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Pathology of Merkel Cell Carcinoma (Primary Neuroendocrine Carcinoma of the Skin)

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Neuroendocrine Tumors: Review of Pathology, Molecular and Therapeutic Advances

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Abstract

Merkel cell carcinoma (MCC) is an aggressive carcinoma with neuroendocrine features that arises preferentially in chronically sun-damaged skin of elderly and immunosuppressed individuals. As the annual yearly incidence steadily increases, likely due to increased detection in an aging population, our understating of MCC continues to improve with recent discoveries. One such breakthrough is the characterization of the Merkel cell polyomavirus (MCPyV), which is present in up to 80 % of tumors, shedding light on MCC pathogenesis. MCC is characteristically composed of a monomorphous population of small round blue cells that express epithelial and neuroendocrine markers by immunohistochemistry. Immunohistochemical stains are invaluable in the diagnosis of this tumor and aid in excluding other histologic mimics. Regarding MCC prognosis, the strongest predictor for outcome is tumor staging, chiefly size of the tumor. Other recently added prognostic factors include the MCPyV status of the tumor, tumor thickness, and regional nodal involvement, including sentinel lymph node status. In this chapter, we will provide an update regarding the latest developments in terms of pathogenesis, immunohistochemical evaluation, and prognostic factors of MCC.

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References

  1. Toker C. Trabecular carcinoma of the skin. Arch Dermatol. 1972;105(1):107–10.

    Article  CAS  PubMed  Google Scholar 

  2. Toker C. Trabecular carcinoma of the skin. A question of title. Am J Dermatopathol. 1982;4(6):497–500.

    Article  CAS  PubMed  Google Scholar 

  3. De Wolff-Peeters C, Marien K, Mebis J, Desmet V. A cutaneous APUDoma or Merkel cell tumor? A morphologically recognizable tumor with a biological and histological malignant aspect in contrast with its clinical behavior. Cancer. 1980;46(8):1810–6.

    Article  PubMed  Google Scholar 

  4. Sidhu GS, Chandra P, Cassai ND. Merkel cells, normal and neoplastic: an update. Ultrastruct Pathol. 2005;29(3–4):287–94.

    Article  PubMed  Google Scholar 

  5. Boulais N, Misery L. Merkel cells. J Am Acad Dermatol. 2007;57(1):147–65.

    Article  PubMed  Google Scholar 

  6. Lemasson G, Coquart N, Lebonvallet N, Boulais N, Galibert MD, Marcorelles P, et al. Presence of putative stem cells in Merkel cell carcinomas. J Eur Acad Dermatol Venereol. 2012;26(6):789–95.

    Article  CAS  PubMed  Google Scholar 

  7. 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 

  8. 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 

  9. 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 

  10. 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 

  11. 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 

  12. 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 

  13. Kaae J, Hansen AV, Biggar RJ, Boyd HA, Moore PS, Wohlfahrt J, et al. Merkel cell carcinoma: incidence, mortality, and risk of other cancers. J Natl Cancer Inst. 2010;102(11):793–801.

    Article  PubMed  Google Scholar 

  14. Heath M, Jaimes N, Lemos B, Mostaghimi A, Wang LC, Penas PF, 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 

  15. Paulson KG, Iyer JG, Blom A, Warton EM, Sokil M, Yelistratova L, 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 

  16. Tadmor T, Aviv A, Polliack A. Merkel cell carcinoma, chronic lymphocytic leukemia and other lymphoproliferative disorders: an old bond with possible new viral ties. Ann Oncol. 2011;22(2):250–6.

    Article  CAS  PubMed  Google Scholar 

  17. 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 

  18. Walsh NM. Primary neuroendocrine (Merkel cell) carcinoma of the skin: morphologic diversity and implications thereof. Hum Pathol. 2001;32(7):680–9.

    Article  CAS  PubMed  Google Scholar 

  19. Kanitakis J, Euvrard S, Chouvet B, Butnaru AC, Claudy A. Merkel cell carcinoma in organ-transplant recipients: report of two cases with unusual histological features and literature review. J Cutan Pathol. 2006;33(10):686–94.

    Article  PubMed  Google Scholar 

  20. Brenner B, Sulkes A, Rakowsky E, Feinmesser M, Yukelson A, Bar-Haim E, et al. Second neoplasms in patients with Merkel cell carcinoma. Cancer. 2001;91(7):1358–62.

    Article  CAS  PubMed  Google Scholar 

  21. Gass JK, Chan SK, Rytina E, Greenberg DC, Burrows NP. Multiple primary malignancies in patients with Merkel cell carcinoma. J Eur Acad Dermatol Venereol. 2010;24(5):601–3.

    Article  CAS  PubMed  Google Scholar 

  22. Hitchcock CL, Bland KI, Laney 3rd RG, Franzini D, Harris B, Copeland 3rd EM. Neuroendocrine (Merkel cell) carcinoma of the skin. Its natural history, diagnosis, and treatment. Ann Surg. 1988;207(2):201–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. 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  CAS  PubMed  Google Scholar 

  24. 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 

  25. Hohaus K, Kostler E, Schonlebe J, Klemm E, Wollina U. Merkel cell carcinoma – a retrospective analysis of 17 cases. J Eur Acad Dermatol Venereol. 2003;17(1):20–4.

    Article  CAS  PubMed  Google Scholar 

  26. Inoue T, Shimono M, Takano N, Saito C, Tanaka Y. Merkel cell carcinoma of palatal mucosa in a young adult: immunohistochemical and ultrastructural features. Oral Oncol. 1997;33(3):226–9.

    Article  CAS  PubMed  Google Scholar 

  27. Longo F, Califano L, Mangone GM, Errico ME. Neuroendocrine (Merkel cell) carcinoma of the oral mucosa: report of a case with immunohistochemical study and review of the literature. J Oral Pathol Med. 1999;28(2):88–91.

    Article  CAS  PubMed  Google Scholar 

  28. Baker P, Alguacil-Garcia A. Moderately differentiated neuroendocrine carcinoma in the floor of the mouth: a case report. J Oral Maxillofac Surg. 1999;57(9):1143–7.

    Article  CAS  PubMed  Google Scholar 

  29. Prabhu S, Smitha RS, Punnya VA. Merkel cell carcinoma of the alveolar mucosa in a young adult: a rare case report. Br J Oral Maxillofac Surg. 2010;48(1):48–50.

    Article  PubMed  Google Scholar 

  30. Yom SS, Rosenthal DI, El-Naggar AK, Kies MS, Hessel AC. Merkel cell carcinoma of the tongue and head and neck oral mucosal sites. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2006;101(6):761–8.

    Article  PubMed  Google Scholar 

  31. Snow SN, Larson PO, Hardy S, Bentz M, Madjar D, Landeck A, et al. Merkel cell carcinoma of the skin and mucosa: report of 12 cutaneous cases with 2 cases arising from the nasal mucosa. Dermatol Surg. 2001;27(2):165–70.

    CAS  PubMed  Google Scholar 

  32. Hierro I, Blanes A, Matilla A, Muñoz S, Vicioso L, Nogales FF. Merkel cell (neuroendocrine) carcinoma of the vulva. Pathol Res Pract. 2000;196(7):503–9.

    Article  CAS  PubMed  Google Scholar 

  33. Tomic S, Warner TF, Messing E, Wilding G. Penile Merkel cell carcinoma. Urology. 1995;45(6):1062–5.

    Article  CAS  PubMed  Google Scholar 

  34. Eusebi V, Capella C, Cossu A, Rosai J. Neuroendocrine carcinoma within lymph nodes in the absence of a primary tumor, with special reference to Merkel cell carcinoma. Am J Surg Pathol. 1992;16(7):658–66.

