Vitiligo and Melanoma-Associated Vitiligo: Understanding Their Similarities and Differences

Abstract

Background

There has been a significant increase in the number and efficacy of therapies for advanced melanoma. Immunotherapies, such as anti-cytotoxic T-lymphocyte antigen-4 and programmed cell death-1 inhibitors, have improved the prognosis for patients with advanced melanoma. While spontaneous melanoma-associated vitiligo is a known phenomenon, the occurrence of melanoma-associated vitiligo following melanoma therapy is now recognized to associate with favorable outcomes.

Objective

The objective of this article is to provide a comprehensive literature review of melanoma-associated vitiligo and explore the insights these findings provide about the pathobiology of vitiligo and mechanisms underlying melanoma therapies.

Methods

PubMed and Science Direct databases were searched for studies pertaining to melanoma-associated vitiligo. The 36 studies reviewed included meta-analyses (n = 2), prospective cohort studies (n = 4), prospective observational studies (n = 3), retrospective studies (n = 12), case series (n = 2), and case reports (n = 13).

Results

The basic mechanisms underlying melanoma-associated vitiligo and vitiligo may be shared. Characterization of these mechanisms will identify new biomarkers and therapeutic targets for both melanoma and vitiligo.

Conclusions

Co-opting the immune system to target tumor antigens highlights the potential overlap between anti-tumor immunity and autoimmunity. The development of vitiligo-like depigmentation in association with immunotherapy for melanoma may provide insights into both the immune response against melanoma as well as the pathogenesis of vitiligo.

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References

  1. 1.

    Teulings HE, Willemsen KJ, Glykofridis I, Krebbers G, Komen L, Kroon MW, et al. The antibody response against MART-1 differs in patients with melanoma-associated leucoderma and vitiligo. Pigment Cell Melanoma Res. 2014;27(6):1086–96.

    CAS  PubMed  Google Scholar 

  2. 2.

    Boasberg PD, Hoon DS, Piro LD, Martin MA, Fujimoto A, Kristedja TS, et al. Enhanced survival associated with vitiligo expression during maintenance biotherapy for metastatic melanoma. J Invest Dermatol. 2006;126(12):2658–63.

    CAS  PubMed  Google Scholar 

  3. 3.

    Merimsky O, Shoenfeld Y, Baharav E, Altomonte M, Chaitchik S, Maio M, et al. Melanoma-associated hypopigmentation: where are the antibodies? Am J Clin Oncol. 1996;19(6):613–8.

    CAS  PubMed  Google Scholar 

  4. 4.

    Failla CM, Carbone ML, Fortes C, Pagnanelli G, D'Atri S. Melanoma and vitiligo: in good company. Int J Mol Sci. 2019;20(22):5731.

    CAS  PubMed Central  Google Scholar 

  5. 5.

    Fishman P, Azizi E, Shoenfeld Y, Sredni B, Yecheskel G, Ferrone S, et al. Vitiligo autoantibodies are effective against melanoma. Cancer. 1993;72(8):2365–9.

    CAS  PubMed  Google Scholar 

  6. 6.

    Daneshpazhooh M, Shokoohi A, Dadban A, Raafat J. The course of melanoma-associated vitiligo: report of a case. Melanoma Res. 2006;16(4):371–3.

    PubMed  Google Scholar 

  7. 7.

    Quaglino P, Marenco F, Osella-Abate S, Cappello N, Ortoncelli M, Salomone B, et al. Vitiligo is an independent favourable prognostic factor in stage III and IV metastatic melanoma patients: results from a single-institution hospital-based observational cohort study. Ann Oncol. 2010;21(2):409–14.

    CAS  PubMed  Google Scholar 

  8. 8.

    Yang M, Chang D. Vitiligo after immune checkpoint inhibitor therapy in a woman with metastatic melanoma. J Cancer Res Pract. 2018;5:161–4.

    CAS  Google Scholar 

  9. 9.

    Lommerts JE, Teulings HE, Ezzedine K, van Geel N, Hartmann A, Speeckaert R, et al. Melanoma-associated leukoderma and vitiligo cannot be differentiated based on blinded assessment by experts in the field. J Am Acad Dermatol. 2016;75(6):1198–204.

