Malign Melanom Tanılı Hastalarda Klinikopatolojik Özellikler Ve Nötrofil-Lenfosit Oranının Prognostik Ve Prediktif Önemi

Yıl 2023, Cilt: 45 Sayı: 5, 651 - 664, 27.09.2023

Yasemin Sağdıç Karateke , Lütfiye Demir , Murat Dinçer , Bülent Yıldız

https://doi.org/10.20515/otd.1226498

Öz

Bu çalışmada MM tanılı hastalarda demografik, labaratuvar özellikler ve klinikopatolojik parametrelerle birlikte nötrofil-lenfosit oranının (NLR) prognoz ve sağkalım üzerine etkisi ve diğer parametrelerle ilişkisi araştırıldı. Çalışmamızda 2010-2017 yılları arasında Eskişehir Osmangazi Üniversitesi Tıbbi Onkoloji Kliniği’nde takip edilen MM tanılı 107 hasta retrospektif olarak değerlendirildi. Yaş, cinsiyet, LDH seviyesi, patolojik parametreler, BRAF mutasyon durumu, nötrofil-lenfosit oranı(NLR) ile bu parametrelerin genel sağkalım(OS) ve hastalıksız sağkalım(DFS) üzerine etkisi ve birbirleri ile ilişkisi araştırıldı. Hastaların tanı anında %86’sı erken evredeydi. Kutanöz MM ve nodüler malign melanom (NMM), ağırlıklı saptanan tipti. Medyan NLR cut-off değeri 1.97 saptandı. Non-kutanöz MM olgularının hepsi BRAF negatifti (p<0.0001). Yüksek NLR ileri evre (p=0.001), ileri yaş (p=0.008), ülserasyon varlığı (p=0.011), yüksek mitoz sayısı (p=0.05) ile ilişkiliydi. Yüksek NLR (p<0.0001), yüksek LDH seviyesi (p=0.04), artmış Breslow kalınlığı (p=0.01), artmış Clark düzeyi (p=0.01), yüksek mitoz sayısı (p=0.02), LN (Lenf nodu) tutulumu (p=0.04) anlamlı olarak daha kısa OS süreleri ile ilişkiliydi. Cox çok değişkenli regresyon analizlerinde OS üzerinde en etkili bağımsız değişken parametreler LN tutulumu (HR:3.4 p=0.01) ve yüksek NLR (HR:4.6 p=0.04) olarak saptandı. Nodal tutulum ayrıca nüksü en çok predikte eden bağımsız parametre olarak saptandı (HR:3.2 p=0.03). Klasik parametreler yanında NLR de prognozu öngördürebilecek bir biyobelirteç gibi görünmektedir. Nodal tutulumu olan ve NLR değeri yüksek olan hastalar klinikte daha yakından takip edilmelidir. Verilerin geniş çaplı çalışmalarla desteklenmesine ihtiyaç vardır.

Anahtar Kelimeler

malignant melanoma, NLR, prognostic factors

Destekleyen Kurum

yok

Proje Numarası

yok

Clinicopathological Features of Patients with Malignant Melanoma Diagnosis and Prognostic and Predictive Importance of Neuthrophil-Lymphocyte Ratio

Öz

In this study, the effect of demographic, laboratory and clinicopathological parameters along with neutrophil-lymphocyte ratio (NLR) on prognosis and survival and correlation with other parameters was researched in patients with malignant melanoma (MM) diagnosis. In our study, 107 patients monitored for MM diagnosis in Eskişehir Osmangazi University Medical Oncology clinic from 2010-2017 were retrospectively assessed. Age, gender, LDH level, pathological parameters, BRAF mutation status, neutrophil-lymphocyte ratio (NLR) and the effects of these parameters on overall survival (OS) and disease-free survival (DFS) and correlations with each other were researched. At time of diagnosis, 86% of patients were in the early stage. The dominant types identified were cutaneous MM and nodular MM. Median NLR cut-off value was identified as 1.97. All non-cutaneous MM cases were BRAF negative (p<0.0001). High NLR was associated with advanced stage (p=0.001), advanced age (p=0.008), ulceration presence (p=0.011), and high mitosis count (p=0.05). High NLR (p<0.0001), high LDH level (p=0.04), increased Breslow thickness (p=0.01), increased Clark level (p=0.01), high mitosis count (p=0.02), and lymph node (LN) involvement (p=0.04) were correlated with significantly shorter OS durations. Cox multivariate regression analysis identified the most effective independent parameters on OS were LN involvement (HR: 3.4, p=0.01) and high NLR (HR: 4.6, p=0.04). Nodal involvement was also identified as the most predictive independent parameter for recurrence (HR: 3.2, p=0.03). In addition to classic parameters, NLR appears to be a biomarker which can predict prognosis. Patients with nodal involvement and high NLR values should be monitored more closely in clinics. Data require support with broad-scale studies.

