Clinics in Dermatology
Volume 27, Issue 1 , Pages 75-102 , January 2009

New techniques in dermatopathology that help to diagnose and prognosticate melanoma

  • J. Andrew Carlson, MD

      Affiliations

    • Department of Pathology, Albany Medical College MC-81, Albany, NY 12208, USA
    • Corresponding Author InformationCorresponding author. Tel.: +1 518 262 6252; fax: +1 518 262 6251.
  • ,
  • Jeffrey S. Ross, MD

      Affiliations

    • Department of Pathology, Albany Medical College MC-81, Albany, NY 12208, USA
  • ,
  • Andrze J. Slominski, MD

      Affiliations

    • Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center, Memphis, TN, USA

References 

  1. Slominski A, Tobin D, Shibahara S, Wortsman J. Melanin pigmentation in mammalian skin and its hormonal regulation. Physiol Rev. 2004;84:1155–1228
  2. Slominski A, Wortsman J, Plonka PM, Schallreuter KU, Paus R, Tobin DJ. Hair follicle pigmentation. J Invest Dermatol. 2005;124:13–21
  3. Slominski A, Paus R, Mihm MC. Inhibition of melanogenesis as an adjuvant strategy in the treatment of melanotic melanomas: selective review and hypothesis. Anticancer Res. 1998;18:3709–3715
  4. Slominski A, Pawelek J. Animals under the sun: effects of ultraviolet radiation on mammalian skin. Clin Dermatol. 1998;16:503–515
  5. Curtin JA, Busam K, Pinkel D, Bastian BC. Somatic activation of KIT in distinct subtypes of melanoma. J Clin Oncol. 2006;24:4340–4346
  6. Curtin JA, Fridlyand J, Kageshita T, et al. Distinct sets of genetic alterations in melanoma. N Engl J Med. 2005;353:2135–2147
  7. Lipsker D, Engel F, Cribier B, Velten M, Hedelin G. Trends in melanoma epidemiology suggest three different types of melanoma. Br J Dermatol. 2007;157:338–343
  8. Ragnarsson-Olding BK. Primary malignant melanoma of the vulva–an aggressive tumor for modeling the genesis of non-UV light-associated melanomas. Acta Oncol. 2004;43:421–435
  9. Rigel DS, Carucci JA. Malignant melanoma: prevention, early detection, and treatment in the 21st century. CA Cancer J Clin. 2000;50:215–236quiz 37-40
  10. Beddingfield FC. The melanoma epidemic: res ipsa loquitur. Oncologist. 2003;8:459–465
  11. Desmond RA, Soong SJ. Epidemiology of malignant melanoma. Surg Clin North Am. 2003;83:1–29
  12. Thompson JF, Morton DL, Kroon BBE. Textbook of melanoma. London: Martin Dunitz; 2004;
  13. Thompson JF, Scolyer RA, Kefford RF. Cutaneous melanoma. Lancet. 2005;365:687–701
  14. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2006. CA Cancer J Clin. 2006;56:106–130
  15. Ries L, Melbert D, Krapcho M, et al. SEER Cancer Statistics Review, 1975-2004. Bethesda (Md): National Cancer Institute; 2007;
  16. Tawbi HA, Kirkwood JM. Management of metastatic melanoma. Semin Oncol. 2007;34:532–545
  17. Meyskens FL, Farmer PJ, Yang S, Anton-Culver H. New perspectives on melanoma pathogenesis and chemoprevention. Recent Results Cancer Res. 2007;174:191–195
  18. Berwick M, Wiggins C. The current epidemiology of cutaneous malignant melanoma. Front Biosci. 2006;11:1244–1254
  19. Carlson JA, Slominski A, Linette GP, Mihm MC, Ross JS. Biomarkers in melanoma: predisposition, screening and diagnosis. Expert Rev Mol Diagn. 2003;3:163–184
  20. Brenner S, Tamir E. Early detection of melanoma: the best strategy for a favorable prognosis. Clin Dermatol. 2002;20:203–211
  21. Mackie R. Incidence, risk factors and prevention of melanoma. Eur J Cancer. 1998;34(Supppl 3):S3–S6
  22. mackie R, Bray C, Hole D, et al. Incidence of and survival from malignant melanoma in Scotland: an epidemiological study. Lancet. 2002;360:587
  23. Swerlick RA, Chen S. The melanoma epidemic: more apparent than real?. Mayo Clin Proc. 1997;72:559–564
  24. Jemal A, Devesa SS, Fears TR, Hartge P. Cancer surveillance series: changing patterns of cutaneous malignant melanoma mortality rates among whites in the United States. J Natl Cancer Inst. 2000;92:811–818
  25. Marks R. The changing incidence and mortality of melanoma in Australia. Recent Results Cancer Res. 2002;160:113–121
  26. Bulliard JL, Cox B. Cutaneous malignant melanoma in New Zealand: trends by anatomical site, 1969-1993. Int J Epidemiol. 2000;29:416–423
  27. Lipsker DM, Hedelin G, Heid E, Grosshans EM, Cribier BJ. Striking increase of thin melanomas contrasts with stable incidence of thick melanomas. Arch Dermatol. 1999;135:1451–1456
  28. MacLennan R, Green AC, McLeod GR, Martin NG. Increasing incidence of cutaneous melanoma in Queensland, Australia. J Natl Cancer Inst. 1992;84:1427–1432
  29. Hiatt RA, Fireman B. The possible effect of increased surveillance on the incidence of malignant melanoma. Prev Med. 1986;15:652–660
  30. Dennis LK. Analysis of the melanoma epidemic, both apparent and real: data from the 1973 through 1994 surveillance, epidemiology, and end results program registry. Arch Dermatol. 1999;135:275–280
  31. Richard MA, Grob JJ, Avril MF, et al. Melanoma and tumor thickness: challenges of early diagnosis. Arch Dermatol. 1999;135:269–274
  32. Geller AC, Sober AJ, Zhang Z, et al. Strategies for improving melanoma education and screening for men age >or= 50 years: findings from the American Academy of Dermatological National Skin Cancer Screening Program. Cancer. 2002;95:1554–1561
  33. Murray CS, Stockton DL, Doherty VR. Thick melanoma: the challenge persists. Br J Dermatol. 2005;152:104–109
  34. Liu W, Dowling JP, Murray WK, et al. Rate of growth in melanomas: characteristics and associations of rapidly growing melanomas. Arch Dermatol. 2006;142:1551–1558
  35. Berwick M. Why are people still dying from melanoma?. Arch Dermatol. 1999;135:1534–1536
  36. Melanoma: epidemic or better detection?. Harv Health Lett. 2002;27:7
  37. Newton Bishop JA, Gruis NA. Genetics: what advice for patients who present with a family history of melanoma?. Semin Oncol. 2007;34:452–459
  38. Bishop JN, Bataille V, Gavin A, et al. The prevention, diagnosis, referral and management of melanoma of the skin: concise guidelines. Clin Med. 2007;7:283–290
  39. Singh H, Sethi S, Raber M, Petersen LA. Errors in cancer diagnosis: current understanding and future directions. J Clin Oncol. 2007;25:5009–5018
