Skip to main content

Advertisement

SpringerLink
Log in

Update on Merkel Cell Carcinoma

  • Proceedings of the North American Society of Head and Neck Pathology Companion Meeting, March 18, 2018, Vancouver, British Columbia, Canada
  • Published:
Head and Neck Pathology Aims and scope Submit manuscript

Abstract

Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine carcinoma. Incidence of MCC continues to rise, and risk factors include advanced age, pale skin, chronic sun exposure, and immune suppression. Diagnosing MCC utilizes a combination of morphology and immunohistochemistry. Merkel cell polyomavirus (MCPyV) is present in approximately 70–80% of MCCs and represents a key pathogenic driver in those MCCs. In contrast, MCPyV-negative MCCs arise through progressive accumulation of ultraviolet-light induced somatic mutations. Staging of MCC proceeds according to the American Joint Commission on Cancer (AJCC) 8th Edition, which utilizes features of the primary tumor together with regional lymph node(s) (clinically and/or pathologically detected) and/or distant metastases. Many potentially useful biomarkers have been studied to refine risk stratification in MCC. In recent years, the host immune infiltrate has been leveraged as immune checkpoint blockade has emerged as an efficacious mode of treatment for patients with advanced MCC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Albores-Saavedra J, Batich K, Chable-Montero F, Sagy N, Schwartz AM, Henson DE. Merkel cell carcinoma demographics, morphology, and survival based on 3870 cases: a population based study. J Cutan Pathol. 2010;37(1):20 – 7.

    Article  PubMed  Google Scholar 

  2. 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 

  3. 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 

  4. 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 

  5. Guler-Nizam E, Leiter U, Metzler G, Breuninger H, Garbe C, Eigentler TK. Clinical course and prognostic factors of Merkel cell carcinoma of the skin. Br J Dermatol. 2009;161(1):90–4.

    Article  CAS  PubMed  Google Scholar 

  6. Tarantola TI, Vallow LA, Halyard MY, et al. Prognostic factors in Merkel cell carcinoma: analysis of 240 cases. J Am Acad Dermatol. 2013;68(3):425–32.

    Article  PubMed  Google Scholar 

  7. Warner CL, Cockerell CJ. The new seventh edition American Joint Committee on Cancer staging of cutaneous non-melanoma skin cancer: a critical review. Am J Clin Dermatol. 2011;12(3):147–54.

    Article  PubMed  Google Scholar 

  8. 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  CAS  PubMed  PubMed Central  Google Scholar 

  9. Harms KL, Healy MA, Nghiem P, et al. Analysis of prognostic factors from 9387 Merkel cell carcinoma cases forms the basis for the new 8th edition AJCC staging system. Ann Surg Oncol. 2016;23(11):3564–71.

    Article  PubMed  Google Scholar 

  10. Hodgson NC. Merkel cell carcinoma: changing incidence trends. J Surg Oncol. 2005;89(1):1–4.

    Article  PubMed  Google Scholar 

  11. Paulson KG, Park SY, Vandeven NA, et al. Merkel cell carcinoma: current United States incidence and projected Increases Based on changing demographics. J Am Acad Dermatol. 2017. https://doi.org/10.1016/j.jaad.2017.10.028

    PubMed  Google Scholar 

  12. Tadmor T, Liphshitz I, Aviv A, Landgren O, Barchana M, Polliack A. Increased incidence of chronic lymphocytic leukaemia and lymphomas in patients with Merkel cell carcinoma - a population based study of 335 cases with neuroendocrine skin tumour. Br J Haematol. 2012;157(4):457–62.

    Article  PubMed  Google Scholar 

  13. Heath M, Jaimes N, Lemos B, et al. Clinical characteristics of Merkel cell carcinoma at diagnosis in 195 patients: the AEIOU features. J Am Acad Dermatol. 2008;58(3):375–81.

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  15. Hemminki K, Liu X, Ji J, Sundquist J, Sundquist K. Kaposi sarcoma and Merkel cell carcinoma after autoimmune disease. Int J Cancer 2012;131(3):E326-E8.

