You're using an outdated browser. Please upgrade to a modern browser for the best experience.
Submitted Successfully!
Thank you for your contribution! You can also upload a video entry or images related to this topic. For video creation, please contact our Academic Video Service.
Version Summary Created by Modification Content Size Created at Operation
1
Henry H.L. Wu
 -- 1616 2023-02-06 07:21:13 |
2 format correct
Conner Chen
 Meta information modification 1616 2023-02-06 11:09:29 |

Video Upload Options

We provide professional Academic Video Service to translate complex research into visually appealing presentations. Would you like to try it?
No, upload directly Yes

Confirm

Are you sure to Delete?
Yes No
Cite
If you have any further questions, please contact Encyclopedia Editorial Office.
Wu, H.H.L.;  Pye, I.;  Chinnadurai, R. Etiology and Pathophysiology of Merkel Cell Carcinoma. Encyclopedia. Available online: https://encyclopedia.pub/entry/40856 (accessed on 19 July 2025).
Wu HHL,  Pye I,  Chinnadurai R. Etiology and Pathophysiology of Merkel Cell Carcinoma. Encyclopedia. Available at: https://encyclopedia.pub/entry/40856. Accessed July 19, 2025.
Wu, Henry H. L., Isobel Pye, Rajkumar Chinnadurai. "Etiology and Pathophysiology of Merkel Cell Carcinoma" Encyclopedia, https://encyclopedia.pub/entry/40856 (accessed July 19, 2025).
Wu, H.H.L.,  Pye, I., & Chinnadurai, R. (2023, February 06). Etiology and Pathophysiology of Merkel Cell Carcinoma. In Encyclopedia. https://encyclopedia.pub/entry/40856
Wu, Henry H. L., et al. "Etiology and Pathophysiology of Merkel Cell Carcinoma." Encyclopedia. Web. 06 February, 2023.
Etiology and Pathophysiology of Merkel Cell Carcinoma
Edit
This entry is adapted from the peer-reviewed paper 10.3390/dermato3010003

Merkel cell carcinoma (MCC) is an uncommon form of skin neoplasm with poor histological differentiation and an aggressive disease process, leading to high recurrence and mortality. There are multiple risk factors in which being in an immunocompromised state is a significant factor, and the discovery of Merkel cell polyomavirus (MCPyV) since 2008 has strengthened causal associations between MCC and immunosuppression. Individuals who have undergone kidney transplantation are therefore more susceptible to having MCC, secondary to post-transplant immunosuppression which plays a vital role in reducing the risk of transplant kidney rejection. 

Merkel cell carcinoma kidney transplantation epidemiology

1. Introduction

Merkel Cell Carcinoma (MCC) is a neuroendocrine cancer of the skin [1]. Although this diagnosis is relatively rare compared to other forms of skin neoplasm, MCC is the second most frequent cause of death from skin malignancy after melanoma [2]. Found mostly in sun-exposed areas of the skin such as the head and neck, MCC originates from nerve-associated Merkel cells which lie in the basal epidermal layer [3][4]. Certain demographic characteristics such as older age, being of Caucasian ethnicity, extensive exposure to ultraviolet (UV) radiation and/or immunosuppression are deemed significant risk factors of MCC development [3][4][5][6][7].
Historically, a poor prognosis is expected because of aggressive tumor progression, poor histological differentiation and high recurrence rates [8][9]. Outcomes data over the years have demonstrated the clinical course to be variable, even if these factors were present [3][10][11][12][13]. The presence or absence of metastasis is often considered the most important prognostic marker in MCC [14]. Regional and distant metastasis to various sites—from the lymphatic system, brain, bone, liver, lung, heart and more recently, the kidneys—has been reported in patients with metastatic MCC [15][16][17][18][19][20].
Patients with organ transplants are generally at higher risk of developing MCC and other forms of skin cancers compared to the non-transplanted population, with the risk estimated to be between 66 and 182 fold [21]. In particular, a more aggressive clinical course of MCC is observed for kidney transplant recipients where MCC diagnosis at an earlier age is expected [22][23]. Such patients usually present with localized disease in the form of a red or violaceous nodular lesion in sun-exposed skin before lymphovascular invasion and metastasis.