Anahtar Kelimeler

malignant melanoma, NLR, prognostic factors

Proje Numarası

yok

Kaynakça

• 1. Matthews NH, Li W-Q, Qureshi AA, Weinstock MA, Cho E. Epidemiology of melanoma. Cutaneous Melanoma: Etiology and Therapy. Codon Publications; 2017;3-22.
• 2. Linos E, Swetter SM, Cockburn MG, Colditz GA, Clarke CAJJoID. Increasing burden of melanoma in the United States. 2009;129(7):1666-74.
• 3. Dhawan P, Richmond A. Role of CXCL1 in tumorigenesis of melanoma. Journal of leukocyte biology. 2002;72(1):9-18.
• 4. Genomic Classification of Cutaneous Melanoma. Cell. 2015;161(7):1681-96.
• 5. Ascierto PA, McArthur GA, Dréno B, Atkinson V, Liszkay G, Di Giacomo AM, et al. Cobimetinib combined with vemurafenib in advanced BRAFV600-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial. 2016;17(9):1248-60.
• 6. Long G, Flaherty K, Stroyakovskiy D, Gogas H, Levchenko E, De Braud F, et al. Dabrafenib plus trametinib versus dabrafenib monotherapy in patients with metastatic BRAF V600E/K-mutant melanoma: long-term survival and safety analysis of a phase 3 study. 2017;28(7):1631-9.
• 7. Taube JM, Anders RA, Young GD, Xu H, Sharma R, McMiller TL, et al. Colocalization of inflammatory response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Science translational medicine. 2012;4(127):127ra37.
• 8. Robert C, Ribas A, Hamid O, Daud A, Wolchok JD, Joshua AM, et al. Three-year overall survival for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001. American Society of Clinical Oncology; 2016.
• 9. Wolchok JD, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob J-J, Cowey CL, et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. 2017;377(14):1345-56.
• 10. Uysal-Sonmez O, Tanriverdi O, Esbah O, Uyeturk U, Helvaci K, Bal O, et al. Multicenter evaluation of patients with cutaneous malignant melanoma in Turkey: MELAS study. 2013;14(1):533-7.
• 11. Abali H, Celik I, Karaca B, Turna H, Kaytan ES, Akman T, et al. Cutaneous melanoma in Turkey: analysis of 1157 patients in the Melanoma Turkish Study. 2015;20(4):1137-41.
• 12. Tas F, Kurul S, Camlica H, Topuz EJJjoco. Malignant melanoma in Turkey: a single institution's experience on 475 cases. 2006;36(12):794-9.
• 13. Sula B, Uçmak F, Kaplan MA, Urakçi Z, Arica M, Isikdogan AJPAMJ. Epidemiological and clinical characteristics of malignant melanoma in Southeast Anatolia in Turkey. 2016;24(1).
• 14. Baykal C, Atci T, Akay BNJJoOS. Is the frequency of primary cutaneous melanoma increasing in Turkey? An evaluation of the experiences of two dermatology centers. 2018;4(1):19-23.
• 15. Rastrelli M, Tropea S, Rossi CR, Alaibac MJIv. Melanoma: epidemiology, risk factors, pathogenesis, diagnosis and classification. 2014;28(6):1005-11.
• 16. Batzler WU, Giersiepen K, Hentschel S, Husmann G, Kaatsch P, Katalinic A, et al. Cancer in Germany 2003-2004 Incidence and Trends. 2008.
• 17. Chang AE, Karnell LH, Menck HRJCIIJotACS. The National Cancer Data Base report on cutaneous and noncutaneous melanoma: a summary of 84,836 cases from the past decade. 1998;83(8):1664-78.
• 18. NIH(National Cance İnstitute), Surveillance ,Epidemiology, and Results Programme( SEER) [online]. Available from: https:/ Balch CM, Gershenwald JE, Soong SJ, et al. Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol. 2009;27(36):6199-6206. /seer.cancer.gov/.
• 19. Siegel RL, Miller KD, Jemal AJCACJfC. Cancer statistics, 2020. 2020;70(1):7-30.
• 20. Meyer T, Merkel S, Goehl J, Hohenberger WJCIIJotACS. Surgical therapy for distant metastases of malignant melanoma. 2000;89(9):1983-91.
• 21. Leung AM, Hari DM, Morton DLJCj. Surgery for distant melanoma metastasis. 2012;18(2):176.
• 22. Francken AB, Accortt NA, Shaw HM, Wiener M, Soong S-j, Hoekstra HJ, et al. Prognosis and determinants of outcome following locoregional or distant recurrence in patients with cutaneous melanoma. 2008;15(5):1476-84.