    Article  CAS  Google Scholar 

  16. Van Keymeulen A, Mascre G, Youseff KK, et al. Epidermal progenitors give rise to Merkel cells during embryonic development and adult homeostasis. J Cell Biol. 2009;187(1):91–100.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Sauer CM, Haugg AM, Chteinberg E, et al. Reviewing the current evidence supporting early B-cells as the cellular origin of Merkel cell carcinoma. Crit Rev Oncol/Hematol. 2017;116:99–105.

    Article  CAS  Google Scholar 

  18. Dong HY, Liu W, Cohen P, Mahle CE, Zhang W. B-cell specific activation protein encoded by the PAX-5 gene is commonly expressed in merkel cell carcinoma and small cell carcinomas. Am J Surg Pathol. 2005;29(5):687–92.

    Article  PubMed  Google Scholar 

  19. Kolhe R, Reid MD, Lee JR, Cohen C, Ramalingam P. Immunohistochemical expression of PAX5 and TdT by Merkel cell carcinoma and pulmonary small cell carcinoma: a potential diagnostic pitfall but useful discriminatory marker. Int J Clin Exp Pathol. 2013;6(2):142–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Mhawech-Fauceglia P, Saxena R, Zhang S, et al. Pax-5 immunoexpression in various types of benign and malignant tumours: a high-throughput tissue microarray analysis. J Clin Pathol. 2007;60(6):709 – 14.

    Article  CAS  PubMed  Google Scholar 

  21. Murakami I, Takata K, Matsushita M, et al. Immunoglobulin expressions are only associated with MCPyV-positive Merkel cell carcinomas but not with MCPyV-negative ones: comparison of prognosis. Am J Surg Pathol. 2014;38(12):1627–35.

    Article  PubMed  Google Scholar 

  22. Zur Hausen A, Rennspiess D, Winnepenninckx V, Speel EJ, Kurz AK. Early B-cell differentiation in Merkel cell carcinomas: clues to cellular ancestry. Cancer Res. 2013;73(16):4982–7.

    Article  CAS  PubMed  Google Scholar 

  23. Bhatia K, Goedert JJ, Modali R, Preiss L, Ayers LW. Merkel cell carcinoma subgroups by Merkel cell polyomavirus DNA relative abundance and oncogene expression. Int J Cancer 2010;126(9):2240–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 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 

  25. Sidiropoulos M, Hanna W, Raphael SJ, Ghorab Z. Expression of TdT in Merkel cell carcinoma and small cell lung carcinoma. Am J Clin Pathol. 2011;135(6):831–8.

    Article  CAS  PubMed  Google Scholar 

  26. Sur M, AlArdati H, Ross C, Alowami S. TdT expression in Merkel cell carcinoma: potential diagnostic pitfall with blastic hematological malignancies and expanded immunohistochemical analysis. Mod Pathol. 2007;20(11):1113–20.

    Article  CAS  PubMed  Google Scholar 

  27. Schadendorf D, Lebbe C, Zur Hausen A, et al. Merkel cell carcinoma: epidemiology, prognosis, therapy and unmet medical needs. Eur J Cancer 2017;71:53–69.

    Article  PubMed  Google Scholar 

  28. Harms PW. Update on Merkel cell carcinoma. Clin Lab Med. 2017;37(3):485–501.

    Article  PubMed  Google Scholar 

  29. Becker JC, Stang A, DeCaprio JA, et al. Merkel cell carcinoma. Nat Rev Dis Primers. 2017;3: 170–77.

    Article  Google Scholar 

  30. Wendzicki JA, Moore PS, Chang Y. Large T and small T antigens of Merkel cell polyomavirus. Curr Opin Virol. 2015;11:38–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Sherr CJ. Cancer cell cycles. Science 1996;274(5293):1672–7.

    Article  CAS  PubMed  Google Scholar 

  32. Berrios C, Padi M, Keibler MA, et al. Merkel cell polyomavirus small T antigen promotes pro-glycolytic metabolic perturbations required for transformation. PLoS Pathog. 2016;12(11):e1006020.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. 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  CAS  PubMed  Google Scholar 

  34. Becker JC, Houben R, Ugurel S, Trefzer U, Pfohler C, Schrama D. MC polyomavirus is frequently present in Merkel cell carcinoma of European patients. J Invest Dermatol. 2009;129(1):248–50.

    Article  CAS  PubMed  Google Scholar 

  35. Garneski KM, Warcola AH, Feng Q, Kiviat NB, Leonard JH, Nghiem P. Merkel cell polyomavirus is more frequently present in North American than Australian Merkel cell carcinoma tumors. J Invest Dermatol. 2009;129(1):246–8.