    Article  CAS  PubMed  Google Scholar 

  35. Fotia G, Barni R, Bellan C, Neri A. Lymph nodal Merkel cell carcinoma: primary or metastatic disease? A clinical case. Tumori. 2002;88(5):424–6.

    PubMed  Google Scholar 

  36. Kim EJ, Kim HS, Kim HO, Jung CK, Ko YH, Kim TH, et al. Merkel cell carcinoma of the inguinal lymph node with an unknown primary site. J Dermatol. 2009;36(3):170–3.

    Article  PubMed  Google Scholar 

  37. de Biase D, Ragazzi M, Asioli S, Eusebi V. Extracutaneous Merkel cell carcinomas harbor polyomavirus DNA. Hum Pathol. 2012;43(7):980–5.

    Article  PubMed  CAS  Google Scholar 

  38. Fornelli A, Eusebi V, Pasquinelli G, Quattrone P, Rosai J. Merkel cell carcinoma of the parotid gland associated with Warthin tumour: report of two cases. Histopathology. 2001;39(4):342–6.

    Article  CAS  PubMed  Google Scholar 

  39. Chernock RD, Duncavage EJ, Gnepp DR, El-Mofty SK, Lewis Jr JS. Absence of Merkel cell polyomavirus in primary parotid high-grade neuroendocrine carcinomas regardless of cytokeratin 20 immunophenotype. Am J Surg Pathol. 2011;35(12):1806–11.

    Article  PubMed  Google Scholar 

  40. Capella C, Marando A, Longhi E, Bernasconi B, Finzi G, Parravicini C, et al. Primary gastric Merkel cell carcinoma harboring DNA polyomavirus: first description of an unusual high-grade neuroendocrine carcinoma. Hum Pathol. 2014;45(6):1310–4.

    Article  CAS  PubMed  Google Scholar 

  41. Bing Z, Levine L, Lucci JA, Hatch SS, Eltorky MA. Primary small cell neuroendocrine carcinoma of the vagina: a clinicopathologic study. Arch Pathol Lab Med. 2004;128(8):857–62.

    PubMed  Google Scholar 

  42. Coleman NM, Smith-Zagone MJ, Tanyi J, Anderson ML, Coleman RL, Dyson SW, et al. Primary neuroendocrine carcinoma of the vagina with Merkel cell carcinoma phenotype. Am J Surg Pathol. 2006;30(3):405–10.

    Article  PubMed  Google Scholar 

  43. Ratner D, Nelson BR, Brown MD, Johnson TM. Merkel cell carcinoma. J Am Acad Dermatol. 1993;29(2 Pt 1):143–56.

    Article  CAS  PubMed  Google Scholar 

  44. Perdikis G, TerKonda SP. Pigmented skin lesions of the upper extremity. Hand Clin. 2004;20(3):283–91. vi.

    Article  PubMed  Google Scholar 

  45. McKee PH, Calonje E, Granter SR. Pathology of the skin: with clinical correlations/[edited by] Phillip H. McKee, Eduardo Calonje, Scott R. Granter. 3rd ed. Edinburgh: Philadelphia Elsevier Mosby; 2005. v <1 > p.

    Google Scholar 

  46. Smith PD, Patterson JW. Merkel cell carcinoma (neuroendocrine carcinoma of the skin). Am J Clin Pathol. 2001;115(Suppl):S68–78.

    PubMed  Google Scholar 

  47. Satter EK, Derienzo DP. Synchronous onset of multiple cutaneous neuroendocrine (Merkel cell) carcinomas localized to the scalp. J Cutan Pathol. 2008;35(7):685–91.

    Article  PubMed  Google Scholar 

  48. Grandpeix C, Bonvalot S, Petrow P, Fraitag S, Gounod N, Avril MF. Continued complete remission of Merkel cell carcinoma with in-transit metastasis after treatment with isolated limb perfusion regional chemotherapy. Ann Dermatol Venereol. 2006;133(8–9 Pt 1):700–3.

    Article  CAS  PubMed  Google Scholar 

  49. Grotz TE, Tarantola TI, Otley CC, Weaver AL, McGree ME, Jakub JW. Natural history of Merkel cell carcinoma following locoregional recurrence. Ann Surg Oncol. 2012;19(8):2556–62.

    Article  PubMed  Google Scholar 

  50. Howle JR, Veness MJ. Outcome of patients with microscopic and macroscopic metastatic nodal Merkel cell carcinoma: an Australian experience. Dermatol Surg. 2014;40(1):46–51.

    Article  CAS  PubMed  Google Scholar 

  51. Iyer JG, Storer BE, Paulson KG, Lemos B, Phillips JL, Bichakjian CK, et al. Relationships among primary tumor size, number of involved nodes, and survival for 8044 cases of Merkel cell carcinoma. J Am Acad Dermatol. 2014;70(4):637–43.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Kirwan C, Carney D, O’Keefe M. Merkel cell carcinoma metastasis to the iris in a 23 year old female. Ir Med J. 2009;102(2):53–4.

    CAS  PubMed  Google Scholar 

  53. Ikawa F, Kiya K, Uozumi T, Yuki K, Takeshita S, Hamasaki O, et al. Brain metastasis of Merkel cell carcinoma. Case report and review of the literature. Neurosurg Rev. 1999;22(1):54–7.

    Article  CAS  PubMed  Google Scholar 

  54. Feletti A, Marton E, Rossi S, Canal F, Longatti P, Billeci D. Pituitary metastasis of Merkel cell carcinoma. J Neurooncol. 2010;97(2):295–9.

    Article  CAS  PubMed  Google Scholar 

  55. Shalin SC, Cifarelli CP, Suen JY, Gao L. Loss of cytokeratin 20 and acquisition of thyroid transcription factor-1 expression in a Merkel cell carcinoma metastasis to the brain. Am J Dermatopathol. 2014.

    Google Scholar 

  56. Chang DT, Mancuso AA, Riggs Jr CE, Mendenhall WM. Merkel cell carcinoma of the skin with leptomeningeal metastases. Am J Otolaryngol. 2005;26(3):210–3.

    Article  PubMed  Google Scholar 

  57. Abul-Kasim K, Soderstrom K, Hallsten L. Extensive central nervous system involvement in Merkel cell carcinoma: a case report and review of the literature. J Med Case Rep. 2011;5:35.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Schmidt-Westhausen A, Reichart PA, Gross UM. Gingival metastasis of Merkel cell carcinoma: a case report. J Oral Pathol Med. 1996;25(1):44–7.

    Article  CAS  PubMed  Google Scholar 

  59. Reichel OA, Mayr D, Issing WJ. Oropharyngeal metastasis of a Merkel cell carcinoma of the skin. Eur Arch Otorhinolaryngol. 2003;260(5):258–60.

    PubMed  Google Scholar 

  60. Jongbloed MR, Kanen BL, Visser M, Niessen H, Flens MJ, Loffeld RJ. Case 2. Intracardiac metastasis from a Merkel cell carcinoma. J Clin Oncol. 2004;22(6):1153–6.

    Article  CAS  PubMed  Google Scholar 

  61. Yamana N, Sueyama H, Hamada M. Cardiac metastasis from Merkel cell skin carcinoma. Int J Clin Oncol. 2004;9(3):210–2.

    Article  PubMed  Google Scholar 

  62. Fong LS, Mathur M, Bhindi R, Figtree GA. Right atrial Merkel cell tumour metastasis characterization using a multimodality approach. Eur Heart J. 2012;33(17):2205.