• 23. Ho J, de Moura MB, Lin Y, Vincent G, Thorne S, Duncan LM, et al. Importance of glycolysis and oxidative phosphorylation in advanced melanoma. 2012;11(1):76.
• 24. Gershenwald JE, Scolyer RA, Hess KR, Sondak VK, Long GV, Ross MI, et al. Melanoma staging: evidence‐based changes in the American Joint Committee on Cancer eighth edition cancer staging manual. 2017;67(6):472-92.
• 25. Balch CM, Gershenwald JE, Soong S-j, Thompson JF, Atkins MB, Byrd DR, et al. Final version of 2009 AJCC melanoma staging and classification. 2009;27(36):6199.
• 26. Sirott MN, Bajorin DF, Wong GY, Tao Y, Chapman PB, Templeton MA, et al. Prognostic factors in patients with metastatic malignant melanoma: a multivariate analysis. 1993;72(10):3091-8.
• 27. Gao D, Ma X. Serum lactate dehydrogenase is a predictor of poor survival in malignant melanoma. Panminerva medica. 2017;59(4):332-7.
• 28. Schmidt H, Bastholt L, Geertsen P, Christensen IJ, Larsen S, Gehl J, et al. Elevated neutrophil and monocyte counts in peripheral blood are associated with poor survival in patients with metastatic melanoma: a prognostic model. 2005;93(3):273.
• 29. Schmidt H, Suciu S, Punt CJ, Gore M, Kruit W, Patel P, et al. Pretreatment levels of peripheral neutrophils and leukocytes as independent predictors of overall survival in patients with American Joint Committee on Cancer Stage IV Melanoma: results of the EORTC 18951 Biochemotherapy Trial. 2007;25(12):1562.
• 30. Manola J, Atkins M, Ibrahim J, Kirkwood J. Prognostic factors in metastatic melanoma: a pooled analysis of Eastern Cooperative Oncology Group trials. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2000;18(22):3782-93.
• 31. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417(6892):949-54.
• 32. Rabbie R, Ferguson P, Molina‐Aguilar C, Adams DJ, Robles‐Espinoza CDJTJop. Melanoma subtypes: genomic profiles, prognostic molecular markers and therapeutic possibilities. 2019;247(5):539-51.
• 33. Van Raamsdonk CD, Bezrookove V, Green G, Bauer J, Gaugler L, O'Brien JM, et al. Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi. Nature. 2009;457(7229):599-602.
• 34. Van Raamsdonk CD, Griewank KG, Crosby MB, Garrido MC, Vemula S, Wiesner T, et al. Mutations in GNA11 in uveal melanoma. The New England journal of medicine. 2010;363(23):2191-9.
• 35. Sehdev A, Hayden R, Kuhar MJ, Cheng L, Warren SJ, Mark LA, et al. Prognostic role of BRAF mutation in malignant cutaneous melanoma. American Society of Clinical Oncology; 2018.
• 36. Kim SY, Kim SN, Hahn HJ, Lee YW, Choe YB, Ahn KJJJotAAoD. Metaanalysis of BRAF mutations and clinicopathologic characteristics in primary melanoma. 2015;72(6):1036-46. e2.
• 37. Long GV, Menzies AM, Nagrial AM, Haydu LE, Hamilton AL, Mann GJ, et al. Prognostic and clinicopathologic associations of oncogenic BRAF in metastatic melanoma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2011;29(10):1239-46.
• 38. Lee HW, Song KH, Hong JW, Jeon SY, Ko DY, Kim KH, et al. Frequency of BRAF mutation and clinical relevance for primary melanomas. 2012;46(3):246.
• 39. Frauchiger AL, Mangana J, Rechsteiner M, Moch H, Seifert B, Braun R, et al. Prognostic relevance of lactate dehydrogenase and serum S100 levels in stage IV melanoma with known BRAF mutation status. 2016;174(4):823-30.
• 40. Ny L, Nyakas M, Hernberg M, Koivunen J, Oddershede L, Yoon M-R, et al. BRAF mutation as a prognostic marker for survival in malignant melanoma: A systematic review and meta-analysis. American Society of Clinical Oncology; 2018;371(20):1877-1888
• 41. Jablonska J, Leschner S, Westphal K, Lienenklaus S, Weiss SJTJoci. Neutrophils responsive to endogenous IFN-β regulate tumor angiogenesis and growth in a mouse tumor model. 2010;120(4):1151-64.
