Melanoma pp 351-359 | Cite as

Management of Melanoma Locoregional Recurrence

  • Clara R. FarleyEmail author
  • Keith A. Delman


The incidence of melanoma continues to rise, and while most patients are diagnosed and treated early, up to 25% of patients may ultimately develop recurrent disease locally or within regional lymph nodes. Locoregional recurrence is defined as recurrence locally at the site of the primary lesion, regionally in the draining lymph node basin, and/or anywhere in between, but excludes distant metastatic disease. It can be characterized by as a “true recurrence” following adequate excision or “persistent” disease due to inadequate excision. Locoregional recurrence can also occur as in-transit metastases, defined as cutaneous or subcutaneous recurrence proximal to the primary lesion site and distal to the regional lymph node basin, generally greater than two centimeters from the original site of resection. Surgical removal is the mainstay of therapy for locoregional recurrence of melanoma and, at present, still offers the best chance for long-term cure. For those with unresectable disease, there are several additional treatment modalities. Regional therapy options include hyperthermic isolated limb perfusion (HILP) or isolated limb infusion (ILI), topical therapies, intralesional injection therapies, laser ablation, radiation therapy, and systemic therapy. With recent progress in systemic treatment options this approach can also be considered in those with unresectable, locoregional disease, especially when a clinical trial is available.