The aggressive nature of MCC development in kidney transplant recipients is primarily explained by these patients almost universally requiring post-transplant immunosuppression. Systemic immunosuppression displayed the strongest association with poor survival prognosis, irrespective of MCC stage and metastatic status compared to other established risk factors of MCC which occur following kidney transplantation [24]. Previous studies highlighted that MCC-specific mortality in immunosuppressed individuals nearly doubles that of non-immunosuppressed individuals over 3 years follow-up [25]. UV radiation-induced immunosuppression, Human Immunodeficiency Virus (HIV), autoimmune disorders, lymphoproliferative disorders and more importantly specific to this scenario, Merkel cell polyomavirus (MCPyV), are other risk factors of MCC which compound the effects from immunosuppression in kidney transplant recipients [26][27][28]. Conditions of immunosuppression might increase the viral replication activity of MCPyV. This increase could lead, in turn, to an increased risk of MCPyV-driven MCC. In a similar fashion, MCPyV-positive MCC has been reported to arise in rheumatoid arthritis patients under iatrogenic immunosuppressive therapy [29], so the connecting link between MCPyV and MCC may be the anti-viral immune system which is unable to control the oncogenic activity of MCPyV oncoproteins [30].
Though radiotherapy or cytotoxic chemotherapy followed by palliative care if these treatments fail are traditionally mainstays of management, significant developments have been made on the medical treatment options for advanced stage and metastatic MCC, particularly with the advent of immunotherapies for this condition. Positive findings demonstrated in numerous phase 2 multi-center clinical trials have led to the European Association of Dermato-Oncology (EADO) proposing the potential use of medications such as Avelumab, Pembrolizumab or Nivolumab as first-line standard treatment for metastatic MCC [31][32][33][34]. The United States Food and Drug Administration (FDA) approved the use of Avelumab and Pembrolizumab for this purpose [35][36]. Other novel therapeutic options include the use of epigenetic-based therapies such as histone deacetylase (HDAC) inhibitors [37]. Continued investigation is warranted to fully validate the use of medications as well as other treatment options for MCC.

2. Etiology and Pathophysiology of Merkel Cell Carcinoma

MCC was thought to originate from Merkel cell precursors which are likely derived from epidermal or hair follicle stem cells, pre-B/pro-B cells, or dermal fibroblasts, though the cells of origin in MCC remains not fully established at present [38][39][40][41]. Since normal Merkel cells are terminally differentiated and do not undergo cell division, they are deemed unlikely to be the cell of origin for MCC development [42].
The carcinogenesis process of MCCs is primarily linked to two main etiologies—clonal integration of MCPyV and long-term sunlight exposure leading to ultraviolet-mediated DNA damage (Figure 1) [43][44]. MCPyV is a recently identified human polyomavirus that is clonally integrated into the genome of MCC cells, as determined by whole-transcriptome sequencing [45]. In earlier studies, Southern blot patterns of the primary tumor and a metastatic lymph node isolated from the same patient appeared identical, suggesting the MCPyV integration event was clonal and likely occurred in early phases of the tumorigenic process [45]. MCPyV can usually be acquired during childhood and is detected in the skin of most healthy individuals [46][47]. Despite the widespread and lifelong infection with MCPyV in most individuals, very few MCPyV-exposed subjects actually have MCC [48]. Antibodies against MCPyV viral capsid proteins, particularly immunoglobulin G (IgG), are detected in between 60 and 80% of healthy, immunocompetent adults [49][50][51][52]. Maternally derived antibodies might account for the seropositivity in newborn babies and are probably effective in preventing primary infection [46]. When the maternal antibodies are no longer present by around 18 months of age, children are susceptible to de novo infection and are capable to mount antibody responses of their own [46].
Dermato 03 00003 g001
Figure 1. Clonal integration of MCPyV and UV-mediated DNA damage from sunlight exposure carcinogenesis models of MCC. DNA: Deoxyribonucleic acid; MCC: Merkel Cell Carcinoma; MCPyV: Merkel Cell Polyomavirus; UV: Ultraviolet.