    Article  PubMed  Google Scholar 

  63. Suttie CF, Hruby G, Horvath L, Thompson J. Cardiac metastasis in Merkel cell carcinoma. J Clin Oncol. 2014;32(13):e52–3.

    Article  PubMed  Google Scholar 

  64. Idowu MO, Contos M, Gill S, Powers C. Merkel cell carcinoma: a report of gastrointestinal metastasis and review of the literature. Arch Pathol Lab Med. 2003;127(3):367–9.

    PubMed  Google Scholar 

  65. Syal NG, Dang S, Rose J, Chen C, Aduli F. Gastric metastasis of Merkel cell cancer – uncommon complication of a rare neoplasm. J Ark Med Soc. 2012;109(7):134–6.

    PubMed  Google Scholar 

  66. Parikh MP, Samo S, Ganipisetti V, Krishnan S, Dhandha M, Yungbluth M, et al. Gastric metastasis of Merkel cell carcinoma, a rare cause of gastrointestinal bleeding: case report and review of the literature. J Gastrointest Oncol. 2014;5(4):E68–72.

    PubMed  PubMed Central  Google Scholar 

  67. Ouellette JR, Woodyard L, Toth L, Termuhlen PM. Merkel cell carcinoma metastatic to the head of the pancreas. JOP. 2004;5(2):92–6.

    PubMed  Google Scholar 

  68. Bachmann J, Kleeff J, Bergmann F, Shrikhande SV, Hartschuh W, Buchler MW, et al. Pancreatic metastasis of Merkel cell carcinoma and concomitant insulinoma: case report and literature review. World J Surg Oncol. 2005;3:58.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Woo HH, Kencian JD. Metastatic Merkel cell tumour to the bladder. Int Urol Nephrol. 1995;27(3):301–5.

    Article  CAS  PubMed  Google Scholar 

  70. Santis WF, Billings EJ, DeWolf WC. Metastatic Merkel cell tumor to bladder presenting as an encroachment tumor with gross hematuria. Urology. 1999;54(1):163.

    Article  CAS  PubMed  Google Scholar 

  71. Mack DP, Moussa M, Cook A, Izawa JI. Metastatic Merkel cell tumor to the prostate and bladder. Urology. 2004;64(1):156–8.

    Article  PubMed  Google Scholar 

  72. Gleason JM, Kohler TS, Monga M. Merkel cell carcinoma metastatic to testis. Urology. 2006;67(2):423.e13–e14.

    Article  Google Scholar 

  73. Strasser H, Amann K, Schrott KM, Krause FS. Solitary metastasis of a Merkel cell tumor to the urinary bladder. Anticancer Res. 2008;28(2b):1361–4.

    PubMed  Google Scholar 

  74. Wang W, Veness M. Metastatic Merkel cell carcinoma to the soft tissues of the lower back. Australas J Dermatol. 2004;45(1):38–41.

    Article  PubMed  Google Scholar 

  75. Lentz SR, Krewson L, Zutter MM. Recurrent neuroendocrine (Merkel cell) carcinoma of the skin presenting as marrow failure in a man with systemic lupus erythematosus. Med Pediatr Oncol. 1993;21(2):137–41.

    Article  CAS  PubMed  Google Scholar 

  76. Nemoto I, Sato-Matsumura KC, Fujita Y, Natsuga K, Ujiie H, Tomita Y, et al. Leukaemic dissemination of Merkel cell carcinoma in a patient with systemic lupus erythematosus. Clin Exp Dermatol. 2008;33(3):270–2.

    Article  CAS  PubMed  Google Scholar 

  77. Kayashima K, Ono T, Johno M, Kojo Y, Yamashita N, Matsunaga W. Spontaneous regression in Merkel cell (neuroendocrine) carcinoma of the skin. Arch Dermatol. 1991;127(4):550–3.

    Article  CAS  PubMed  Google Scholar 

  78. Duncan WC, Tschen JA. Spontaneous regression of Merkel cell (neuroendocrine) carcinoma of the skin. J Am Acad Dermatol. 1993;29(4):653–4.

    Article  CAS  PubMed  Google Scholar 

  79. Yanguas I, Goday JJ, Gonzalez-Guemes M, Oleaga JM, Lozano M, Soloeta R. Spontaneous regression of Merkel cell carcinoma of the skin. Br J Dermatol. 1997;137(2):296–8.

    Article  CAS  PubMed  Google Scholar 

  80. Connelly TJ, Cribier B, Brown TJ, Yanguas I. Complete spontaneous regression of Merkel cell carcinoma: a review of the 10 reported cases. Dermatol Surg. 2000;26(9):853–6.

    Article  CAS  PubMed  Google Scholar 

  81. Maruo K, Kayashima KI, Ono T. Regressing Merkel cell carcinoma-a case showing replacement of tumour cells by foamy cells. Br J Dermatol. 2000;142(6):1184–9.

    Article  CAS  PubMed  Google Scholar 

  82. Sais G, Admella C, Soler T. Spontaneous regression in primary cutaneous neuroendocrine (Merkel cell) carcinoma: a rare immune phenomenon? J Eur Acad Dermatol Venereol. 2002;16(1):82–3.

    Article  CAS  PubMed  Google Scholar 

  83. Junquera L, Torre A, Vicente JC, Garcia-Consuegra L, Fresno MF. Complete spontaneous regression of Merkel cell carcinoma. Ann Otol Rhinol Laryngol. 2005;114(5):376–80.

    Article  PubMed  Google Scholar 

  84. Missotten GS, de Wolff-Rouendaal D, de Keizer RJ. Merkel cell carcinoma of the eyelid review of the literature and report of patients with Merkel cell carcinoma showing spontaneous regression. Ophthalmology. 2008;115(1):195–201.

    Article  PubMed  Google Scholar 

  85. Karkos PD, Sastry A, Hampal S, Al-Jafari M. Spontaneous regression of Merkel cell carcinoma of the nose. Head Neck. 2010;32(3):411–4.

    PubMed  Google Scholar 

  86. Wooff JC, Trites JR, Walsh NM, Bullock MJ. Complete spontaneous regression of metastatic Merkel cell carcinoma: a case report and review of the literature. Am J Dermatopathol. 2010;32(6):614–7.

    Article  CAS  PubMed  Google Scholar 

  87. Warnick M, Singh S, Boisvert ME, Peck GL. Merkel cell carcinoma presenting as lymphadenopathy without a primary cutaneous lesion: a report of 2 cases. Arch Dermatol. 2008;144(10):1397–8.

    Article  PubMed  Google Scholar 

  88. Cozzolino I, Zeppa R, Zeppa P. Lymph nodal Merkel cell carcinoma: primary tumor or metastasis from unknown primary site? J Cutan Pathol. 2011;38(10):836–7.

    PubMed  Google Scholar 

  89. de Zeeuw S, Schouten van der Velden AP, de Wilt HJ, Wetzels CT, Bonenkamp HJ. A Merkel cell carcinoma presenting as a solitary lymph node metastasis without a primary lesion. Report of a case and review of the literature. Acta Chir Belg. 2012;112(4):317–21.

    PubMed  Google Scholar 

  90. Deneve JL, Messina JL, Marzban SS, Gonzalez RJ, Walls BM, Fisher KJ, et al. Merkel cell carcinoma of unknown primary origin. Ann Surg Oncol. 2012;19(7):2360–6.

    Article  PubMed  PubMed Central  Google Scholar 

  91. Boghossian V, Owen ID, Nuli B, Xiao PQ. Neuroendocrine (Merkel cell) carcinoma of the retroperitoneum with no identifiable primary site. World J Surg Oncol. 2007;5:117.