• 42. Yang Z, Gu J-H, Guo C-S, Li X-H, Yang W-CJO. Preoperative neutrophil-to-lymphocyte ratio is a predictor of survival of epithelial ovarian cancer: a systematic review and meta-analysis of observational studies. 2017;8(28):46414.
• 43. Marchioni M, Cindolo L, Autorino R, Primiceri G, Arcaniolo D, De Sio M, et al. High neutrophil-to-lymphocyte ratio as prognostic factor in patients affected by upper tract urothelial cancer: a systematic review and meta-analysis. 2017;15(3):343-9. e1.
• 44. Cassidy MR, Wolchok RE, Zheng J, Panageas KS, Wolchok JD, Coit D, et al. Neutrophil to lymphocyte ratio is associated with outcome during ipilimumab treatment. 2017;18:56-61.
• 45. Finon A, Zaragoza J, Maillard H, Beneton N, Bens G, Samimi M, et al. A high neutrophil to lymphocyte ratio prior to BRAF inhibitor treatment is a predictor of poor progression-free survival in patients with metastatic melanoma. 2018;28:38-43.
• 46. Rosner S, Kwong E, Shoushtari AN, Friedman CF, Betof AS, Brady MS, et al. Peripheral blood clinical laboratory variables associated with outcomes following combination nivolumab and ipilimumab immunotherapy in melanoma. 2018;7(3):690-7.
• 47. Ding Y, Zhang S, Qiao JJM. Prognostic value of neutrophil-to-lymphocyte ratio in melanoma: Evidence from a PRISMA-compliant meta-analysis. 2018;97(30).
• 48. Zhan H, Ma J-Y, Jian Q-CJCCA. Prognostic significance of pretreatment neutrophil-to-lymphocyte ratio in melanoma patients: A meta-analysis. 2018.
• 49. Ma J, Kuzman J, Ray A, Lawson BO, Khong B, Xuan S, et al. Neutrophil-to-lymphocyte Ratio (NLR) as a predictor for recurrence in patients with stage III melanoma. 2018;8(1):4044.
• 50. Lino-Silva LS, Salcedo-Hernández RA, García-Pérez L, Meneses-García A, Zepeda-Najar CJMr. Basal neutrophil-to-lymphocyte ratio is associated with overall survival in melanoma. 2017;27(2):140-4.
• 51. Khoja L, Atenafu EG, Templeton A, Qye Y, Chappell MA, Saibil S, et al. The full blood count as a biomarker of outcome and toxicity in ipilimumab‐treated cutaneous metastatic melanoma. 2016;5(10):2792-9.
• 52. Nakamura Y, Tanaka R, Maruyama H, Ishitsuka Y, Okiyama N, Watanabe R, et al. Correlation between blood cell count and outcome of melanoma patients treated with anti-PD-1 antibodies. 2019;49(5):431-7.
• 53. Hemadri A, Lin H, Lin Y, Rose A, Sander C, Najjar Y, et al. Association of baseline neutrophil-to-lymphocyte ratio (NLR) with response and survival in advanced melanoma (MEL) receiving PD-1 inhibitors. American Society of Clinical Oncology; 2019.
• 54. Davis JL, Langan RC, Panageas KS, Zheng J, Postow MA, Brady MS, et al. Elevated blood neutrophil-to-lymphocyte ratio: a readily available biomarker associated with death due to disease in high risk nonmetastatic melanoma. 2017;24(7):1989-96.
• 55. Bayoglu IV, Kurtel G, Alacacioglu A, Varim C, Yildiz I, Kucukzeybek Y, et al. Can basal neutrophil/lymphocytes ratio predict clinical outcome of melanoma patients? : American Society of Clinical Oncology; 2015.
• 56. Grözinger G, Mann S, Mehra T, Klumpp B, Grosse U, Nikolaou K, et al. Metastatic patterns and metastatic sites in mucosal melanoma: a retrospective study. 2016;26(6):1826-34.
• 57. Balch CM, Soong S-j, Ross MI, Urist MM, Karakousis CP, Temple WJ, et al. Long-term results of a multi-institutional randomized trial comparing prognostic factors and surgical results for intermediate thickness melanomas (1.0 to 4.0 mm). 2000;7(2):87-97.
• 58. Capone M, Giannarelli D, Mallardo D, Madonna G, Festino L, Grimaldi AM, et al. Baseline neutrophil-to-lymphocyte ratio (NLR) and derived NLR could predict overall survival in patients with advanced melanoma treated with nivolumab. Journal for immunotherapy of cancer. 2018;6(1):74.
• 59. Mays MP, Martin RC, Burton A, Ginter B, Edwards MJ, Reintgen DS, et al. Should all patients with melanoma between 1 and 2 mm Breslow thickness undergo sentinel lymph node biopsy? 2010;116(6):1535-44.