Melanoma pp 87-103 | Cite as

Staging and Classification of Melanoma

  • Michael E. Egger
  • Jeffrey E. GershenwaldEmail author


Cutaneous melanoma is staged according to the TNM-based American Joint Committee of Cancer staging system. Primary tumor thickness (also termed Breslow thickness) and ulceration constitute the T (tumor) category and are important risk factors for survival in both localized and regionally advanced disease. The pathological status of the regional nodal basins is a powerful prognostic factor in cutaneous melanoma and comprises a major component of the N (nodal) category. Sentinel lymph node biopsy is a commonly employed staging technique to assess the status of the clinically negative regional nodal basin and contributes to N category assessment. Non-nodal regional metastases (e.g., satellites, microsatellites, and in-transit metastases) are also components of the N category and along with nodal status constitute stage III disease. Patients with distant (stage IV) disease constitute the M (metastasis) category and are categorized according to the site(s) of distant metastasis: skin/subcutaneous/distant nodal tissue, lung, non-pulmonary/non-CNS visceral, and central nervous system. Serum lactate dehydrogenase level is included in the M category and has been shown to be prognostically significant in patients with stage IV disease. Novel factors that evaluate the immunologic or molecular profile of primary melanoma, metastases, or host may further risk stratify patients beyond classic TNM-based staging. Clinical predictive models that account for multiple clinical and pathological factors may provide a more accurate approach to individualized risk assessment for a given patient and constitute an area of active focus and evolution.


Melanoma Staging Stage I melanoma Stage II melanoma Stage III melanoma Stage IV melanoma Melanoma staging criteria Melanoma risk assessment Melanoma prognosis Sentinel lymph node Satellite metastasis In-transit metastasis Microsatellites Tumor thickness Ulceration Mitotic rate 


  1. 1.
    Gershenwald JE, Scolyer RA, Hess KR, Thompson JF, Long GV, Ross MI, et al. Melanoma of the skin. In: Amin MB, Edge SB, Greene FL, Byrd DR, Brookland RK, Washington MK, et al., editors. AJCC cancer staging manual. 8th ed. New York: Springer; 2017.Google Scholar
  2. 2.
    Breslow A. Thickness, cross-sectional areas and depth of invasion in the prognosis of cutaneous melanoma. Ann Surg. 1970;172(5):902–8.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Clark WH Jr, From L, Bernardino EA, Mihm MC. The histogenesis and biologic behavior of primary human malignant melanomas of the skin. Cancer Res. 1969;29(3):705–27.PubMedPubMedCentralGoogle Scholar
  4. 4.
    Breslow A. Tumor thickness, level of invasion and node dissection in stage I cutaneous melanoma. Ann Surg. 1975;182(5):572–5.PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Ge L, Vilain RE, Lo S, Aivazian K, Scolyer RA, Thompson JF. Breslow thickness measurements of melanomas around American Joint Committee on Cancer staging cut-off points: imprecision and terminal digit bias have important implications for staging and patient management. Ann Surg Oncol. 2016;23(8):2658–63.PubMedCrossRefPubMedCentralGoogle Scholar
  6. 6.
    Balch CM, Gershenwald JE, Soong SJ, Thompson JF, Atkins MB, Byrd DR, et al. Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol. 2009;27(36):6199–206.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Thompson JF, Soong SJ, Balch CM, Gershenwald JE, Ding S, Coit DG, et al. Prognostic significance of mitotic rate in localized primary cutaneous melanoma: an analysis of patients in the multi-institutional American Joint Committee on Cancer melanoma staging database. J Clin Oncol. 2011;29(16):2199–205.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Balch CM, Gershenwald JE, Soong SJ, Thompson JF, Ding S, Byrd DR, et al. Multivariate analysis of prognostic factors among 2313 patients with stage III melanoma: comparison of nodal micrometastases versus macrometastases. J Clin Oncol. 2010;28(14):2452–9.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Kimsey TF, Cohen T, Patel A, Busam KJ, Brady MS. Microscopic satellitosis in patients with primary cutaneous melanoma: implications for nodal basin staging. Ann Surg Oncol. 2009;16(5):1176–83.PubMedCrossRefPubMedCentralGoogle Scholar
  10. 10.
    Bartlett EK, Gupta M, Datta J, Gimotty PA, Guerry D, Xu X, et al. Prognosis of patients with melanoma and microsatellitosis undergoing sentinel lymph node biopsy. Ann Surg Oncol. 2014;21(3):1016–23.PubMedCrossRefPubMedCentralGoogle Scholar
  11. 11.
    Balch CM, Soong SJ, Murad TM, Smith JW, Maddox WA, Durant JR. A multifactorial analysis of melanoma. IV. Prognostic factors in 200 melanoma patients with distant metastases (stage III). J Clin Oncol. 1983;1(2):126–34.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Barth A, Wanek LA, Morton DL. Prognostic factors in 1521 melanoma patients with distant metastases. J Am Coll Surg. 1995;181(3):193–201.PubMedPubMedCentralGoogle Scholar
  13. 13.
