, Sheng X, Chi Z, et al. Randomized phase II study of bevacizumab in combination with carboplatin plus paclitaxel in patients with previously untreated advanced mucosal melanoma. J Clin Oncol 2021;39:881-889.
Mao L, Fang M, Chen Y, et al. Atezolizumab plus bevacizumab in patients with unresectable or metastatic mucosal melanoma: a multicenter, open-label, single-arm phase II study. Clin Cancer Res 2022;28:4642-4648.
Li S, Wu X, Yan X, et al. Toripalimab plus axitinib in patients with metastatic mucosal melanoma: 3-year survival update and biomarker analysis. J Immunother Cancer 2022;10:e004036.
Hodi FS, Corless CL, Giobbie-Hurder A, et al. Imatinib for melanomas harboring mutationally activated or amplified KIT arising on mucosal, acral, and chronically sun-damaged skin. J Clin Oncol 2013;31:3182-3190.
National Comprehensive Cancer Network. (2025). Head and Neck Cancer (version 2.2025). Retrieved from https://www.nccn.org/professionals/physician_gls/pdf/head-and-neck.pdf.
Nenclares P, Ap Dafydd D, Bagwan I, et al. Head and neck mucosal melanoma: The United Kingdom national guidelines. Eur J Cancer. 2020 Oct;138:11-18.
Smith HG, Bagwan I, Board RE, et al. Ano-uro-genital mucosal melanoma UK national guidelines. Eur J Cancer. 2020 Aug;135:22-30.
Vajdic CM, Kricker A, Giblin M, et al. Incidence of ocular melanoma in Australia from 1990 to 1998. Int J Cancer 2003;105:117-122.
Xu Y, Lou L, Wang Y, et al. Epidemiological Study of Uveal Melanoma from US Surveillance, Epidemiology, and End Results Program (20102015). J Ophthalmol 2020;2020:3614039.
Ghazawi FM, Darwich R, Le M, et al. Uveal melanoma incidence trends in Canada: a national comprehensive population-based study. Br J Ophthalmol 2019;103:1872-1876.
Damato EM, Damato BE. Detection and time to treatment of uveal melanoma in the United Kingdom: an evaluation of 2,384 patients. Ophthalmology 2012;119:1582-1589.
Mahendraraj K, Shrestha S, Lau CS, et al. Ocular melanoma-when you have seen one, you have not seen them all: a clinical outcome study from the Surveillance, Epidemiology and End Results (SEER) database (1973-2012). Clin Ophthalmol 2017;11:153160.
Shields CL, Kaliki S, Furuta M, et al. American Joint Committee on Cancer Classification of Uveal Melanoma (Anatomic Stage) Predicts Prognosis in 7,731 Patients: The 2013 Zimmerman Lecture. Ophthalmology 2015;122:1180-1186.
Chang AE, Karnell LH, Menck HR. The National Cancer Data Base report on cutaneous and noncutaneous melanoma: a summary of 84,836 cases from the past decade. The American College of Surgeons Commission on Cancer and the American Cancer Society. Cancer 1998;83:1664-1678.
Kujala E, Damato B, Coupland SE, et al. Staging of ciliary body and choroidal melanomas based on anatomic extent. J Clin Oncol 2013;31:2825-2831.
Lorenzo D, Ochoa M, Piulats JM, et al. Prognostic Factors and Decision Tree for Long-Term Survival in Metastatic Uveal Melanoma. Cancer Res Treat 2018;50:1130-1139.
Khoja L, Atenafu EG, Suciu S, et al. Meta-analysis in metastatic uveal melanoma to determine progression free and overall survival benchmarks: an international rare cancers initiative (IRCI) ocular melanoma study. Ann Oncol 2019;30:1370-1380.
Edmunds SC, Cree IA, Di Nicolantonio F, et al. Absence of BRAF gene mutations in uveal melanomas in contrast to cutaneous melanomas. Br J Cancer 2003;88:1403-1405.
Koopmans AE, Vaarwater J, Paridaens D, et al. Patient survival in uveal melanoma is not affected by oncogenic mutations in GNAQ and GNA11. Br J Cancer 2013;109:493-496.
Van Raamsdonk CD, Griewank KG, Crosby MB, et al. Mutations in GNA11 in uveal melanoma. N Engl J Med 2010;363:2191-2199.
