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Merkel Cell Carcinoma: Current Issues Regarding Diagnosis, Management, and Emerging Treatment Strategies

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Abstract

Merkel cell carcinoma (MCC) is a rare but aggressive cutaneous tumor with a predilection for the head and neck of elderly Caucasian patients. Although much less common than melanoma, MCC has higher rates of sentinel lymph node involvement, local and regional recurrences, and mortality. The majority of MCC cases have been linked to the relatively newly discovered Merkel cell polyomavirus, which is a ubiquitous constituent of the skin flora. Recent discoveries regarding viral integration and carcinogenesis and the immunologic features of MCC have expanded the understanding of MCC. These discoveries have led to the development and application of emerging therapies such as somatostatin analogs, immune checkpoint inhibition, adoptive cell therapy, and other exciting possibilities for targeted therapy.

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References

  1. Bichakjian CK, Lowe L, Lao CD, et al. Merkel cell carcinoma: critical review with guidelines for multidisciplinary management. Cancer. 2007;110(1):1–12.

    Article  PubMed  Google Scholar 

  2. Bichakjian CK, Olencki T, Alam M, et al. Merkel cell carcinoma, version 1.2014. J Natl Compr Cancer Netw JNCCN. 2014;12(3):410–24.

    PubMed  Google Scholar 

  3. Gillenwater AM, Hessel AC, Morrison WH, et al. Merkel cell carcinoma of the head and neck: effect of surgical excision and radiation on recurrence and survival. Arch Otolaryngol Head Neck Surg. 2001;127(2):149–54.

    Article  PubMed  CAS  Google Scholar 

  4. Enzenhofer E, Ubl P, Czerny C, Erovic BM. Imaging in patients with merkel cell carcinoma. J Skin Cancer. 2013;2013:973123.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Chapman PB, Hauschild A, Sondak VK. Frontline approach to metastatic BRAF-mutant melanoma diagnosis, molecular evaluation, and treatment choice. American Society of Clinical Oncology educational book/ASCO. American Society of Clinical Oncology. Meeting. 2014:e412-421.

  6. Fitzgerald TL, Dennis S, Kachare SD, Vohra NA, Wong JH, Zervos EE. Dramatic Increase in the Incidence and Mortality from Merkel Cell Carcinoma in the United States. Am Surg. 2015;81(8):802–6.

    PubMed  Google Scholar 

  7. National Cancer Institute. SEER Stat Fact Sheet: melanoma of the skin. 2015. http://seer.cancer.gov/statfcts/html/melan.html. Accessed 9 Oct 2015.

  8. National Cancer Institute. Merkel cell carcinoma-incidence and mortalitiy. 2015. http://www.cancer.gov/types/skin/hp/merkel-cell. Accessed 9 Oct 2015.

  9. Allen PJ, Bowne WB, Jaques DP, Brennan MF, Busam K, Coit DG. Merkel cell carcinoma: prognosis and treatment of patients from a single institution. J Clin Oncol Off J Am Soc Clin Oncol. 2005;23(10):2300–9.

    Article  Google Scholar 

  10. Akhtar S, Oza KK, Wright J. Merkel cell carcinoma: report of 10 cases and review of the literature. J Am Acad Dermatol. 2000;43(5 Pt 1):755–67.

    Article  PubMed  CAS  Google Scholar 

  11. Hughes MP, Hardee ME, Cornelius LA, Hutchins LF, Becker JC, Gao L. Merkel cell carcinoma: epidemiology, target, and therapy. Curr Dermatol Rep. 2014;3:46–53.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Feng H, Shuda M, Chang Y, Moore PS. Clonal integration of a polyomavirus in human Merkel cell carcinoma. Science. 2008;319(5866):1096–100.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  13. Ma JE, Brewer JD. Merkel cell carcinoma in immunosuppressed patients. Cancers. 2014;6(3):1328–50.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Paulson KG, Iyer JG, Tegeder AR, et al. Transcriptome-wide studies of merkel cell carcinoma and validation of intratumoral CD8+ lymphocyte invasion as an independent predictor of survival. J Clin Oncol Off J Am Soc Clin Oncol. 2011;29(12):1539–46.

    Article  CAS  Google Scholar 

  15. Agelli M, Clegg LX. Epidemiology of primary Merkel cell carcinoma in the United States. J Am Acad Dermatol. 2003;49(5):832–41.