    Article  PubMed  PubMed Central  Google Scholar 

  92. Nazarian Y, Shalmon B, Horowitz Z, Bedrin L, Pfeffer MR, Talmi YP. Merkel cell carcinoma of unknown primary site. J Laryngol Otol. 2007;121(4), e1.

    Article  CAS  PubMed  Google Scholar 

  93. Tarantola TI, Vallow LA, Halyard MY, Weenig RH, Warschaw KE, Weaver AL, 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 

  94. Rossini D, Caponnetto S, Lapadula V, De Filippis L, Del Bene G, Emiliani A, et al. Merkel cell carcinoma of the retroperitoneum with no identifiable primary site. Case Rep Oncol Med. 2013;2013:131695.

    PubMed  PubMed Central  Google Scholar 

  95. Haider K, Hu Q, McFadden AJ, Shoker A, Barton JW, Ahmed S. Thrombocytopenia: an unusual manifestation of advanced composite Merkel cell carcinoma and in situ squamous cell carcinoma. Am J Clin Oncol. 2007;30(4):442–3.

    Article  PubMed  Google Scholar 

  96. Anzai S, Sato T, Takayasu S, Asada Y, Terashi H, Takasaki S. Postoperative hyponatremia in a patient with ACTH-producing Merkel cell carcinoma. J Dermatol. 2000;27(6):397–400.

    Article  CAS  PubMed  Google Scholar 

  97. Eggers SD, Salomao DR, Dinapoli RP, Vernino S. Paraneoplastic and metastatic neurologic complications of Merkel cell carcinoma. Mayo Clin Proc. 2001;76(3):327–30.

    Article  CAS  PubMed  Google Scholar 

  98. Rocamora A, Badia N, Vives R, Carrillo R, Ulloa J, Ledo A. Epidermotropic primary neuroendocrine (Merkel cell) carcinoma of the skin with Pautrier-like microabscesses. Report of three cases and review of the literature. J Am Acad Dermatol. 1987;16(6):1163–8.

    Article  CAS  PubMed  Google Scholar 

  99. LeBoit PE, Crutcher WA, Shapiro PE. Pagetoid intraepidermal spread in Merkel cell (primary neuroendocrine) carcinoma of the skin. Am J Surg Pathol. 1992;16(6):584–92.

    Article  CAS  PubMed  Google Scholar 

  100. Smith KJ, Skelton 3rd HG, Holland TT, Morgan AM, Lupton GP. Neuroendocrine (Merkel cell) carcinoma with an intraepidermal component. Am J Dermatopathol. 1993;15(6):528–33.

    Article  CAS  PubMed  Google Scholar 

  101. 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 

  102. 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 

  103. Al-Ahmadie HA, Mutasim DF, Mutema GK. A case of intraepidermal Merkel cell carcinoma within squamous cell carcinoma in-situ: Merkel cell carcinoma in-situ? Am J Dermatopathol. 2004;26(3):230–3.

    Article  PubMed  Google Scholar 

  104. Ferringer T, Rogers HC, Metcalf JS. Merkel cell carcinoma in situ. J Cutan Pathol. 2005;32(2):162–5.

    Article  PubMed  Google Scholar 

  105. Panelos J, Batistatou A, Paglierani M, Zioga A, Maio V, Santi R, et al. Expression of Notch-1 and alteration of the E-cadherin/beta-catenin cell adhesion complex are observed in primary cutaneous neuroendocrine carcinoma (Merkel cell carcinoma). Mod Pathol. 2009;22(7):959–68.

    Article  CAS  PubMed  Google Scholar 

  106. Knapp CF, Sayegh Z, Schell MJ, Rawal B, Ochoa T, Sondak VK, et al. Expression of CXCR4, E-cadherin, Bcl-2, and survivin in Merkel cell carcinoma: an immunohistochemical study using a tissue microarray. Am J Dermatopathol. 2012;34(6):592–6.

    Article  PubMed  PubMed Central  Google Scholar 

  107. Pilotti S, Rilke F, Bartoli C, Grisotti A. Clinicopathologic correlations of cutaneous neuroendocrine Merkel cell carcinoma. J Clin Oncol. 1988;6(12):1863–73.

    CAS  PubMed  Google Scholar 

  108. Wick MR, Goellner JR, Scheithauer BW, Thomas 3rd JR, Sanchez NP, Schroeter AL. Primary neuroendocrine carcinomas of the skin (Merkel cell tumors). A clinical, histologic, and ultrastructural study of thirteen cases. Am J Clin Pathol. 1983;79(1):6–13.

    Article  CAS  PubMed  Google Scholar 

  109. Silva EG, Mackay B, Goepfert H, Burgess MA, Fields RS. Endocrine carcinoma of the skin (Merkel cell carcinoma). Pathol Annu. 1984;19(Pt 2):1–30.

    PubMed  Google Scholar 

  110. Plaza JA, Suster S. The Toker tumor: spectrum of morphologic features in primary neuroendocrine carcinomas of the skin (Merkel cell carcinoma). Ann Diagn Pathol. 2006;10(6):376–85.

    Article  PubMed  Google Scholar 

  111. Vazmitel M, Michal M, Kazakov DV. Merkel cell carcinoma and Azzopardi phenomenon. Am J Dermatopathol. 2007;29(3):314–5.

    Article  PubMed  Google Scholar 

  112. Vazmitel M, Michal M, Shelekhova KV, Sima R, Mukensnabl P, Kazakov DV. Vascular changes in Merkel cell carcinoma based on a histopathological study of 92 cases. Am J Dermatopathol. 2008;30(2):106–11.

    Article  PubMed  Google Scholar 

  113. Vazmitel M, Michal M, Kempf W, Mukensnabl P, Kazakov DV. Merkel cell carcinoma with a follicular lymphocytic infiltrate: report of 2 cases. Am J Dermatopathol. 2008;30(4):389–91.

    Article  PubMed  Google Scholar 

  114. Gould E, Albores-Saavedra J, Dubner B, Smith W, Payne CM. Eccrine and squamous differentiation in Merkel cell carcinoma. An immunohistochemical study. Am J Surg Pathol. 1988;12(10):768–72.

    Article  CAS  PubMed  Google Scholar 

  115. 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 

  116. Cooper L, Debono R, Alsanjari N, Al-Nafussi A. Merkel cell tumour with leiomyosarcomatous differentiation. Histopathology. 2000;36(6):540–3.

    Article  CAS  PubMed  Google Scholar 

  117. Foschini MP, Eusebi V. Divergent differentiation in endocrine and nonendocrine tumors of the skin. Semin Diagn Pathol. 2000;17(2):162–8.

    CAS  PubMed  Google Scholar 

  118. 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 

  119. Fernandez-Figueras MT, Puig L, Gilaberte M, Gomez-Plaza Mdel C, Rex J, Ferrandiz C, et al. Merkel cell (primary neuroendocrine) carcinoma of the skin with nodal metastasis showing rhabdomyosarcomatous differentiation. J Cutan Pathol. 2002;29(10):619–22.

    Article  PubMed  Google Scholar 

  120. 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 

  121. Tan KB, Murali R, Karim RZ, Dutta B, Dutta R, McCarthy SW, et al. Merkel cell carcinoma with fibrosarcomatous differentiation. Pathology. 2008;40(3):314–6.

    Article  PubMed  Google Scholar 

  122. Lau PP, Ting SH, Ip YT, Tsang WY, Chan JK. Merkel cell carcinosarcoma: Merkel cell carcinoma with embryonal rhabdomyosarcoma-like component. Ann Diagn Pathol. 2012;16(5):388–91.