MCPyV-specific T-cell responses detected in the serum blood samples of post-transplant patients with MCC are characterized by CD4+ helper cells, which react to a broad range of peptides derived from viral capsid and oncoproteins [53]. The action of IgG antibodies against small T (ST) and large T (LT) antigens of MCC are relatively specific, with this mechanism observed in more than 40% of post-transplant patients with MCC but less than 1% of normal controls [54]. It has been shown that the levels of ST and LT antibodies correlate to tumor mass in MCPyV-positive MCC and will increase in the event of spread or metastatic disease [54]. It should be taken into account that surveillance for MCPyV-positive MCC is not only mediated by humoral immunity and CD4+ T-helper cells, but also by cell-mediated immunity [55]. MCPyV-specific CD8+ T-lymphocytes were found in serum blood samples for over half of MCPyV-positive MCC patients, in which its levels correlate with disease progression and degree of remission following MCC treatment [55]. It is known that MCPyV-positive MCC contain increased numbers of tumor-infiltrating CD8+ and CD3+ lymphocytes, natural killer cells, macrophages and Fox P3+ regulatory T-cells, when compared to MCPyV-negative MCC [56][57]. The tumor-infiltrating CD8+ lymphocytes are associated with a favorable prognosis of MCC [56][58]. Another important feature relating to the immune surveillance of MCC cells is that they are able to employ certain mechanisms to evade tumor surveillance by tumor-infiltrating lymphocytes (TILs) [10][42][59]. The loss of vascular E-selectin expression, an important factor in T-cell entry to the skin, displays significant association with poor intra-tumoral CD8+ infiltration and worsened prognosis of MCC cells [60]. A decreased activity of TILs in MCC signifies the decreased expression of co-stimulatory signal molecules, as well as expression of specific T-cell exhaustion markers [61]. Restriction of T-cell entry into tumor cells and reduction in T-cell function might be considerable and targetable forms of immuno-evasion in MCC [61]. Besides clonal integration, chronic expression of the two MCPyV oncoproteins also contributes significantly to MCC pathophysiology. This probably occurs due to the loss of expression of the MCPyV miRNA that negatively regulates MCPyV LT transcript [62].
Medium- to long-term ultraviolet exposure may result in the manifestation of MCPyV-positive MCC as chronic sunlight exposure leads to local immunosuppression [42][59]. This is explained by the fact that ultraviolet radiation induces the expression of inflammatory mediators and functional alterations in the antigen-presenting dendritic cells, resulting in a cascade of events that modulate immune sensitivity [63]. Nevertheless, the frequency of DNA mutations occurring in ultraviolet-induced MCPyV-negative MCC is significantly higher (between 25 and 90-fold) compared to MCPyV-positive MCC, in similarity with other ultraviolet-induced skin cancers such as melanoma and squamous cell carcinoma [64][65][66][67][68]. This finding further distinguishes the MCPyV-positive and negative subtypes of MCC, according to DNA sequencing studies of MCC samples which rely on sequencing of cancer-specific genes, whole exomes or whole genomes. The MCPyV-negative MCC that is typically characterized by numerous mutations reflecting DNA damage from ultraviolet exposure, and MCPyV-positive MCC containing integrated MCPyV DNA, few somatic mutations and scarce evidence of ultraviolet-induced damage [64]. Amongst MCPyV-negative MCC cells, the mutational patterns frequently reflected faulty repair of pyrimidine dimers induced by UV radiation [66][67]. MCPyV-positive MCC cells usually had low mutation numbers in the range of 0.4 per megabase [42][68].
Within the context of kidney transplantation, iatrogenic immunosuppression is frequently observed due to the medications administered to prevent graft rejection. Whilst details regarding the impact of each individual immunosuppressant medication on MCC development in kidney transplant recipients are not fully known, it is established that calcineurin inhibitors and Azathioprine use significant increase risk of non-melanoma skin cancer including MCC [28][69]. Calcineurin inhibitors such as Cyclosporine and Tacrolimus were shown to display tumorigenic effects through interference with DNA repair and other mutational changes, raising risks of non-melanoma skin cancer by up to 200-fold even in previously immunocompetent individuals [70][71]. Pathophysiological associations between immunosuppressant use and MCPyV-positive and negative MCC disease activity are supported by findings that amongst patients who developed metastatic MCC following kidney transplantation, regression of MCC following withdrawal of immunosuppressants was observed although remission did not persist for more than 12 months in reported cases [72][73].

References

  1. Goessling, W.; McKee, P.H.; Mayer, R.J. Merkel cell carcinoma. J. Clin. Oncol. 2002, 20, 588–598.
  2. Schadendorf, D.; Lebbé, C.; Zur Hausen, A.; Avril, M.F.; Hariharan, S.; Bharmal, M.; Becker, J.C. Merkel cell carcinoma: Epidemiology, prognosis, therapy and unmet medical needs. Eur. J. Cancer 2017, 71, 53–69.
  3. Albores-Saavedra, J.; Batich, K.; Chable-Montero, F.; Sagy, N.; Schwartz, A.M.; Henson, D.E. Merkel cell carcinoma demographics, morphology, and survival based on 3870 cases: A population based study. J. Cutan. Pathol. 2010, 37, 20–27.
  4. Brissett, A.E.; Olsen, K.D.; Kasperbauer, J.L.; Lewis, J.E.; Goellner, J.R.; Spotts, B.E.; Weaver, A.L.; Strome, S.E. Merkel cell carcinoma of the head and neck: A retrospective case series. Head Neck 2002, 24, 982–988.