    Article  PubMed  Google Scholar 

  16. Medina-Franco H, Urist MM, Fiveash J, Heslin MJ, Bland KI, Beenken SW. Multimodality treatment of Merkel cell carcinoma: case series and literature review of 1024 cases. Ann Surg Oncol. 2001;8(3):204–8.

    Article  PubMed  CAS  Google Scholar 

  17. Rollison DE, Giuliano AR, Becker JC. New virus associated with merkel cell carcinoma development. J Natl Compr Cancer Netw JNCCN. 2010;8(8):874–80.

    PubMed  Google Scholar 

  18. Becker JC. Merkel cell carcinoma. Ann Oncol Off J Eur Soc Med Oncol/ESMO. 2010;21(Suppl 7):vii81–5.

    Google Scholar 

  19. Widera D, Hauser S, Kaltschmidt C, Kaltschmidt B. Origin and regenerative potential of vertebrate mechanoreceptor-associated stem cells. Anat Res Int. 2012;2012:837626.

    PubMed  PubMed Central  Google Scholar 

  20. Halata Z, Grim M, Baumann KI. The Merkel cell: morphology, developmental origin, function. Cas Lek Cesk. 2003;142(1):4–9.

    PubMed  CAS  Google Scholar 

  21. Morrison KM, Miesegaes GR, Lumpkin EA, Maricich SM. Mammalian Merkel cells are descended from the epidermal lineage. Dev Biol. 2009;336(1):76–83.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  22. Maricich SM, Wellnitz SA, Nelson AM, et al. Merkel cells are essential for light-touch responses. Science. 2009;324(5934):1580–2.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  23. Calder KB, Coplowitz S, Schlauder S, Morgan MB. A case series and immunophenotypic analysis of CK20-/CK7+ primary neuroendocrine carcinoma of the skin. J Cutan Pathol. 2007;34(12):918–23.

    Article  PubMed  Google Scholar 

  24. Tang CK, Toker C, Nedwich A, Zaman AN. Unusual cutaneous carcinoma with features of small cell (oat cell-like) and squamous cell carcinomas. A variant of malignant Merkel cell neoplasm. Am J Dermatopathol. 1982;4(6):537–48.

    Article  PubMed  CAS  Google Scholar 

  25. Erovic I, Erovic BM. Merkel cell carcinoma: the past, the present, and the future. J Skin Cancer. 2013;2013:6.

    Article  Google Scholar 

  26. Norval M. The effect of ultraviolet radiation on human viral infections. Photochem Photobiol. 2006;82(6):1495–504.

    Article  PubMed  CAS  Google Scholar 

  27. Krynitz B, Edgren G, Lindelof B, et al. Risk of skin cancer and other malignancies in kidney, liver, heart and lung transplant recipients 1970 to 2008—a Swedish population-based study. Int J Cancer J Int Cancer. 2013;132(6):1429–38.

    Article  CAS  Google Scholar 

  28. Stockfleth E, Nindl I, Sterry W, Ulrich C, Schmook T, Meyer T. Human papillomaviruses in transplant-associated skin cancers. Dermatol Surg Off Publ Am Soc Dermatol Surg [et al.]. 2004;30(4 Pt 2):604–9.

    Google Scholar 

  29. Engels EA, Frisch M, Goedert JJ, Biggar RJ, Miller RW. Merkel cell carcinoma and HIV infection. Lancet. 2002;359(9305):497–8.

    Article  PubMed  Google Scholar 

  30. Penn I, First MR. Merkel’s cell carcinoma in organ recipients: report of 41 cases. Transplantation. 1999;68(11):1717–21.

    Article  PubMed  CAS  Google Scholar 

  31. Kassem A, Schopflin A, Diaz C, et al. Frequent detection of Merkel cell polyomavirus in human Merkel cell carcinomas and identification of a unique deletion in the VP1 gene. Cancer Res. 2008;68(13):5009–13.