    Article  PubMed  Google Scholar 

  123. Adhikari LA, McCalmont TH, Folpe AL. Merkel cell carcinoma with heterologous rhabdomyoblastic differentiation: the role of immunohistochemistry for Merkel cell polyomavirus large T-antigen in confirmation. J Cutan Pathol. 2012;39(1):47–51.

    Article  PubMed  Google Scholar 

  124. Martin B, Poblet E, Rios JJ, Kazakov D, Kutzner H, Brenn T, 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 

  125. Koba S, Misago N, Nagase K, Tsuruta N, Inoue T, Ikeda S, et al. Triphasic differentiations of Merkel cell carcinoma in primary and metastatic lesions. J Cutan Pathol. 2014;41(5):469–74.

    Article  PubMed  Google Scholar 

  126. Roncaroli F, Mauri F, Pasquinelli G. Primary neuroendocrine carcinoma with ganglion cell differentiation in a crural lymph node. Virchows Arch. 2000;437(6):675–9.

    Article  CAS  PubMed  Google Scholar 

  127. Vanchinathan V, Marinelli EC, Kartha RV, Uzieblo A, Ranchod M, Sundram UN. A malignant cutaneous neuroendocrine tumor with features of Merkel cell carcinoma and differentiating neuroblastoma. Am J Dermatopathol. 2009;31(2):193–6.

    Article  PubMed  Google Scholar 

  128. Iwasaki T, Kodama H, Matsushita M, Kuroda N, Yamasaki Y, Murakami I, et al. Merkel cell polyomavirus infection in both components of a combined Merkel cell carcinoma and basal cell carcinoma with ductal differentiation; each component had a similar but different novel Merkel cell polyomavirus large T antigen truncating mutation. Hum Pathol. 2013;44(3):442–7.

    Article  PubMed  Google Scholar 

  129. Rosso R, Paulli M, Carnevali L. Neuroendocrine carcinoma of the skin with lymphoepithelioma-like features. Am J Dermatopathol. 1998;20(5):483–6.

    Article  CAS  PubMed  Google Scholar 

  130. Ben Abdelkrim S, Dhouibi A, Moussa A, Hadhri R, Njim L, Mighri K, et al. Merkel cell carcinoma with lymphoepithelioma-like pattern: a case report of an exceedingly rare variant of Merkel cell carcinoma with lymph node metastases at presentation. Case Rep Pathol. 2011;2011:840575.

    PubMed  PubMed Central  Google Scholar 

  131. Li N, Wolgamot G, Argenyi Z. Primary cutaneous neuroendocrine cell carcinoma (Merkel cell carcinoma) with prominent microcystic features, mimicking eccrine carcinoma. J Cutan Pathol. 2007;34(5):410–4.

    Article  PubMed  Google Scholar 

  132. Aydin A, Kocer NE, Bekerecioglu M, Sari I. Cutaneous undifferentiated small (Merkel) cell carcinoma, that developed synchronously with multiple actinic keratoses, squamous cell carcinomas and basal cell carcinoma. J Dermatol. 2003;30(3):241–4.

    Article  PubMed  Google Scholar 

  133. Busam KJ, Jungbluth AA, Rekthman N, Coit D, Pulitzer M, Bini J, 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 

  134. 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 

  135. 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 

  136. Hewitt JB, Sherif A, Kerr KM, Stankler L. Merkel cell and squamous cell carcinomas arising in erythema ab igne. Br J Dermatol. 1993;128(5):591–2.

    Article  CAS  PubMed  Google Scholar 

  137. Iwafuchi M, Watanabe H, Ishihara N, Takahashi Y, Yoshimura M. A neuroendocrine (Merkel) cell carcinoma with coexisting intraepidermal squamous cell carcinoma of the skin. Its growth accelerated by an extrinsic factor. Acta Pathol Jpn. 1986;36(7):1099–108.

    CAS  PubMed  Google Scholar 

  138. Jones CS, Tyring SK, Lee PC, Fine JD. Development of neuroendocrine (Merkel cell) carcinoma mixed with squamous cell carcinoma in erythema ab igne. Arch Dermatol. 1988;124(1):110–3.

    Article  CAS  PubMed  Google Scholar 

  139. 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 

  140. Vieites B, Suarez-Penaranda JM, Delgado V, Vazquez-Veiga H, Varela J, Forteza J. Merkel cell carcinoma associated with in situ and invasive squamous cell carcinoma. Acta Derm Venereol. 2009;89(2):184–6.

    PubMed  Google Scholar 

  141. Tan BH, Busam KJ, Pulitzer MP. Combined intraepidermal neuroendocrine (Merkel cell) and squamous cell carcinoma in situ with CM2B4 negativity and p53 overexpression(*). J Cutan Pathol. 2012;39(6):626–30.

    Article  PubMed  Google Scholar 

  142. Popp S, Waltering S, Herbst C, Moll I, Boukamp P. UV-B-type mutations and chromosomal imbalances indicate common pathways for the development of Merkel and skin squamous cell carcinomas. Int J Cancer. 2002;99(3):352–60.

    Article  CAS  PubMed  Google Scholar 

  143. Kuwamoto S. Recent advances in the biology of Merkel cell carcinoma. Hum Pathol. 2011;42(8):1063–77.

    Article  CAS  PubMed  Google Scholar 

  144. Iwasaki T, Matsushita M, Kuwamoto S, Kato M, Murakami I, Higaki-Mori H, 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 

  145. Kuwamoto S, Higaki H, Kanai K, Iwasaki T, Sano H, Nagata K, et al. Association of Merkel cell polyomavirus infection with morphologic differences in Merkel cell carcinoma. Hum Pathol. 2011;42(5):632–40.

    Article  CAS  PubMed  Google Scholar 

  146. Tanahashi J, Kashima K, Daa T, Yada N, Fujiwara S, Yokoyama S. Merkel cell carcinoma co-existent with sebaceous carcinoma of the eyelid. J Cutan Pathol. 2009;36(9):983–6.

    Article  PubMed  Google Scholar 

  147. Youker SR, Billingsley EM. Combined Merkel cell carcinoma and atypical fibroxanthoma. J Cutan Med Surg. 2005;9(1):6–9.

    Article  PubMed  Google Scholar 

  148. Ivan D, Bengana C, Lazar AJ, Diwan AH, Prieto VG. Merkel cell tumor in a trichilemmal cyst: collision or association? Am J Dermatopathol. 2007;29(2):180–3.

    Article  PubMed  Google Scholar 

  149. Su W, Kheir SM, Berberian B, Cockerell CJ. Merkel cell carcinoma in situ arising in a trichilemmal cyst: a case report and literature review. Am J Dermatopathol. 2008;30(5):458–61.

    Article  PubMed  Google Scholar 

  150. Requena L, Jaqueti G, Rutten A, Mentzel T, Kutzner H. Merkel cell carcinoma within follicular cysts: report of two cases. J Cutan Pathol. 2008;35(12):1127–33.

    Article  PubMed  Google Scholar 

  151. Craig PJ, Calonje JE, Harries M, Stefanato CM. Incidental chronic lymphocytic leukaemia in a biopsy of Merkel cell carcinoma. J Cutan Pathol. 2009;36(6):706–10.

    Article  PubMed  Google Scholar 

  152. Koljonen V, Kukko H, Pukkala E, Sankila R, Bohling T, Tukiainen E, et al. Chronic lymphocytic leukaemia patients have a high risk of Merkel-cell polyomavirus DNA-positive Merkel-cell carcinoma. Br J Cancer. 2009;101(8):1444–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Li Z, Yang JJ, Wu M. Collision tumor of primary Merkel cell carcinoma and chronic lymphocytic leukemia/small lymphocytic lymphoma, diagnosed on ultrasound-guided fine-needle aspiration biopsy: A unique case report and review of literature. Diagn Cytopathol. 2015;43:66–71.