  5. Paulson, K.G.; Park, S.Y.; Vandeven, N.A.; Lachance, K.; Thomas, H.; Chapuis, A.G.; Harms, K.L.; Thompson, J.A.; Bhatia, S.; Stang, A.; et al. Merkel cell carcinoma: Current US incidence and projected increases based on changing demographics. J. Am. Acad Dermatol. 2018, 78, 457–463.
  6. Ezaldein, H.H.; Ventura, A.; DeRuyter, N.P.; Yin, E.S.; Giunta, A. Understanding the influence of patient demographics on disease severity, treatment strategy, and survival outcomes in merkel cell carcinoma: A surveillance, epidemiology, and end-results study. Oncoscience 2017, 4, 106–114.
  7. Tetzlaff, M.T.; Harms, P.W. Danger is only skin deep: Aggressive epidermal carcinomas. An overview of the diagnosis, demographics, molecular-genetics, staging, prognostic biomarkers, and therapeutic advances in Merkel cell carcinoma. Mod. Pathol. 2020, 33, 42–55.
  8. Llombart, B.; Monteagudo, C.; Lopez-Guerrero, J.A.; Carda, C.; Jorda, E.; Sanmartín, O.; Almenar, S.; Molina, I.; Martin, J.M.; Llombart-Bosch, A. Clinicopathological and immunohistochemical analysis of 20 cases of Merkel cell carcinoma in search of prognostic markers. Histopathology 2005, 46, 622–634.
  9. Güler-Nizam, E.; Leiter, U.; Metzler, G.; Breuninger, H.; Garbe, C.; Eigentler, T.K. Clinical course and prognostic factors of Merkel cell carcinoma of the skin. Br. J. Dermatol. 2009, 161, 90–94.
  10. Koljonen, V.; Sahi, H.; Bohling, T.; Mäkisalo, H. Post-transplant Merkel cell carcinoma. Acta. Dermato Venereol. 2016, 96, 442–447.
  11. Tarantola, T.I.; Vallow, L.A.; Halyard, M.Y.; Weenig, R.H.; Warschaw, K.E.; Grotz, T.E.; Jakub, J.W.; Roenigk, R.K.; Brewer, J.D.; Weaver, A.L.; et al. Prognostic factors in Merkel cell carcinoma: Analysis of 240 cases. J. Am. Acad Dermatol. 2013, 68, 425–432.
  12. Muñoz, I.P.; Masferrer, J.P.; Vegas, J.O.; Montalvo, M.S.; Díaz, R.J.; Casas, A.M. Merkel cell carcinoma from 2008 to 2012, reaching a new level of understanding. Cancer Treat. Rev. 2013, 39, 421–429.
  13. Lemos, B.D.; Storer, B.E.; Iyer, J.G.; Phillips, J.L.; Bichakjian, C.K.; Fang, L.C.; Johnson, T.M.; Liegeois-Kwon, N.J.; Otley, C.C.; Paulson, K.G.; et al. Pathologic nodal evaluation improves prognostic accuracy in Merkel cell carcinoma: Analysis of 5823 cases as the basis of the first consensus staging system. J. Am. Acad Dermatol. 2010, 63, 751–761.
  14. Lewis, C.W.; Qazi, J.; Hippe, D.S.; Lachance, K.; Thomas, H.; Cook, M.M.; Juhlin, I.; Singh, N.; Thuesmunn, Z.; Takagishi, S.R.; et al. Patterns of distant metastases in 215 Merkel cell carcinoma patients: Implications for prognosis and surveillance. Cancer Med. 2020, 9, 1374–1382.
  15. Ikawa, F.; Kiya, K.; Uozumi, T.; Yuki, K.; Takeshita, S.; Hamasaki, O.; Arita, K.; Kurisu, K. Brain metastasis of Merkel cell carcinoma. Neurosurg. Rev. 1999, 22, 54–57.
  16. Kamijo, A.; Koshino, T.; Hirakawa, K.; Saito, T. Merkel cell carcinoma with bone metastasis: A case report. J. Orthop. Sci. 2002, 7, 574–577.
  17. An, K.P.; Ratner, D. Merkel cell carcinoma in the setting of HIV infection. J. Am. Acad Dermatol. 2001, 45, 309–312.
  18. Pellitteri, P.K.; Takes, R.P.; Lewis, J.S., Jr.; Devaney, K.O.; Harlor, E.J.; Strojan, P.; Rodrigo, J.P.; Suárez, C.; Rinaldo, A.; Medina, J.E.; et al. Merkel cell carcinoma of the head and neck. Head Neck 2012, 34, 1346–1354.