    Article  CAS  PubMed  Google Scholar 

  36. Duncavage EJ, Zehnbauer BA, Pfeifer JD. Prevalence of Merkel cell polyomavirus in Merkel cell carcinoma. Mod Pathol. 2009;22(4):516 – 21.

    Article  CAS  PubMed  Google Scholar 

  37. 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  CAS  PubMed  Google Scholar 

  38. 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 2009;125(6):1243–9.

    Article  CAS  PubMed  Google Scholar 

  39. 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  CAS  PubMed  Google Scholar 

  40. Loyo M, Guerrero-Preston R, Brait M, et al. Quantitative detection of Merkel cell virus in human tissues and possible mode of transmission. Int J Cancer 2010;126(12):2991–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 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 

  42. Andres C, Belloni B, Puchta U, Sander CA, Flaig MJ. Prevalence of MCPyV in Merkel cell carcinoma and non-MCC tumors. J Cutan Pathol. 2010;37(1):28–34.

    Article  PubMed  Google Scholar 

  43. Houben R, Schrama D, Alb M, et al. Comparable expression and phosphorylation of the retinoblastoma protein in Merkel cell polyoma virus-positive and negative Merkel cell carcinoma. Int J Cancer 2010;126(3):796–8.

    Article  CAS  PubMed  Google Scholar 

  44. Bhatia K, Goedert JJ, Modali R, Preiss L, Ayers LW. Immunological detection of viral large T antigen identifies a subset of Merkel cell carcinoma tumors with higher viral abundance and better clinical outcome. Int J Cancer 2010;127(6):1493–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Mertz KD, Paasinen A, Arnold A, et al. Merkel cell polyomavirus large T antigen is detected in rare cases of nonmelanoma skin cancer. J Cutan Pathol. 2013;40(6):543–9.

    Article  PubMed  Google Scholar 

  46. Duncavage EJ, Le BM, Wang D, Pfeifer JD. Merkel cell polyomavirus: a specific marker for Merkel cell carcinoma in histologically similar tumors. Am J Surg Pathol. 2009;33(12):1771–7.

    Article  PubMed  Google Scholar 

  47. Jung HS, Choi YL, Choi JS, et al. Detection of Merkel cell polyomavirus in Merkel cell carcinomas and small cell carcinomas by PCR and immunohistochemistry. Histol Histopathol. 2011;26(10):1231–41.

    CAS  PubMed  Google Scholar 

  48. Leitz M, Stieler K, Grundhoff A, Moll I, Brandner JM, Fischer N. Merkel cell polyomavirus detection in Merkel cell cancer tumors in Northern Germany using PCR and protein expression. J Med Virol. 2014;86(10):1813–9.

    Article  CAS  PubMed  Google Scholar 

  49. 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  CAS  PubMed  Google Scholar 

  50. D’Agostino M, Cinelli C, Willard R, Hofmann J, Jellinek N, Robinson-Bostom L. Epidermotropic Merkel cell carcinoma: a case series with histopathologic examination. J Am Acad Dermatol. 2010;62(3):463–8.

    Article  PubMed  Google Scholar 

  51. Gomez LG, DiMaio S, Silva EG, Mackay B. Association between neuroendocrine (Merkel cell) carcinoma and squamous carcinoma of the skin. Am J Surg Pathol. 1983;7(2):171–7.

    Article  CAS  PubMed  Google Scholar 

  52. Cerroni L, Kerl H. Primary cutaneous neuroendocrine (Merkel cell) carcinoma in association with squamous- and basal-cell carcinoma. Am J Dermatopathol. 1997;19(6):610–3.

    Article  CAS  PubMed  Google Scholar 

  53. Iacocca MV, Abernethy JL, Stefanato CM, Allan AE, Bhawan J. Mixed Merkel cell carcinoma and squamous cell carcinoma of the skin. J Am Acad Dermatol. 1998;39(5 Pt 2):882–7.

    Article  CAS  PubMed  Google Scholar 

  54. Boutilier R, Desormeau L, Cragg F, Roberts P, Walsh N. Merkel cell carcinoma: squamous and atypical fibroxanthoma-like differentiation in successive local tumor recurrences. Am J Dermatopathol. 2001;23(1):46 – 9.

