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Skin Tumors

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Practical Oncologic Molecular Pathology

Part of the book series: Practical Anatomic Pathology ((PAP))

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Abstract

Skin tumors range from indolent to highly aggressive. Molecular pathology is playing an increasingly important role in diagnosing, treating, and determining prognosis in cutaneous malignancies. Melanocytic neoplasms are relatively common. Histologically, the diagnosis is often straightforward; however, challenging cases provide a dilemma with critical clinical and prognostic implications. Molecular diagnostic strategies are emerging as important tools to distinguish between benign and malignant melanocytic neoplasm with fluorescence in situ hybridization and comparative genomic hybridization at the forefront. Identifying mutations and translocations in specific genes is necessary for determining which tumors will respond to targeted therapies including BRAF inhibitors for melanoma. Prognostic gene expression profiling panels are available for various cutaneous malignancies and are helping clinicians make treatment and surveillance decisions. Other molecular tools commonly used in the assessment of cutaneous lesions include microsatellite instability testing in patients with sebaceous neoplasms and T-cell gene rearrangements in cases of suspected cutaneous T-cell lymphoma. Understanding the limitations, utility, and appropriate use of molecular tests as adjuncts to histopathologic investigations will improve patient care and outcomes. Although molecular tests will not replace standard light microscopy and immunohistochemistry, they will continue to grow in importance in the assessment of cutaneous lesions.

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References

  1. Cancer Genome Atlas N. Genomic classification of cutaneous melanoma. Cell. 2015;161(7):1681–96.

    Article  CAS  Google Scholar 

  2. Shain AH, Bastian BC. From melanocytes to melanomas. Nat Rev Cancer. 2016;16(6):345–58.

    Article  CAS  PubMed  Google Scholar 

  3. Elder DE, Bastian BC, Cree IA, Massi D, Scolyer RA. The 2018 World Health Organization classification of cutaneous, mucosal, and uveal melanoma: detailed analysis of 9 distinct subtypes defined by their evolutionary pathway. Arch Pathol Lab Med. 2020;144(4):500–22.

    Article  CAS  PubMed  Google Scholar 

  4. Bastian BC. The molecular pathology of melanoma: an integrated taxonomy of melanocytic neoplasia. Annu Rev Pathol. 2014;9:239–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SAJR, Behjati S, Biankin AV, et al. Signatures of mutational processes in human cancer. Nature. 2013;500(7463):415–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Trucco LD, Mundra PA, Hogan K, Garcia-Martinez P, Viros A, Mandal AK, et al. Ultraviolet radiation-induced DNA damage is prognostic for outcome in melanoma. Nat Med. 2019;25(2):221–4.

    Article  CAS  PubMed  Google Scholar 

  7. Vidal CI, Armbrect EA, Andea AA, Bohlke AK, Comfere NI, Hughes SR, et al. Appropriate use criteria in dermatopathology: initial recommendations from the American Society of Dermatopathology. J Cutan Pathol. 2018;45(8):563–80.

    Article  PubMed  Google Scholar 

  8. Harvey NT, Wood BA. A practical approach to the diagnosis of melanocytic lesions. Arch Pathol Lab Med. 2019;143(7):789–810.

    Article  PubMed  Google Scholar 

  9. Emanuel PO, Andea AA, Vidal CI, Missall TA, Novoa RA, Bohlke AK, et al. Evidence behind the use of molecular tests in melanocytic lesions and practice patterns of these tests by dermatopathologists. J Cutan Pathol. 2018;45(11):839–46.

    Article  PubMed  Google Scholar 

  10. Alomari AK, Miedema JR, Carter MD, Harms PW, Lowe L, Durham AB, et al. DNA copy number changes correlate with clinical behavior in melanocytic neoplasms: proposal of an algorithmic approach. Mod Pathol. 2020;33(7):1307–17.

    Article  CAS  PubMed  Google Scholar 

  11. Wang L, Rao M, Fang Y, Hameed M, Viale A, Busam K, et al. A genome-wide high-resolution array-CGH analysis of cutaneous melanoma and comparison of array-CGH to FISH in diagnostic evaluation. J Mol Diagn. 2013;15(5):581–91.

    Article  CAS  PubMed  Google Scholar 

  12. Mesbah Ardakani N, Thomas C, Robinson C, Mina K, Harvey NT, Amanuel B, et al. Detection of copy number variations in melanocytic lesions utilising array based comparative genomic hybridisation. Pathology. 2017;49(3):285–91.