  19. Yamana, N.; Sueyama, H.; Hamada, M. Cardiac metastasis from Merkel cell skin carcinoma. Int. J. Clin. Oncol. 2004, 9, 210–212.
  20. Motaouakil, A.; Boukhannous, I.; Chennoufi, M.; El Moudane, A.; Mokhtari, M.; Barki, A. Kidney metastasis in a case of Merkel cell carcinoma. Urol. Case. Rep. 2021, 37, 101704.
  21. Krynitz, B.; Edgren, G.; Lindelöf, B.; Baecklund, E.; Brattström, C.; Wilczek, H.; Smedby, K.E. Risk of skin cancer and other malignancies in kidney, liver, heart and lung transplant recipients 1970 to 2008—A Swedish population-based study. Int. J. Cancer 2013, 132, 1429–1438.
  22. Penn, I.; First, M.R. Merkel’s cell carcinoma in organ recipients: Report of 41 cases1. Transplantation 1999, 68, 1717–1721.
  23. Heath, M.; Jaimes, N.; Lemos, B.; Mostaghimi, A.; Wang, L.C.; Peñas, P.F.; Nghiem, P. Clinical characteristics of Merkel cell carcinoma at diagnosis in 195 patients: The AEIOU features. J. Am. Acad Dermatol. 2008, 58, 375–381.
  24. Paulson, K.G.; Iyer, J.G.; Blom, A.; Warton, E.M.; Sokil, M.; Yelistratova, L.; Schuman, L.; Nagase, K.; Bhatia, S.; Asgari, M.M.; et al. Systemic immune suppression predicts diminished merkel cell carcinoma–specific survival independent of stage. J. Investig. Dermatol. 2013, 133, 642–646.
  25. Cook, M.; Baker, K.; Redman, M.; Lachance, K.; Nguyen, M.; Parvathaneni, U.; Bhatia, S.; Nghiem, P.T.; Tseng, Y.D. Differential outcomes among immunosuppressed patients with Merkel cell carcinoma: Impact of immunosuppression type on cancer-specific and overall survival. Am. J. Clin. Oncol. 2019, 42, 82–88.
  26. Clarke, C.A.; Robbins, H.A.; Tatalovich, Z.; Lynch, C.F.; Pawlish, K.S.; Finch, J.L.; Hernandez, B.Y.; Fraumeni, J.F., Jr.; Madeleine, M.M.; Engels, E.A. Risk of merkel cell carcinoma after solid organ transplantation. J. Natl. Cancer Inst. 2015, 107, dju382.
  27. Sahi, H.; Kukko, H.; Böhling, T.; Tukiainen, E.; Sihto, H.; Joensuu, H.; Koljonen, V. Unusually young Merkel cell carcinoma patients are Merkel cell polyomavirus positive and frequently immunocompromised. Eur. J. Plast. Surg. 2010, 33, 349–353.
  28. Ma, J.E.; Brewer, J.D. Merkel cell carcinoma in immunosuppressed patients. Cancers 2014, 6, 1328–1350.
  29. Rotondo, J.C.; Bononi, I.; Puozzo, A.; Govoni, M.; Foschi, V.; Lanza, G.; Gafà, R.; Gaboriaud, P.; Touzé, F.A.; Selvatici, R.; et al. Merkel Cell Carcinomas Arising in Autoimmune Disease Affected Patients Treated with Biologic Drugs, Including Anti-TNFMCC in Autoimmune Disease Patients. Clin. Cancer. Res. 2017, 23, 3929–3934.
  30. Schlemeyer, T.; Ohnezeit, D.; Virdi, S.; Körner, C.; Weißelberg, S.; Starzonek, S.; Schumacher, U.; Grundhoff, A.; Indenbirken, D.; Albertini, S.; et al. Merkel cell carcinoma and immune evasion: Merkel cell polyomavirus small T-antigen induced surface changes can be reverted by therapeutic intervention. J. Investig. Dermatol. 2022, 142, 3071–3081.e13.
  31. D’Angelo, S.P.; Bhatia, S.; Brohl, A.S.; Hamid, O.; Mehnert, J.M.; Terheyden, P.; Shih, K.C.; Brownell, I.; Lebbé, C.; Lewis, K.D.; et al. Avelumab in patients with previously treated metastatic Merkel cell carcinoma: Long-term data and biomarker analyses from the single-arm phase 2 JAVELIN Merkel 200 trial. J. Immunother. Cancer 2020, 8, e000674.