    Article  CAS  PubMed  Google Scholar 

  55. Hwang JH, Alanen K, Dabbs KD, Danyluk J, Silverman S. Merkel cell carcinoma with squamous and sarcomatous differentiation. J Cutan Pathol. 2008;35(10):955–9.

    Article  PubMed  Google Scholar 

  56. Sirikanjanapong S, Melamed J, Patel RR. Intraepidermal and dermal Merkel cell carcinoma with squamous cell carcinoma in situ: a case report with review of literature. J Cutan Pathol. 2010;37(8):881–5.

    Article  PubMed  Google Scholar 

  57. Ball NJ, Tanhuanco-Kho G. Merkel cell carcinoma frequently shows histologic features of basal cell carcinoma: a study of 30 cases. J Cutan Pathol. 2007;34(8):612–9.

    Article  PubMed  Google Scholar 

  58. Moll R, Lowe A, Laufer J, Franke WW. Cytokeratin 20 in human carcinomas. A new histodiagnostic marker detected by monoclonal antibodies. Am J Pathol. 1992;140(2):427–47.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Chan JK, Suster S, Wenig BM, Tsang WY, Chan JB, Lau AL. Cytokeratin 20 immunoreactivity distinguishes Merkel cell (primary cutaneous neuroendocrine) carcinomas and salivary gland small cell carcinomas from small cell carcinomas of various sites. Am J Surg Pathol. 1997;21(2):226–34.

    Article  CAS  PubMed  Google Scholar 

  60. Schirren CG, Rutten A, Kaudewitz P, Diaz C, McClain S, Burgdorf WH. Trichoblastoma and basal cell carcinoma are neoplasms with follicular differentiation sharing the same profile of cytokeratin intermediate filaments. Am J Dermatopathol. 1997;19(4):341–50.

    Article  CAS  PubMed  Google Scholar 

  61. Scott MP, Helm KF. Cytokeratin 20: a marker for diagnosing Merkel cell carcinoma. Am J Dermatopathol. 1999;21(1):16–20.

    Article  CAS  PubMed  Google Scholar 

  62. McNiff JM, Eisen RN, Glusac EJ. Immunohistochemical comparison of cutaneous lymphadenoma, trichoblastoma, and basal cell carcinoma: support for classification of lymphadenoma as a variant of trichoblastoma. J Cutan Pathol. 1999;26(3):119 – 24.

    Article  CAS  PubMed  Google Scholar 

  63. Poniecka AW, Alexis JB. An immunohistochemical study of basal cell carcinoma and trichoepithelioma. Am J Dermatopathol. 1999;21(4):332–6.

    Article  CAS  PubMed  Google Scholar 

  64. Hanly AJ, Elgart GW, Jorda M, Smith J, Nadji M. Analysis of thyroid transcription factor-1 and cytokeratin 20 separates merkel cell carcinoma from small cell carcinoma of lung. J Cutan Pathol. 2000;27(3):118–20.

    Article  CAS  PubMed  Google Scholar 

  65. Nicholson SA, McDermott MB, Swanson PE, Wick MR. CD99 and cytokeratin-20 in small-cell and basaloid tumors of the skin. Appl Immunohistochem Mol Morphol. 2000;8(1):37–41.

    CAS  PubMed  Google Scholar 

  66. Leech SN, Kolar AJ, Barrett PD, Sinclair SA, Leonard N. Merkel cell carcinoma can be distinguished from metastatic small cell carcinoma using antibodies to cytokeratin 20 and thyroid transcription factor 1. J Clin Pathol. 2001;54(9):727–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Yang DT, Holden JA, Florell SR. CD117, CK20, TTF-1, and DNA topoisomerase II-alpha antigen expression in small cell tumors. J Cutan Pathol. 2004;31(3):254 – 61.

    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  CAS  PubMed  Google Scholar 

  69. Bobos M, Hytiroglou P, Kostopoulos I, Karkavelas G, Papadimitriou CS. Immunohistochemical distinction between merkel cell carcinoma and small cell carcinoma of the lung. Am J Dermatopathol. 2006;28(2):99–104.