  40. Carlson JA, Ross JS, Slominski A, et al. Molecular diagnostics in melanoma. J Am Acad Dermatol. 2005;52:743–775quiz 75-8
  41. Ross MI. Early-stage melanoma: staging criteria and prognostic modeling. Clin Cancer Res. 2006;12(7 Pt 2):2312s–2319s
  42. Clark WH, Elder DE, Guerry D, et al. Model predicting survival in stage I melanoma based on tumor progression. J Natl Cancer Inst. 1989;81:1893–1904
  43. Carlson JA, Slominski A, Linette GP, Mihm MC, Ross JS. Biomarkers in melanoma: staging, prognosis and detection of early metastases. Expert Rev Mol Diagn. 2003;3:303–330
  44. Guitart J, Lowe L, Piepkorn M, et al. Histological characteristics of metastasizing thin melanomas: a case-control study of 43 cases. Arch Dermatol. 2002;138:603–608
  45. Cook MG, Spatz A, Brocker EB, Ruiter DJ. Identification of histological features associated with metastatic potential in thin (<1.0 mm) cutaneous melanoma with metastases. A study on behalf of the EORTC Melanoma Group. J Pathol. 2002;197:188–193
  46. McKinnon JG, Yu XQ, McCarthy WH, Thompson JF. Prognosis for patients with thin cutaneous melanoma: long-term survival data from New South Wales Central Cancer Registry and the Sydney Melanoma Unit. Cancer. 2003;98:1223–1231
  47. Gimotty PA, Botbyl J, Soong SJ, Guerry D. A population-based validation of the American Joint Committee on Cancer melanoma staging system. J Clin Oncol. 2005;23:8065–8075
  48. Balch CM, Buzaid AC, Soong SJ, et al. Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma. J Clin Oncol. 2001;19:3635–3648
  49. Meier F, Will S, Ellwanger U, et al. Metastatic pathways and time courses in the orderly progression of cutaneous melanoma. Br J Dermatol. 2002;147:62–70
  50. Li Y, McClay EF. Systemic chemotherapy for the treatment of metastatic melanoma. Semin Oncol. 2002;29:413–426
  51. Lorigan P, Eisen T, Hauschild A. Systemic therapy for metastatic malignant melanoma - from deeply disappointing to bright future?. Exp Dermatol. 2008;17:383–394
  52. Linette GP, Carlson JA, Slominski A, Mihm MC, Ross JS. Biomarkers in melanoma: stage III and IV disease. Expert Rev Mol Diagn. 2005;5:65–74
  53. Sosman JA, Puzanov I. Molecular targets in melanoma from angiogenesis to apoptosis. Clin Cancer Res. 2006;12(7 Pt 2):2376s–2383s
  54. Herlyn M. Molecular targets in melanoma: strategies and challenges for diagnosis and therapy. Int J Cancer. 2006;118:523–526
  55. Chin L, Garraway LA, Fisher DE. Malignant melanoma: genetics and therapeutics in the genomic era. Genes Dev. 2006;20:2149–2182
  56. Carlson JA, Linette GP, Aplin A, Ng B, Slominski A. Melanocyte receptors: clinical implications and therapeutic relevance. Dermatol Clin. 2007;25:541–557
  57. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57–70
  58. Crowson AN, Magro C, Miller A, Mihm MC. The molecular basis of melanomagenesis and the metastatic phenotype. Semin Oncol. 2007;34:476–490
  59. Clark WH, Elder DE, Guerry D, Epstein MN, Greene MH, Van Horn M. A study of tumor progression: the precursor lesions of superficial spreading and nodular melanoma. Hum Pathol. 1984;15:1147–1165
  60. Miller AJ, Mihm MC. Melanoma. N Engl J Med. 2006;355:51–65
  61. Tuthill RJ, Reed RJ. Failure of senescence in the dysplasia-melanoma sequence: demonstration using a tissue microarray and a revised paradigm for melanoma. Semin Oncol. 2007;34:467–475
  62. de Vries E, Elder D, Bray F, et al. Melanocytic tumors. In:  Leboit P,  Burg G,  Weedon D,  Sarasin A editor. WHO classification of tumors: pathology & genetics of skin tumors. Lyon: IARC Press; 2006;p. 52–65
  63. Haluska FG, Tsao H, Wu H, Haluska FS, Lazar A, Goel V. Genetic alterations in signaling pathways in melanoma. Clin Cancer Res. 2006;12(7 Pt 2):2301s–2307s
  64. Haqq C, Nosrati M, Sudilovsky D, et al. The gene expression signatures of melanoma progression. Proc Natl Acad Sci U S A. 2005;102:6092–6097
  65. Winnepenninckx V, Lazar V, Michiels S, et al. Gene expression profiling of primary cutaneous melanoma and clinical outcome. J Natl Cancer Inst. 2006;98:472–482
  66. Bittner M, Meltzer P, Chen Y, et al. Molecular classification of cutaneous malignant melanoma by gene expression profiling. Nature. 2000;406:536–540
  67. Bagheri S, Nosrati M, Li S, et al. Genes and pathways downstream of telomerase in melanoma metastasis. Proc Natl Acad Sci U S A. 2006;103:11306–11311
  68. Brozyna A, Zbytek B, Granese J, Carlson JA, Ross J, Slominski A. Mechanism of UV-related carcinogenesis and its contribution to nevi/melanoma. Expert Rev Dermatol. 2007;2:451–469
  69. Rivers JK. Is there more than one road to melanoma?. Lancet. 2004;363:728–730
  70. Merlino G, Noonan FP. Modeling gene-environment interactions in malignant melanoma. Trends Mol Med. 2003;9:102–108
  71. Houghton AN, Polsky D. Focus on melanoma. Cancer Cell. 2002;2:275–278
  72. Chin L. The genetics of malignant melanoma: lessons from mouse and man. Nat Rev Cancer. 2003;3:559–570
  73. Hayward NK. Genetics of melanoma predisposition. Oncogene. 2003;22:3053–3062
  74. Sabatino M, Zhao Y, Voiculescu S, et al. Conservation of genetic alterations in recurrent melanoma supports the melanoma stem cell hypothesis. Cancer Res. 2008;68:122–131
  75. Tsao H, Nelson BR. The molecular era and genetics of melanoma. Clin Dermatol. 2008;in press
  76. Kim M, Gans JD, Nogueira C, et al. Comparative oncogenomics identifies NEDD9 as a melanoma metastasis gene. Cell. 2006;125:1269–1281
  77. Mocellin S, Rossi CR, Traldi P, Nitti D, Lise M. Molecular oncology in the post-genomic era: the challenge of proteomics. Trends Mol Med. 2004;10:24–32
  78. Bernard K, Litman E, Fitzpatrick JL, et al. Functional proteomic analysis of melanoma progression. Cancer Res. 2003;63:6716–6725
  79. Garraway LA, Widlund HR, Rubin MA, et al. Integrative genomic analyses identify MITF as a lineage survival oncogene amplified in malignant melanoma. Nature. 2005;436:117–122
  80. Hornberg JJ, Bruggeman FJ, Westerhoff HV, Lankelma J. Cancer: a systems biology disease. Biosystems. 2006;83:81–90