  32. Nghiem, P.; Bhatia, S.; Lipson, E.J.; Sharfman, W.H.; Kudchadkar, R.R.; Brohl, A.S.; Friedlander, P.A.; Daud, A.; Kluger, H.M.; Reddy, S.A.; et al. Durable tumor regression and overall survival in patients with advanced Merkel cell carcinoma receiving pembrolizumab as first-line therapy. J. Clin. Oncol. 2019, 37, 693–702.
  33. Kim, S.; Wuthrick, E.; Blakaj, D.; Eroglu, Z.; Verschraegen, C.; Thapa, R.; Mills, M.; Dibs, K.; Liveringhouse, C.; Russell, J.; et al. Combined nivolumab and ipilimumab with or without stereotactic body radiation therapy for advanced Merkel cell carcinoma: A randomised, open label, phase 2 trial. Lancet 2022, 400, 1008–1019.
  34. Gauci, M.L.; Aristei, C.; Becker, J.C.; Blom, A.; Bataille, V.; Dreno, B.; Del Marmol, V.; Forsea, A.M.; Fargnoli, M.C.; Grob, J.J.; et al. Diagnosis and treatment of Merkel cell carcinoma: European consensus-based interdisciplinary guideline—Update 2022. Eur. J. Cancer. 2022, 171, 203–231.
  35. U.S. Food and Drug Administration. FDA Approves First Treatment for Rare form of Skin Cancer. Available online: https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-rare-form-skin-cancer (accessed on 15 November 2022).
  36. U.S. Food and Drug Administration. FDA Approves Pembrolizumab for Merkel Cell Carcinoma. Available online: https://www.fda.gov/drugs/fda-approves-pembrolizumab-merkel-cell-carcinoma (accessed on 15 November 2022).
  37. Song, L.; Bretz, A.C.; Gravemeyer, J.; Spassova, I.; Muminova, S.; Gambichler, T.; Sriram, A.; Ferrone, S.; Becker, J.C. The HDAC Inhibitor domatinostat promotes cell-cycle arrest, induces apoptosis, and increases immunogenicity of Merkel cell carcinoma cells. J. Investig. Dermatol. 2021, 141, 903–912.e4.
  38. Zur Hausen, A.; Rennspiess, D.; Winnepenninckx, V.; Speel, E.J.; Kurz, A.K. Early B-cell differentiation in Merkel cell carcinomas: Clues to cellular ancestry. Cancer Res. 2013, 73, 4982–4987.
  39. Tilling, T.; Wladykowski, E.; Failla, A.V.; Houdek, P.; Brandner, J.M.; Moll, I. Immunohistochemical analyses point to epidermal origin of human Merkel cells. Histochem. Cell Biol. 2014, 141, 407–421.
  40. Tilling, T.; Moll, I. Which are the cells of origin in merkel cell carcinoma? J. Skin Cancer 2012, 2012, 680410.
  41. Sunshine, J.C.; Jahchan, N.S.; Sage, J.; Choi, J. Are there multiple cells of origin of Merkel cell carcinoma? Oncogene 2018, 37, 1409–1416.
  42. Becker, J.C.; Stang, A.; DeCaprio, J.A.; Cerroni, L.; Lebbé, C.; Veness, M.; Nghiem, P. Merkel cell carcinoma. Nat. Rev. Dis. Prim. 2017, 3, 1–7.
  43. Duncavage, E.J.; Zehnbauer, B.A.; Pfeifer, J.D. Prevalence of Merkel cell polyomavirus in Merkel cell carcinoma. Mod. Pathol. 2009, 22, 516–521.
  44. 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, 352–360.
  45. Feng, H.; Shuda, M.; Chang, Y.; Moore, P.S. Clonal integration of a polyomavirus in human Merkel cell carcinoma. Science 2008, 319, 1096–1100.
  46. Martel-Jantin, C.; Pedergnana, V.; Nicol, J.T.; Leblond, V.; Trégouët, D.A.; Tortevoye, P.; Plancoulaine, S.; Coursaget, P.; Touzé, A.; Abel, L.; et al. Merkel cell polyomavirus infection occurs during early childhood and is transmitted between siblings. J. Clin. Virol. 2013, 58, 288–291.
  47. Loyo, M.; Guerrero-Preston, R.; Brait, M.; Hoque, M.O.; Chuang, A.; Kim, M.S.; Sharma, R.; Liégeois, N.J.; Koch, W.M.; Califano, J.A.; et al. Quantitative detection of Merkel cell virus in human tissues and possible mode of transmission. Int. J. Cancer 2010, 126, 2991–2996.
  48. Liu, W.; You, J. Molecular mechanisms of merkel cell polyomavirus transformation and replication. Ann. Rev. Virol. 2020, 7, 289–307.