    Article  PubMed  Google Scholar 

  154. Papalas JA, McKinney MS, Kulbacki E, Dave SS, Wang E. Merkel cell carcinoma with partial B-cell blastic immunophenotype: a potential mimic of cutaneous richter transformation in a patient with chronic lymphocytic lymphoma. Am J Dermatopathol. 2014;36(2):148–52.

    Article  PubMed  PubMed Central  Google Scholar 

  155. Tolstov YL, Arora R, Scudiere SC, Busam K, Chaudhary PM, Chang Y, et al. Lack of evidence for direct involvement of Merkel cell polyomavirus (MCV) in chronic lymphocytic leukemia (CLL). Blood. 2010;115(23):4973–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Shingde MV, Buckland M, Busam KJ, McCarthy SW, Wilmott J, Thompson JF, et al. Primary cutaneous Ewing sarcoma/primitive neuroectodermal tumour: a clinicopathological analysis of seven cases highlighting diagnostic pitfalls and the role of FISH testing in diagnosis. J Clin Pathol. 2009;62(10):915–9.

    Article  CAS  PubMed  Google Scholar 

  157. Terrier-Lacombe MJ, Guillou L, Chibon F, Gallagher G, Benhattar J, Terrier P, et al. Superficial primitive Ewing’s sarcoma: a clinicopathologic and molecular cytogenetic analysis of 14 cases. Mod Pathol. 2009;22(1):87–94.

    Article  CAS  PubMed  Google Scholar 

  158. Machado I, Llombart B, Calabuig-Farinas S, Llombart-Bosch A. Superficial Ewing’s sarcoma family of tumors: a clinicopathological study with differential diagnoses. J Cutan Pathol. 2011;38(8):636–43.

    Article  PubMed  Google Scholar 

  159. Fernandez-Flores A, Suarez-Penaranda JM, Alonso S. Study of EWS/FLI-1 rearrangement in 18 cases of CK20+/CM2B4+ Merkel cell carcinoma using FISH and correlation to the differential diagnosis of Ewing sarcoma/peripheral neuroectodermal tumor. Appl Immunohistochem Mol Morphol. 2013;21(5):379–85.

    Article  CAS  PubMed  Google Scholar 

  160. Lloyd RV, Cano M, Rosa P, Hille A, Huttner WB. Distribution of chromogranin A and secretogranin I (chromogranin B) in neuroendocrine cells and tumors. Am J Pathol. 1988;130(2):296–304.

    CAS  PubMed  PubMed Central  Google Scholar 

  161. Leong AS, Milios J. Cytokeratin distribution in Merkel cell tumor of the skin. Hum Pathol. 1987;18(3):308–9.

    Article  CAS  PubMed  Google Scholar 

  162. Battifora H, Silva EG. The use of antikeratin antibodies in the immunohistochemical distinction between neuroendocrine (Merkel cell) carcinoma of the skin, lymphoma, and oat cell carcinoma. Cancer. 1986;58(5):1040–6.

    Article  CAS  PubMed  Google Scholar 

  163. Allen PJ, Busam K, Hill AD, Stojadinovic A, Coit DG. Immunohistochemical analysis of sentinel lymph nodes from patients with Merkel cell carcinoma. Cancer. 2001;92(6):1650–5.

    Article  CAS  PubMed  Google Scholar 

  164. Miettinen M. Synaptophysin and neurofilament proteins as markers for neuroendocrine tumors. Arch Pathol Lab Med. 1987;111(9):813–8.

    CAS  PubMed  Google Scholar 

  165. Narisawa Y, Hashimoto K, Kohda H. Immunohistochemical demonstration of the expression of neurofilament proteins in Merkel cells. Acta Derm Venereol. 1994;74(6):441–3.

    CAS  PubMed  Google Scholar 

  166. Arnold MA, Schoenfield L, Limketkai BN, Arnold CA. Diagnostic pitfalls of differentiating desmoplastic small round cell tumor (DSRCT) from Wilms tumor (WT): overlapping morphologic and immunohistochemical features. Am J Surg Pathol. 2014;38(9):1220–6.

    Article  PubMed  Google Scholar 

  167. Jerome Marson V, Mazieres J, Groussard O, Garcia O, Berjaud J, Dahan M, et al. Expression of TTF-1 and cytokeratins in primary and secondary epithelial lung tumours: correlation with histological type and grade. Histopathology. 2004;45(2):125–34.

    Article  CAS  PubMed  Google Scholar 

  168. Rund CR, Fischer EG. Perinuclear dot-like cytokeratin 20 staining in small cell neuroendocrine carcinoma of the ovary (pulmonary-type). Appl Immunohistochem Mol Morphol. 2006;14(2):244–8.

    Article  PubMed  Google Scholar 

  169. Schmidt U, Muller U, Metz KA, Leder LD. Cytokeratin and neurofilament protein staining in Merkel cell carcinoma of the small cell type and small cell carcinoma of the lung. Am J Dermatopathol. 1998;20(4):346–51.

    Article  CAS  PubMed  Google Scholar 

  170. Gu M, Antonescu CR, Guiter G, Huvos AG, Ladanyi M, Zakowski MF. Cytokeratin immunoreactivity in Ewing’s sarcoma: prevalence in 50 cases confirmed by molecular diagnostic studies. Am J Surg Pathol. 2000;24(3):410–6.

    Article  CAS  PubMed  Google Scholar 

  171. 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 

  172. 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 

  173. Beer TW. Merkel cell carcinomas with CK20 negative and CK7 positive immunostaining. J Cutan Pathol. 2009;36(3):385–6; author reply 7.

    Article  PubMed  Google Scholar 

  174. Lundquist K, Kohler S, Rouse RV. Intraepidermal cytokeratin 7 expression is not restricted to Paget cells but is also seen in Toker cells and Merkel cells. Am J Surg Pathol. 1999;23(2):212–9.

    Article  CAS  PubMed  Google Scholar 

  175. Asioli S, Righi A, de Biase D, Morandi L, Caliendo V, Picciotto F, 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 

  176. Dabner M, McClure RJ, Harvey NT, Budgeon CA, Beer TW, Amanuel B, et al. Merkel cell polyomavirus and p63 status in Merkel cell carcinoma by immunohistochemistry: Merkel cell polyomavirus positivity is inversely correlated with sun damage, but neither is correlated with outcome. Pathology. 2014;46(3):205–10.

    Article  CAS  PubMed  Google Scholar 

  177. 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 

  178. Lim CS, Whalley D, Haydu LE, Murali R, Tippett J, Thompson JF, 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 

  179. Shuda M, Arora R, Kwun HJ, Feng H, Sarid R, Fernandez-Figueras MT, 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 

  180. Rodig SJ, Cheng J, Wardzala J, DoRosario A, Scanlon JJ, Laga AC, et al. Improved detection suggests all Merkel cell carcinomas harbor Merkel polyomavirus. J Clin Invest. 2012;122(12):4645–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Waltari M, Sihto H, Kukko H, Koljonen V, Sankila R, Bohling T, et al. Association of Merkel cell polyomavirus infection with tumor p53, KIT, stem cell factor, PDGFR-alpha and survival in Merkel cell carcinoma. Int J Cancer. 2011;129(3):619–28.