  81. Marincola FM. Translational medicine: a two-way road. J Transl Med. 2003;1:1
  82. Carlson JA, Ross J, Murphy M. Markers of high-risk cutaneous melanoma: is there a winning combination for individualized prognosis?. J Cutan Pathol. 2005;32:700–703
  83. Frohlich E, Mack AF, Garbe C, Klessen C. Distribution and colocalization of markers for proliferation, invasion, motility and neoangiogenesis in benign melanocytic naevi and malignant melanomas. Br J Dermatol. 2005;153:1159–1165
  84. Murphy M, Carlson JA. Can we reliably use markers of cell cycle regulation (eg, Ki-67, p21, p27, p53) to differentiate between benign and malignant skin tumors?. J Cutan Pathol. 2001;28:219–221
  85. Li Q, Murphy M, Ross J, Sheehan C, Carlson JA. Skp2 and p27 expression in melanocytic nevi and melanoma: an inverse relationship. J Cutan Pathol. 2004;31:633–642
  86. Murphy M, Carlson JA, Keough MP, Claffey KP, Signoretti S, Loda M. Hypoxia regulation of the cell cycle in malignant melanoma: putative role for the cyclin-dependent kinase inhibitor p27. J Cutan Pathol. 2004;31:477–482
  87. Svensson S, Nilsson K, Ringberg A, Landberg G. Invade or proliferate? Two contrasting events in malignant behavior governed by p16(INK4a) and an intact Rb pathway illustrated by a model system of basal cell carcinoma. Cancer Res. 2003;63:1737–1742
  88. Nilsson K, Svensson S, Landberg G. Retinoblastoma protein function and p16ink4a expression in actinic keratosis, squamous cell carcinoma in situ and invasive squamous cell carcinoma of the skin and links between p16ink4a expression and infiltrative behavior. Mod Pathol. 2004;17:1464–1474
  89. Cheung M, Sharma A, Madhunapantula SV, Robertson GP. Akt3 and mutant V600E B-Raf cooperate to promote early melanoma development. Cancer Res. 2008;68:3429–3439
  90. Jaeger J, Koczan D, Thiesen HJ, et al. Gene expression signatures for tumor progression, tumor subtype, and tumor thickness in laser-microdissected melanoma tissues. Clin Cancer Res. 2007;13:806–815
  91. Winnepenninckx V, Van den Oord JJ. Gene expression profiling of primary cutaneous melanoma. Ver K Acad Geneeskd Belg. 2007;69:23–45
  92. Talantov D, Mazumder A, Yu JX, et al. Novel genes associated with malignant melanoma but not benign melanocytic lesions. Clin Cancer Res. 2005;11:7234–7242
  93. Crotty K, McCarthy SW, Mihm MC. The histologic diagnosis and classification of melanoma. In:  Thompson JF,  Morton DL,  Kroon BB editor. Textbook of melanoma: pathology, diagnosis and management. London: Martin Dunitz; 2004;p. 115–121
  94. Sagebiel RW. Pigmented lesion pathology: the specimen and its report. A personal and probably biased approach. Pathology (Phila). 1994;2:281–298
  95. Banerjee SS, Harris M. Morphological and immunophenotypic variations in malignant melanoma. Histopathology. 2000;36:387–402
  96. Kirkham N. Optimal handling and criteria for melanoma diagnosis. Histopathology. 2000;37:467–469
  97. Cerroni L, Kerl H. Tutorial on melanocytic lesions. Am J Dermatopathol. 2001;23:237–241
  98. Jackson R. Malignant melanoma: a review of 75 malpractice cases. Int J Dermatol. 1997;36:497–498
  99. Troxel DB. Pitfalls in the diagnosis of malignant melanoma: findings of a risk management panel study. Am J Surg Pathol. 2003;27:1278–1283
  100. Cerroni L. A new perspective for spitz tumors?. Am J Dermatopathol. 2005;27:366–367
  101. Farmer ER, Gonin R, Hanna MP. Discordance in the histopathologic diagnosis of melanoma and melanocytic nevi between expert pathologists. Hum Pathol. 1996;27:528–531
  102. McGinnis KS, Lessin SR, Elder DE, et al. Pathology review of cases presenting to a multidisciplinary pigmented lesion clinic. Arch Dermatol. 2002;138:617–621
  103. Corona R, Mele A, Amini M, et al. Interobserver variability on the histopathologic diagnosis of cutaneous melanoma and other pigmented skin lesions. J Clin Oncol. 1996;14:1218–1223
  104. Heenan PJ, Matz LR, Blackwell JB, et al. Inter-observer variation between pathologists in the classification of cutaneous malignant melanoma in western Australia. Histopathology. 1984;8:717–729
  105. Cook MG. Diagnostic discord with melanoma. J Pathol. 1997;182:247–249
  106. Cook MG, Clarke TJ, Humphreys S, et al. The evaluation of diagnostic and prognostic criteria and the terminology of thin cutaneous malignant melanoma by the CRC Melanoma Pathology Panel. Histopathology. 1996;28:497–512
  107. Miller JM, Slater DN. Do histopathology reports of primary cutaneous melanoma contain enough essential information?. J Clin Pathol. 1996;49:202–204
  108. Veenhuizen KC, De Wit PE, Mooi WJ, Scheffer E, Verbeek AL, Ruiter DJ. Quality assessment by expert opinion in melanoma pathology: experience of the pathology panel of the Dutch Melanoma Working Party. J Pathol. 1997;182:266–272
  109. Barnhill RL. The Spitzoid lesion: rethinking Spitz tumors, atypical variants, ‘Spitzoid melanoma’ and risk assessment. Mod Pathol. 2006;19(Suppl 2):S21–S33
  110. Wechsler J, Bastuji-Garin S, Spatz A, et al. Reliability of the histopathologic diagnosis of malignant melanoma in childhood. Arch Dermatol. 2002;138:625–628
  111. Brochez L, Verhaeghe E, Grosshans E, et al. Inter-observer variation in the histopathological diagnosis of clinically suspicious pigmented skin lesions. J Pathol. 2002;196:459–466
  112. Piepkorn MW, Barnhill RL, Cannon-Albright LA, et al. A multiobserver, population-based analysis of histologic dysplasia in melanocytic nevi. J Am Acad Dermatol. 1994;30(5 Pt 1):707–714
  113. Ackerman AB. Discordance among expert pathologists in diagnosis of melanocytic neoplasms. Hum Pathol. 1996;27:1115–1116
  114. de Wit PE, van't Hof-Grootenboer B, Ruiter DJ, et al. Validity of the histopathological criteria used for diagnosing dysplastic naevi. An interobserver study by the pathology subgroup of the EORTC Malignant Melanoma Cooperative Group. Eur J Cancer. 1993;29A:831–839
  115. Troxel DB. Medicolegal aspects of error in pathology. Arch Pathol Lab Med. 2006;130:617–619
  116. Smolle J, Gerger A. Tissue counter analysis of tissue components in skin biopsies: evaluation using CART (Classification and Regression Trees). Am J Dermatopathol. 2003;25:215–222