    Article  PubMed  CAS  Google Scholar 

  32. Spurgeon ME, Lambert PF. Merkel cell polyomavirus: a newly discovered human virus with oncogenic potential. Virology. 2013;435(1):118–30.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  33. Tolstov YL, Knauer A, Chen JG, et al. Asymptomatic primary Merkel cell polyomavirus infection among adults. Emerg Infect Dis. 2011;17(8):1371–80.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Tolstov YL, Pastrana DV, Feng H, et al. Human Merkel cell polyomavirus infection II. MCV is a common human infection that can be detected by conformational capsid epitope immunoassays. Int J Cancer. 2009;125(6):1250–6.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  35. Foulongne V, Dereure O, Kluger N, Moles JP, Guillot B, Segondy M. Merkel cell polyomavirus DNA detection in lesional and nonlesional skin from patients with Merkel cell carcinoma or other skin diseases. Br J Dermatol. 2010;162(1):59–63.

    Article  PubMed  CAS  Google Scholar 

  36. Aldabagh B, Joo J, Yu SS. Merkel cell carcinoma: current status of targeted and future potential for immunotherapies. Semin Cutan Med Surg. 2014;33(2):76–82.

    Article  PubMed  Google Scholar 

  37. Johne R, Buck CB, Allander T, et al. Taxonomical developments in the family Polyomaviridae. Arch Virol. 2011;156(9):1627–34.

    Article  PubMed  CAS  Google Scholar 

  38. Shuda M, Feng H, Kwun HJ, et al. T antigen mutations are a human tumor-specific signature for Merkel cell polyomavirus. Proc Natl Acad Sci USA. 2008;105(42):16272–7.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  39. Busam KJ, Jungbluth AA, Rekthman N, et al. Merkel cell polyomavirus expression in merkel cell carcinomas and its absence in combined tumors and pulmonary neuroendocrine carcinomas. Am J Surg Pathol. 2009;33(9):1378–85.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Houben R, Shuda M, Weinkam R, et al. Merkel cell polyomavirus-infected Merkel cell carcinoma cells require expression of viral T antigens. J Virol. 2010;84(14):7064–72.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  41. Shuda M, Arora R, Kwun HJ, et al. Human Merkel cell polyomavirus infection I. MCV T antigen expression in Merkel cell carcinoma, lymphoid tissues and lymphoid tumors. Int J Cancer J Int Cancer. 2009;125(6):1243–9.

    Article  CAS  Google Scholar 

  42. Pastrana DV, Tolstov YL, Becker JC, Moore PS, Chang Y, Buck CB. Quantitation of human seroresponsiveness to Merkel cell polyomavirus. PLoS Pathog. 2009;5(9):e1000578.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Sastre-Garau X, Peter M, Avril MF, et al. Merkel cell carcinoma of the skin: pathological and molecular evidence for a causative role of MCV in oncogenesis. J Pathol. 2009;218(1):48–56.

    Article  PubMed  CAS  Google Scholar 

  44. Richter JD, Sonenberg N. Regulation of cap-dependent translation by eIF4E inhibitory proteins. Nature. 2005;433(7025):477–80.

    Article  PubMed  CAS  Google Scholar 

  45. Pause A, Methot N, Svitkin Y, Merrick WC, Sonenberg N. Dominant negative mutants of mammalian translation initiation factor eIF-4A define a critical role for eIF-4F in cap-dependent and cap-independent initiation of translation. EMBO J. 1994;13(5):1205–15.

    PubMed  CAS  PubMed Central  Google Scholar 

  46. Leroux-Kozal V, Leveque N, Brodard V, et al. Merkel cell carcinoma: histopathologic and prognostic features according to the immunohistochemical expression of Merkel cell polyomavirus large T antigen correlated with viral load. Hum Pathol. 2015;46(3):443–53.

    Article  PubMed  CAS  Google Scholar 

  47. Higaki-Mori H, Kuwamoto S, Iwasaki T, et al. Association of Merkel cell polyomavirus infection with clinicopathological differences in Merkel cell carcinoma. Hum Pathol. 2012;43(12):2282–91.

    Article  PubMed  Google Scholar 

  48. Sihto H, Kukko H, Koljonen V, Sankila R, Bohling T, Joensuu H. Clinical factors associated with Merkel cell polyomavirus infection in Merkel cell carcinoma. J Natl Cancer Inst. 2009;101(13):938–45.

    Article  PubMed  CAS  Google Scholar 

  49. Lipson EJ, Vincent JG, Loyo M, et al. PD-L1 expression in the Merkel cell carcinoma microenvironment: association with inflammation, Merkel cell polyomavirus and overall survival. Cancer Immunol Res. 2013;1(1):54–63.