  49. Tolstov, Y.L.; Pastrana, D.V.; Feng, H.; Becker, J.C.; Jenkins, F.J.; Moschos, S.; Chang, Y.; Buck, C.B.; Moore, P.S. 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, 1250–1256.
  50. Zhang, C.; Liu, F.; He, Z.; Deng, Q.; Pan, Y.; Liu, Y.; Zhang, C.; Ning, T.; Guo, C.; Liang, Y.; et al. Seroprevalence of Merkel cell polyomavirus in the general rural population of Anyang, China. PLoS ONE 2014, 9, e106430.
  51. Vahabpour, R.; Aghasadeghi, M.R.; Salehi-Vaziri, M.; Mohajel, N.; Keyvani, H.; Nasimi, M.; Esghaei, M.; Monavari, S.H. Prevalence of Merkel cell polyomavirus in Tehran: An age-specific serological study. Iran Red. Crescent Med. J. 2016, 18, e26097.
  52. Van der Meijden, E.; Bialasiewicz, S.; Rockett, R.J.; Tozer, S.J.; Sloots, T.P.; Feltkamp, M.C. Different serologic behavior of MCPyV, TSPyV, HPyV6, HPyV7 and HPyV9 polyomaviruses found on the skin. PloS ONE 2013, 8, e81078.
  53. Iyer, J.G.; Afanasiev, O.K.; McClurkan, C.; Paulson, K.; Nagase, K.; Jing, L.; Marshak, J.O.; Dong, L.; Carter, J.; Lai, I.; et al. Merkel Cell Polyomavirus-Specific CD8+ and CD4+ T-cell Responses Identified in Merkel Cell Carcinomas and Blood T-cell Responses against Merkel Cell Polyomavirus. Clin. Cancer Res. 2011, 17, 6671–6680.
  54. Paulson, K.G.; Carter, J.J.; Johnson, L.G.; Cahill, K.W.; Iyer, J.G.; Schrama, D.; Becker, J.C.; Madeleine, M.M.; Nghiem, P.; Galloway, D.A. Antibodies to merkel cell polyomavirus T antigen oncoproteins reflect tumor burden in merkel cell carcinoma patients. Cancer Res. 2010, 70, 8388–8397.
  55. Afanasiev, O.K.; Yelistratova, L.; Miller, N.; Nagase, K.; Paulson, K.; Iyer, J.G.; Ibrani, D.; Koelle, D.M.; Nghiem, P. Merkel Polyomavirus-Specific T Cells Fluctuate with Merkel Cell Carcinoma Burden and Express Therapeutically Targetable PD-1 and Tim-3 Exhaustion Markers Fluctuating and Exhausted CD8 T Cells in MCC. Clin. Cancer Res. 2013, 19, 5351–5360.
  56. Harms, P.W.; Patel, R.M.; Verhaegen, M.E.; Giordano, T.J.; Nash, K.T.; Johnson, C.N.; Daignault, S.; Thomas, D.G.; Gudjonsson, J.E.; Elder, J.T.; et al. Distinct gene expression profiles of viral-and nonviral-associated merkel cell carcinoma revealed by transcriptome analysis. J. Investig. Dermatol. 2013, 133, 936–945.
  57. Sihto, H.; Joensuu, H. Tumor-infiltrating lymphocytes and outcome in Merkel cell carcinoma, a virus-associated cancer. Oncoimmunology 2012, 1, 1420–1421.
  58. Paulson, K.G.; Iyer, J.G.; Tegeder, A.R.; Thibodeau, R.; Schelter, J.; Koba, S.; Schrama, D.; Simonson, W.T.; Lemos, B.D.; Byrd, D.R.; 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, 1539–1546.
  59. Hernandez, L.E.; Mohsin, N.; Yaghi, M.; Frech, F.S.; Dreyfuss, I.; Nouri, K. Merkel cell carcinoma: An updated review of pathogenesis, diagnosis, and treatment options. Dermatol. Ther. 2022, 35, e15292.
  60. Afanasiev, O.K.; Nagase, K.; Simonson, W.; Vandeven, N.; Blom, A.; Koelle, D.M.; Clark, R.; Nghiem, P. Vascular E-selectin expression correlates with CD8 lymphocyte infiltration and improved outcome in Merkel cell carcinoma. J. Investig. Dermatol. 2013, 133, 2065–2073.
  61. Dowlatshahi, M.; Huang, V.; Gehad, A.E.; Jiang, Y.; Calarese, A.; Teague, J.E.; Dorosario, A.A.; Cheng, J.; Nghiem, P.; Schanbacher, C.F.; et al. Tumor-specific T cells in human Merkel cell carcinomas: A possible role for Tregs and T-cell exhaustion in reducing T-cell responses. J. Investig. Dermatol. 2013, 133, 1879–1889.
