Das Merkelzellkarzinom – neue Ideen zur Histogenese

Zusammenfassung

Die Inzidenz des Merkelzellkarzinoms, eines aggressiven neuroendokrinen Karzinoms der Haut, nahm in den letzten 20 Jahren deutlich zu. Dies ist einerseits auf eine verbesserte Diagnostik, andererseits auf die Alterung der Bevölkerung und vor allem auf das längere Überleben immunsupprimierter Patienten zurückzuführen. Deshalb wurde eine virale Genese postuliert und schließlich das Merkelzellpolyomavirus in 80 % der Merkelzellkarzinome entdeckt. Aufgrund der monoklonalen Integration dieses Virus ist seine Beteiligung an der Tumorentstehung sehr wahrscheinlich. Trotzdem bleiben noch Fragen offen, wie die Genese der Virus-negativen Karzinome und auch die Frage nach den Ursprungszellen des Karzinoms. Meist wird die Merkelzelle als Ursprungszelle postuliert. Jedoch stellen Merkelzellen postmitotische Zellen dar, die in der fetalen Entstehung und bei der Regeneration in adulter Haut aus epidermalen Progenitorzellen entstehen. Zwischen den Merkelzellen und den Zellen des Merkelzellkarzinoms bestehen eine Reihe von Konkordanzen, vor allem die typischen neuroendokrinen Granula und das sehr spezielle Keratin 20. Auf diese phänotypischen Parallelen geht auch die Benennung „Merkelzellkarzinom“ zurück. Aber es bestehen auch eine Reihe von Diskordanzen, vor allem die unterschiedliche Lokalisation in der Epidermis bzw. in der Dermis und das unterschiedliche Zytoskelett aus diffusen Filamenten bzw. paranukleären Plaques. Eine Entstehung des Merkelzellkarzinoms aus Merkelzellen ist daher unwahrscheinlich. Daneben werden epidermale Progenitor-/Stammzellen, skin-derived precursors, dermal stem cells und neuerdings auch pro-/prä-B-Zellen diskutiert. Für keine der Theorien gibt es einen Beweis. Ein starkes Argument gibt es allerdings für die epidermale Progenitor-/Stammzelle. Die Merkelzellkarzinomzellen würden daraus, ähnlich den Merkelzellen, ohne Änderung der Differenzierungslinie entstehen. Die einzelnen Argumente werden in der vorliegenden Arbeit diskutiert.

Abstract

The incidence of Merkel cell carcinoma, an aggressive neuroendocrine carcinoma of skin, has increased during the last two decades due to the improved immunohistochemical diagnosis, but also due to increase of elderly and the much longer survival of immunocompromised patients. Mostly because of the increased incidence among the latter patients, a viral pathogenesis has been assumed, and a new virus called Merkel cell polyomavirus has been detected in roughly 80 % of Merkel cell carcinomas. The monoclonal integration of the virus strongly argues for its importance for tumorigenesis. But there are still some open questions. For instance, the pathogenesis of virus-negative carcinomas and the cells of origin of Merkel cell carcinoma have to be addressed. Usually, the Merkel cell is postulated to be the cell of origin. The Merkel cell develops during fetal development and regeneration in adult skin from epidermal progenitor cells and represents a postmitotic cell. The concordances between Merkel cells and cells of Merkel cell carcinoma, especially the typical neuroendocrine granules and the very specific keratin 20 are obvious, and have led to the designation „Merkel cell carcinoma“. But there are various discordances, especially the localization. The Merkel cell is localized in the basal layer of epidermis, and the carcinoma develops within the dermis. Also the cytoskeleton is different, made up by diffuse filaments within the Merkel cell, but paranuclear plaques in the carcinoma. Thus, the Merkel cell is most probably not the cell of origin. Further putative cells of origin are discussed, mostly the epidermal progenitor/stem cells, skin derived precursors, dermal stem cells and the pro/pre-B-cells. None of these cells has been definitely identified as a cell of origin of Merkel cell carcinoma yet. However, there are strong arguments for the epidermal progenitor/stem cells, because carcinoma cells are very similar to Merkel cells, which originate from these epidermal precursors. Importantly, such a mechanism of Merkel cell carcinoma development would not include any change in the lineage of differentiation. These arguments concerning the different potential cell types of origin are discussed in the present paper.