    Article  CAS  PubMed  Google Scholar 

  182. Van Gele M, Kaghad M, Leonard JH, Van Roy N, Naeyaert JM, Geerts ML, et al. Mutation analysis of P73 and TP53 in Merkel cell carcinoma. Br J Cancer. 2000;82(4):823–6.

    Article  PubMed  PubMed Central  Google Scholar 

  183. Lassacher A, Heitzer E, Kerl H, Wolf P. p14ARF hypermethylation is common but INK4a-ARF locus or p53 mutations are rare in Merkel cell carcinoma. J Invest Dermatol. 2008;128(7):1788–96.

    Article  CAS  PubMed  Google Scholar 

  184. Sahi H, Savola S, Sihto H, Koljonen V, Bohling T, Knuutila S. RB1 gene in Merkel cell carcinoma: hypermethylation in all tumors and concurrent heterozygous deletions in the polyomavirus-negative subgroup. APMIS. 2014;122:1157–66.

    Article  CAS  PubMed  Google Scholar 

  185. Llombart B, Monteagudo C, Lopez-Guerrero JA, Carda C, Jorda E, Sanmartin O, 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 

  186. Fernandez-Figueras MT, Puig L, Musulen E, Gilaberte M, Lerma E, Serrano S, et al. Expression profiles associated with aggressive behavior in Merkel cell carcinoma. Mod Pathol. 2007;20(1):90–101.

    Article  CAS  PubMed  Google Scholar 

  187. 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 

  188. Feinmesser M, Halpern M, Kaganovsky E, Brenner B, Fenig E, Hodak E, et al. c-kit expression in primary and metastatic Merkel cell carcinoma. Am J Dermatopathol. 2004;26(6):458–62.

    Article  PubMed  Google Scholar 

  189. Andea AA, Patel R, Ponnazhagan S, Kumar S, DeVilliers P, Jhala D, 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 

  190. Swick BL, Ravdel L, Fitzpatrick JE, Robinson WA. Merkel cell carcinoma: evaluation of KIT (CD117) expression and failure to demonstrate activating mutations in the C-KIT proto-oncogene – implications for treatment with imatinib mesylate. J Cutan Pathol. 2007;34(4):324–9.

    Article  PubMed  Google Scholar 

  191. Kartha RV, Sundram UN. Silent mutations in KIT and PDGFRA and coexpression of receptors with SCF and PDGFA in Merkel cell carcinoma: implications for tyrosine kinase-based tumorigenesis. Mod Pathol. 2008;21(2):96–104.

    CAS  PubMed  Google Scholar 

  192. Ordonez NG. Value of thyroid transcription factor-1 immunostaining in distinguishing small cell lung carcinomas from other small cell carcinomas. Am J Surg Pathol. 2000;24(9):1217–23.

    Article  CAS  PubMed  Google Scholar 

  193. Byrd-Gloster AL, Khoor A, Glass LF, Messina JL, Whitsett JA, Livingston SK, et al. Differential expression of thyroid transcription factor 1 in small cell lung carcinoma and Merkel cell tumor. Hum Pathol. 2000;31(1):58–62.

    Article  CAS  PubMed  Google Scholar 

  194. 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 

  195. 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 

  196. 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 

  197. McNiff JM, Cowper SE, Lazova R, Subtil A, Glusac EJ. CD56 staining in Merkel cell carcinoma and natural killer-cell lymphoma: magic bullet, diagnostic pitfall, or both? J Cutan Pathol. 2005;32(8):541–5.

    Article  PubMed  Google Scholar 

  198. 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 Central  PubMed  Google Scholar 

  199. Feinmesser M, Halpern M, Fenig E, Tsabari C, Hodak E, Sulkes J, et al. Expression of the apoptosis-related oncogenes bcl-2, bax, and p53 in Merkel cell carcinoma: can they predict treatment response and clinical outcome? Hum Pathol. 1999;30(11):1367–72.

    Article  CAS  PubMed  Google Scholar 

  200. Verhaegen ME, Mangelberger D, Weick JW, Vozheiko TD, Harms PW, Nash KT, et al. Merkel cell carcinoma dependence on bcl-2 family members for survival. J Invest Dermatol. 2014;134(8):2241–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Filtenborg-Barnkob BE, Bzorek M. Expression of anaplastic lymphoma kinase in Merkel cell carcinomas. Hum Pathol. 2013;44(8):1656–64.

    Article  CAS  PubMed  Google Scholar 

  202. Rickelt S, Moll I, Franke WW. Intercellular adhering junctions with an asymmetric molecular composition: desmosomes connecting Merkel cells and keratinocytes. Cell Tissue Res. 2011;346(1):65–77.

    Article  CAS  PubMed  Google Scholar 

  203. Kazem S, van der Meijden E, Wang RC, Rosenberg AS, Pope E, Benoit T, et al. Polyomavirus-Associated Trichodysplasia Spinulosa Involves Hyperproliferation, pRB Phosphorylation and Upregulation of p16 and p21. PLoS One. 2014;9(10):e108947.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  204. Tolstov YL, Pastrana DV, Feng H, Becker JC, Jenkins FJ, Moschos S, 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  CAS  PubMed  PubMed Central  Google Scholar 

  205. Touze A, Gaitan J, Maruani A, Le Bidre E, Doussinaud A, Clavel C, et al. Merkel cell polyomavirus strains in patients with Merkel cell carcinoma. Emerg Infect Dis. 2009;15(6):960–2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Touze A, Le Bidre E, Laude H, Fleury MJ, Cazal R, Arnold F, et al. High levels of antibodies against Merkel cell polyomavirus identify a subset of patients with Merkel cell carcinoma with better clinical outcome. J Clin Oncol. 2011;29(12):1612–9.

    Article  CAS  PubMed  Google Scholar 

  207. Foulongne V, Kluger N, Dereure O, Mercier G, Moles JP, Guillot B, et al. Merkel cell polyomavirus in cutaneous swabs. Emerg Infect Dis. 2010;16(4):685–7.

    Article  PubMed  PubMed Central  Google Scholar 

  208. Pancaldi C, Corazzari V, Maniero S, Mazzoni E, Comar M, Martini F, et al. Merkel cell polyomavirus DNA sequences in the buffy coats of healthy blood donors. Blood. 2011;117(26):7099–101.

    Article  CAS  PubMed  Google Scholar 

  209. Faust H, Andersson K, Ekstrom J, Hortlund M, Robsahm TE, Dillner J. Prospective study of Merkel cell polyomavirus and risk of Merkel cell carcinoma. Int J Cancer. 2014;134(4):844–8.

    Article  CAS  PubMed  Google Scholar 

  210. Martel-Jantin C, Pedergnana V, Nicol JT, Leblond V, Tregouet DA, Tortevoye P, et al. Merkel cell polyomavirus infection occurs during early childhood and is transmitted between siblings. J Clin Virol. 2013;58(1):288–91.

    Article  CAS  PubMed  Google Scholar 

  211. Loyo M, Guerrero-Preston R, Brait M, Hoque MO, Chuang A, Kim MS, 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 

  212. 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 

  213. 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 

  214. Kassem A, Schopflin A, Diaz C, Weyers W, Stickeler E, Werner M, 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 

  215. 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 

  216. Andres C, Puchta U, Flaig MJ. Detection of Merkel cell polyomavirus DNA in atypical fibroxanthoma in correlation to clinical features. Am J Dermatopathol. 2010;32(8):799–803.