Melanoma Recurrence Morbidity Survival Metastases Immunotherapy 



Bacilli Calmette-Guérin


Cytotoxic T lymphocyte-associated antigen 4




Granuloctye-macrophage colony stimulating factor


Hyperthermic isolated limb perfusion


Isolated limb infusion


National Comprehensive Cancer Network


programmed cell death 1


Sentinel lymph node biopsy


  1. 1.
    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin. 2017;67:7–30. Scholar
  2. 2.
    Karakousis CP, Balch CM, Urist MM, et al. Local recurrence in malignant melanoma: long-term results of the multiinstitutional randomized surgical trial. Ann Surg Oncol. 1996;3(5):446–52.CrossRefPubMedGoogle Scholar
  3. 3.
    Karakousis CP, Choe KJ, Holyoke ED. Biologic behavior and treatment of intransit metastasis of melanoma. Surg Gynecol Obstet. 1980;150(1):29–32.PubMedGoogle Scholar
  4. 4.
    Singletary SE, Tucker SL, Boddie Jr AW. Multivariate analysis of prognostic factors in regional cutaneous metastases of extremity melanoma. Cancer. 1988;61(7):1437–40.CrossRefPubMedGoogle Scholar
  5. 5.
    Francken AB, Accortt NA, Shaw HM, et al. Prognosis and determinants of outcome following locoregional or distant recurrence in patients with cutaneous melanoma. Ann Surg Oncol. 2008;15(5):1476–84.CrossRefPubMedGoogle Scholar
  6. 6.
    Balch CM, Soong SJ, Gershenwald JE, et al. Prognostic factors analysis of 17,600 melanoma patients: validation of the American Joint Committee on Cancer melanoma staging system. J Clin Oncol. 2001;19(16):3622–34.CrossRefPubMedGoogle Scholar
  7. 7.
    Stucky CC, Gray RJ, Dueck AC, et al. Risk factors associated with local and in-transit recurrence of cutaneous melanoma. Am J Surg. 2010;200(6):770–4; discussion 744–5CrossRefPubMedGoogle Scholar
  8. 8.
    Pawlik TM, Ross MI, Johnson MM, et al. Predictors and natural history of in-transit melanoma after sentinel lymphadenectomy. Ann Surg Oncol. 2005;12(8):587–96.CrossRefPubMedGoogle Scholar
  9. 9.
    Kesmodel SB, Karakousis GC, Botbyl JD, et al. Mitotic rate as a predictor of sentinel lymph node positivity in patients with thin melanomas. Ann Surg Oncol. 2005;12(6):449–58.CrossRefPubMedGoogle Scholar
  10. 10.
    Dong XD, Tyler D, Johnson JL, et al. Analysis of prognosis and disease progression after local recurrence of melanoma. Cancer. 2000;88(5):1063–71.CrossRefPubMedGoogle Scholar
  11. 11.
    Coit DG, Andtbacka R, Bichakjian CK, et al. Melanoma. J Natl Compr Cancer Netw. 2009;7(3):250–75.CrossRefGoogle Scholar
  12. 12.
    Yao KA, Hsueh EC, Essner R, et al. Is sentinel lymph node mapping indicated for isolated local and in-transit recurrent melanoma? Ann Surg. 2003;238(5):743–7.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Coventry BJ, Chatterton B, Whitehead F, et al. Sentinel lymph node dissection and lymphatic mapping for local subcutaneous recurrence in melanoma treatment: longer-term follow-up results. Ann Surg Oncol. 2004;11(3 Suppl):203S–7S.CrossRefPubMedGoogle Scholar
  14. 14.
    Beasley GM, Tyler DS. Treatment of in-transit melanoma: an opportunity to discover critical knowledge. Oncology (Williston Park). 2011;25(14):1351–2, 1355Google Scholar
  15. 15.
    Badgwell B, Xing Y, Gershenwald JE, et al. Pelvic lymph node dissection is beneficial in subsets of patients with node-positive melanoma. Ann Surg Oncol. 2007;14(10):2867–75.CrossRefPubMedGoogle Scholar
  16. 16.
    Love TP, Delman KA. Management of regional lymph node basins in melanoma. Ochsner J. 2010;10(2):99–107.PubMedPubMedCentralGoogle Scholar
  17. 17.
    Davis PG, Serpell JW, Kelly JW, Paul E. Axillary lymph node dissection for malignant melanoma. ANZ J Surg. 2011;81(6):462–6.CrossRefPubMedGoogle Scholar
  18. 18.
    Shada AL, Walters DM, Tierney SN, Slingluff CL Jr. Surgical resection for bulky or recurrent axillary metastatic melanoma. J Surg Oncol. 2012;105(1):21–5.CrossRefPubMedGoogle Scholar
  19. 19.
    Sawh-Martinez R, Salameh B, Colebunders B, et al. Level I sparing radical neck dissections for cutaneous melanoma in the lymphoscintigram era. Ann Plast Surg. 2012;69(4):422–4.CrossRefPubMedGoogle Scholar
  20. 20.