  117. Li LX, Crotty KA, Palmer AA, et al. Differentiating benign nevi from malignant melanoma using DNA microdensitometry and karyometry and maturation: a zonal comparison, correlation and multivariate analysis. Anal Quant Cytol Histol. 2002;24:234–243
  118. Ruiter D, Mooi W, van Muijen GN, Cochran AJ. Immunohistochemistry and special diagnostic techniques. In:  Thompson JF,  Morton DL,  Kroon BB editor. Textbook of melanoma: pathology, diagnosis and management. London: Martin Dunitz; 2004;p. 129–147
  119. Busam KJ. The use and application of special techniques in assessing melanocytic tumours. Pathology. 2004;36:462–469
  120. Hammock L, Cohen C, Carlson G, et al. Chromogenic in situ hybridization analysis of melastatin mRNA expression in melanomas from American Joint Committee on Cancer stage I and II patients with recurrent melanoma. J Cutan Pathol. 2006;33:599–607
  121. North JP, Kageshita T, Pinkel D, Leboit PE, Bastian BC. Distribution and significance of occult intraepidermal tumor cells surrounding primary melanoma. J Invest Dermatol. 2008;128:2024–2030
  122. Patel RM, Downs-Kelly E, Weiss SW, et al. Dual-color, break-apart fluorescence in situ hybridization for EWS gene rearrangement distinguishes clear cell sarcoma of soft tissue from malignant melanoma. Mod Pathol. 2005;18:1585–1590
  123. Bauer J, Bastian BC. Distinguishing melanocytic nevi from melanoma by DNA copy number changes: comparative genomic hybridization as a research and diagnostic tool. Dermatol Ther. 2006;19:40–49
  124. Takata M, Suzuki T, Ansai S, et al. Genome profiling of melanocytic tumors using multiplex ligation-dependent probe amplification (MLPA): its usefulness as an adjunctive diagnostic tool for melanocytic tumors. J Dermatol Sci. 2005;40:51–57
  125. Itakura E, Huang RR, Wen DR, Paul E, Wunsch PH, Cochran AJ. RT in situ PCR detection of MART-1 and TRP-2 mRNA in formalin-fixed, paraffin-embedded tissues of melanoma and nevi. Mod Pathol. 2008;21:326–333
  126. Gjerdrum LM, Abrahamsen HN, Villegas B, Sorensen BS, Schmidt H, Hamilton-Dutoit SJ. The influence of immunohistochemistry on mRNA recovery from microdissected frozen and formalin-fixed, paraffin-embedded sections. Diagn Mol Pathol. 2004;13:224–233
  127. van Dijk MC, Rombout PD, Mooi WJ, et al. Allelic imbalance in the diagnosis of benign, atypical and malignant Spitz tumours. J Pathol. 2002;197:170–178
  128. Ohsie SJ, Sarantopoulos GP, Cochran AJ, Binder SW. Immunohistochemical characteristics of melanoma. J Cutan Pathol. 2008;35:433–444
  129. Winfield HL, Kirkland F, Ramos-Ceballos FI, Horn TD. Osteopontin expression in spitz nevi. Arch Dermatol. 2007;143:1076–1077
  130. Li LX, Crotty KA, Palmer AA, et al. Argyrophilic staining of nucleolar organizer region count and morphometry in benign and malignant melanocytic lesions. Am J Dermatopathol. 2003;25:190–197
  131. Schmidt B, Weinberg DS, Hollister K, Barnhill RL. Analysis of melanocytic lesions by DNA image cytometry. Cancer. 1994;73:2971–2977
  132. Fleming MG, Wied GL, Dytch HE. Image analysis cytometry of dysplastic nevi. J Invest Dermatol. 1990;95:287–291
  133. Korabiowska M, Brinck U, Middel P, et al. Proliferative activity in the progression of pigmented skin lesions, diagnostic and prognostic significance. Anticancer Res. 2000;20:1781–1785
  134. Rieger E, Hofmann-Wellenhof R, Soyer HP, et al. Comparison of proliferative activity as assessed by proliferating cell nuclear antigen (PCNA) and Ki-67 monoclonal antibodies in melanocytic skin lesions. A quantitative immunohistochemical study. J Cutan Pathol. 1993;20:229–236
  135. Li LX, Crotty KA, McCarthy SW, Palmer AA, Kril JJ. A zonal comparison of MIB1-Ki67 immunoreactivity in benign and malignant melanocytic lesions. Am J Dermatopathol. 2000;22:489–495
  136. Shanks JH, Banerjee SS. VS38 immunostaining in melanocytic lesions. J Clin Pathol. 1996;49:205–207
  137. Slominski A. Coming of age of melanogenesis-related proteins. Arch Pathol Lab Med. 2002;126:775–777
  138. Heintz PW, White CR. Diagnosis: atypical fibroxanthoma or not? Evaluating spindle cell malignancies on sun damaged skin: a practical approach. Semin Cutan Med Surg. 1999;18:78–83
  139. Carlson JA, Dickersin GR, Sober AJ, Barnhill RL. Desmoplastic neurotropic melanoma. A clinicopathologic analysis of 28 cases. Cancer. 1995;75:478–494
  140. Kanik AB, Yaar M, Bhawan J. P75 nerve growth factor receptor staining helps identify desmoplastic and neurotropic melanoma. J Cutan Pathol. 1996;23:205–210Epub, ahead of print, DOI:10.1111/j.1600-0560.2007.00866.x
  141. Fanburg-Smith JC, Miettinen M. Low-affinity nerve growth factor receptor (p75) in dermatofibrosarcoma protuberans and other nonneural tumors: a study of 1,150 tumors and fetal and adult normal tissues. Hum Pathol. 2001;32:976–983
  142. Boyle JL, Haupt HM, Stern JB, Multhaupt HA. Tyrosinase expression in malignant melanoma, desmoplastic melanoma, and peripheral nerve tumors. Arch Pathol Lab Med. 2002;126:816–822
  143. Fullen DR, Garrisi AJ, Sanders D, Thomas D. Expression of S100A6 protein in a broad spectrum of cutaneous tumors using tissue microarrays. J Cutan Pathol. 2008;
  144. Orchard GE. Comparison of immunohistochemical labelling of melanocyte differentiation antibodies melan-A, tyrosinase and HMB 45 with NKIC3 and S100 protein in the evaluation of benign naevi and malignant melanoma. Histochem J. 2000;32:475–481
  145. Miettinen M, Fernandez M, Franssila K, Gatalica Z, Lasota J, Sarlomo-Rikala M. Microphthalmia transcription factor in the immunohistochemical diagnosis of metastatic melanoma: comparison with four other melanoma markers. Am J Surg Pathol. 2001;25:205–211
  146. Mangini J, Li N, Bhawan J. Immunohistochemical markers of melanocytic lesions: a review of their diagnostic usefulness. Am J Dermatopathol. 2002;24:270–281
  147. Granter SR, Weilbaecher KN, Quigley C, Fisher DE. Role for microphthalmia transcription factor in the diagnosis of metastatic malignant melanoma. Appl Immunohistochem Mol Morphol. 2002;10:47–51