    Bowen GM, Chang AE, Lowe L, Hamilton T, Patel R, Johnson TM. Solitary melanoma confined to the dermal and/or subcutaneous tissue: evidence for revisiting the staging classification. Arch Dermatol. 2000;136(11):1397–9.PubMedCrossRefPubMedCentralGoogle Scholar
  14. 14.
    de Waal AC, Aben KK, van Rossum MM, Kiemeney LA. Melanoma of unknown primary origin: a population-based study in the Netherlands. Eur J Cancer. 2013;49(3):676–83.PubMedCrossRefPubMedCentralGoogle Scholar
  15. 15.
    Velez A, Walsh D, Karakousis CP. Treatment of unknown primary melanoma. Cancer. 1991;68(12):2579–81.PubMedCrossRefPubMedCentralGoogle Scholar
  16. 16.
    Anbari KK, Schuchter LM, Bucky LP, Mick R, Synnestvedt M, Guerry D, et al. Melanoma of unknown primary site: presentation, treatment, and prognosis--a single institution study. University of Pennsylvania Pigmented Lesion Study Group. Cancer. 1997;79(9):1816–21.PubMedCrossRefPubMedCentralGoogle Scholar
  17. 17.
    Cormier JN, Xing Y, Feng L, Huang X, Davidson L, Gershenwald JE, et al. Metastatic melanoma to lymph nodes in patients with unknown primary sites. Cancer. 2006;106(9):2012–20.PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    Prens SP, van der Ploeg AP, van Akkooi AC, van Montfort CA, van Geel AN, de Wilt JH, et al. Outcome after therapeutic lymph node dissection in patients with unknown primary melanoma site. Ann Surg Oncol. 2011;18(13):3586–92.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Lee CC, Faries MB, Wanek LA, Morton DL. Improved survival after lymphadenectomy for nodal metastasis from an unknown primary melanoma. J Clin Oncol. 2008;26(4):535–41.PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Weide B, Faller C, Elsasser M, Buttner P, Pflugfelder A, Leiter U, et al. Melanoma patients with unknown primary site or nodal recurrence after initial diagnosis have a favourable survival compared to those with synchronous lymph node metastasis and primary tumour. PLoS One. 2013;8(6):e66953.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    van der Ploeg AP, Haydu LE, Spillane AJ, Scolyer RA, Quinn MJ, Saw RP, et al. Melanoma patients with an unknown primary tumor site have a better outcome than those with a known primary following therapeutic lymph node dissection for macroscopic (clinically palpable) nodal disease. Ann Surg Oncol. 2014;21(9):3108–16.PubMedCrossRefGoogle Scholar
  22. 22.
    Smoller BR, Balch CB, Balzer BL, Crowson AN, Didolkar M, Lazar A, et al. Protocol for the examination of specimens from patients with melanoma of the skin: College of American Pathologists; 2016 [updated January 2016; cited 2016 4/12/2016].
  23. 23.
    Kashani-Sabet M, Sagebiel RW, Ferreira CM, Nosrati M, Miller JR 3rd. Vascular involvement in the prognosis of primary cutaneous melanoma. Arch Dermatol. 2001;137(9):1169–73.PubMedCrossRefGoogle Scholar
  24. 24.
    Straume O, Akslen LA. Lymphatic vessel density and prognosis in cutaneous melanoma. Br J Cancer. 2004;91(6):1224–5.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Nagore E, Oliver V, Botella-Estrada R, Moreno-Picot S, Insa A, Fortea JM. Prognostic factors in localized invasive cutaneous melanoma: high value of mitotic rate, vascular invasion and microscopic satellitosis. Melanoma Res. 2005;15(3):169–77.PubMedCrossRefGoogle Scholar
  26. 26.
    Egger ME, Gilbert JE, Burton AL, McMasters KM, Callender GG, Quillo AR, et al. Lymphovascular invasion as a prognostic factor in melanoma. Am Surg. 2011;77(8):992–7.PubMedGoogle Scholar
  27. 27.
    Storr SJ, Safuan S, Mitra A, Elliott F, Walker C, Vasko MJ, et al. Objective assessment of blood and lymphatic vessel invasion and association with macrophage infiltration in cutaneous melanoma. Mod Pathol. 2012;25(4):493–504.PubMedCrossRefGoogle Scholar
  28. 28.
    Xu X, Chen L, Guerry D, Dawson PR, Hwang WT, VanBelle P, et al. Lymphatic invasion is independently prognostic of metastasis in primary cutaneous melanoma. Clin Cancer Res. 2012;18(1):229–37.PubMedCrossRefGoogle Scholar
  29. 29.
    Taylor RC, Patel A, Panageas KS, Busam KJ, Brady MS. Tumor-infiltrating lymphocytes predict sentinel lymph node positivity in patients with cutaneous melanoma. J Clin Oncol. 2007;25(7):869–75.PubMedCrossRefGoogle Scholar
  30. 30.