  62. Theiss, J.M.; Günther, T.; Alawi, M.; Neumann, F.; Tessmer, U.; Fischer, N.; Grundhoff, A. A comprehensive analysis of replicating Merkel cell polyomavirus genomes delineates the viral transcription program and suggests a role for mcv-miR-M1 in episomal persistence. PLoS Pathog. 2015, 11, e1004974.
  63. Harms, P.W.; Vats, P.; Verhaegen, M.E.; Robinson, D.R.; Wu, Y.M.; Dhanasekaran, S.M.; Palanisamy, N.; Siddiqui, J.; Cao, X.; Su, F.; et al. The distinctive mutational spectra of polyomavirus-negative Merkel cell carcinoma. Cancer Res. 2015, 75, 3720–3727.
  64. Goh, G.; Walradt, T.; Markarov, V.; Blom, A.; Riaz, N.; Doumani, R.; Stafstrom, K.; Moshiri, A.; Yelistratova, L.; Levinsohn, J.; et al. Mutational landscape of MCPyV-positive and MCPyV-negative Merkel cell carcinomas with implications for immunotherapy. Oncotarget 2016, 7, 3403–3415.
  65. Starrett, G.J.; Marcelus, C.; Cantalupo, P.G.; Katz, J.P.; Cheng, J.; Akagi, K.; Thakuria, M.; Rabinowits, G.; Wang, L.C.; Symer, D.E.; et al. Merkel cell polyomavirus exhibits dominant control of the tumor genome and transcriptome in virus-associated Merkel cell carcinoma. MBio 2017, 8, e02079-16.
  66. Del Carmen Gonzalez-Vela, M.; Curiel-Olmo, S.; Derdak, S.; Beltran, S.; Santibanez, M.; Martinez, N.; Castillo-Trujillo, A.; Gut, M.; Sanchez-Pacheco, R.; Almaraz, C.; et al. Shared oncogenic pathways implicated in both virus-positive and UV-induced Merkel cell carcinomas. J. Investig. Dermatol. 2017, 137, 197–206.
  67. Wong, S.Q.; Waldeck, K.; Vergara, I.A.; Schröder, J.; Madore, J.; Wilmott, J.S.; Colebatch, A.J.; De Paoli-Iseppi, R.; Li, J.; Lupat, R.; et al. UV-associated mutations underlie the etiology of MCV-negative Merkel cell carcinomas. Cancer Res. 2015, 75, 5228–5234.
  68. Ahmed, M.M.; Cushman, C.H.; DeCaprio, J.A. Merkel cell polyomavirus: Oncogenesis in a stable genome. Viruses 2021, 14, 58.
  69. Bottomley, M.J.; Thomson, J.; Harwood, C.; Leigh, I. The role of the immune system in cutaneous squamous cell carcinoma. Int. J. Mol. Sci. 2019, 20, 2009.
  70. Harwood, C.A.; Mesher, D.; McGregor, J.M.; Mitchell, L.; Leedham-Green, M.; Raftery, M.; Cerio, R.; Leigh, I.M.; Sasieni, P.; Proby, C.M. A surveillance model for skin cancer in organ transplant recipients: A 22-year prospective study in an ethnically diverse population. Am. J. Transplant. 2013, 13, 119–129.
  71. Kuschal, C.; Thoms, K.M.; Schubert, S.; Schäfer, A.; Boeckmann, L.; Schön, M.P.; Emmert, S. Skin cancer in organ transplant recipients: Effects of immunosuppressive medications on DNA repair. Exp. Dermatol. 2012, 21, 2–6.
  72. Muirhead, R.; Ritchie, D.M. Partial regression of Merkel cell carcinoma in response to withdrawal of azathioprine in an immunosuppression-induced case of metastatic Merkel cell carcinoma. Clin. Oncol. 2007, 19, 96.
  73. Friedlaender, M.M.; Rubinger, D.; Rosenbaum, E.; Amir, G.; Siguencia, E. Temporary regression of Merkel cell carcinoma metastases after cessation of cyclosporine. Transplantation 2002, 73, 1849–1850.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
Upload a video for this entry
Information
Subjects: Oncology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Henry H. L. Wu
,
Isobel Pye
,
Rajkumar Chinnadurai
View Times: 483
Revisions: 2 times (View History)
Update Date: 07 Feb 2023
Table of Contents
    1000/1000
    Hot Most Recent
    Academic Video Service
    Feedback