    Article  PubMed  CAS  Google Scholar 

  50. Handschel J, Muller D, Depprich RA, et al. The new polyomavirus (MCPyV) does not affect the clinical course in MCCs. Int J Oral Maxillofac Surg. 2010;39(11):1086–90.

    Article  PubMed  CAS  Google Scholar 

  51. Schrama D, Peitsch WK, Zapatka M, et al. Merkel cell polyomavirus status is not associated with clinical course of Merkel cell carcinoma. J Invest Dermatol. 2011;131(8):1631–8.

    Article  PubMed  CAS  Google Scholar 

  52. Hall BJ, Pincus LB, Yu SS, Oh DH, Wilson AR, McCalmont TH. Immunohistochemical prognostication of Merkel cell carcinoma: p63 expression but not polyomavirus status correlates with outcome. J Cutan Pathol. 2012;39(10):911–7.

    Article  PubMed  Google Scholar 

  53. Taylor G, Mollick DK, Heilman ER. Merkel cell carcinoma. In: Rigel DS, editor. Cancer of the Skin. 1st ed. Philadelphia: Elsevier Inc; 2005. p. 323–7.

    Google Scholar 

  54. Becker JC, Assaf C, Vordermark D, et al. Brief S2k guidelines—Merkel cell carcinoma. J Dtsch Dermatol Ges J Ger Soc Dermatol JDDG. 2013;11(Suppl 3):29–36 (31–28).

    Article  Google Scholar 

  55. Honarpisheh H, Glusac EJ, Ko CJ. Cytokeratin 20 expression in basaloid follicular hamartoma and infundibulocystic basal cell carcinoma. J Cutan Pathol. 2014;41(12):916–21.

    Article  PubMed  Google Scholar 

  56. Bowen AR, LeBoit PE. Fibroepithelioma of pinkus is a fenestrated trichoblastoma. Am J Dermatopathol. 2005;27(2):149–54.

    Article  PubMed  Google Scholar 

  57. Sierakowski A, Al-Janabi K, Dam H, Sood M. Metastatic Merkel cell carcinoma with positive expression of thyroid transcription factor-1—a case report. Am J Dermatopathol. 2009;31(4):384–6.

    Article  PubMed  Google Scholar 

  58. Reddi DM, Puri PK. Expression of focal TTF-1 expression in a case of CK7/CK20-positive Merkel cell carcinoma. J Cutan Pathol. 2013;40(4):431–3.

    Article  PubMed  Google Scholar 

  59. Ralston J, Chiriboga L, Nonaka D. MASH1: a useful marker in differentiating pulmonary small cell carcinoma from Merkel cell carcinoma. Mod Pathol Off J US Can Acad Pathol Inc. 2008;21(11):1357–1362.

  60. Koba S, Inoue T, Okawa T, et al. Merkel cell carcinoma with cytokeratin 20-negative and thyroid transcription factor-1-positive immunostaining admixed with squamous cell carcinoma. J Dermatol Sci. 2011;64(1):77–9.

    Article  PubMed  CAS  Google Scholar 

  61. Buresh CJ, Oliai BR, Miller RT. Reactivity with TdT in Merkel cell carcinoma: a potential diagnostic pitfall. Am J Clin Pathol. 2008;129(6):894–8.

    Article  PubMed  Google Scholar 

  62. Succaria F, Radfar A, Bhawan J. Merkel cell carcinoma (primary neuroendocrine carcinoma of skin) mimicking basal cell carcinoma with review of different histopathologic features. Am J Dermatopathol. 2014;36(2):160–6.

    Article  PubMed  Google Scholar 

  63. Asioli S, Righi A, Volante M, Eusebi V, Bussolati G. p63 expression as a new prognostic marker in Merkel cell carcinoma. Cancer. 2007;110(3):640–7.

    Article  PubMed  Google Scholar 

  64. Asioli S, Righi A, de Biase D, et al. Expression of p63 is the sole independent marker of aggressiveness in localised (stage I–II) Merkel cell carcinomas. Modern Pathol Off J US Can Acad Pathol Inc. 2011;24(11):1451–1461.

  65. Lim CS, Whalley D, Haydu LE, et al. Increasing tumor thickness is associated with recurrence and poorer survival in patients with Merkel cell carcinoma. Ann Surg Oncol. 2012;19(11):3325–34.