    Article  PubMed  Google Scholar 

  70. Rekhi B, Kane SV, Jambhekar NA. Clinicopathological spectrum of a series of Merkel cell carcinomas diagnosed at a tertiary cancer referral center in India, with current concepts. Ann Diagn Pathol. 2015;19(5):341–6.

    Article  PubMed  Google Scholar 

  71. Hashimoto K, Lee MW, D’Annunzio DR, Balle MR, Narisawa Y. Pagetoid Merkel cell carcinoma: epidermal origin of the tumor. J Cutan Pathol. 1998;25(10):572–9.

    Article  CAS  PubMed  Google Scholar 

  72. Miraflor AP, LeBoit PE, Hirschman SA. Intraepidermal Merkel cell carcinoma with pagetoid Bowen’s disease. J Cutan Pathol. 2016;43(11):921–6.

    Article  PubMed  Google Scholar 

  73. 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  CAS  PubMed  Google Scholar 

  74. Kontochristopoulos GJ, Stavropoulos PG, Krasagakis K, Goerdt S, Zouboulis CC. Differentiation between merkel cell carcinoma and malignant melanoma: an immunohistochemical study. Dermatology 2000;201(2):123–6.

    Article  CAS  PubMed  Google Scholar 

  75. Acebo E, Vidaurrazaga N, Varas C, Burgos-Bretones JJ, Diaz-Perez JL. Merkel cell carcinoma: a clinicopathological study of 11 cases. J Eur Acad Dermatol Venereol. 2005;19(5):546 – 51.

    Article  CAS  PubMed  Google Scholar 

  76. Ralston J, Chiriboga L, Nonaka D. MASH1: a useful marker in differentiating pulmonary small cell carcinoma from Merkel cell carcinoma. Mod Pathol. 2008;21(11):1357–62.

    Article  CAS  PubMed  Google Scholar 

  77. Andres C, Ihrler S, Puchta U, Flaig MJ. Merkel cell polyomavirus is prevalent in a subset of small cell lung cancer: a study of 31 patients. Thorax. 2009;64(11):1007–8.

    Article  CAS  PubMed  Google Scholar 

  78. Moshiri AS, Nghiem P. Milestones in the staging, classification, and biology of Merkel cell carcinoma. J Natl Compr Canc Netw. 2014;12(9):1255–62.

    Article  PubMed  PubMed Central  Google Scholar 

  79. Su LD, Lowe L, Bradford CR, Yahanda AI, Johnson TM, Sondak VK. Immunostaining for cytokeratin 20 improves detection of micrometastatic Merkel cell carcinoma in sentinel lymph nodes. J Am Acad Dermatol. 2002;46(5):661–80.

    Article  PubMed  Google Scholar 

  80. Foote M, Veness M, Zarate D, Poulsen M. Merkel cell carcinoma: the prognostic implications of an occult primary in stage IIIB (nodal) disease. J Am Acad Dermatol. 2012;67(3):395–9.

    Article  PubMed  Google Scholar 

  81. Tarantola TI, Vallow LA, Halyard MY, et al. Unknown primary Merkel cell carcinoma: 23 new cases and a review. J Am Acad Dermatol. 2013;68(3):433–40.

    Article  PubMed  Google Scholar 

  82. Chen KT, Papavasiliou P, Edwards K, et al. A better prognosis for Merkel cell carcinoma of unknown primary origin. Am J Surg. 2013;206(5):752–7.

    Article  PubMed  Google Scholar 

  83. Andea AA, Patel R, Ponnazhagan S, et al. Merkel cell carcinoma: correlation of KIT expression with survival and evaluation of KIT gene mutational status. Hum Pathol. 2010;41(10):1405–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Swick BL, Srikantha R, Messingham KN. Specific analysis of KIT and PDGFR-alpha expression and mutational status in Merkel cell carcinoma. J Cutan Pathol. 2013;40(7):623–30.

    Article  PubMed  Google Scholar 

  85. Kim J, McNiff JM. Nuclear expression of survivin portends a poor prognosis in Merkel cell carcinoma. Mod Pathol. 2008;21(6):764–9.

    Article  CAS  PubMed  Google Scholar 

  86. Nardi V, Song Y, Santamaria-Barria JA, et al. Activation of PI3K signaling in Merkel cell carcinoma. Clin Cancer Res. 2012;18(5):1227–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Brunner M, Thurnher D, Pammer J, et al. Expression of hedgehog signaling molecules in Merkel cell carcinoma. Head Neck 2010;32(3):333–40.