    Burton AL, Roach BA, Mays MP, Chen AF, Ginter BA, Vierling AM, et al. Prognostic significance of tumor infiltrating lymphocytes in melanoma. Am Surg. 2011;77(2):188–92.PubMedPubMedCentralGoogle Scholar
  31. 31.
    Azimi F, Scolyer RA, Rumcheva P, Moncrieff M, Murali R, McCarthy SW, et al. Tumor-infiltrating lymphocyte grade is an independent predictor of sentinel lymph node status and survival in patients with cutaneous melanoma. J Clin Oncol. 2012;30(21):2678–83.PubMedCrossRefPubMedCentralGoogle Scholar
  32. 32.
    Thomas NE, Busam KJ, From L, Kricker A, Armstrong BK, Anton-Culver H, et al. Tumor-infiltrating lymphocyte grade in primary melanomas is independently associated with melanoma-specific survival in the population-based genes, environment and melanoma study. J Clin Oncol. 2013;31(33):4252–9.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Schatton T, Scolyer RA, Thompson JF, Mihm MC Jr. Tumor-infiltrating lymphocytes and their significance in melanoma prognosis. Methods Mol Biol. 2014;1102:287–324.PubMedCrossRefPubMedCentralGoogle Scholar
  34. 34.
    Quinn MJ, Crotty KA, Thompson JF, Coates AS, O'Brien CJ, McCarthy WH. Desmoplastic and desmoplastic neurotropic melanoma: experience with 280 patients. Cancer. 1998;83(6):1128–35.PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Morton DL, Wen DR, Wong JH, Economou JS, Cagle LA, Storm FK, et al. Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch Surg. 1992;127(4):392–9.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Gershenwald JE, Thompson W, Mansfield PF, Lee JE, Colome MI, Tseng CH, et al. Multi-institutional melanoma lymphatic mapping experience: the prognostic value of sentinel lymph node status in 612 stage I or II melanoma patients. J Clin Oncol. 1999;17(3):976–83.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Ross MI, Reintgen D, Balch CM. Selective lymphadenectomy: emerging role for lymphatic mapping and sentinel node biopsy in the management of early stage melanoma. Semin Surg Oncol. 1993;9(3):219–23.PubMedPubMedCentralGoogle Scholar
  38. 38.
    Reintgen D, Cruse CW, Wells K, Berman C, Fenske N, Glass F, et al. The orderly progression of melanoma nodal metastases. Ann Surg. 1994;220(6):759–67.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Thompson JF, McCarthy WH, Bosch CM, O'Brien CJ, Quinn MJ, Paramaesvaran S, et al. Sentinel lymph node status as an indicator of the presence of metastatic melanoma in regional lymph nodes. Melanoma Res. 1995;5(4):255–60.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Balch CM, Buzaid AC, Soong SJ, Atkins MB, Cascinelli N, Coit DG, et al. Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma. J Clin Oncol. 2001;19(16):3635–48.PubMedCrossRefPubMedCentralGoogle Scholar
  41. 41.
    Morton DL, Thompson JF, Essner R, Elashoff R, Stern SL, Nieweg OE, et al. Validation of the accuracy of intraoperative lymphatic mapping and sentinel lymphadenectomy for early-stage melanoma: a multicenter trial. Multicenter Selective Lymphadenectomy Trial Group. Ann Surg. 1999;230(4):453–63. discussion 63-5PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Kesmodel SB, Karakousis GC, Botbyl JD, Canter RJ, Lewis RT, Wahl PM, 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.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Rousseau DL Jr, Ross MI, Johnson MM, Prieto VG, Lee JE, Mansfield PF, et al. Revised American Joint Committee on cancer staging criteria accurately predict sentinel lymph node positivity in clinically node-negative melanoma patients. Ann Surg Oncol. 2003;10(5):569–74.PubMedCrossRefPubMedCentralGoogle Scholar
  44. 44.
    McMasters KM, Wong SL, Edwards MJ, Ross MI, Chao C, Noyes RD, et al. Factors that predict the presence of sentinel lymph node metastasis in patients with melanoma. Surgery. 2001;130(2):151–6.PubMedCrossRefPubMedCentralGoogle Scholar
  45. 45.
    Sondak VK, Taylor JM, Sabel MS, Wang Y, Lowe L, Grover AC, et al. Mitotic rate and younger age are predictors of sentinel lymph node positivity: lessons learned from the generation of a probabilistic model. Ann Surg Oncol. 2004;11(3):247–58.PubMedCrossRefPubMedCentralGoogle Scholar
  46. 46.
    Cecchi R, Buralli L, Innocenti S, De Gaudio C. Sentinel lymph node biopsy in patients with thin melanomas. J Dermatol. 2007;34(8):512–5.PubMedCrossRefPubMedCentralGoogle Scholar
  47. 47.
    Faries MB, Wanek LA, Elashoff D, Wright BE, Morton DL. Predictors of occult nodal metastasis in patients with thin melanoma. Arch Surg. 2010;145(2):137–42.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Han D, Zager JS, Shyr Y, Chen H, Berry LD, Iyengar S, et al. Clinicopathologic predictors of sentinel lymph node metastasis in thin melanoma. J Clin Oncol. 2013;31(35):4387–93.PubMedCrossRefPubMedCentralGoogle Scholar
  49. 49.