    Article  PubMed  Google Scholar 

  66. Rao P, Balzer BL, Lemos BD, et al. Protocol for the examination of specimens from patients with merkel cell carcinoma of the skin. Arch Pathol Lab Med. 2010;134(3):341–4.

    PubMed  Google Scholar 

  67. Andea AA, Coit DG, Amin B, Busam KJ. Merkel cell carcinoma: histologic features and prognosis. Cancer. 2008;113(9):2549–58.

    Article  PubMed  Google Scholar 

  68. Llombart B, Monteagudo C, Lopez-Guerrero JA, et al. Clinicopathological and immunohistochemical analysis of 20 cases of Merkel cell carcinoma in search of prognostic markers. Histopathology. 2005;46(6):622–34.

    Article  PubMed  CAS  Google Scholar 

  69. Skelton HG, Smith KJ, Hitchcock CL, McCarthy WF, Lupton GP, Graham JH. Merkel cell carcinoma: analysis of clinical, histologic, and immunohistologic features of 132 cases with relation to survival. J Am Acad Dermatol. 1997;37(5 Pt 1):734–9.

    Article  PubMed  CAS  Google Scholar 

  70. Gupta SG, Wang LC, Penas PF, Gellenthin M, Lee SJ, Nghiem P. Sentinel lymph node biopsy for evaluation and treatment of patients with Merkel cell carcinoma: the Dana-Farber experience and meta-analysis of the literature. Arch Dermatol. 2006;142(6):685–90.

    Article  PubMed  Google Scholar 

  71. Lens MB, Dawes M, Goodacre T, Newton-Bishop JA. Elective lymph node dissection in patients with melanoma: systematic review and meta-analysis of randomized controlled trials. Arch Surg. 2002;137(4):458–61.

    Article  PubMed  Google Scholar 

  72. Santamaria-Barria JA, Boland GM, Yeap BY, Nardi V, Dias-Santagata D, Cusack JC Jr. Merkel cell carcinoma: 30-year experience from a single institution. Ann Surg Oncol. 2013;20(4):1365–73.

    Article  PubMed  Google Scholar 

  73. Leiter U, Eigentler TK, Hafner HM, et al. Sentinel lymph node dissection in head and neck melanoma has prognostic impact on disease-free and overall survival. Ann Surg Oncol. 2015;22(12):4073–80.

    Article  PubMed  Google Scholar 

  74. Siva S, Byrne K, Seel M, et al. 18F-FDG PET provides high-impact and powerful prognostic stratification in the staging of Merkel cell carcinoma: a 15-year institutional experience. J Nucl Med Off Publ Soc Nucl Med. 2013;54(8):1223–9.

    CAS  Google Scholar 

  75. Lemos BD, Storer BE, Iyer JG, et al. Pathologic nodal evaluation improves prognostic accuracy in Merkel cell carcinoma: analysis of 5823 cases as the basis of the first consensus staging system. J Am Acad Dermatol. 2010;63(5):751–61.

    Article  PubMed  PubMed Central  Google Scholar 

  76. Lebbe C, Becker JC, Grob JJ, et al. Diagnosis and treatment of Merkel Cell Carcinoma. European consensus-based interdisciplinary guideline. Eur J Cancer. 2015;51(16):2396–403.

    Article  PubMed  Google Scholar 

  77. Gollard R, Weber R, Kosty MP, Greenway HT, Massullo V, Humberson C. Merkel cell carcinoma: review of 22 cases with surgical, pathologic, and therapeutic considerations. Cancer. 2000;88(8):1842–51.

    Article  PubMed  CAS  Google Scholar 

  78. Garneski KM, Nghiem P. Merkel cell carcinoma adjuvant therapy: current data support radiation but not chemotherapy. J Am Acad Dermatol. 2007;57(1):166–9.

    Article  PubMed  PubMed Central  Google Scholar 

  79. Ott MJ, Tanabe KK, Gadd MA, et al. Multimodality management of Merkel cell carcinoma. Arch Surg. 1999;134(4):388–92 (discussion 392–383).

    Article  PubMed  CAS  Google Scholar 

  80. Poulsen MG, Rischin D, Porter I, et al. Does chemotherapy improve survival in high-risk stage I and II Merkel cell carcinoma of the skin? Int J Radiat Oncol Biol Phys. 2006;64(1):114–9.

