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01-01-2019 | Original Paper

Evidence of proliferative activity in human Merkel cells: implications in the histogenesis of Merkel cell carcinoma

Authors: Yutaka Narisawa, Takuya Inoue, Kotaro Nagase

Published in: Archives of Dermatological Research | Issue 1/2019

Abstract

The cellular origin of Merkel cell carcinoma (MCC) is controversial. We previously hypothesized that MCC originates from hair follicle stem cells or Merkel cell (MC) progenitors residing within the hair follicle bulge. Examination of three cases of combined MCC led to the unexpected discovery that numerous keratin 20 (CK20)-positive MCs within the squamous cell carcinoma (SCC) component of combined MCC appeared morphologically normal with dendritic and oval shapes. Moreover, one extremely rare case of combined SCC and MCC showed both intra-epidermal and dermal MCCs. These three cases represent the first documentation of MC hyperplasia in MCC, besides various benign follicular neoplasms associated with MC hyperplasia. Therefore, to elucidate the proliferating potential of MCs and their histogenetic relationship with MCCs, we further investigated these cases based on pathological observations. We identified numerous cells co-expressing CK20 and the proliferation marker Ki-67, identical to the morphological and immunohistochemical features of normal MCs. This finding indicated that MCs can no longer be considered as pure post-mitotic cells. Instead, they have proliferative potential under specific conditions in the diseased or wounded skin, or adjacent to various skin tumors, including MCC. Intimate co-existence of two malignant cell components composed of intradermal and intra-epidermal MCCs, with the proliferation of normal-appearing MCs in the same lesion, lends support to the hypothesis that MCs and MCC cells are derived from MC progenitors residing within the hair follicle bulge. Specifically, MCCs are derived from transformed MC progenitors with potential for dual-directional differentiation towards neuroendocrine and epithelial lineages.

Busam KJ, Jungbluth AA, Rekthman N, Coit D, Pulitzer M, Bini J, Arora R, Hanson NC, Tassello JA, frosina D, Moore P, Chang Y (2009) Merkel cell polyomavirus expression in merkel cell carcinomas and its absence in combined tumors and pulmonary neuroendocrine carcinomas. Am J Surg Pathol 33:1378–1385. https://doi.org/10.1097/PAS.0b013e3181aa30a5 CrossRefPubMedPubMedCentral

Claudinot S, Nicolas M, Oshima H, Rochat A, Barrandon Y (2005) Long-term renewal of hair follicles from clonogenic multipotent stem cells. Proc Natl Acad Sci USA 102:14677–14682. https://doi.org/10.1073/pnas.0507250102 CrossRefPubMedPubMedCentral

Commo S, Gaillard O, Bernard BA (2000) The human hair follicle contains two distinct K19 positive compartments in the outer root sheath: a unifying hypothesis for stem cell reservoir? Differentiation 66:157–164. https://doi.org/10.1046/j.1432-0436.2000.660401.x CrossRefPubMed

Cotsarelis G, Sun TT, Lavker RM (1990) Label-retaining cells reside in the bulge area of pilosebaceous unit: implications for follicular stem cells, hair cycle, and skin carcinogenesis. Cell 61:1329–1337CrossRefPubMed

Cotsarelis G (2006) Epithelial stem cells: a folliculocentric view. J Invest Dermatol 126:1459–1468. https://doi.org/10.1038/sj.jid.5700376 CrossRefPubMed

Garza LA, Yang CC, Zhao T, Blatt HB, Lee M, He H, Stanton DC, Carrasco L, Spiegel JH, Tobias JW, Cotsarelis G (2011) Bald scalp in men with androgenetic alopecia retains hair follicle stem cells but lacks CD200-rich and CD34-positive hair follicle progenitor cells. J Clin Invest 121:613–622. https://doi.org/10.1172/JCI44478 CrossRefPubMedPubMedCentral

Hartschuh W, Schulz T (1999) Immunohistochemical investigation of the different developmental stages of trichofolliculoma with special reference to the Merkel cell. Am J Dermatopathol 21:8–15CrossRefPubMed

Hartschuh W, Schulz T (1997) Merkel cell hyperplasia in chronic radiation-damaged skin: its possible relationship to fibroepithelioma of Pinkus. J Cutan Pathol 24:477–483CrossRefPubMed

Hartschuh W, Schulz T (1995) Merkel cells are integral constituents of desmoplastic trichoepithelioma: an immunohistochemical and electron microscopic study. J Cutan Pathol 22:413–421CrossRefPubMed

10.

Hawkshaw NJ, Haslam IS, Ansell DM, Shamalak A, Paus R (2015) Re-evaluating cyclosporine A as a hair growth-promoting agent in human scalp hair follicles. J Invest Dermatol 135:2129–2132. https://doi.org/10.1038/jid.2015.121 CrossRefPubMed

11.