    White RL Jr, Ayers GD, Stell VH, Ding S, Gershenwald JE, Salo JC, et al. Factors predictive of the status of sentinel lymph nodes in melanoma patients from a large multicenter database. Ann Surg Oncol. 2011;18(13):3593–600.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Faries MB, Thompson JF, Cochran AJ, Andtbacka RH, Mozzillo N, Zager JS, et al. Completion Dissection or Observation for Sentinel-Node Metastasis in Melanoma. N Engl J Med. 2017;376(23):2211–22.Google Scholar
  51. 51.
    Leiter U, Stadler R, Mauch C, Hohenberger W, Brockmeyer N, Berking C, et al. Complete lymph node dissection versus no dissection in patients with sentinel lymph node biopsy positive melanoma (DeCOG-SLT): a multicentre, randomised, phase 3 trial. Lancet Oncol. 17(6):757–67.PubMedCrossRefPubMedCentralGoogle Scholar
  52. 52.
    Bilimoria KY, Balch CM, Bentrem DJ, Talamonti MS, Ko CY, Lange JR, et al. Complete lymph node dissection for sentinel node-positive melanoma: assessment of practice patterns in the United States. Ann Surg Oncol. 2008;15(6):1566–76.PubMedCrossRefPubMedCentralGoogle Scholar
  53. 53.
    Wong SL, Morton DL, Thompson JF, Gershenwald JE, Leong SP, Reintgen DS, et al. Melanoma patients with positive sentinel nodes who did not undergo completion lymphadenectomy: a multi-institutional study. Ann Surg Oncol. 2006;13(6):809–16.PubMedCrossRefPubMedCentralGoogle Scholar
  54. 54.
    van der Ploeg AP, van Akkooi AC, Rutkowski P, Cook M, Nieweg OE, Rossi CR, et al. Prognosis in patients with sentinel node-positive melanoma without immediate completion lymph node dissection. Br J Surg. 2012;99(10):1396–405.PubMedCrossRefPubMedCentralGoogle Scholar
  55. 55.
    Gershenwald JE, Andtbacka RH, Prieto VG, Johnson MM, Diwan AH, Lee JE, et al. Microscopic tumor burden in sentinel lymph nodes predicts synchronous nonsentinel lymph node involvement in patients with melanoma. J Clin Oncol. 2008;26(26):4296–303.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Ghaferi AA, Wong SL, Johnson TM, Lowe L, Chang AE, Cimmino VM, et al. Prognostic significance of a positive nonsentinel lymph node in cutaneous melanoma. Ann Surg Oncol. 2009;16(11):2978–84.PubMedCrossRefPubMedCentralGoogle Scholar
  57. 57.
    Ariyan C, Brady MS, Gonen M, Busam K, Coit D. Positive nonsentinel node status predicts mortality in patients with cutaneous melanoma. Ann Surg Oncol. 2009;16(1):186–90.PubMedCrossRefPubMedCentralGoogle Scholar
  58. 58.
    Egger ME, Callender GG, McMasters KM, Ross MI, Martin RC 2nd, Edwards MJ, et al. Diversity of stage III melanoma in the era of sentinel lymph node biopsy. Ann Surg Oncol. 2013;20(3):956–63.PubMedCrossRefPubMedCentralGoogle Scholar
  59. 59.
    Jakub JW, Huebner M, Shivers S, Nobo C, Puleo C, Harmsen WS, et al. The number of lymph nodes involved with metastatic disease does not affect outcome in melanoma patients as long as all disease is confined to the sentinel lymph node. Ann Surg Oncol. 2009;16(8):2245–51.PubMedCrossRefPubMedCentralGoogle Scholar
  60. 60.
    Brown RE, Ross MI, Edwards MJ, Noyes RD, Reintgen DS, Hagendoorn LJ, et al. The prognostic significance of nonsentinel lymph node metastasis in melanoma. Ann Surg Oncol. 2010;17(12):3330–5.PubMedCrossRefPubMedCentralGoogle Scholar
  61. 61.
    Reintgen M, Murray L, Akman K, Giuliano R, Lozicki A, Shivers S, et al. Evidence for a better nodal staging system for melanoma: the clinical relevance of metastatic disease confined to the sentinel lymph nodes. Ann Surg Oncol. 2013;20(2):668–74.PubMedCrossRefPubMedCentralGoogle Scholar
  62. 62.
    Sabel MS, Griffith K, Sondak VK, Lowe L, Schwartz JL, Cimmino VM, et al. Predictors of nonsentinel lymph node positivity in patients with a positive sentinel node for melanoma. J Am Coll Surg. 2005;201(1):37–47.PubMedCrossRefPubMedCentralGoogle Scholar
  63. 63.
    Cadili A, Smylie M, Danyluk J, Dabbs K. Prediction of nonsentinel lymph node metastasis in malignant melanoma. J Surg Res. 2009;154(2):324–9.PubMedCrossRefPubMedCentralGoogle Scholar
  64. 64.