    PubMed  Google Scholar 

  88. Kuromi T, Matsushita M, Iwasaki T, et al. Association of expression of the hedgehog signal with Merkel cell polyomavirus infection and prognosis of Merkel cell carcinoma. Hum Pathol. 2017;69:8–14.

    Article  CAS  PubMed  Google Scholar 

  89. Carroll TM, Williams JS, Daily K, et al. Hedgehog signaling inhibitors fail to reduce Merkel cell carcinoma viability. J Invest Dermatol. 2017;137(5):1187–90.

    Article  CAS  PubMed  Google Scholar 

  90. Fernandez-Figueras MT, Puig L, Musulen E, et al. Prognostic significance of p27Kip1, p45Skp2 and Ki67 expression profiles in Merkel cell carcinoma, extracutaneous small cell carcinoma, and cutaneous squamous cell carcinoma. Histopathology 2005;46(6):614–21.

    Article  CAS  PubMed  Google Scholar 

  91. Henderson SA, Tetzlaff MT, Pattanaprichakul P, et al. Detection of mitotic figures and G2 + tumor nuclei with histone markers correlates with worse overall survival in patients with Merkel cell carcinoma. J Cutan Pathol. 2014;41(11):846 – 52.

    Article  PubMed  PubMed Central  Google Scholar 

  92. Sihto H, Kukko H, Koljonen V, Sankila R, Bohling T, Joensuu H. Merkel cell polyomavirus infection, large T antigen, retinoblastoma protein and outcome in Merkel cell carcinoma. Clin Cancer Res. 2011;17(14):4806–13.

    Article  CAS  PubMed  Google Scholar 

  93. 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 

  94. Haymerle G, Janik S, Fochtmann A, et al. Expression of Merkelcell polyomavirus (MCPyV) large T-antigen in Merkel cell carcinoma lymph node metastases predicts poor outcome. PLoS ONE. 2017;12(8):e0180426.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  95. 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  CAS  PubMed  Google Scholar 

  96. 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 

  97. 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 

  98. 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. Mod Pathol. 2011;24(11):1451–61.

    Article  CAS  PubMed  Google Scholar 

  99. Fleming KE, Ly TY, Pasternak S, Godlewski M, Doucette S, Walsh NM. Support for p63 expression as an adverse prognostic marker in Merkel cell carcinoma: report on a Canadian cohort. Hum Pathol. 2014;45(5):952 – 60.

    Article  CAS  PubMed  Google Scholar 

  100. Stetsenko GY, Malekirad J, Paulson KG, et al. p63 expression in Merkel cell carcinoma predicts poorer survival yet may have limited clinical utility. Am J Clin Pathol. 2013;140(6):838 – 44.

    Article  PubMed  PubMed Central  Google Scholar 

  101. 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  CAS  PubMed  Google Scholar 

  102. 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. 2011;29(12):1539–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Sihto H, Bohling T, Kavola H, et al. Tumor infiltrating immune cells and outcome of Merkel cell carcinoma: a population-based study. Clin Cancer Res. 2012;18(10):2872–81.

    Article  CAS  PubMed  Google Scholar 

  104. Feldmeyer L, Hudgens CW, Ray-Lyons G, et al. Density, distribution, and composition of immune infiltrates correlate with survival in Merkel cell carcinoma. Clin Cancer Res. 2016;22(22):5553–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Wong SQ, Waldeck K, Vergara IA, et al. UV-Associated mutations underlie the etiology of MCV-negative Merkel cell carcinomas. Cancer Res. 2015;75(24):5228–34.

    Article  CAS  PubMed  Google Scholar 

  106. Harms PW, Vats P, Verhaegen ME, et al. The distinctive mutational spectra of polyomavirus-negative Merkel CELL carcinoma. Cancer Res. 2015;75(18):3720–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Bloom R, Amber KT, Nouri K. An increased risk of non-Hodgkin lymphoma and chronic lymphocytic leukemia in US patients with Merkel cell carcinoma versus Australian patients: a clinical clue to a different mechanism of pathogenesis? Australas J Dermatol. 2016;57(3):e114-6.