Hoefler H, Kerl H, Rauch HJ, Denk H (1984) New immunocytochemical observations with diagnostic significance in cutaneous neuroendocrine carcinoma. Am J Dermatopathol 6:525–530CrossRefPubMed

12.

Inoue K, Aoi N, Sato T, Yamauchi Y, Suga H, Eto H, Kato H, Araki J, Yoshimura K (2009) Differential expression of stem-cell-associated markers in human hair follicle epithelial cells. Lab Invest 89:844–856. https://doi.org/10.1038/labinvest.2009.48 CrossRefPubMed

13.

Kanitakis J, Bourchany D, Faure M, Claudy A (1998) Merkel cells in hyperplastic and neoplastic lesions of the skin. An immunohistochemical study using an antibody to keratin 20. Dermatology 196:208–212. https://doi.org/10.1159/000017900 CrossRefPubMed

14.

Kloepper JE, Tiede S, Brinckmann J, Reinhardt DP, Meyer W, Faessier R, Paus R (2008) Immunophenotyping of the human bulge region: the quest to define useful in situ markers for human epithelial hair follicle stem cells and their niche. Exp Dermatol 17:592–609. https://doi.org/10.1111/j.1600-0625.2008.00720.x CrossRefPubMed

15.

Kroll MH, Toker C (1982) Trabecular carcinoma of the skin: further clinicopathologic and morphologic study. Arch Pathol Lab Med 106:404–408PubMed

16.

Kurzen H, Esposito L, Langbein L, Hartschuh W (2001) Cytokeratins as markers of follicular differentiation: an immunohistochemical study of trichoblastoma and basal cell carcinoma. Am J Dermatopathol 23:501–509CrossRefPubMed

17.

Lyle S, Christofidou-Solomidou M, Liu Y, Elder DE, Albelda S, Cotsarelis G (1998) The C8/144B monoclonal antibody recognizes cytokeratin 15 and defines the location of human hair follicle stem cells. J Cell Sci 111:3179–3188PubMed

18.

McCardle TW, Sondak VK, Zager J, Messina JL (2010) Merkel cell carcinoma: pathologic findings and prognostic factors. Curr Probl Cancer 34:47–64. https://doi.org/10.1016/j.currproblcancer.2010.02.002 CrossRefPubMed

19.

Merot Y (1990) Is the neuroendocrine carcinoma of the skin a Merkel cell tumor? What we can learn from immunohistochemical and ultrastructural studies. Int J Dermatol 29:102–104CrossRefPubMed

20.

Michel M, Török N, Godbout MJ, Lussier M, Gaudreau P, Royal A, Germain L (1996) Keratin 19 as a biochemical marker of skin stem cells in vivo and in vitro: keratin 19 expressing cells are differentially localized in function of anatomic sites, and their number varies with donor age and culture stage. J Cell Sci 109:1017–1028PubMed

21.

Moll I, Zieger W, Schmelz M (1996) Proliferative Merkel cells were not detected in human skin. Arch Dermatol Res 288:184–187CrossRefPubMed

22.

Morris RJ, Potten CS (1999) Highly persistent label-retaining cells in the hair follicles of mice and their fate following induction of anagen. J Invest Dermatol 112:470–475. https://doi.org/10.1046/j.1523-1747.1999.00537.x CrossRefPubMed

23.

Morrison KM, Miesegaes GR, Lumpkin EA, Maricich SM (2009) Mammalian Merkel cells are descended from the epidermal lineage. Dev Biol 336:76–83. https://doi.org/10.1016/j.ydbio.2009.09.032 CrossRefPubMedPubMedCentral

24.

Mott RT, Smoller BR, Morgan MB (2004) Merkel cell carcinoma: a clinicopathological study with prognostic implications. J Cutan Pathol 31:217–223CrossRefPubMed

25.

Narisawa Y, Hashimoto K, Kohda H (1993) Epithelial skirt and bulge of human facial vellus hair follicles and associated Merkel cell-nerve complex. Arch Dermatol Res 285:269–277CrossRefPubMed

26.

Narisawa Y, Hashimoto K, Kohda H (1994) Merkel cells of the terminal hair follicle of the adult human scalp. J Invest Dermatol 102:506–510CrossRefPubMed

27.

Narisawa Y, Koba S, Inoue T, Nagase K (2015) Histogenesis of pure and combined Merkel cell carcinomas: An immunohistochemical study of 14 cases. J Dermatol 42:445–452. https://doi.org/10.1111/1346-8138.12808 CrossRefPubMed

28.