    McMasters KM, Wong SL, Edwards MJ, Chao C, Ross MI, Noyes RD, et al. Frequency of nonsentinel lymph node metastasis in melanoma. Ann Surg Oncol. 2002;9(2):137–41.PubMedCrossRefPubMedCentralGoogle Scholar
  65. 65.
    Page AJ, Carlson GW, Delman KA, Murray D, Hestley A, Cohen C. Prediction of nonsentinel lymph node involvement in patients with a positive sentinel lymph node in malignant melanoma. Am Surg. 2007;73(7):674–8. discussion 8-9PubMedPubMedCentralGoogle Scholar
  66. 66.
    Ranieri JM, Wagner JD, Azuaje R, Davidson D, Wenck S, Fyffe J, et al. Prognostic importance of lymph node tumor burden in melanoma patients staged by sentinel node biopsy. Ann Surg Oncol. 2002;9(10):975–81.PubMedCrossRefPubMedCentralGoogle Scholar
  67. 67.
    Carlson GW, Murray DR, Lyles RH, Staley CA, Hestley A, Cohen C. The amount of metastatic melanoma in a sentinel lymph node: does it have prognostic significance? Ann Surg Oncol. 2003;10(5):575–81.PubMedCrossRefPubMedCentralGoogle Scholar
  68. 68.
    Dewar DJ, Newell B, Green MA, Topping AP, Powell BW, Cook MG. The microanatomic location of metastatic melanoma in sentinel lymph nodes predicts nonsentinel lymph node involvement. J Clin Oncol. 2004;22(16):3345–9.PubMedCrossRefPubMedCentralGoogle Scholar
  69. 69.
    Starz H, Siedlecki K, Balda BR. Sentinel lymphonodectomy and s-classification: a successful strategy for better prediction and improvement of outcome of melanoma. Ann Surg Oncol. 2004;11(3 Suppl):162S–8S.PubMedCrossRefPubMedCentralGoogle Scholar
  70. 70.
    Debarbieux S, Duru G, Dalle S, Beatrix O, Balme B, Thomas L. Sentinel lymph node biopsy in melanoma: a micromorphometric study relating to prognosis and completion lymph node dissection. Br J Dermatol. 2007;157(1):58–67.PubMedCrossRefPubMedCentralGoogle Scholar
  71. 71.
    van Akkooi AC, Nowecki ZI, Voit C, Schafer-Hesterberg G, Michej W, de Wilt JH, et al. Sentinel node tumor burden according to the Rotterdam criteria is the most important prognostic factor for survival in melanoma patients: a multicenter study in 388 patients with positive sentinel nodes. Ann Surg. 2008;248(6):949–55.PubMedCrossRefPubMedCentralGoogle Scholar
  72. 72.
    Scolyer RA, Li LX, McCarthy SW, Shaw HM, Stretch JR, Sharma R, et al. Micromorphometric features of positive sentinel lymph nodes predict involvement of nonsentinel nodes in patients with melanoma. Am J Clin Pathol. 2004;122(4):532–9.PubMedCrossRefPubMedCentralGoogle Scholar
  73. 73.
    Frankel TL, Griffith KA, Lowe L, Wong SL, Bichakjian CK, Chang AE, et al. Do micromorphometric features of metastatic deposits within sentinel nodes predict nonsentinel lymph node involvement in melanoma? Ann Surg Oncol. 2008;15(9):2403–11.PubMedCrossRefPubMedCentralGoogle Scholar
  74. 74.
    Cadili A, Scolyer RA, Brown PT, Dabbs K, Thompson JF. Total sentinel lymph node tumor size predicts nonsentinel node metastasis and survival in patients with melanoma. Ann Surg Oncol. 2010;17(11):3015–20.PubMedCrossRefPubMedCentralGoogle Scholar
  75. 75.
    Satzger I, Volker B, Meier A, Kapp A, Gutzmer R. Criteria in sentinel lymph nodes of melanoma patients that predict involvement of nonsentinel lymph nodes. Ann Surg Oncol. 2008;15(6):1723–32.PubMedCrossRefPubMedCentralGoogle Scholar
  76. 76.
    van der Ploeg AP, van Akkooi AC, Rutkowski P, Nowecki ZI, Michej W, Mitra A, et al. Prognosis in patients with sentinel node-positive melanoma is accurately defined by the combined Rotterdam tumor load and Dewar topography criteria. J Clin Oncol. 2011;29(16):2206–14.PubMedCrossRefPubMedCentralGoogle Scholar
  77. 77.
    Murali R, Cochran AJ, Cook MG, Hillman JD, Karim RZ, Moncrieff M, et al. Interobserver reproducibility of histologic parameters of melanoma deposits in sentinel lymph nodes: implications for management of patients with melanoma. Cancer. 2009;115(21):5026–37.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Fink AM, Weihsengruber F, Duschek N, Schierl M, Wondratsch H, Jurecka W, et al. Value of micromorphometric criteria of sentinel lymph node metastases in predicting further nonsentinel lymph node metastases in patients with melanoma. Melanoma Res. 2011;21(2):139–43.PubMedCrossRefPubMedCentralGoogle Scholar
  79. 79.