    Article  PubMed  Google Scholar 

  81. Tai P. Merkel cell cancer: update on biology and treatment. Curr Opin Oncol. 2008;20(2):196–200.

    Article  PubMed  Google Scholar 

  82. Chen MM, Roman SA, Sosa JA, Judson BL. The role of adjuvant therapy in the management of head and neck merkel cell carcinoma: an analysis of 4815 patients. JAMA Otolaryngol Head Neck Surg. 2015;141(2):137–41.

    Article  PubMed  Google Scholar 

  83. Voog E, Biron P, Martin JP, Blay JY. Chemotherapy for patients with locally advanced or metastatic Merkel cell carcinoma. Cancer. 1999;85(12):2589–95.

    Article  PubMed  CAS  Google Scholar 

  84. Inoue T, Yoneda K, Manabe M, Demitsu T. Spontaneous regression of merkel cell carcinoma: a comparative study of TUNEL index and tumor-infiltrating lymphocytes between spontaneous regression and non-regression group. J Dermatol Sci. 2000;24(3):203–11.

    Article  PubMed  CAS  Google Scholar 

  85. Paulson KG, Iyer JG, Blom A, et al. Systemic immune suppression predicts diminished Merkel cell carcinoma-specific survival independent of stage. J Invest Dermatol. 2013;133(3):642–6.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  86. Ferrau F, Micali G, Guitart J. Merkel cell carcinoma of the scalp: dramatic resolution with primary chemotherapy. J Am Acad Dermatol. 1994;31(2 Pt 1):271–2.

    Article  PubMed  CAS  Google Scholar 

  87. Poulsen M, Rischin D, Walpole E, et al. High-risk Merkel cell carcinoma of the skin treated with synchronous carboplatin/etoposide and radiation: a Trans-Tasman Radiation Oncology Group Study—TROG 96:07. J Clin Oncol Off J Am Soc Clin Oncol. 2003;21(23):4371–6.

    Article  CAS  Google Scholar 

  88. Sharma D, Flora G, Grunberg SM. Chemotherapy of metastatic Merkel cell carcinoma: case report and review of the literature. Am J Clin Oncol. 1991;14(2):166–9.

    Article  PubMed  CAS  Google Scholar 

  89. Kearsley JH, Hurst T, Khoo SK. Chemosensitivity testing of primary cultures of Merkel cell cancer. Anticancer Drugs. 1993;4(5):571–5.

    Article  PubMed  CAS  Google Scholar 

  90. Krasagakis K, Almond-Roesler B, Zouboulis CC, et al. Merkel cell carcinoma: report of ten cases with emphasis on clinical course, treatment, and in vitro drug sensitivity. J Am Acad Dermatol. 1997;36(5 Pt 1):727–32.

    Article  PubMed  CAS  Google Scholar 

  91. Sainz-Esteban A, Baum RP. Successful treatment of metastasized pancreatic vasoactive intestinal polypeptide-secreting tumor unresponsive to high-dose octreotide by peptide receptor radionuclide therapy using 90Y DOTATATE. Clin Nucl Med. 2013;38(12):996–7.

    PubMed  Google Scholar 

  92. Cirillo F, Filippini L, Lima GF, Caresana G, Alquati P. Merkel cell tumor. Report of case and treatment with octreotide. Minerva Chir. 1997;52(11):1359–65.

    PubMed  CAS  Google Scholar 

  93. National Cancer Institute. Cixutumumab, everolimus, and octreotide acetate in treating patients with advanced low to intermediate grade neuroendocrine carcinoma. 2015. https://clinicaltrials.gov/ct2/show/NCT01204476. Accessed 20 Oct 2015.

  94. National Cancer Institute. A phase I, exploratory, intra-patient dose escalation study to investigate the preliminary safety, pharmacokinetics, and anti-tumor activity of pasireotide (SOM230) s.c.followed by pasireotide LAR in patients with metastaticmelanoma or metastatic merkel cell carcinoma. 2015. https://clinicaltrials.gov/ct2/show/NCT01652547. Accessed 20 Oct 2015.