    Khan N, Khan MK, Almasan A, et al. The evolving role of radiation therapy in the management of malignant melanoma. Int J Radiat Oncol Biol Phys. 2011;80(3):645–54.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Burmeister BH, Henderson MA, Ainslie J, et al. Adjuvant radiotherapy versus observation alone for patients at risk of lymph-node field relapse after therapeutic lymphadenectomy for melanoma: a randomised trial. Lancet Oncol. 2012;13(6):589–97.CrossRefPubMedGoogle Scholar
  22. 22.
    Agrawal S, Kane JM 3rd, Guadagnolo BA, et al. The benefits of adjuvant radiation therapy after therapeutic lymphadenectomy for clinically advanced, high-risk, lymph node-metastatic melanoma. Cancer. 2009;115(24):5836–44.CrossRefPubMedGoogle Scholar
  23. 23.
    Guadagnolo BA, Zagars GK. Adjuvant radiation therapy for high-risk nodal metastases from cutaneous melanoma. Lancet Oncol. 2009;10(4):409–16.CrossRefPubMedGoogle Scholar
  24. 24.
    Wong SL, Coit DG. Role of surgery in patients with stage IV melanoma. Curr Opin Oncol. 2004;16(2):155–60. ReviewCrossRefPubMedGoogle Scholar
  25. 25.
    Ollila DW. Complete metastasectomy in patients with stage IV metastatic melanoma. Lancet Oncol. 2006;7(11):919–24. ReviewCrossRefPubMedGoogle Scholar
  26. 26.
    Allen PJ, Coit DG. The surgical management of metastatic melanoma. Ann Surg Oncol. 2002;9(8):762–70. ReviewCrossRefPubMedGoogle Scholar
  27. 27.
    Wornom IL 3rd, Smith JW, Soong SJ, McElvein R, Urist MM, Balch CM. Surgery as palliative treatment for distant metastases of melanoma. Ann Surg. 1986;204(2):181–5.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Creech O Jr, Krementz ET, Ryan RF, Winblad JN. Chemotherapy of cancer: regional perfusion utilizing an extracorporeal circuit. Ann Surg. 1958;148(4):616–32.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Testori A, Verhoef C, Kroon HM, et al. Treatment of melanoma metastases in a limb by isolated limb perfusion and isolated limb infusion. J Surg Oncol. 2011;104(4):397–404.CrossRefPubMedGoogle Scholar
  30. 30.
    Raymond AK, Beasley GM, Broadwater G, et al. Current trends in regional therapy for melanoma: lessons learned from 225 regional chemotherapy treatments between 1995 and 2010 at a single institution. J Am Coll Surg. 2011;213(2):306–16.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Gimbel MI, Delman KA, Zager JS. Therapy for unresectable recurrent and in-transit extremity melanoma. Cancer Control. 2008;15(3):225–32.CrossRefPubMedGoogle Scholar
  32. 32.
    Alexander Jr HR, Fraker DL, Bartlett DL, et al. Analysis of factors influencing outcome in patients with in-transit malignant melanoma undergoing isolated limb perfusion using modern treatment parameters. J Clin Oncol. 2010;28(1):114–8.CrossRefGoogle Scholar
  33. 33.
    Beasley GM, Petersen RP, Yoo J, et al. Isolated limb infusion for in-transit malignant melanoma of the extremity: a well-tolerated but less effective alternative to hyperthermic isolated limb perfusion. Ann Surg Oncol. 2008;15(8):2195–205.CrossRefPubMedGoogle Scholar
  34. 34.
    Rossi CR, Pasquali S, Mocellin S, et al. Long-term results of melphalan-based isolated limb perfusion with or without low-dose TNF for in-transit melanoma metastases. Ann Surg Oncol. 2010;17(11):3000–7.CrossRefPubMedGoogle Scholar
  35. 35.
    Thompson JF, Kam PC, Waugh RC, Harman CR. Isolated limb infusion with cytotoxic agents: a simple alternative to isolated limb perfusion. Semin Surg Oncol. 1998;14(3):238–47.CrossRefPubMedGoogle Scholar
  36. 36.
    Kroon HM, Moncrieff M, Kam PC, Thompson JF. Outcomes following isolated limb infusion for melanoma. A 14-year experience. Ann Surg Oncol. 2008;15(11):3003–13.CrossRefPubMedGoogle Scholar
  37. 37.
    Wong J, Chen YA, Fisher KJ, Zager JS. Isolated limb infusion in a series of over 100 infusions: a single-center experience. Ann Surg Oncol. 2013;20(4):1121–7.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Beasley GM, Caudle A, Petersen RP, et al. A multi-institutional experience of isolated limb infusion: defining response and toxicity in the US. J Am Coll Surg. 2009;208(5):706–15; discussion 715–7CrossRefPubMedGoogle Scholar
  39. 39.