    Egger ME, Bower MR, Czyszczon IA, Farghaly H, Noyes RD, Reintgen DS, et al. Comparison of sentinel lymph node micrometastatic tumor burden measurements in melanoma. J Am Coll Surg. 2014;218(4):519–28.PubMedCrossRefPubMedCentralGoogle Scholar
  80. 80.
    van der Ploeg AP, van Akkooi AC, Haydu LE, Scolyer RA, Murali R, Verhoef C, et al. The prognostic significance of sentinel node tumour burden in melanoma patients: an international, multicenter study of 1539 sentinel node-positive melanoma patients. Eur J Cancer. 2014;50(1):111–20.PubMedCrossRefPubMedCentralGoogle Scholar
  81. 81.
    Day CL Jr, Harrist TJ, Gorstein F, Sober AJ, Lew RA, Friedman RJ, et al. Malignant melanoma. Prognostic significance of “microscopic satellites” in the reticular dermis and subcutaneous fat. Ann Surg. 1981;194(1):108–12.PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Leon P, Daly JM, Synnestvedt M, Schultz DJ, Elder DE, Clark WH Jr. The prognostic implications of microscopic satellites in patients with clinical stage I melanoma. Arch Surg. 1991;126(12):1461–8.PubMedCrossRefPubMedCentralGoogle Scholar
  83. 83.
    Buzaid AC, Ross MI, Balch CM, Soong S, McCarthy WH, Tinoco L, et al. Critical analysis of the current American joint committee on cancer staging system for cutaneous melanoma and proposal of a new staging system. J Clin Oncol. 1997;15(3):1039–51.PubMedCrossRefPubMedCentralGoogle Scholar
  84. 84.
    Read RL, Haydu L, Saw RP, Quinn MJ, Shannon K, Spillane AJ, et al. In-transit melanoma metastases: incidence, prognosis, and the role of lymphadenectomy. Ann Surg Oncol. 2015;22(2):475–81.PubMedCrossRefPubMedCentralGoogle Scholar
  85. 85.
    Castiglione R, Ihle MA, Heydt C, Schultheis AM, Merkelbach-Bruse S, Mauch C, et al. The impact of sequencing on diagnosis and treatment of malignant melanoma. Expert Rev Mol Diagn. 2016;16(4):423–33.PubMedCrossRefPubMedCentralGoogle Scholar
  86. 86.
    Lee CY, Gerami P. Molecular techniques for predicting behaviour in melanocytic neoplasms. Pathology. 2016;48(2):142–6.PubMedCrossRefPubMedCentralGoogle Scholar
  87. 87.
    Curtin JA, Fridlyand J, Kageshita T, Patel HN, Busam KJ, Kutzner H, et al. Distinct sets of genetic alterations in melanoma. N Engl J Med. 2005;353(20):2135–47.PubMedCrossRefPubMedCentralGoogle Scholar
  88. 88.
    Horn S, Figl A, Rachakonda PS, Fischer C, Sucker A, Gast A, et al. TERT promoter mutations in familial and sporadic melanoma. Science. 2013;339(6122):959–61.PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Shain AH, Yeh I, Kovalyshyn I, Sriharan A, Talevich E, Gagnon A, et al. The genetic evolution of melanoma from precursor lesions. N Engl J Med. 2015;373(20):1926–36.PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Bittner M, Meltzer P, Chen Y, Jiang Y, Seftor E, Hendrix M, et al. Molecular classification of cutaneous malignant melanoma by gene expression profiling. Nature. 2000;406(6795):536–40.PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Jaeger J, Koczan D, Thiesen HJ, Ibrahim SM, Gross G, Spang R, et al. Gene expression signatures for tumor progression, tumor subtype, and tumor thickness in laser-microdissected melanoma tissues. Clin Cancer Res. 2007;13(3):806–15.PubMedCrossRefPubMedCentralGoogle Scholar
  92. 92.
    Koh SS, Wei JP, Li X, Huang RR, Doan NB, Scolyer RA, et al. Differential gene expression profiling of primary cutaneous melanoma and sentinel lymph node metastases. Mod Pathol. 2012;25(6):828–37.PubMedCrossRefPubMedCentralGoogle Scholar
  93. 93.
    Gerami P, Cook RW, Russell MC, Wilkinson J, Amaria RN, Gonzalez R, et al. Gene expression profiling for molecular staging of cutaneous melanoma in patients undergoing sentinel lymph node biopsy. J Am Acad Dermatol. 2015;72(5):780–5. e3PubMedCrossRefPubMedCentralGoogle Scholar
  94. 94.
    Rajkumar S, Watson IR. Molecular characterisation of cutaneous melanoma: creating a framework for targeted and immune therapies. Br J Cancer. 2016;115(2):145–55.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Hodis E, Watson IR, Kryukov GV, Arold ST, Imielinski M, Theurillat JP, et al. A landscape of driver mutations in melanoma. Cell. 2012;150(2):251–63.PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Akbani R, Akdemir Kadir C, Aksoy BA, Albert M, Ally A, Amin Samirkumar B, et al. Genomic classification of cutaneous melanoma. Cell. 2015;161(7):1681–96.CrossRefGoogle Scholar
  97. 97.