  95. National Cancer Institute. Treatment of unresectable and/or metastatic merkel cell carcinoma by somatostatine analogues (PHRC-Merkel). 2015. https://clinicaltrials.gov/ct2/show/NCT02351128. Accessed 20 Oct 2015.

  96. Fakiha M, Letertre P, Vuillez JP, Lebeau J. Remission of Merkel cell tumor after somatostatin analog treatment. J Cancer Res Ther. 2010;6(3):382–4.

    Article  PubMed  CAS  Google Scholar 

  97. Treatment of unresecable and/or metastatic Merkel cell carcinoma by somatostatine analogues (PHRC-Merkel). 2015; The purpose of this trial is to evaluate the efficacy of lanreotide on locally evolving and/or metastatic MCC in a national prospective multicentre phase II study (centres belonging to the skin cancer task force of the French Society of Dermatology namely “Groupe de Cancérologie Cutanée de la Société Française de Dermatologie”). https://clinicaltrials.gov/ct2/show/NCT02351128?term=02351128&rank=1. Accessed 20 Oct 2015.

  98. Buder K, Lapa C, Kreissl MC, et al. Somatostatin receptor expression in Merkel cell carcinoma as target for molecular imaging. BMC Cancer. 2014;14:268.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  99. Hofmann M, Maecke H, Borner R, et al. Biokinetics and imaging with the somatostatin receptor PET radioligand (68)Ga-DOTATOC: preliminary data. Eur J Nucl Med. 2001;28(12):1751–7.

    Article  PubMed  CAS  Google Scholar 

  100. Rosenberg SA, Yang JC, Sherry RM, et al. Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin Cancer Res Off J Am Assoc Cancer Res. 2011;17(13):4550–7.

    Article  CAS  Google Scholar 

  101. Dudley ME, Yang JC, Sherry R, et al. Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens. J Clin Oncol Off J Am Soc Clin Oncol. 2008;26(32):5233–9.

    Article  CAS  Google Scholar 

  102. Heylmann D, Bauer M, Becker H, et al. Human CD4+CD25+ regulatory T cells are sensitive to low dose cyclophosphamide: implications for the immune response. PLoS One. 2013;8(12):e83384.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  103. Suzuki E, Kapoor V, Jassar AS, Kaiser LR, Albelda SM. Gemcitabine selectively eliminates splenic Gr-1+/CD11b+ myeloid suppressor cells in tumor-bearing animals and enhances antitumor immune activity. Clin Cancer Res Off J Am Assoc Cancer Res. 2005;11(18):6713–21.

    Article  CAS  Google Scholar 

  104. Huilgol SC, Selva D, Chen C, et al. Surgical margins for lentigo maligna and lentigo maligna melanoma: the technique of mapped serial excision. Arch Dermatol. 2004;140(9):1087–92.

    Article  PubMed  Google Scholar 

  105. National Cancer Institute. Viral oncoprotein targeted autologous T cell therapy for Merkel cell carcinoma. 2015. https://clinicaltrials.gov/ct2/show/NCT01758458. Accessed 20 Oct 2015.

  106. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711–23.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  107. National Cancer Institute. Adjuvant therapy of completely resected Merkel cell carcinoma with 3 mg/kg BW ipilimumab (Yervoy®) versus observation (ADMEC). 2015. https://clinicaltrials.gov/ct2/show/NCT02196961. Accessed 20 Oct 2015.

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

    Article  PubMed  CAS  Google Scholar 

  109. Postow MA, Chesney J, Pavlick AC, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015;372(21):2006–17.

    Article  PubMed  Google Scholar 

  110. Nghiem P. Activity of PD-1 blockade with pembrolizumab as first systemic therapy in patients with advanced Merkel cell carcinoma. Paper presented at: European Cancer Congress, September 25–29, Vienna, Austria; 2015.

  111. Su LD, Fullen DR, Lowe L, Uherova P, Schnitzer B, Valdez R. CD117 (KIT receptor) expression in Merkel cell carcinoma. Am J Dermatopathol. 2002;24(4):289–93.

    Article  PubMed  Google Scholar 

  112. Shtivelman E, Lifshitz B, Gale RP, Canaani E. Fused transcript of abl and bcr genes in chronic myelogenous leukaemia. Nature. 1985;315(6020):550–4.