    Sharma K, Beasley G, Turley R, et al. Patterns of recurrence following complete response to regional chemotherapy for in-transit melanoma. Ann Surg Oncol. 2012;19(8):2563–71.CrossRefPubMedGoogle Scholar
  40. 40.
    Chai CY, Deneve JL, Beasley GM, et al. A multi-institutional experience of repeat regional chemotherapy for recurrent melanoma of extremities. Ann Surg Oncol. 2012;19(5):1637–43.CrossRefPubMedGoogle Scholar
  41. 41.
    Kroon HM, Lin DY, Kam PC, Thompson JF. Efficacy of repeat isolated limb infusion with melphalan and actinomycin D for recurrent melanoma. Cancer. 2009;115(9):1932–40.CrossRefPubMedGoogle Scholar
  42. 42.
    Beasley GM, Parsons C, Broadwater G, et al. A multicenter prospective evaluation of the clinical utility of F-18 FDG-PET/CT in patients with AJCC stage IIIB or IIIC extremity melanoma. Ann Surg. 2012;256(2):350–6.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Testori A, Faries MB, Thompson JF, et al. Local and intralesional therapy of in-transit melanoma metastases. J Surg Oncol. 2011;104(4):391–6.CrossRefPubMedGoogle Scholar
  44. 44.
    Martiniuk F, Damian DL, Thompson JF, et al. TH17 is involved in the remarkable regression of metastatic malignant melanoma to topical diphencyprone. J Drugs Dermatol. 2010;9(11):1368–72.PubMedPubMedCentralGoogle Scholar
  45. 45.
    Damian DL, Thompson JF. Treatment of extensive cutaneous metastatic melanoma with topical diphencyprone. J Am Acad Dermatol. 2007;56(5):869–71.CrossRefPubMedGoogle Scholar
  46. 46.
    Damian DL, Shannon KF, Saw RP, Thompson JF. Topical diphencyprone immunotherapy for cutaneous metastatic melanoma. Australas J Dermatol. 2009;50(4):266–71.CrossRefPubMedGoogle Scholar
  47. 47.
    Hemmi H, Kaisho T, Takeuchi O, et al. Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway. Nat Immunol. 2002;3(2):196–200.CrossRefPubMedGoogle Scholar
  48. 48.
    Wagner TL, Ahonen CL, Couture AM, et al. Modulation of TH1 and TH2 cytokine production with the immune response modifiers, R-848 and imiquimod. Cell Immunol. 1999;191(1):10–9.CrossRefPubMedGoogle Scholar
  49. 49.
    Berman B, Poochareon VN, Villa AM. Novel dermatologic uses of the immune response modifier imiquimod 5% cream. Skin Therapy Lett. 2002;7(9):1–6.PubMedGoogle Scholar
  50. 50.
    Florin V, Desmedt E, Vercambre-Darras S, Mortier L. Topical treatment of cutaneous metastases of malignant melanoma using combined imiquimod and 5-fluorouracil. Investig New Drugs. 2012;30(4):1641–5.CrossRefGoogle Scholar
  51. 51.
    Grotz TE, Mansfield AS, Kottschade LA, et al. In-transit melanoma: an individualized approach. Oncology (Williston Park). 2011;25(14):1340–8.Google Scholar
  52. 52.
    Morton D, Eilber FR, Malmgren RA, Wood WC. Immunological factors which influence response to immunotherapy in malignant melanoma. Surgery. 1970;68(1):158–63; discussion 163–4PubMedGoogle Scholar
  53. 53.
    Kidner TB, Morton DL, Lee DJ, et al. Combined intralesional bacille Calmette-Guérin (BCG) and topical imiquimod for in-transit melanoma. J Immunother. 2012;35(9):716–20.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Thompson JF, Hersey P, Wachter E. Chemoablation of metastatic melanoma using intralesional rose Bengal. Melanoma Res. 2008;18(6):405–11.CrossRefPubMedGoogle Scholar
  55. 55.
    Boyd KU, Wehrli BM, Temple CL. Intra-lesional interleukin-2 for the treatment of in-transit melanoma. J Surg Oncol. 2011;104(7):711–7.CrossRefPubMedGoogle Scholar
  56. 56.
    Radny P, Caroli UM, Bauer J, et al. Phase II trial of intralesional therapy with interleukin-2 in soft-tissue melanoma metastases. Br J Cancer. 2003;89(9):1620–6.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Green DS, Bodman-Smith MD, Dalgleish AG, Fischer MD. Phase I/II study of topical imiquimod and intralesional interleukin-2 in the treatment of accessible metastases in malignant melanoma. Br J Dermatol. 2007;156(2):337–45.CrossRefPubMedGoogle Scholar
  58. 58.
    von Wussow P, Block B, Hartmann F, Deicher H. Intralesional interferon-alpha therapy in advanced malignant melanoma. Cancer. 1988;61(6):1071–4.CrossRefGoogle Scholar
  59. 59.
    Fujimura T, Okuyama R, Ohtani T, et al. Perilesional treatment of metastatic melanoma with interferon-beta. Clin Exp Dermatol. 2009;34(7):793–9.CrossRefPubMedGoogle Scholar