    Article  PubMed  Google Scholar 

  13. Chan MP, Andea AA, Harms PW, Durham AB, Patel RM, Wang M, et al. Genomic copy number analysis of a spectrum of blue nevi identifies recurrent aberrations of entire chromosomal arms in melanoma ex blue nevus. Mod Pathol. 2016;29(3):227–39.

    Article  CAS  PubMed  Google Scholar 

  14. Yelamos O, Arva NC, Obregon R, Yazdan P, Wagner A, Guitart J, et al. A comparative study of proliferative nodules and lethal melanomas in congenital nevi from children. Am J Surg Pathol. 2015;39(3):405–15.

    Article  PubMed  Google Scholar 

  15. Lee JJ, Lian CG. Molecular testing for cutaneous melanoma: an update and review. Arch Pathol Lab Med. 2019;143(7):811–20.

    Article  CAS  PubMed  Google Scholar 

  16. Gerami P, Li G, Pouryazdanparast P, Blondin B, Beilfuss B, Slenk C, et al. A highly specific and discriminatory FISH assay for distinguishing between benign and malignant melanocytic neoplasms. Am J Surg Pathol. 2012;36(6):808–17.

    Article  PubMed  Google Scholar 

  17. Carter MD, Durham AB, Miedema JR, Harms PW, Chan MP, Patel RM, et al. Molecular testing of borderline cutaneous melanocytic lesions: SNP array is more sensitive and specific than FISH. Hum Pathol. 2019;86:115–23.

    Article  CAS  PubMed  Google Scholar 

  18. March J, Hand M, Truong A, Grossman D. Practical application of new technologies for melanoma diagnosis: part II. Molecular approaches. J Am Acad Dermatol. 2015;72(6):943–58; quiz 59-60

    Article  PubMed  Google Scholar 

  19. Hillen LM, Van den Oord J, Geybels MS, Becker JC, Zur Hausen A, Winnepenninckx V. Genomic landscape of Spitzoid neoplasms impacting patient management. Front Med. 2018;5:344.

    Article  Google Scholar 

  20. Wiesner T, Kutzner H, Cerroni L, Mihm MC Jr, Busam KJ, Murali R. Genomic aberrations in spitzoid melanocytic tumours and their implications for diagnosis, prognosis and therapy. Pathology. 2016;48(2):113–31.

    Article  CAS  PubMed  Google Scholar 

  21. Amin SM, Haugh AM, Lee CY, Zhang B, Bubley JA, Merkel EA, et al. A comparison of morphologic and molecular features of BRAF, ALK, and NTRK1 fusion Spitzoid neoplasms. Am J Surg Pathol. 2017;41(4):491–8.

    Article  PubMed  Google Scholar 

  22. Tetzlaff MT, Reuben A, Billings SD, Prieto VG, Curry JL. Toward a molecular-genetic classification of Spitzoid neoplasms. Clin Lab Med. 2017;37(3):431–48.

    Article  PubMed  Google Scholar 

  23. Zhang AJ, Rush PS, Tsao H, Duncan LM. BRCA1-associated protein (BAP1)-inactivated melanocytic tumors. J Cutan Pathol. 2019;46(12):965–72.

    Article  PubMed  Google Scholar 

  24. Lee S, Barnhill RL, Dummer R, Dalton J, Wu J, Pappo A, et al. TERT promoter mutations are predictive of aggressive clinical behavior in patients with Spitzoid melanocytic neoplasms. Sci Rep. 2015;5:11200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Gerami P, Scolyer RA, Xu X, Elder DE, Abraham RM, Fullen D, et al. Risk assessment for atypical spitzoid melanocytic neoplasms using FISH to identify chromosomal copy number aberrations. Am J Surg Pathol. 2013;37(5):676–84.

    Article  PubMed  Google Scholar 

  26. Ali L, Helm T, Cheney R, Conroy J, Sait S, Guitart J, et al. Correlating array comparative genomic hybridization findings with histology and outcome in spitzoid melanocytic neoplasms. Int J Clin Exp Pathol. 2010;3(6):593–9.

    PubMed  PubMed Central  Google Scholar 

  27. Bastian BC, Xiong J, Frieden IJ, Williams ML, Chou P, Busam K, et al. Genetic changes in neoplasms arising in congenital melanocytic nevi: differences between nodular proliferations and melanomas. Am J Pathol. 2002;161(4):1163–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. AJCC Cancer Staging Manual. 8th ed. New York: Springer International Publishing; 2017.