  148. Sheffield MV, Yee H, Dorvault CC, et al. Comparison of five antibodies as markers in the diagnosis of melanoma in cytologic preparations. Am J Clin Pathol. 2002;118:930–936
  149. Blessing K, Sanders DS, Grant JJ. Comparison of immunohistochemical staining of the novel antibody melan-A with S100 protein and HMB-45 in malignant melanoma and melanoma variants. Histopathology. 1998;32:139–146
  150. Plaza JA, Suster D, Perez-Montiel D. Expression of immunohistochemical markers in primary and metastatic malignant melanoma: a comparative study in 70 patients using a tissue microarray technique. Appl Immunohistochem Mol Morphol. 2007;15:421–425
  151. McNutt NS, Urmacher C, Hakimian J, Hoss DM, Lugo J. Nevoid malignant melanoma: morphologic patterns and immunohistochemical reactivity. J Cutan Pathol. 1995;22:502–517
  152. Crotty KA, Scolyer RA, Li L, Palmer AA, Wang L, McCarthy SW. Spitz naevus versus Spitzoid melanoma: when and how can they be distinguished?. Pathology. 2002;34:6–12
  153. Ribe A, McNutt NS. S100A6 Protein expression is different in Spitz nevi and melanomas. Mod Pathol. 2003;16:505–511
  154. Timar J, Udvarhelyi N, Banfalvi T, Gilde K, Orosz Z. Accuracy of the determination of S100B protein expression in malignant melanoma using polyclonal or monoclonal antibodies. Histopathology. 2004;44:180–184
  155. Ribe A, McNutt NS. S100A protein expression in the distinction between lentigo maligna and pigmented actinic keratosis. Am J Dermatopathol. 2003;25:93–99
  156. Bottoni U, Izzo P, Richetta A, et al. S100 serum level: a tumour marker for metastatic melanoma. Melanoma Res. 2003;13:427–429
  157. Hendi A, Brodland DG, Zitelli JA. Melanocytes in long-standing sun-exposed skin: quantitative analysis using the MART-1 immunostain. Arch Dermatol. 2006;142:871–876
  158. Shirasaki F, Takata M, Hatta N, Takehara K. Loss of expression of the metastasis suppressor gene kiss1 during melanoma progression and its association with LOH of chromosome 6q16.3-q23. Cancer Res. 2001;61:7422–7425
  159. Mu XC, Tran TA, Ross JS, Carlson JA. Topoisomerase II-alpha expression in melanocytic nevi and malignant melanoma. J Cutan Pathol. 2000;27:242–248
  160. Sparrow LE, English DR, Taran JM, Heenan PJ. Prognostic significance of MIB-1 proliferative activity in thin melanomas and immunohistochemical analysis of MIB-1 proliferative activity in melanocytic tumors. Am J Dermatopathol. 1998;20:12–16
  161. Fogt F, Vortmeyer AO, Tahan SR. Nucleolar organizer regions (agnor) and Ki-67 immunoreactivity in cutaneous melanocytic lesions. Am J Dermatopathol. 1995;17:12–17
  162. Kanoko M, Ueda M, Ichihashi M. PCNA expression and nucleolar organizer regions in malignant melanoma and nevus cell nevus. Kobe J Med Sci. 1994;40:107–123
  163. Hussein MR, Roggero E, Sudilovsky EC, Tuthill RJ, Wood GS, Sudilovsky O. Alterations of mismatch repair protein expression in benign melanocytic nevi, melanocytic dysplastic nevi, and cutaneous malignant melanomas. Am J Dermatopathol. 2001;23:308–314
  164. Ruiter DJ, Brocker EB. Immunohistochemistry in the evaluation of melanocytic tumors. Semin Diagn Pathol. 1993;10:76–91
  165. Keehn CA, Smoller BR, Morgan MB. Expression of the ets-1 proto-oncogene in melanocytic lesions. Mod Pathol. 2003;16:772–777
  166. Wang H, Shen SS, Wang H, et al. Expression of insulin-like growth factor-binding protein 2 in melanocytic lesions. J Cutan Pathol. 2003;30:599–605
  167. Shen SS, Zhang PS, Eton O, Prieto VG. Analysis of protein tyrosine kinase expression in melanocytic lesions by tissue array. J Cutan Pathol. 2003;30:539–547
  168. Demunter A, Libbrecht L, Degreef H, De Wolf-Peeters C, van den Oord JJ. Loss of membranous expression of beta-catenin is associated with tumor progression in cutaneous melanoma and rarely caused by exon 3 mutations. Mod Pathol. 2002;15:454–461
  169. Tsao H, Mihm MC, Sheehan C. PTEN expression in normal skin, acquired melanocytic nevi, and cutaneous melanoma. J Am Acad Dermatol. 2003;49:865–872
  170. Ivan D, Diwan AH, Esteva FJ, Prieto VG. Expression of cell cycle inhibitor p27Kip1 and its inactivator Jab1 in melanocytic lesions. Mod Pathol. 2004;17:811–818
  171. Alonso SR, Ortiz P, Pollan M, et al. Progression in cutaneous malignant melanoma is associated with distinct expression profiles: a tissue microarray-based study. Am J Pathol. 2004;164:193–203
  172. Seykora JT, Jih D, Elenitsas R, Horng WH, Elder DE. Gene expression profiling of melanocytic lesions. Am J Dermatopathol. 2003;25:6–11
  173. Leiter U, Schmid RM, Kaskel P, Peter RU, Krahn G. Antiapoptotic bcl-2 and bcl-xl in advanced malignant melanoma. Arch Dermatol Res. 2000;292:225–232
  174. Radhi JM. Malignant melanoma arising from nevi, p53, p16, and Bcl-2: expression in benign versus malignant components. J Cutan Med Surg. 1999;3:293–297
  175. Korabiowska M, Brinck U, Ruschenburg I, Schlott T, Droese M, Stachura J. Bcl2 and Bax expression in naevi and melanomas and their relation to ploidy status and proliferation. Pol J Pathol. 1999;50:17–21
  176. Utikal J, Leiter U, Udart M, Kaskel P, Peter RU, Krahn GM. Expression of c-myc and bcl-2 in primary and advanced cutaneous melanoma. Cancer Invest. 2002;20:914–921
  177. Cerroni L, Soyer HP, Kerl H. Bcl-2 protein expression in cutaneous malignant melanoma and benign melanocytic nevi. Am J Dermatopathol. 1995;17:7–11
  178. Tran TA, Ross JS, Carlson JA, Mihm MC. Mitotic cyclins and cyclin-dependent kinases in melanocytic lesions. Hum Pathol. 1998;29:1085–1090
  179. Goncharuk VN, Ross JS, Carlson JA. Actin-binding protein fascin expression in skin neoplasia. J Cutan Pathol. 2002;29:430–438
  180. Hafner C, Bataille F, Meyer S, et al. Loss of ephb6 expression in metastatic melanoma. Int J Oncol. 2003;23:1553–1559
  181. Becker B, Roesch A, Hafner C, et al. Discrimination of melanocytic tumors by cdna array hybridization of tissues prepared by laser pressure catapulting. J Invest Dermatol. 2004;122:361–368
  182. Li Q, Murphy M, Sheehan C, Ross J, Carlson J. Skp-2 and p27 expression in melanocytic nevi and melanoma: an inverse relationship. J Cutan Pathol. 2004;31:633–642