    PubMed  Google Scholar 

  10. 10.

    Teulings HE, Limpens J, Jansen SN, Zwinderman AH, Reitsma JB, Spuls PI, et al. Vitiligo-like depigmentation in patients with stage III-IV melanoma receiving immunotherapy and its association with survival: a systematic review and meta-analysis. J Clin Oncol. 2015;33(7):773–81.

    CAS  PubMed  Google Scholar 

  11. 11.

    Rosenberg SA, White DE. Vitiligo in patients with melanoma: normal tissue antigens can be targets for cancer immunotherapy. J Immunother Emphasis Tumor Immunol. 1996;19(1):81–4.

    CAS  PubMed  Google Scholar 

  12. 12.

    Gathings R, Lewallen R, Yosipovitch G. Immunotherapy-induced leukoderma from treatment of melanoma with IL-2: a case report and a review of the literature. Acta Derm Venereol. 2015;95(2):197–200.

    PubMed  Google Scholar 

  13. 13.

    Khan R, Gupta S, Sharma A. Circulatory levels of T-cell cytokines (interleukin [IL]-2, IL-4, IL-17, and transforming growth factor-beta) in patients with vitiligo. J Am Acad Dermatol. 2012;66(3):510–1.

    PubMed  Google Scholar 

  14. 14.

    Shi YL, Li K, Hamzavi I, Lim HW, Zhou L, Mi QS. Elevated circulating soluble interleukin-2 receptor in patients with non-segmental vitiligo in North American. J Dermatol Sci. 2013;71(3):212–4.

    CAS  PubMed  Google Scholar 

  15. 15.

    Senzer NN, Kaufman HL, Amatruda T, Nemunaitis M, Reid T, Daniels G, et al. Phase II clinical trial of a granulocyte-macrophage colony-stimulating factor-encoding, second-generation oncolytic herpesvirus in patients with unresectable metastatic melanoma. J Clin Oncol. 2009;27(34):5763–71.

    CAS  PubMed  Google Scholar 

  16. 16.

    Iglesias P, Ribero S, Barreiro A, Podlipnik S, Carrera C, Malvehy J, et al. Induced vitiligo due to talimogene laherparepvec injection for metastatic melanoma associated with long-term complete response. Acta Derm Venereol. 2019;99(2):232–3.

    CAS  PubMed  Google Scholar 

  17. 17.

    Freeman-Keller M, Kim Y, Cronin H, Richards A, Gibney G, Weber JS. Nivolumab in resected and unresectable metastatic melanoma: characteristics of immune-related adverse events and association with outcomes. Clin Cancer Res. 2016;22(4):886–94.

    CAS  PubMed  Google Scholar 

  18. 18.

    de Golian E, Kwong BY, Swetter SM, Pugliese SB. Cutaneous complications of targeted melanoma therapy. Curr Treat Options Oncol. 2016;17(11):57.

    PubMed  Google Scholar 

  19. 19.

    Downey SG, Klapper JA, Smith FO, Yang JC, Sherry RM, Royal RE, et al. Prognostic factors related to clinical response in patients with metastatic melanoma treated by CTL-associated antigen-4 blockade. Clin Cancer Res. 2007;13(22 Pt 1):6681–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Phan GQ, Yang JC, Sherry RM, Hwu P, Topalian SL, Schwartzentruber DJ, et al. Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc Natl Acad Sci USA. 2003;100(14):8372–7.

    CAS  PubMed  Google Scholar 

  21. 21.

    Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, et al. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. 2015;372(26):2521–32.

    CAS  PubMed  Google Scholar 

  22. 22.

    Belum VR, Benhuri B, Postow MA, Hellmann MD, Lesokhin AM, Segal NH, et al. Characterisation and management of dermatologic adverse events to agents targeting the PD-1 receptor. Eur J Cancer. 2016;60:12–25.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Hwang SJ, Carlos G, Wakade D, Byth K, Kong BY, Chou S, et al. Cutaneous adverse events (AEs) of anti-programmed cell death (PD)-1 therapy in patients with metastatic melanoma: a single-institution cohort. J Am Acad Dermatol. 2016;74(3):455–61.e1.