• Literatur

• 1 Toker C. Trabecular carcinoma of the skin. Arch Dermatol 1972; 105: 107-110
• 2 Tang CK, Toker C. Trabecular carcinoma of the skin. An ultrastructural study. Cancer 1978; 42: 2311-2321
• 3 Moll R, Löwe A, Laufer J et al. Cytokeratin 20 in human carcinomas. A new histodiagnostic marker detected by monoclonal antibodies. Am J Pathol 1992; 140: 427-447
• 4 Moll R, Franke WW, Schiller DL et al. The catalog of human cytokeratins: patterns of expression in normal epithelia, tumors and cultured cells. Cell 1982; 31: 11-24
• 5 Moll I, Kuhn C, Moll R. Cytokeratin 20 is a general marker of cutaneous Merkel cells while certain neuronalproteins are absent. J Invest Dermatol 1995; 104: 910-915
• 6 Feng H, Shuda M, Chang Y et al. Clonal integration of a polyomavirus in human Merkel cell carcinoma. Science 2008; 319: 1.096-1.100
• 7 White AC, Tran K, Khuu J et al. Defining the origins of Ras/p53-mediated squamous cell carcinoma. PNAS 2011; 108: 7425-7430
• 8 Lapouge G, Youssef KK, Vokaer B et al. Identifying the cellular origin of squamous skin tumors. PNAS 2011; 108: 7431-7436
• 9 Visvader JE. Cells of origin in cancer. Nature 2011; 469: 314-322
• 10 Friedlander SYG, Chu GC, Snyder EL et al. Context-dependent transformation of adult pancreatic cells by onkogenic K-Ras. Cancer Cell 2009; 16: 379-389
• 11 Tilling T, Moll I. Which are the cells of origin in Merkel cell carcinoma?. J Skin Cancer 2012; 680410
• 12 Eispert AC, Fuchs F, Brandner JM et al. Evidence for distinct populations of human Merkel cells. Histochem Cell Biol 2009; 132: 83-93
• 13 Deichmann M, Kurzen H, Egner U et al. Adhesion molecules CD171 (I1CAM) and CD24 are expressed by primary neuroendocrine carcinomas of the skin (Merkel cell carcinomas). J Cutan Pathol 2003; 30: 363-368
• 14 Su LD, Fullen DR, Lowe L et al. CD117 (KIT receptor) expression in Merkel cell carcinoma. Am J Dermatopathol 2002; 24: 289-293
• 15 Moll I, Roessler M, Brandner JM et al. Human Merkel cells – aspects of cell biology, distribution and functions. Eur J Cell Biol 2005; 84: 259-271
• 16 Hashimoto K. The ultrastructure of human embryos. X. Merkel tactile cells in the finger and nail. J Anat 1972; 111: 99-120
• 17 Moll I, Moll R, Franke WW. Formation of Epidermal and Dermal Merkel Cells During Human Fetal Skin Development. J Invest Dermatol 1986; 87: 779-787
• 18 Moll I, Lane AT, Franke WW et al. Intraepidermal Formation of Merkel Cells in Xenografts of Human Fetal Skin. J Invest Dermatol 1990; 94: 359-364
• 19 Van Keymeulen A, Mascre G, Yousseff KK et al. Epidermal progenitors give rise to Merkel cells during embryonic development and adult homeostasis. J Cell Biol 2009; 187: 91-100
• 20 Moll I, Zieger W, Schmelz M. Proliferative Merkel cells were not detected in human skin. Arch Dematol Res 1996; 4: 184-187
• 21 Pincelli C, Marconi A. Keratinocyte stem cells: friends and foes. J Cell Physiol 2010; 225: 310-315
• 22 Kim J, McNiff JM. Nuclear expression of survivin portends a poor prognosis in Merkel cell carcinoma. Mod Pathol 2008; 21: 764-769
• 23 Moll I, Gillardon F, Waltering S et al. Differences of bcl-2 protein expression between Merkel cells and Merkel cell carcinomas. J Cutan Pathol 1996; 23: 109-117
• 24 McCardle TW, Sondak VK, Zager J et al. Merkel cell carcinoma: pathologic findings and prognostic factors. Curr Probl Canc 2010; 34: 47-64
• 25 Lemasson G, Coquart N, Lebonvallet N et al. Presence of putative stem cells in Merkel cell carcinomas. J Eur Acad Dermatol Venerol 2012; 6: 789-795
• 26 Toma JG, McKenzie IA, Bagli D et al. Isolation and characterization of multipotent skin-derived precursors from human skin. Stem Cells 2005; 23: 727-737
• 27 Zabierowski SE, Fukunaga-Kalabis M, Li L et al. Dermis-derived stem cells: a source of epidermal melanocytes and melanoma?. Pigment Cell Melanoma Res 2011; 24: 422-429
• 28 Shakhova O, Sommer L. Neural crest-derived stem cells. StemBook. (Internet) (May 4, 2010) Cambridge (MA): Harvard Stem Cell Institute; 2008. http://www.ncbi.nlm.nih.gov/books/NBK44752/pdf/Neural_crest-derived_stem_cells.pdf
• 29 Zur Hausen A, Rennspiess D, Winnepenninckx V et al. Early B-cell differentiation in Merkel cell carcinomas: clues to cellular ancestry. Cancer Res 2013; 73: 4982-4987