    Rutkowski P, Gos A, Jurkowska M, Switaj T, Dziewirski W, Zdzienicki M, et al. Molecular alterations in clinical stage III cutaneous melanoma: correlation with clinicopathological features and patient outcome. Oncol Lett. 2014;8(1):47–54.PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Thomas NE, Edmiston SN, Alexander A, Groben PA, Parrish E, Kricker A, et al. Association between NRAS and BRAF mutational status and melanoma-specific survival among patients with higher-risk primary melanoma. JAMA Oncol. 2015;1(3):359–68.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Saldanha G, Elshaw S, Sachs P, Alharbi H, Shah P, Jothi A, et al. microRNA-10b is a prognostic biomarker for melanoma. Mod Pathol. 2016;29(2):112–21.PubMedCrossRefPubMedCentralGoogle Scholar
  100. 100.
    Shimizu A, Kaira K, Yasuda M, Asao T, Ishikawa O. Clinical and pathological significance of ER stress marker (BiP/GRP78 and PERK) expression in malignant melanoma. Pathol Oncol Res. 2017;23(1):111–6.PubMedCrossRefGoogle Scholar
  101. 101.
    Pieniazek M, Donizy P, Halon A, Leskiewicz M, Matkowski R. Prognostic significance of immunohistochemical epithelial-mesenchymal transition markers in skin melanoma patients. Biomark Med. 2016;10(9):975–85.PubMedCrossRefGoogle Scholar
  102. 102.
    Ma MW, Medicherla RC, Qian M, Vega-Saenz de Miera E, Friedman EB, Berman RS, et al. Immune response in melanoma: an in-depth analysis of the primary tumor and corresponding sentinel lymph node. Mod Pathol. 2012;25(7):1000–10.PubMedCrossRefGoogle Scholar
  103. 103.
    Mohos A, Sebestyen T, Liszkay G, Plotar V, Horvath S, Gaudi I, et al. Immune cell profile of sentinel lymph nodes in patients with malignant melanoma—FOXP3+ cell density in cases with positive sentinel node status is associated with unfavorable clinical outcome. J Transl Med. 2013;11:43.PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Vallacchi V, Vergani E, Camisaschi C, Deho P, Cabras AD, Sensi M, et al. Transcriptional profiling of melanoma sentinel nodes identify patients with poor outcome and reveal an association of CD30(+) T lymphocytes with progression. Cancer Res. 2014;74(1):130–40.PubMedCrossRefGoogle Scholar
  105. 105.
    Vallacchi V, Camisaschi C, Dugo M, Vergani E, Deho P, Gualeni A, et al. microRNA expression in sentinel nodes from progressing melanoma patients identifies networks associated with dysfunctional immune response. Genes. 2016;7(12):124.PubMedCentralCrossRefPubMedGoogle Scholar
  106. 106.
    Hao H, Xiao D, Pan J, Qu J, Egger M, Waigel S, et al. Sentinel lymph node genes to predict prognosis in node-positive melanoma patients. Ann Surg Oncol. 2017;24(1):108–16.PubMedCrossRefGoogle Scholar
  107. 107.
    Huang SK, Hoon DS. Liquid biopsy utility for the surveillance of cutaneous malignant melanoma patients. Mol Oncol. 2016;10(3):450–63.PubMedCrossRefGoogle Scholar
  108. 108.
    Gandini S, Ferrucci PF, Botteri E, Tosti G, Barberis M, Pala L, et al. Prognostic significance of hematological profiles in melanoma patients. Int J Cancer. 2016;139(7):1618–25.PubMedCrossRefGoogle Scholar
  109. 109.
    Jacquelot N, Enot DP, Flament C, Vimond N, Blattner C, Pitt JM, et al. Chemokine receptor patterns in lymphocytes mirror metastatic spreading in melanoma. J Clin Invest. 2016;126(3):921–37.PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Toia F, Buccheri S, Anfosso A, Moschella F, Dieli F, Meraviglia S, et al. Skewed differentiation of circulating Vgamma9Vdelta2 T lymphocytes in melanoma and impact on clinical outcome. PLoS One. 2016;11(2):e0149570.PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Thery C, Ostrowski M, Segura E. Membrane vesicles as conveyors of immune responses. Nat Rev Immunol. 2009;9(8):581–93.PubMedCrossRefPubMedCentralGoogle Scholar
  112. 112.
    Alegre E, Zubiri L, Perez-Gracia JL, Gonzalez-Cao M, Soria L, Martin-Algarra S, et al. Circulating melanoma exosomes as diagnostic and prognosis biomarkers. Clin Chim Acta. 2016;454:28–32.PubMedCrossRefPubMedCentralGoogle Scholar
  113. 113.