    PubMed  Google Scholar 

  24. 24.

    Wolner ZJ, Marghoob AA, Pulitzer MP, Postow MA, Marchetti MA. A case report of disappearing pigmented skin lesions associated with pembrolizumab treatment for metastatic melanoma. Br J Dermatol. 2018;178(1):265–9.

    CAS  PubMed  Google Scholar 

  25. 25.

    Hua C, Boussemart L, Mateus C, Routier E, Boutros C, Cazenave H, et al. Association of vitiligo with tumor response in patients with metastatic melanoma treated with pembrolizumab. JAMA Dermatol. 2016;152(1):45–51.

    PubMed  Google Scholar 

  26. 26.

    Larsabal M, Marti A, Jacquemin C, Rambert J, Thiolat D, Dousset L, et al. Vitiligo-like lesions occurring in patients receiving anti-programmed cell death-1 therapies are clinically and biologically distinct from vitiligo. J Am Acad Dermatol. 2017;76(5):863–70.

    PubMed  Google Scholar 

  27. 27.

    Nakamura Y, Tanaka R, Asami Y, Teramoto Y, Imamura T, Sato S, et al. Correlation between vitiligo occurrence and clinical benefit in advanced melanoma patients treated with nivolumab: a multi-institutional retrospective study. J Dermatol. 2017;44(2):117–22.

    CAS  PubMed  Google Scholar 

  28. 28.

    Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015;372(4):320–30.

    CAS  PubMed  Google Scholar 

  29. 29.

    Indini A, Di Guardo L, Cimminiello C, Prisciandaro M, Randon G, De Braud F, et al. Immune-related adverse events correlate with improved survival in patients undergoing anti-PD1 immunotherapy for metastatic melanoma. J Cancer Res Clin Oncol. 2019;145(2):511–21.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Nardin C, Jeand'heur A, Bouiller K, Valnet-Rabier MB, Dresco F, Castagna J, et al. Vitiligo under anti-programmed cell death-1 therapy is associated with increased survival in melanoma patients. J Am Acad Dermatol. 2020;82(3):770–2.

    PubMed  Google Scholar 

  31. 31.

    Hwang SJE, Park JJW, Wakade D, Chou S, Byth K, Fernandez-Penas P. Cutaneous adverse events of anti-programmed death 1 antibodies combined with anti-cytotoxic T-lymphocyte-associated protein 4 therapy use in patients with metastatic melanoma. Melanoma Res. 2019;29(2):172–7.

    CAS  PubMed  Google Scholar 

  32. 32.

    Quach HT, Dewan AK, Davis EJ, Ancell KK, Fan R, Ye F, et al. Association of anti-programmed cell death 1 cutaneous toxic effects with outcomes in patients with advanced melanoma. JAMA Oncol. 2019;5(6):906–8.

    PubMed  PubMed Central  Google Scholar 

  33. 33.

    Babai S, Voisin AL, Bertin C, Gouverneur A, Le-Louet H. Occurrences and outcomes of immune checkpoint inhibitors-induced vitiligo in cancer patients: a retrospective cohort study. Drug Saf. 2020;43(2):111–7.

    CAS  PubMed  Google Scholar 

  34. 34.

    Nardin C, Pelletier F, Puzenat E, Aubin F. Vitiligo repigmentation with melanoma progression during pembrolizumab treatment. Acta Derm Venereol. 2019;99(10):913–4.

    PubMed  Google Scholar 

  35. 35.

    Plaquevent M, Greliak A, Pinard C, Duval-Modeste AB, Joly P. Simultaneous long-lasting regression of multiple nevi and melanoma metastases after ipilimumab therapy. Melanoma Res. 2019;29(3):311–2.

    CAS  PubMed  Google Scholar 

  36. 36.

    Schwager Z, Laird ME, Latkowski JA. Regression of pigmented lesions in a patient with metastatic melanoma treated with immunotherapy. JAAD Case Rep. 2018;4(5):421–3.