  183. Wang YL, Uhara H, Yamazaki Y, Nikaido T, Saida T. Immunohistochemical detection of CDK4 and p16ink4 proteins in cutaneous malignant melanoma. Br J Dermatol. 1996;134:269–275
  184. Wilsher M, Cheerala B. WT1 as a complementary marker of malignant melanoma: an immunohistochemical study of whole sections. Histopathology. 2007;51:605–610
  185. Bergman R, Malkin L, Sabo E, Kerner H. MIB-1 monoclonal antibody to determine proliferative activity of Ki-67 antigen as an adjunct to the histopathologic differential diagnosis of Spitz nevi. J Am Acad Dermatol. 2001;44:500–504
  186. Chorny JA, Barr RJ, Kyshtoobayeva A, Jakowatz J, Reed RJ. Ki-67 and p53 expression in minimal deviation melanomas as compared with other nevomelanocytic lesions. Mod Pathol. 2003;16:525–529
  187. Rudolph P, Schubert C, Schubert B, Parwaresch R. Proliferation marker Ki-S5 as a diagnostic tool in melanocytic lesions. J Am Acad Dermatol. 1997;37(2 Pt 1):169–178
  188. Lassam NJ, From L, Kahn HJ. Overexpression of p53 is a late event in the development of malignant melanoma. Cancer Res. 1993;53(10 Suppl):2235–2238
  189. Miracco C, Pacenti L, Santopietro R, Laurini L, Biagioli M, Luzi P. Evaluation of telomerase activity in cutaneous melanocytic proliferations. Hum Pathol. 2000;31:1018–1021
  190. Simonetti O, Lucarini G, Brancorsini D, et al. Immunohistochemical expression of vascular endothelial growth factor, matrix metalloproteinase 2, and matrix metalloproteinase 9 in cutaneous melanocytic lesions. Cancer. 2002;95:1963–1970
  191. Bayer-Garner IB, Hough AJ, Smoller BR. Vascular endothelial growth factor expression in malignant melanoma: prognostic versus diagnostic usefulness. Mod Pathol. 1999;12:770–774
  192. Graeven U, Fiedler W, Karpinski S, et al. Melanoma-associated expression of vascular endothelial growth factor and its receptors FLT-1 and KDR. J Cancer Res Clin Oncol. 1999;125:621–629
  193. Cahill DP, Kinzler KW, Vogelstein B, Lengauer C. Genetic instability and darwinian selection in tumours. Trends Cell Biol. 1999;9:M57–M60
  194. Jones PA, Baylin SB. The fundamental role of epigenetic events in cancer. Nat Rev Genet. 2002;3:415–428
  195. Michaloglou C, Vredeveld LC, Soengas MS, et al. BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature. 2005;436:720–724
  196. Maldonado JL, Timmerman L, Fridlyand J, Bastian BC. Mechanisms of cell-cycle arrest in Spitz nevi with constitutive activation of the MAP-kinase pathway. Am J Pathol. 2004;164:1783–1787
  197. Korabiowska M, Betke H, Kellner S, Stachura J, Schauer A. Differential expression of growth arrest, DNA damage genes and tumour suppressor gene p53 in naevi and malignant melanomas. Anticancer Res. 1997;17:3697–3700
  198. Carr J, Mackie RM. Point mutations in the N-ras oncogene in malignant melanoma and congenital naevi. Br J Dermatol. 1994;131:72–77
  199. Pollock PM, Harper UL, Hansen KS, et al. High frequency of BRAF mutations in nevi. Nat Genet. 2003;33:19–20
  200. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417:949–954
  201. Bastian BC, Leboit PE, Pinkel D. Mutations and copy number increase of HRAS in Spitz nevi with distinctive histopathological features. Am J Pathol. 2000;157:967–972
  202. Sharpless NE, depinho RA. Cancer: crime and punishment. Nature. 2005;436:636–637
  203. Fecker LF, Geilen CC, Tchernev G, et al. Loss of proapoptotic Bcl-2-related multidomain proteins in primary melanomas is associated with poor prognosis. J Invest Dermatol. 2006;126:1366–1371
  204. Zucman J, Melot T, Desmaze C, et al. Combinatorial generation of variable fusion proteins in the Ewing family of tumours. Embo J. 1993;12:4481–4487
  205. Bastian BC. Molecular cytogenetics as a diagnostic tool for typing melanocytic tumors. Recent Results Cancer Res. 2002;160:92–99
  206. Maitra A, Gazdar AF, Moore TO, Moore AY. Loss of heterozygosity analysis of cutaneous melanoma and benign melanocytic nevi: laser capture microdissection demonstrates clonal genetic changes in acquired nevocellular nevi. Hum Pathol. 2002;33:191–197
  207. Udart M, Utikal J, Krahn GM, Peter RU. Chromosome 7 aneusomy. A marker for metastatic melanoma? Expression of the epidermal growth factor receptor gene and chromosome 7 aneusomy in nevi, primary malignant melanomas and metastases. Neoplasia. 2001;3:245–254
  208. Korabiowska M, Brinck U, Kotthaus I, Berger H, Droese M. Analysis of the DNA content in the progression of recurrent and metastatic melanomas. Anticancer Res. 2000;20:2791–2794
  209. Bastian BC, Olshen AB, leboit PE, Pinkel D. Classifying melanocytic tumors based on DNA copy number changes. Am J Pathol. 2003;163:1765–1770
  210. Bastian BC, Xiong J, Frieden IJ, et al. Genetic changes in neoplasms arising in congenital melanocytic nevi : differences between nodular proliferations and melanomas. Am J Pathol. 2002;161:1163–1169
  211. Leech SN, Bell H, Leonard N, et al. Neonatal giant congenital nevi with proliferative nodules: a clinicopathologic study and literature review of neonatal melanoma. Arch Dermatol. 2004;140:83–88
  212. Cohn-Cedermark G, Mansson-Brahme E, Rutqvist LE, Larsson O, Singnomklao T, Ringborg U. Metastatic patterns, clinical outcome, and malignant phenotype in malignant cutaneous melanoma. Acta Oncol. 1999;38:549–557
  213. Gershenwald JE, Thompson W, Mansfield PF, 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;17:976–983
  214. Mellado B, Del Carmen Vela M, Colomer D, et al. Tyrosinase mRNA in blood of patients with melanoma treated with adjuvant interferon. J Clin Oncol. 2002;20:4032–4039
  215. Gogas H, Kefala G, Bafaloukos D, et al. Prognostic significance of the sequential detection of circulating melanoma cells by RT-PCR in high-risk melanoma patients receiving adjuvant interferon. Br J Cancer. 2002;87:181–186
  216. Osella-Abate S, Savoia P, Quaglino P, et al. Tyrosinase expression in the peripheral blood of stage III melanoma patients is associated with a poor prognosis: a clinical follow-up study of 110 patients. Br J Cancer. 2003;89:1457–1462