    Google Scholar 

  29. Newman MD, Lertsburapa T, Mirzabeigi M, Mafee M, Guitart J, Gerami P. Fluorescence in situ hybridization as a tool for microstaging in malignant melanoma. Mod Pathol. 2009;22(8):989–95.

    Article  CAS  PubMed  Google Scholar 

  30. Cheng L, Lopez-Beltran A, Massari F, MacLennan GT, Montironi R. Molecular testing for BRAF mutations to inform melanoma treatment decisions: a move toward precision medicine. Mod Pathol. 2018;31(1):24–38.

    Article  CAS  PubMed  Google Scholar 

  31. Kim SY, Kim SN, Hahn HJ, Lee YW, Choe YB, Ahn KJ. Metaanalysis of BRAF mutations and clinicopathologic characteristics in primary melanoma. J Am Acad Dermatol. 2015;72(6):1036–46 e2.

    Article  CAS  PubMed  Google Scholar 

  32. Yao Z, Yaeger R, Rodrik-Outmezguine VS, Tao A, Torres NM, Chang MT, et al. Tumours with class 3 BRAF mutants are sensitive to the inhibition of activated RAS. Nature. 2017;548(7666):234–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Menzies AM, Haydu LE, Visintin L, Carlino MS, Howle JR, Thompson JF, et al. Distinguishing clinicopathologic features of patients with V600E and V600K BRAF-mutant metastatic melanoma. Clin Cancer Res. 2012;18(12):3242–9.

    Article  CAS  PubMed  Google Scholar 

  34. Pollock PM, Harper UL, Hansen KS, Yudt LM, Stark M, Robbins CM, et al. High frequency of BRAF mutations in nevi. Nat Genet. 2003;33(1):19–20.

    Article  CAS  PubMed  Google Scholar 

  35. McArthur GA, Ribas A. Targeting oncogenic drivers and the immune system in melanoma. J Clin Oncol. 2013;31(4):499–506.

    Article  CAS  PubMed  Google Scholar 

  36. Devji T, Levine O, Neupane B, Beyene J, Xie F. Systemic therapy for previously untreated advanced BRAF-mutated melanoma: a systematic review and network meta-analysis of randomized clinical trials. JAMA Oncol. 2017;3(3):366–73.

    Article  PubMed  Google Scholar 

  37. Robert C, Grob JJ, Stroyakovskiy D, Karaszewska B, Hauschild A, Levchenko E, et al. Five-year outcomes with dabrafenib plus trametinib in metastatic melanoma. N Engl J Med. 2019;381(7):626–36.

    Article  CAS  PubMed  Google Scholar 

  38. Robert C, Karaszewska B, Schachter J, Rutkowski P, Mackiewicz A, Stroiakovski D, et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med. 2015;372(1):30–9.

    Article  PubMed  CAS  Google Scholar 

  39. Santiago-Walker A, Gagnon R, Mazumdar J, Casey M, Long GV, Schadendorf D, et al. Correlation of BRAF mutation status in circulating-free DNA and tumor and association with clinical outcome across four BRAFi and MEKi clinical trials. Clin Cancer Res. 2016;22(3):567–74.

    Article  CAS  PubMed  Google Scholar 

  40. Vanni I, Tanda ET, Spagnolo F, Andreotti V, Bruno W, Ghiorzo P. The current state of molecular testing in the BRAF-mutated melanoma landscape. Front Mol Biosci. 2020;7:113.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Long GV, Wilmott JS, Capper D, Preusser M, Zhang YE, Thompson JF, et al. Immunohistochemistry is highly sensitive and specific for the detection of V600E BRAF mutation in melanoma. Am J Surg Pathol. 2013;37(1):61–5.

    Article  PubMed  Google Scholar 

  42. Network NCC. Cutaneous Melanoma (Version 3.2020) 2020 [Available from: https://www.nccn.org/professionals/physician_gls/default.aspx#melanoma

  43. Bisschop C, Ter Elst A, Bosman LJ, Platteel I, Jalving M, van den Berg A, et al. Rapid BRAF mutation tests in patients with advanced melanoma: comparison of immunohistochemistry, droplet digital PCR, and the Idylla mutation platform. Melanoma Res. 2018;28(2):96–104.