    Article  PubMed  Google Scholar 

  108. Paik JY, Hall G, Clarkson A, et al. Immunohistochemistry for Merkel cell polyomavirus is highly specific but not sensitive for the diagnosis of Merkel cell carcinoma in the Australian population. Hum Pathol. 2011;42(10):1385–90.

    Article  PubMed  Google Scholar 

  109. Martin B, Poblet E, Rios JJ, et al. Merkel cell carcinoma with divergent differentiation: histopathological and immunohistochemical study of 15 cases with PCR analysis for Merkel cell polyomavirus. Histopathology 2013;62(5):711 – 22.

    Article  PubMed  Google Scholar 

  110. Iwasaki T, Matsushita M, Kuwamoto S, et al. Usefulness of significant morphologic characteristics in distinguishing between Merkel cell polyomavirus-positive and Merkel cell polyomavirus-negative Merkel cell carcinomas. Hum Pathol. 2013;44(9):1912–7.

    Article  CAS  PubMed  Google Scholar 

  111. Pulitzer MP, Brannon AR, Berger MF, et al. Cutaneous squamous and neuroendocrine carcinoma: genetically and immunohistochemically different from Merkel cell carcinoma. Mod Pathol. 2015;28(8):1023–32.

    Article  PubMed  PubMed Central  Google Scholar 

  112. Harms PW, Collie AM, Hovelson DH, et al. Next generation sequencing of Cytokeratin 20-negative Merkel cell carcinoma reveals ultraviolet-signature mutations and recurrent TP53 and RB1 inactivation. Mod Pathol. 2016;29(3):240–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Harms PW, Patel RM, Verhaegen ME, et al. Distinct gene expression profiles of viral- and paxnonviral-associated merkel cell carcinoma revealed by transcriptome analysis. J Invest Dermatol. 2013;133(4):936–45.

    Article  CAS  PubMed  Google Scholar 

  114. Bichakjian CK, National Comprehensive Cancer Network Guidelines Version 1.2017 Merkel cell carcinoma http://merkelcell.org/wp-content/uploads/2015/10/MccNccn.pdf (2017). Accessed 4 June 2017.

  115. Bhatia S, Storer BE, Iyer JG, et al. Adjuvant radiation therapy and chemotherapy in Merkel cell carcinoma: survival analyses of 6908 cases from the national cancer data base. J Natl Cancer Inst. 2016;108(9).

  116. Mortier L, Mirabel X, Fournier C, Piette F, Lartigau E. Radiotherapy alone for primary Merkel cell carcinoma. Arch Dermatol. 2003;139(12):1587–90.

    Article  PubMed  Google Scholar 

  117. Nghiem PT, Bhatia S, Lipson EJ, et al. PD-1 blockade with Pembrolizumab in advanced Merkel-Cell carcinoma. N Engl J Med. 2016;374(26):2542–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Kaufman HL, Russell J, Hamid O, et al. Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial. Lancet Oncol. 2016;17(10):1374–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Winkler JK, Bender C, Kratochwil C, Enk A, Hassel JC. PD-1 blockade: a therapeutic option for treatment of metastatic Merkel cell carcinoma. Br J Dermatol. 2017;176(1):216–9.

    Article  CAS  PubMed  Google Scholar 

  120. Walocko FM, Scheier BY, Harms PW, Fecher LA, Lao CD. Metastatic Merkel cell carcinoma response to nivolumab. J Immunother Cancer 2016;4:79.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pathology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 85, Houston, TX, 77030, USA

    Michael T. Tetzlaff & Priyadharsini Nagarajan

  2. Department of Translational and Molecular Pathology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 85, Houston, TX, 77030, USA

    Michael T. Tetzlaff

Authors
  1. Michael T. Tetzlaff
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Priyadharsini Nagarajan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael T. Tetzlaff.

Ethics declarations

Conflict of interest

MTT has received an honorarium from Myriad Genetics, Seattle Genetics and Novartis for Advisory Boards. MTT declares no relevant conflicts of interest to the material presented herein.

Ethical Approval

This article does not contain any studies with human participants performed by any of the authors. This article does not contain any studies with animals performed by any of the authors.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tetzlaff, M.T., Nagarajan, P. Update on Merkel Cell Carcinoma. Head and Neck Pathol 12, 31–43 (2018). https://doi.org/10.1007/s12105-018-0898-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12105-018-0898-2

Keywords

Search

Navigation