    PubMed  PubMed Central  Google Scholar 

  37. 37.

    Mihailovic N, Dyballa J, Herz S, Fluck M, Alnawaiseh M, Merte RL, et al. Vogt-Koyanagi-Harada-like uveitis under immune checkpoint inhibitor treatment for metastasized malignant melanoma [in German]. Ophthalmologe. 2020;117(5):467–71.

    PubMed  Google Scholar 

  38. 38.

    Obata S, Saishin Y, Teramura K, Ohji M. Vogt-Koyanagi-Harada disease-like uveitis during nivolumab (anti-PD-1 antibody) treatment for metastatic cutaneous malignant melanoma. Case Rep Ophthalmol. 2019;10(1):67–74.

    PubMed  PubMed Central  Google Scholar 

  39. 39.

    Sibaud V. Dermatologic reactions to immune checkpoint inhibitors: skin toxicities and immunotherapy. Am J Clin Dermatol. 2018;19(3):345–61.

    Google Scholar 

  40. 40.

    Sanlorenzo M, Vujic I, Daud A, Algazi A, Gubens M, Luna SA, et al. Pembrolizumab cutaneous adverse events and their association with disease progression. JAMA Dermatol. 2015;151(11):1206–12.

    PubMed  PubMed Central  Google Scholar 

  41. 41.

    Billon E, Walz J, Brunelle S, Thomassin J, Salem N, Guerin M, et al. Vitiligo adverse event observed in a patient with durable complete response after nivolumab for metastatic renal cell carcinoma. Front Oncol. 2019;9:1033.

    PubMed  PubMed Central  Google Scholar 

  42. 42.

    Liu RC, Consuegra G, Chou S, Fernandez PP. Vitiligo-like depigmentation in oncology patients treated with immunotherapies for nonmelanoma metastatic cancers. Clin Exp Dermatol. 2019;44(6):643–6.

    CAS  PubMed  Google Scholar 

  43. 43.

    Yin ES, Totonchy MB, Leventhal JS. Nivolumab-associated vitiligo-like depigmentation in a patient with acute myeloid leukemia: a novel finding. JAAD Case Rep. 2017;3(2):90–2.

    PubMed  PubMed Central  Google Scholar 

  44. 44.

    Kosche C, Mohindra N, Choi JN. Vitiligo in a patient undergoing nivolumab treatment for non-small cell lung cancer. JAAD Case Rep. 2018;4(10):1042–4.

    PubMed  PubMed Central  Google Scholar 

  45. 45.

    Byrne EH, Fisher DE. Immune and molecular correlates in melanoma treated with immune checkpoint blockade. Cancer. 2017;123(S11):2143–53.

    PubMed  PubMed Central  Google Scholar 

  46. 46.

    Lo JA, Fisher DE, Flaherty KT. Prognostic significance of cutaneous adverse events associated with pembrolizumab therapy. JAMA Oncol. 2015;1(9):1340–1.

    PubMed  PubMed Central  Google Scholar 

  47. 47.

    Le Gal FA, Avril MF, Bosq J, Lefebvre P, Deschemin JC, Andrieu M, et al. Direct evidence to support the role of antigen-specific CD8(+) T cells in melanoma-associated vitiligo. J Invest Dermatol. 2001;117(6):1464–70.

    PubMed  Google Scholar 

  48. 48.

    Yee C, Thompson JA, Roche P, Byrd DR, Lee PP, Piepkorn M, et al. Melanocyte destruction after antigen-specific immunotherapy of melanoma: direct evidence of T cell-mediated vitiligo. J Exp Med. 2000;192(11):1637–44.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Byrne KT, Turk MJ. New perspectives on the role of vitiligo in immune responses to melanoma. Oncotarget. 2011;2(9):684–94.

    PubMed  PubMed Central  Google Scholar 

  50. 50.

    Okamoto T, Irie RF, Fujii S, Huang SK, Nizze AJ, Morton DL, et al. Anti-tyrosinase-related protein-2 immune response in vitiligo patients and melanoma patients receiving active-specific immunotherapy. J Invest Dermatol. 1998;111(6):1034–9.