    Article  CAS  PubMed  Google Scholar 

  44. Spittle C, Ward MR, Nathanson KL, Gimotty PA, Rappaport E, Brose MS, et al. Application of a BRAF pyrosequencing assay for mutation detection and copy number analysis in malignant melanoma. J Mol Diagn. 2007;9(4):464–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Tan YH, Liu Y, Eu KW, Ang PW, Li WQ, Salto-Tellez M, et al. Detection of BRAF V600E mutation by pyrosequencing. Pathology. 2008;40(3):295–8.

    Article  CAS  PubMed  Google Scholar 

  46. Mancini I, Simi L, Salvianti F, Castiglione F, Sonnati G, Pinzani P. Analytical evaluation of an NGS testing method for routine molecular diagnostics on melanoma formalin-fixed, paraffin-embedded tumor-derived DNA. Diagnostics. 2019;9(3):1–14.

    Google Scholar 

  47. Davis EJ, Johnson DB, Sosman JA, Chandra S. Melanoma: what do all the mutations mean? Cancer. 2018;124(17):3490–9.

    Article  PubMed  Google Scholar 

  48. Vanni I, Tanda ET, Dalmasso B, Pastorino L, Andreotti V, Bruno W, et al. Non-BRAF mutant melanoma: molecular features and therapeutical implications. Front Mol Biosci. 2020;7:172.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Hodi FS, Corless CL, Giobbie-Hurder A, Fletcher JA, Zhu M, Marino-Enriquez A, et al. Imatinib for melanomas harboring mutationally activated or amplified KIT arising on mucosal, acral, and chronically sun-damaged skin. J Clin Oncol. 2013;31(26):3182–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Carvajal RD, Antonescu CR, Wolchok JD, Chapman PB, Roman RA, Teitcher J, et al. KIT as a therapeutic target in metastatic melanoma. JAMA. 2011;305(22):2327–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Queirolo P, Spagnolo F. Binimetinib for the treatment of NRAS-mutant melanoma. Expert Rev Anticancer Ther. 2017;17(11):985–90.

    Article  CAS  PubMed  Google Scholar 

  52. Dummer R, Schadendorf D, Ascierto PA, Arance A, Dutriaux C, Di Giacomo AM, et al. Binimetinib versus dacarbazine in patients with advanced NRAS-mutant melanoma (NEMO): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2017;18(4):435–45.

    Article  CAS  PubMed  Google Scholar 

  53. Hirsch D, Kemmerling R, Davis S, Camps J, Meltzer PS, Ried T, et al. Chromothripsis and focal copy number alterations determine poor outcome in malignant melanoma. Cancer Res. 2013;73(5):1454–60.

    Article  CAS  PubMed  Google Scholar 

  54. Gerami P, Jewell SS, Pouryazdanparast P, Wayne JD, Haghighat Z, Busam KJ, et al. Copy number gains in 11q13 and 8q24 [corrected] are highly linked to prognosis in cutaneous malignant melanoma. J Mol Diagn. 2011;13(3):352–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Gerami P, Cook RW, Wilkinson J, Russell MC, Dhillon N, Amaria RN, et al. Development of a prognostic genetic signature to predict the metastatic risk associated with cutaneous melanoma. Clin Cancer Res. 2015;21(1):175–83.

    Article  CAS  PubMed  Google Scholar 

  56. Marchetti MA, Coit DG, Dusza SW, Yu A, McLean L, Hu Y, et al. Performance of gene expression profile tests for prognosis in patients with localized cutaneous melanoma: a systematic review and meta-analysis. JAMA Dermatol. 2020;

    Google Scholar 

  57. Farberg AS, Hall MA, Douglas L, Covington KR, Kurley SJ, Cook RW, et al. Integrating gene expression profiling into NCCN high-risk cutaneous squamous cell carcinoma management recommendations: impact on patient management. Curr Med Res Opin. 2020;36(8):1301–7.

    Article  PubMed  Google Scholar 

  58. Iacobelli J, Harvey NT, Wood BA. Sebaceous lesions of the skin. Pathology. 2017;49(7):688–97.

    Article  PubMed  Google Scholar 

  59. John AM, Schwartz RA. Muir-Torre syndrome (MTS): an update and approach to diagnosis and management. J Am Acad Dermatol. 2016;74(3):558–66.

    Article  PubMed  Google Scholar 

  60. Jessup CJ, Redston M, Tilton E, Reimann JD. Importance of universal mismatch repair protein immunohistochemistry in patients with sebaceous neoplasia as an initial screening tool for Muir-Torre syndrome. Hum Pathol. 2016;49:1–9.