  60. 60.
    Ridolfi L, Ridolfi R. Preliminary experiences of intralesional immunotherapy in cutaneous metastatic melanoma. Hepato-Gastroenterology. 2002;49(44):335–9.PubMedGoogle Scholar
  61. 61.
    Kaufman HL, Kim DW, DeRaffele G, et al. Local and distant immunity induced by intralesional vaccination with an oncolytic herpes virus encoding GM-CSF in patients with stage IIIc and IV melanoma. Ann Surg Oncol. 2010;17(3):718–30.CrossRefPubMedGoogle Scholar
  62. 62.
    Kaufman HL, Bines SD. OPTIM trial: a phase III trial of an oncolytic herpes virus encoding GM-CSF for unresectable stage III or IV melanoma. Future Oncol. 2010;6(6):941–9.CrossRefPubMedGoogle Scholar
  63. 63.
    Andtbacka R, Kaufman HL, Collicho F, et al. Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J Clin Oncol. 2015;33(25):2780–8.CrossRefGoogle Scholar
  64. 64.
    Pol J, Kroemer G, Galluzzi L. First oncolytic virus approved for melanoma immunotherapy. Oncoimmunology. 2015;5(1):e1115641.CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Kottschade LA, Weenig RH, Otley CC, et al. The use of pulsed dye laser in the treatment of melanoma metastatic to the skin: a Mayo Clinic case series. J Am Acad Dermatol. 2010;62(6):e22–5.CrossRefPubMedGoogle Scholar
  66. 66.
    Gibson SC, Byrne DS, McKay AJ. Ten-year experience of carbon dioxide laser ablation as treatment for cutaneous recurrence of malignant melanoma. Br J Surg. 2004;91(7):893–5.CrossRefPubMedGoogle Scholar
  67. 67.
    Testori A, Intelisano A, Verrecchia F, et al. Alternatives for the treatment of local advanced disease: electrochemotherapy, limb perfusion, limb infusion, intralesional IL2. What is the role? Dermatol Ther. 2012;25(5):443–51.CrossRefPubMedGoogle Scholar
  68. 68.
    Olivier KR, Schild SE, Morris CG, et al. A higher radiotherapy dose is associated with more durable palliation and longer survival in patients with metastatic melanoma. Cancer. 2007;110(8):1791–5.CrossRefPubMedGoogle Scholar
  69. 69.
    Barker CA, Lee NY. Radiation therapy for cutaneous melanoma. Dermatol Clin. 2012;30(3):525–33.CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Seegenschmiedt MH, Keilholz L, Altendorf-Hofmann A, et al. Palliative radiotherapy for recurrent and metastatic malignant melanoma: prognostic factors for tumor response and long-term outcome: a 20-year experience. Int J Radiat Oncol Biol Phys. 1999;44(3):607–18.CrossRefPubMedGoogle Scholar
  71. 71.
    Stevens G, Thompson JF, Firth I, et al. Locally advanced melanoma: results of postoperative hypofractionated radiation therapy. Cancer. 2000;88(1):88–94.CrossRefPubMedGoogle Scholar
  72. 72.
    Stevens G, McKay MJ. Dispelling the myths surrounding radiotherapy for treatment of cutaneous melanoma. Lancet Oncol. 2006;7(7):575–83.CrossRefPubMedGoogle Scholar
  73. 73.
    Rao NG, Yu HH, Trotti A 3rd, Sondak VK. The role of radiation therapy in the management of cutaneous melanoma. Surg Oncol Clin N Am. 2011;20(1):115–31.CrossRefPubMedGoogle Scholar
  74. 74.
    Hodi FS, O'Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711–23.CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Eggermont AM, Chiarion-Sileni V, Grob JJ, et al. Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2015;16(5):522–3.CrossRefPubMedGoogle Scholar
  76. 76.
    Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364:2507–16.CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Zhu Z, Liu W, Gotlieb V. The rapidly evolving therapies for advanced melanoma—towards immunotherapy, molecular targeted therapy, and beyond. Crit Rev Oncol Hematol. 2016;99:91–9. Scholar
  78. 78.
    Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M, Larkin J, Lorigan P, Neyns B, Blank CU, Hamid O, Mateus C, Shapira-Frommer R, Kosh M, Zhou H, Ibrahim N, Ebbinghaus S, Ribas A, KEYNOTE-006 investigators. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. 2015;372(26):2521–32. Scholar
  79. 79.
    Larkin J, Hodi FS, Wolchok JD. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373(13):1270–1. Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Surgical OncologyEmory University HospitalAtlantaUSA

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