Ohyama M, Terunuma A, Tock CL, Radonovich MF, Pise-Masison CA, Hopping SB, Brady JN, Udey MC, Vogel JC (2006) Characterization and isolation of stem cell-enriched human hair follicle bulge cells. J Clin Invest 116:249–260. https://doi.org/10.1172/JCI26043 CrossRefPubMedPubMedCentral

29.

Oshima H, Rochat A, Kedzia C, Kobayashi K, Barrandon Y (2001) Morphogenesis and renewal of hair follicles from adult multipotent stem cells. Cell 104:233–245CrossRefPubMed

30.

Pontiggia L, Biedermann T, Meuli M, Widmer D, Böttcher-Haberzeth S, Schiestl C, Schneider J, Braziulis E, Montaño I, Meuli-Simmen C, Reichmann E (2009) Markers to evaluate the quality and self-renewing potential of engineered human skin substitutes in vitro and after transplantation. J Invest Dermatol 129:480–490. https://doi.org/10.1038/jid.2008.254 CrossRefPubMed

31.

Purba TS, Haslam IS, Poblet E, Jiménez F, Gandarillas A, Izeta A, Paus R (2014) Human epithelial hair follicle stem cells and their progeny: current state of knowledge, the widening gap in translational research and future challenges. Bioessays 36:513–525. https://doi.org/10.1002/bies.201300166 CrossRefPubMed

32.

Purba TS, Haslam IS, Shahmalak A, Bhogal RK, Paus R (2015) Mapping the expression of epithelial hair follicle stem cell-related transcription factors LHX2 and SOX9 in the human hair follicle. Exp Dermatol 24:462–467. https://doi.org/10.1111/exd.12700 CrossRefPubMed

33.

Rathman-Josserand M, Genty G, Lecardonnel J, Chabane S, Cousson A, François Michelet J, Bernard BA (2013) Human hair follicle stem/progenitor cells express hypoxia markers. J Invest Dermatol 133:2094–2097. https://doi.org/10.1038/jid.2013.113 CrossRefPubMed

34.

Requena L, Jaqueti G, Rütten A, Mentzel T, Kutzner H (2008) Merkel cell carcinoma within follicular cysts: report of two cases. J Cutan Pathol 35:1127–1133CrossRefPubMed

35.

Schulz T, Hartschuh W (1997) Merkel cells are absent in basal cell carcinomas but frequently found in trichoblastomas. An immunohistochemical study. J Cutan Pathol 24:14–24CrossRefPubMed

36.

Schulz T, Hartschuh W (1995) Merkel cells in nevus sebaceus. An immunohistochemical study. Am J Dermatopathol 17:570–579CrossRefPubMed

37.

Taylor G, Lehrer MS, Jensen PJ, Sun TT, Lavker RM (2000) Involvement of follicular stem cells in forming not only the follicle but also the epidermis. Cell 102:451–461CrossRefPubMed

38.

Tiede S, Koop N, Kloepper JE, Fässler R, Paus R (2009) Nonviral in situ green fluorescent protein labeling and culture of primary, adult human hair follicle epithelial progenitor cells. Stem Cells 27:2793–2803. https://doi.org/10.1002/stem.213 CrossRefPubMed

39.

Tilling T, Moll I (2012) Which are the cells of origin in merkel cell carcinoma? J Skin Cancer 2012:680410. https://doi.org/10.1155/2012/680410 CrossRefPubMedPubMedCentral

40.

Van Keymeulen A, Mascre G, Youseff KK, Harel I, Michaux C, De Geest N, Szpalski C, Achouri Y, Bloch W, Hassan BA, Blanpain C (2009) Epidermal progenitors give rise to Merkel cells during embryonic development and adult homeostasis. J Cell Biol 187:91–100. https://doi.org/10.1083/jcb.200907080 CrossRefPubMedPubMedCentral

41.

Yamamoto O, Tanimoto A, Yasuda H, Suenaga Y, Asahi M (1993) A combined occurrence of neuroendocrine carcinoma of the skin and a benign appendageal neoplasm. J Cutan Pathol 20:173–176CrossRefPubMed

Title: Evidence of proliferative activity in human Merkel cells: implications in the histogenesis of Merkel cell carcinoma
Authors: Yutaka Narisawa
Takuya Inoue
Kotaro Nagase
Publication date: 01-01-2019
Publisher: Springer Berlin Heidelberg
Published in: Archives of Dermatological Research / Issue 1/2019
Print ISSN: 0340-3696
Electronic ISSN: 1432-069X
DOI: https://doi.org/10.1007/s00403-018-1877-x

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Evidence of proliferative activity in human Merkel cells: implications in the histogenesis of Merkel cell carcinoma

Abstract

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Abstract

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