    CAS  PubMed  Google Scholar 

  51. 51.

    Edmondson LA, Smith LV, Mallik A. Nivolumab-induced vitiligo in a metastatic melanoma patient: a case report. J Oncol Pharm Pract. 2017;23(8):629–34.

    PubMed  Google Scholar 

  52. 52.

    Ramondetta A, Ribero S, Conti L, Fava P, Marra E, Broganelli P, et al. Clinical and pathological relevance of drug-induced vitiligo in patients treated for metastatic melanoma with anti-PD1 or BRAF/MEK inhibitors. Acta Derm Venereol. 2020;100(1):adv00001.

  53. 53.

    Pala L, Conforti F, Cocorocchio E, Ferrucci PF. Extensive vitiligo associated to response to c-kit inhibitor in metastatic mucosal melanoma. Anticancer Drugs. 2020. https://doi.org/10.1097/CAD.0000000000000906.

    Article  PubMed  Google Scholar 

  54. 54.

    Arowojolu OA, Orlow SJ, Elbuluk N, Manga P. The nuclear factor (erythroid-derived 2)-like 2 (NRF2) antioxidant response promotes melanocyte viability and reduces toxicity of the vitiligo-inducing phenol monobenzone. Exp Dermatol. 2017;26(7):637–44.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55.

    Jian Z, Li K, Song P, Zhu G, Zhu L, Cui T, et al. Impaired activation of the Nrf2-ARE signaling pathway undermines H2O2-induced oxidative stress response: a possible mechanism for melanocyte degeneration in vitiligo. J Invest Dermatol. 2014;134(8):2221–30.

    CAS  PubMed  Google Scholar 

  56. 56.

    Toosi S, Orlow SJ, Manga P. Vitiligo-inducing phenols activate the unfolded protein response in melanocytes resulting in upregulation of IL6 and IL8. J Invest Dermatol. 2012;132(11):2601–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57.

    Kapoor R, Dhatwalia SK, Kumar R, Rani S, Parsad D. Emerging role of dermal compartment in skin pigmentation: comprehensive review. J Eur Acad Dermatol Venereol. 2020. https://doi.org/10.1111/jdv.16404.

    Article  PubMed  Google Scholar 

  58. 58.

    Taieb A, Picardo M. Clinical practice: vitiligo. N Engl J Med. 2009;360(2):160–9.

    CAS  PubMed  Google Scholar 

  59. 59.

    Hartmann A, Bedenk C, Keikavoussi P, Becker JC, Hamm H, Brocker EB. Vitiligo and melanoma-associated hypopigmentation (MAH): shared and discriminative features. J Dtsch Dermatol Ges. 2008;6(12):1053–9.

    PubMed  Google Scholar 

  60. 60.

    Fukuda K, Harris JE. Vitiligo-like depigmentation in patients receiving programmed cell death-1 inhibitor reflects active vitiligo. J Am Acad Dermatol. 2018;78(1):e15–e1616.

    PubMed  Google Scholar 

  61. 61.

    Nakashima C, Ishida Y, Nakagawa K, Irie H, Hirata M, Kataoka T, et al. Identification of CD49a+ CD8+ resident memory T cells in vitiligo-like lesions associated with nivolumab treatment for melanoma. J Eur Acad Dermatol Venereol. 2020;34(2):e79–82.

    CAS  PubMed  Google Scholar 

  62. 62.

    Spritz RA. The genetics of generalized vitiligo: autoimmune pathways and an inverse relationship with malignant melanoma. Genome Med. 2010;2(10):78.

    PubMed  PubMed Central  Google Scholar 

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Correspondence to Nada Elbuluk.

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This study was in part funded by the Leo Foundation (Grant number LF16101).

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Brandon E. Cohen, Prashiela Manga, Krysta Lin, and Nada Elbuluk have no conflicts of interest that might be directly relevant to the content of this article.

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Cohen, B.E., Manga, P., Lin, K. et al. Vitiligo and Melanoma-Associated Vitiligo: Understanding Their Similarities and Differences. Am J Clin Dermatol 21, 669–680 (2020). https://doi.org/10.1007/s40257-020-00524-0

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