  217. Wascher RA, Morton DL, Kuo C, et al. Molecular tumor markers in the blood: early prediction of disease outcome in melanoma patients treated with a melanoma vaccine. J Clin Oncol. 2003;21:2558–2563
  218. 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;19:3622–3634
  219. Estourgie SH, Nieweg OE, Valdes Olmos RA, Hoefnagel CA, Kroon BB. Review and evaluation of sentinel node procedures in 250 melanoma patients with a median follow-up of 6 years. Ann Surg Oncol. 2003;10:681–688
  220. Yu LL, Flotte TJ, Tanabe KK, et al. Detection of microscopic melanoma metastases in sentinel lymph nodes. Cancer. 1999;86:617–627
  221. Gibbs JF, Huang PP, Zhang PJ, Kraybill WG, Cheney R. Accuracy of pathologic techniques for the diagnosis of metastatic melanoma in sentinel lymph nodes. Ann Surg Oncol. 1999;6:699–704
  222. Cochran AJ. The pathologist's role in sentinel lymph node evaluation. Semin Nucl Med. 2000;30:11–17
  223. Messina JL, Glass LF, Cruse CW, Berman C, Ku NK, Reintgen DS. Pathologic examination of the sentinel lymph node in malignant melanoma. Am J Surg Pathol. 1999;23:686–690
  224. Morton DL, Hoon DS, Cochran AJ, et al. Lymphatic mapping and sentinel lymphadenectomy for early-stage melanoma: therapeutic utility and implications of nodal microanatomy and molecular staging for improving the accuracy of detection of nodal micrometastases. Ann Surg. 2003;238:538–549discussion 49-50
  225. Shivers SC, Li W, Lin J, et al. The clinical relevance of molecular staging for melanoma. Recent Results Cancer Res. 2001;158:187–199
  226. Kuo CT, Hoon DS, Takeuchi H, et al. Prediction of disease outcome in melanoma patients by molecular analysis of paraffin-embedded sentinel lymph nodes. J Clin Oncol. 2003;21:3566–3572
  227. Davids V, Kidson SH, Hanekom GS. Melanoma patient staging: histopathological versus molecular evaluation of the sentinel node. Melanoma Res. 2003;13:313–324
  228. Perrott RE, Glass LF, Reintgen DS, Fenske NA. Reassessing the role of lymphatic mapping and sentinel lymphadenectomy in the management of cutaneous malignant melanoma. J Am Acad Dermatol. 2003;49:567–588quiz 89-92
  229. Rimoldi D, Lemoine R, Kurt AM, et al. Detection of micrometastases in sentinel lymph nodes from melanoma patients: direct comparison of multimarker molecular and immunopathological methods. Melanoma Res. 2003;13:511–520
  230. Ruiter DJ, Spatz A, van den Oord JJ, Cook MG. Microstaging in cutaneous melanoma. J Pathol. 2001;195:525–529
  231. Balch CM, Buzaid AC, Atkins MB, et al. A new American Joint Committee on Cancer staging system for cutaneous melanoma. Cancer. 2000;88:1484–1491
  232. McMasters KM, Wong SL, Edwards MJ, et al. Factors that predict the presence of sentinel lymph node metastasis in patients with melanoma. Surgery. 2001;130:151–156
  233. Retsas S, Henry K, Mohammed MQ, MacRae K. Prognostic factors of cutaneous melanoma and a new staging system proposed by the American Joint Committee on Cancer (AJCC): validation in a cohort of 1284 patients. Eur J Cancer. 2002;38:511–516
  234. Merkel S, Meyer T, Papadopoulos T, et al. Testing a new staging system for cutaneous melanoma proposed by the American Joint Committee on Cancer. Eur J Cancer. 2002;38:517–526
  235. Cochran AJ, Elashoff D, Morton DL, Elashoff R. Individualized prognosis for melanoma patients. Hum Pathol. 2000;31:327–331
  236. Szymik B, Woosley JT. Further validation of the prognostic model for stage I malignant melanoma based on tumor progression. J Cutan Pathol. 1993;20:50–53
  237. Gimotty PA, Guerry D, Ming ME, et al. Thin primary cutaneous malignant melanoma: a prognostic tree for 10-year metastasis is more accurate than American Joint Committee on Cancer staging. J Clin Oncol. 2004;22:3668–3676
  238. Mraz-Gernhard S, Sagebiel RW, Kashani-Sabet M, Miller JR, Leong SP. Prediction of sentinel lymph node micrometastasis by histological features in primary cutaneous malignant melanoma. Arch Dermatol. 1998;134:983–987
  239. 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;25:869–875
  240. Kashani-Sabet M, Sagebiel RW, Ferreira CM, Nosrati M, Miller JR. Tumor vascularity in the prognostic assessment of primary cutaneous melanoma. J Clin Oncol. 2002;20:1826–1831
  241. Thompson JF, Scolyer RA. Cooperation between surgical oncologists and pathologists: a key element of multidisciplinary care for patients with cancer. Pathology. 2004;36:496–503
  242. Karim RZ, van den Berg KS, Colman MH, McCarthy SW, Thompson JF, Scolyer RA. The advantage of using a synoptic pathology report format for cutaneous melanoma. Histopathology. 2008;52:130–138
  243. Busam KJ. Lack of relevant information for tumor staging in pathology reports of primary cutaneous melanoma. Am J Clin Pathol. 2001;115:743–746
  244. Ruiter DJ, Spatz A, van den Oord JJ, Cook MG. Pathologic staging of melanoma. Semin Oncol. 2002;29:370–381
  245. Azzola MF, Shaw HM, Thompson JF, et al. Tumor mitotic rate is a more powerful prognostic indicator than ulceration in patients with primary cutaneous melanoma: an analysis of 3661 patients from a single center. Cancer. 2003;97:1488–1498
  246. Francken AB, Shaw HM, Thompson JF, et al. The prognostic importance of tumor mitotic rate confirmed in 1317 patients with primary cutaneous melanoma and long follow-up. Ann Surg Oncol. 2004;11:426–433
  247. 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;15:169–177
  248. Gimotty PA, Van Belle P, Elder DE, et al. Biologic and prognostic significance of dermal Ki67 expression, mitoses, and tumorigenicity in thin invasive cutaneous melanoma. J Clin Oncol. 2005;23:8048–8056
  249. Attis MN, Vollmer RT. Mitotic rate in melanoma: a reexamination. Am J Clin Pathol. 2007;127:1–5
  250. Retsas S, Mastrangelo MJ. Reflecting on the 2001 American Joint Committee on Cancer Staging System for melanoma. Semin Oncol. 2007;34:491–497
  251. Kang S, Barnhill RL, Mihm MC, Sober AJ. Histologic regression in malignant melanoma: an interobserver concordance study. J Cutan Pathol. 1993;20:126–129
  252. Kashani-Sabet M, Sagebiel RW, Ferreira CM, Nosrati M, Miller JR. Vascular involvement in the prognosis of primary cutaneous melanoma. Arch Dermatol. 2001;137:1169–1173