    Article  CAS  PubMed  Google Scholar 

  61. Li K, Luo H, Huang L, Luo H, Zhu X. Microsatellite instability: a review of what the oncologist should know. Cancer Cell Int. 2020;20:16.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Smoller BR. Mycosis fungoides: what do/do not we know? J Cutan Pathol. 2008;35(Suppl 2):35–9.

    Article  PubMed  Google Scholar 

  63. Bagherani N, Smoller BR. An overview of cutaneous T cell lymphomas. F1000Res. 2016;5.

    Google Scholar 

  64. Hodak E, Amitay-Laish I. Mycosis fungoides: a great imitator. Clin Dermatol. 2019;37(3):255–67.

    Article  PubMed  Google Scholar 

  65. Hristov AC, Tejasvi T, Wilcox RA. Mycosis fungoides and Sezary syndrome: 2019 update on diagnosis, risk-stratification, and management. Am J Hematol. 2019;94(9):1027–41.

    Article  PubMed  Google Scholar 

  66. Sufficool KE, Lockwood CM, Abel HJ, Hagemann IS, Schumacher JA, Kelley TW, et al. T-cell clonality assessment by next-generation sequencing improves detection sensitivity in mycosis fungoides. J Am Acad Dermatol. 2015;73(2):228–36. e2

    Article  CAS  PubMed  Google Scholar 

  67. Fujii K, Kanekura T. Next-generation sequencing Technologies for Early-Stage Cutaneous T-cell lymphoma. Front Med. 2019;6:181.

    Article  Google Scholar 

  68. Kirsch IR, Watanabe R, O'Malley JT, Williamson DW, Scott LL, Elco CP, et al. TCR sequencing facilitates diagnosis and identifies mature T cells as the cell of origin in CTCL. Sci Transl Med. 2015;7(308):308ra158.

    Article  PubMed  PubMed Central  Google Scholar 

  69. de Masson A, O'Malley JT, Elco CP, Garcia SS, Divito SJ, Lowry EL, et al. High-throughput sequencing of the T cell receptor beta gene identifies aggressive early-stage mycosis fungoides. Sci Transl Med. 2018;10(440):1–28.

    Google Scholar 

  70. Allen A, Ahn C, Sangueza OP. Dermatofibrosarcoma Protuberans. Dermatol Clin. 2019;37(4):483–8.

    Article  CAS  PubMed  Google Scholar 

  71. Carter JM, Weiss SW, Linos K, DiCaudo DJ, Folpe AL. Superficial CD34-positive fibroblastic tumor: report of 18 cases of a distinctive low-grade mesenchymal neoplasm of intermediate (borderline) malignancy. Mod Pathol. 2014;27(2):294–302.

    Article  CAS  PubMed  Google Scholar 

  72. Karanian M, Perot G, Coindre JM, Chibon F, Pedeutour F, Neuville A. Fluorescence in situ hybridization analysis is a helpful test for the diagnosis of dermatofibrosarcoma protuberans. Mod Pathol. 2015;28(2):230–7.

    Article  CAS  PubMed  Google Scholar 

  73. Ha SY, Lee SE, Kwon MJ, Kim YJ, Lee EH, Seo J, et al. PDGFB rearrangement in dermatofibrosarcoma protuberans: correlation with clinicopathologic characteristics and clinical implications. Hum Pathol. 2013;44(7):1300–9.

    Article  CAS  PubMed  Google Scholar 

  74. Navarrete-Dechent C, Mori S, Barker CA, Dickson MA, Nehal KS. Imatinib treatment for locally advanced or metastatic dermatofibrosarcoma protuberans: a systematic review. JAMA Dermatol. 2019;155(3):361–9.

    Article  PubMed  PubMed Central  Google Scholar 

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  1. Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA

    Cynthia Reyes Barron & Bruce R. Smoller

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Correspondence to Bruce R. Smoller .

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  1. Department of Laboratory Medicine, Geisinger Health, Danville, PA, USA

    Yi Ding

  2. Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA

    Linsheng Zhang

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Reyes Barron, C., Smoller, B.R. (2021). Skin Tumors. In: Ding, Y., Zhang, L. (eds) Practical Oncologic Molecular Pathology. Practical Anatomic Pathology. Springer, Cham. https://doi.org/10.1007/978-3-030-73227-1_9

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