    Article  CAS  PubMed  Google Scholar 

  217. Sastre-Garau X, Peter M, Avril MF, Laude H, Couturier J, Rozenberg F, 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 

  218. 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 

  219. Bhatia S, Afanasiev O, Nghiem P. Immunobiology of Merkel cell carcinoma: implications for immunotherapy of a polyomavirus-associated cancer. Curr Oncol Rep. 2011;13(6):488–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  220. Borchert S, Czech-Sioli M, Neumann F, Schmidt C, Wimmer P, Dobner T, et al. High-affinity Rb binding, p53 inhibition, subcellular localization, and transformation by wild-type or tumor-derived shortened Merkel cell polyomavirus large T antigens. J Virol. 2014;88(6):3144–60.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  221. Houben R, Adam C, Baeurle A, Hesbacher S, Grimm J, Angermeyer S, et al. An intact retinoblastoma protein-binding site in Merkel cell polyomavirus large T antigen is required for promoting growth of Merkel cell carcinoma cells. Int J Cancer. 2012;130(4):847–56.

    Article  CAS  PubMed  Google Scholar 

  222. Houben R, Dreher C, Angermeyer S, Borst A, Utikal J, Haferkamp S, et al. Mechanisms of p53 restriction in Merkel cell carcinoma cells are independent of the Merkel cell polyoma virus T antigens. J Invest Dermatol. 2013;133(10):2453–60.

    Article  CAS  PubMed  Google Scholar 

  223. 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 

  224. 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 

  225. Paulson KG, Carter JJ, Johnson LG, Cahill KW, Iyer JG, Schrama D, et al. Antibodies to Merkel cell polyomavirus T antigen oncoproteins reflect tumor burden in Merkel cell carcinoma patients. Cancer Res. 2010;70(21):8388–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  226. 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. 2005;23(10):2300–9.

    Article  PubMed  Google Scholar 

  227. Schwartz JL, Griffith KA, Lowe L, Wong SL, McLean SA, Fullen DR, et al. Features predicting sentinel lymph node positivity in Merkel cell carcinoma. J Clin Oncol. 2011;29(8):1036–41.

    Article  PubMed  Google Scholar 

  228. Fields RC, Busam KJ, Chou JF, Panageas KS, Pulitzer MP, Kraus DH, et al. Recurrence and survival in patients undergoing sentinel lymph node biopsy for Merkel cell carcinoma: analysis of 153 patients from a single institution. Ann Surg Oncol. 2011;18(9):2529–37.

    Article  PubMed  PubMed Central  Google Scholar 

  229. 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 

  230. Mott RT, Smoller BR, Morgan MB. Merkel cell carcinoma: a clinicopathologic study with prognostic implications. J Cutan Pathol. 2004;31(3):217–23.

    Article  PubMed  Google Scholar 

  231. Suomela S, Koljonen V, Skoog T, Kukko H, Bohling T, Saarialho-Kere U. Expression of MMP-10, MMP-21, MMP-26, and MMP-28 in Merkel cell carcinoma. Virchows Arch. 2009;455(6):495–503.

    Article  CAS  PubMed  Google Scholar 

  232. Fields RC, Busam KJ, Chou JF, Panageas KS, Pulitzer MP, Allen PJ, et al. Five hundred patients with Merkel cell carcinoma evaluated at a single institution. Ann Surg. 2011;254(3):465–73; discussion 73–5.

    Article  PubMed  Google Scholar 

  233. Fernandez-Figueras MT, Puig L, Musulen E, Gilaberte M, Ferrandiz C, Lerma 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 

  234. Koljonen V, Tukiainen E, Haglund C, Bohling T. Proliferative activity detected by Ki67 correlates with poor outcome in Merkel cell carcinoma. Histopathology. 2006;49(5):551–3.

    Article  CAS  PubMed  Google Scholar 

  235. Tseng J, Dhungel B, Mills JK, Diggs BS, Weerasinghe R, Fortino J, et al. Merkel cell carcinoma: what makes a difference? Am J Surg. 2015;209:342–6.

    Article  PubMed  Google Scholar 

  236. Lipson EJ, Vincent JG, Loyo M, Kagohara LT, Luber BS, Wang H, 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  CAS  PubMed  Google Scholar 

  237. Shahzad N, Shuda M, Gheit T, Kwun HJ, Cornet I, Saidj D, et al. The T antigen locus of Merkel cell polyomavirus downregulates human Toll-like receptor 9 expression. J Virol. 2013;87(23):13009–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  238. Afanasiev OK, Yelistratova L, Miller N, Nagase K, Paulson K, Iyer JG, et al. Merkel polyomavirus-specific T cells fluctuate with Merkel cell carcinoma burden and express therapeutically targetable PD-1 and Tim-3 exhaustion markers. Clin Cancer Res. 2013;19(19):5351–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  239. Sihto H, Bohling T, Kavola H, Koljonen V, Salmi M, Jalkanen S, 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 

  240. Fan R. PAX immunoreactivity in poorly differentiated small round cell tumors of childhood. Fetal Pediatr Pathol. 2014;33(4):244–52.

    Article  CAS  PubMed  Google Scholar 

  241. Desouki MM, Post GR, Cherry D, Lazarchick J. PAX-5: a valuable immunohistochemical marker in the differential diagnosis of lymphoid neoplasms. Clin Med Res. 2010;8(2):84–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Abbreviations

AJCC American Joint Committee on Cancer

APUD Amine precursor uptake and decarboxylation

BCC Basal cell carcinoma

CK Cytokeratin

CLL Chronic lymphocytic leukemia

ACTH Adrenocorticotropic hormone

HIV/AIDS Human immunodeficiency virus/acquired immunodeficiency syndrome

LT-Ag Large T antigen

LVI Lymphovascular invasion

MASH1/hASH1 Mammalian/human achaete-scute complex homolog 1

MCC Merkel cell carcinoma

MCPyV Merkel cell polyomavirus

NCCN National Comprehensive Cancer Network

NSE Neuron-specific enolase

PNET Peripheral neuroectodermal tumor

Rb Retinoblastoma

SCC Squamous cell carcinoma

SCLC Small cell lung carcinoma

SEER Surveillance, Epidemiology, and End Results

SLN Sentinel lymph node

SRBC Small round blue cell

TILs Tumor-infiltrating lymphocytes

TTF-1 Thyroid transcription factor 1

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Authors and Affiliations

  1. Dermatopathology, Department of Cutaneous Surgery and Oncology, Moffitt Cancer Center/USF Morsani College of Medicine, 12902 USF Magnolia Dr., Tampa, FL, 33612, USA

    Carlos N. Prieto-Granada MD

  2. Departments of Anatomic Pathology and Cutaneous Oncology, Moffitt Cancer Center, 12902 USF Magnolia Dr., Tampa, FL, 33612, USA

    Jane L. Messina MD

  3. Pathology and Cell Biology, Oncologic Sciences, and Dermatology, USF Morsani College of Medicine, Tampa, FL, USA

    Jane L. Messina MD

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  1. Carlos N. Prieto-Granada MD
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  2. Jane L. Messina MD
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Correspondence to Carlos N. Prieto-Granada MD .

Editor information

Editors and Affiliations

  1. Diagnostic & Experimental Pathology Lilly Res Laboratories, Eli Lilly & Co., Indianapolis, Indiana, USA

    Aejaz Nasir

  2. H. Lee Moffitt Cancer Ctr & Res, University of South Florida, Tampa, Florida, USA

    Domenico Coppola

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Prieto-Granada, C.N., Messina, J.L. (2016). Pathology of Merkel Cell Carcinoma (Primary Neuroendocrine Carcinoma of the Skin). In: Nasir, A., Coppola, D. (eds) Neuroendocrine Tumors: Review of Pathology, Molecular and Therapeutic Advances. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-3426-3_21

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