  253. Spatz A, Shaw HM, Crotty KA, Thompson JF, McCarthy SW. Analysis of histopathological factors associated with prolonged survival of 10 years or more for patients with thick melanomas (>5 mm). Histopathology. 1998;33:406–413
  254. Quinn MJ, Crotty KA, Thompson JF, Coates AS, O'Brien CJ, McCarthy WH. Desmoplastic and desmoplastic neurotropic melanoma: experience with 280 patients. Cancer. 1998;83:1128–1135
  255. Agarwala SS. Intermediate- and high-risk melanoma. Curr Treat Options Oncol. 2002;3:205–217
  256. Thome SD, Loprinzi CL, Heldebrant MP. Determination of potential adjuvant systemic therapy benefits for patients with resected cutaneous melanomas. Mayo Clin Proc. 2002;77:913–917
  257. Bockmann B, Grill HJ, Giesing M. Molecular characterization of minimal residual cancer cells in patients with solid tumors. Biomol Eng. 2001;17:95–111
  258. Salti GI, Kansagra A, Warso MA, Ronan SG, Das Gupta TK. Clinical node-negative thick melanoma. Arch Surg. 2002;137:291–295
  259. Cascinelli N, Clemente C, Bifulco C, et al. Do patients with tumor-positive sentinel nodes constitute a homogeneous group?. Ann Surg Oncol. 2001;8(9 Suppl):35S–37S
  260. Sartore L, Papanikolaou GE, Biancari F, Mazzoleni F. Prognostic factors of cutaneous melanoma in relation to metastasis at the sentinel lymph node. Int J Surg. 2008;6:205–209
  261. Wong SL, Kattan MW, McMasters KM, Coit DG. A nomogram that predicts the presence of sentinel node metastasis in melanoma with better discrimination than the American Joint Committee on Cancer staging system. Ann Surg Oncol. 2005;12:282–288
  262. Niakosari F, Kahn HJ, McCready D, et al. Lymphatic invasion identified by monoclonal antibody D2-40, younger age, and ulceration: predictors of sentinel lymph node involvement in primary cutaneous melanoma. Arch Dermatol. 2008;144:462–467
  263. Massi D, Puig S, Franchi A, Malvehy J, et al. Tumour lymphangiogenesis is a possible predictor of sentinel lymph node status in cutaneous melanoma: a case-control study. J Clin Pathol. 2006;59:166–173
  264. Rangel J, Nosrati M, Torabian S, et al. Osteopontin as a molecular prognostic marker for melanoma. Cancer. 2008;112:144–150
  265. Berman DM. Lack of agreement on predictors for metastasizing thin melanomas. Histopathology. 2006;48:217–219
  266. Eigentler TK, Radny P, Kamin A, Weide B, Caroli UM, Garbe C. [Experiences with the new American Joint Committee on Cancer (AJCC) classification of cutaneous melanoma]. German. J Dtsch Dermatol Ges. 2005;3:592–598
  267. Gutzmer R, Satzger I, Thoms KM, et al. Sentinel lymph node status is the most important prognostic factor for thick (>/= 4 mm) melanomas. J Dtsch Dermatol Ges. 2007;6:198–203
  268. Zettersten E, Sagebiel RW, Miller JR, Tallapureddy S, Leong SP, Kashani-Sabet M. Prognostic factors in patients with thick cutaneous melanoma (> 4 mm). Cancer. 2002;94:1049–1056
  269. Torabian S, Kashani-Sabet M. Biomarkers for melanoma. Curr Opin Oncol. 2005;17:167–171
  270. Carr KM, Bittner M, Trent JM. Gene-expression profiling in human cutaneous melanoma. Oncogene. 2003;22:3076–3080
  271. Gershenwald JE, Bar-Eli M. Gene expression profiling of human cutaneous melanoma: are we there yet?. Cancer Biol Ther. 2004;3:121–123
  272. Bachmann IM, Puntervoll HE, Otte AP, Akslen LA. Loss of BMI-1 expression is associated with clinical progress of malignant melanoma. Mod Pathol. 2008;21:583–590
  273. Polsky D, Melzer K, Hazan C, et al. HDM2 protein overexpression and prognosis in primary malignant melanoma. J Natl Cancer Inst. 2002;94:1803–1806
  274. Straume O, Jackson DG, Akslen LA. Independent prognostic impact of lymphatic vessel density and presence of low-grade lymphangiogenesis in cutaneous melanoma. Clin Cancer Res. 2003;9:250–256
  275. Linette G, Ross J, Li Q, et al. Melastatin expression determined by chromogenic in situ hybridization (CISH) in primary cutaneous melanoma. Proc Am Soc Clin Oncol. 2004;23:7517
  276. Duncan LM, Deeds J, Cronin FE, et al. Melastatin expression and prognosis in cutaneous malignant melanoma. J Clin Oncol. 2001;19:568–576
  277. Straume O, Sviland L, Akslen LA. Loss of nuclear p16 protein expression correlates with increased tumor cell proliferation (Ki-67) and poor prognosis in patients with vertical growth phase melanoma. Clin Cancer Res. 2000;6:1845–1853
  278. Andersen K, Nesland JM, Holm R, Florenes VA, Fodstad O, Maelandsmo GM. Expression of S100A4 combined with reduced E-cadherin expression predicts patient outcome in malignant melanoma. Mod Pathol. 2004;17:990–997
  279. Kreizenbeck GM, Berger AJ, Subtil A, Rimm DL, Gould Rothberg BE. Prognostic significance of cadherin-based adhesion molecules in cutaneous malignant melanoma. Cancer Epidemiol Biomarkers Prev. 2008;17:949–958
  280. Ostmeier H, Fuchs B, Otto F, et al. Can immunohistochemical markers and mitotic rate improve prognostic precision in patients with primary melanoma?. Cancer. 1999;85:2391–2399
  281. Brown E, Lewis PH, Nocera J. In search of the silver bullet. Fortune 2001;143:166-70, 72, 74 passim.
  282. Lemonick MD, Park A. New hope for cancer. Time. 2001;157:62–69
  283. Kalinsky K, Haluska FG. Novel inhibitors in the treatment of metastatic melanoma. Expert Rev Anticancer Ther. 2007;7:715–724
  284. Lejeune FJ, Rimoldi D, Speiser D. New approaches in metastatic melanoma: biological and molecular targeted therapies. Expert Rev Anticancer Ther. 2007;7:701–713
  285. Queirolo P, Acquati M. Targeted therapies in melanoma. Cancer Treat Rev. 2006;32:524–531
  286. Haluska F, Pemberton T, Ibrahim N, Kalinsky K. The RTK/RAS/BRAF/PI3K pathways in melanoma: biology, small molecule inhibitors, and potential applications. Semin Oncol. 2007;34:546–554
  287. Flaherty KT. Sorafenib: delivering a targeted drug to the right targets. Expert Rev Anticancer Ther. 2007;7:617–626
  288. Messersmith WA, Hidalgo M, Carducci M, Eckhardt SG. Novel targets in solid tumors: MEK inhibitors. Clin Adv Hematol Oncol. 2006;4:831–836

PII: S0738-081X(08)00184-3

doi: 10.1016/j.clindermatol.2008.09.007

Clinics in Dermatology
Volume 27, Issue 1 , Pages 75-102 , January 2009