    Article  PubMed  CAS  Google Scholar 

  113. Rowley JD. Letter: a new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature. 1973;243(5405):290–3.

    Article  PubMed  CAS  Google Scholar 

  114. Samlowski WE, Moon J, Tuthill RJ, et al. A phase II trial of imatinib mesylate in merkel cell carcinoma (neuroendocrine carcinoma of the skin): a Southwest Oncology Group study (S0331). Am J Clin Oncol. 2010;33(5):495–9.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  115. Yang Q, Hornick JL, Granter SR, Wang LC. Merkel cell carcinoma: lack of KIT positivity and implications for the use of imatinib mesylate. Appl Immunohistochem Mol Morphol AIMM/Off Publ Soc Appl Immunohistochem. 2009;17(4):276–81.

    Article  CAS  Google Scholar 

  116. Miller NJ, Bhatia S, Parvathaneni U, Iyer JG, Nghiem P. Emerging and mechanism-based therapies for recurrent or metastatic Merkel cell carcinoma. Curr Treat Options Oncol. 2013;14(2):249–63.

    Article  PubMed  PubMed Central  Google Scholar 

  117. National Cancer Institute. Pazopanib hydrochloride in treating patients with progressive carcinoid tumors. [website]. 2015. https://www.clinicaltrials.gov/ct2/show/NCT01841736. Accessed 14 June 2015.

  118. Brunner M, Thurnher D, Pammer J, et al. Expression of VEGF-A/C, VEGF-R2, PDGF-alpha/beta, c-kit, EGFR, Her-2/Neu, Mcl-1 and Bmi-1 in Merkel cell carcinoma. Mod Pathol Off J US Can Acad Pathol Inc. 2008;21(7):876–884.

  119. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417(6892):949–54.

    Article  PubMed  CAS  Google Scholar 

  120. Flaherty KT, Robert C, Hersey P, et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012;367(2):107–14.

    Article  PubMed  CAS  Google Scholar 

  121. Hauschild A, Grob JJ, Demidov LV, Jouary T, Gutzmer R, Millward M, Rutkowski P, Blank CU, Miller WH Jr, Kaempgen E, Martín-Algarra S, Karaszewska B, Mauch C, Chiarion-Sileni V, Martin AM, Swann S, Haney P, Mirakhur B, Guckert ME, Goodman V, Chapman PB. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2012;380(9839):358–65.

    Article  PubMed  CAS  Google Scholar 

  122. Korn EL, Liu PY, Lee SJ, et al. Meta-analysis of phase II cooperative group trials in metastatic stage IV melanoma to determine progression-free and overall survival benchmarks for future phase II trials. J Clin Oncol Off J Am Soc Clin Oncol. 2008;26(4):527–34.

    Article  Google Scholar 

  123. McArthur GA, Chapman PB, Robert C, et al. Safety and efficacy of vemurafenib in BRAF(V600E) and BRAF(V600K) mutation-positive melanoma (BRIM-3): extended follow-up of a phase 3, randomised, open-label study. Lancet Oncol. 2014;15(3):323–32.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  124. Dowlatshahi M, Huang V, Gehad AE, et al. Tumor-specific T cells in human Merkel cell carcinomas: a possible role for Tregs and T-cell exhaustion in reducing T-cell responses. J Invest Dermatol. 2013;133(7):1879–89.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  125. Schneider S, Thurnher D, Erovic BM. Merkel cell carcinoma: interdisciplinary management of a rare disease. J Skin Cancer. 2013;2013:189342.

    Article  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. University of Utah School of Medicine, 30 North 1900 East School of Medicine, Salt Lake City, UT, 84132, USA

    Grace C. Brummer

  2. Department of Dermatology, University of Utah School of Medicine, 30 North 1900 East School of Medicine, 4A 330, Salt Lake City, UT, 84132, USA

    Anneli R. Bowen & Glen M. Bowen

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  1. Grace C. Brummer
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  2. Anneli R. Bowen
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Correspondence to Glen M. Bowen.

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Grace C. Brummer, Anneli R. Bowen, and Glen M. Bowen have no conflicts of interest that are directly relevant to the content of this review.

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Brummer, G.C., Bowen, A.R. & Bowen, G.M. Merkel Cell Carcinoma: Current Issues Regarding Diagnosis, Management, and Emerging Treatment Strategies. Am J Clin Dermatol 17, 49–62 (2016). https://doi.org/10.1007/s40257-015-0163-3

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