    Hoshimoto S, Shingai T, Morton DL, Kuo C, Faries MB, Chong K, et al. Association between circulating tumor cells and prognosis in patients with stage III melanoma with sentinel lymph node metastasis in a phase III international multicenter trial. J Clin Oncol. 2012;30(31):3819–26.PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Hida T, Yoneta A, Wakamatsu K, Yanagisawa K, Ishii-Osai Y, Kan Y, et al. Circulating melanoma cells as a potential biomarker to detect metastasis and evaluate prognosis. Australas J Dermatol. 2016;57(2):145–9.PubMedCrossRefPubMedCentralGoogle Scholar
  115. 115.
    Hoshimoto S, Faries MB, Morton DL, Shingai T, Kuo C, Wang HJ, et al. Assessment of prognostic circulating tumor cells in a phase III trial of adjuvant immunotherapy after complete resection of stage IV melanoma. Ann Surg. 2012;255(2):357–62.PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Egberts F, Kotthoff EM, Gerdes S, Egberts JH, Weichenthal M, Hauschild A. Comparative study of YKL-40, S-100B and LDH as monitoring tools for stage IV melanoma. Eur J Cancer. 2012;48(5):695–702.PubMedCrossRefPubMedCentralGoogle Scholar
  117. 117.
    Damude S, Hoekstra HJ, Bastiaannet E, Muller Kobold AC, Kruijff S, Wevers KP. The predictive power of serum S-100B for non-sentinel node positivity in melanoma patients. Eur J Surg Oncol. 2016;42(4):545–51.PubMedCrossRefPubMedCentralGoogle Scholar
  118. 118.
    Nikolin B, Djan I, Trifunovic J, Dugandzija T, Novkovic D, Djan V, et al. MIA, S100 and LDH as important predictors of overall survival of patients with stage IIb and IIc melanoma. J BUON. 2016;21(3):691–7.PubMedPubMedCentralGoogle Scholar
  119. 119.
    Abusaif S, Jradi Z, Held L, Pflugfelder A, Weide B, Meier F, et al. S100B and lactate dehydrogenase as response and progression markers during treatment with vemurafenib in patients with advanced melanoma. Melanoma Res. 2013;23(5):396–401.PubMedCrossRefPubMedCentralGoogle Scholar
  120. 120.
    Diem S, Kasenda B, Spain L, Martin-Liberal J, Marconcini R, Gore M, et al. Serum lactate dehydrogenase as an early marker for outcome in patients treated with anti-PD-1 therapy in metastatic melanoma. Br J Cancer. 2016;114(3):256–61.PubMedPubMedCentralCrossRefGoogle Scholar
  121. 121.
    Kelderman S, Heemskerk B, van Tinteren H, van den Brom RR, Hospers GA, van den Eertwegh AJ, et al. Lactate dehydrogenase as a selection criterion for ipilimumab treatment in metastatic melanoma. Cancer Immunol Immunother. 2014;63(5):449–58.PubMedPubMedCentralGoogle Scholar
  122. 122.
    Collins GS, Reitsma JB, Altman DG, Moons KG. Transparent reporting of a multivariable prediction model for Individual Prognosis or Diagnosis (TRIPOD): the TRIPOD statement. Br J Surg. 2015;102(3):148–58.PubMedCrossRefPubMedCentralGoogle Scholar
  123. 123.
    Kattan MW, Hess KR, Amin MB, Lu Y, Moons KG, Gershenwald JE, et al. American Joint Committee on cancer acceptance criteria for inclusion of risk models for individualized prognosis in the practice of precision medicine. CA Cancer J Clin. 2016;66(5):370–4.PubMedPubMedCentralCrossRefGoogle Scholar
  124. 124.
    Soong SJ, Ding S, Coit D, Balch CM, Gershenwald JE, Thompson JF, et al. Predicting survival outcome of localized melanoma: an electronic prediction tool based on the AJCC Melanoma Database. Ann Surg Oncol. 2010;17(8):2006–14.PubMedCrossRefPubMedCentralGoogle Scholar
  125. 125.
    Callender GG, Gershenwald JE, Egger ME, Scoggins CR, Martin RC 2nd, Schacherer CW, et al. A novel and accurate computer model of melanoma prognosis for patients staged by sentinel lymph node biopsy: comparison with the American Joint Committee on Cancer model. J Am Coll Surg. 2012;214(4):608–17. discussion 17-9PubMedCrossRefPubMedCentralGoogle Scholar
  126. 126.
    Mahar AL, Compton C, Halabi S, Hess KR, Gershenwald JE, Scolyer RA, et al. Critical assessment of clinical prognostic tools in melanoma. Ann Surg Oncol. 2016;23(9):2753–61.PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Surgical OncologyThe University of Texas MD Anderson Cancer CenterHoustonUSA
  2. 2.Department of SurgeryUniversity of LouisvilleLouisvilleUSA
  3. 3.Department of Cancer BiologyThe University of Texas MD Anderson Cancer CenterHoustonUSA
  4. 4.Melanoma and Skin CenterThe University of Texas MD Anderson Cancer CenterHoustonUSA

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