Periocular Merkel Cell Carcinoma – An Overview of Clinical Aspects and Current Treatment Options

Abstract

Merkel cell carcinoma (MCC) is a rare but highly aggressive and rapidly expanding malignant skin tumor. It affects the periocular region in approximately 10% of cases. The current treatment recommendation for resectable non-metastatic MCC comprises total surgical excision; however, lymph node or distant metastases are often already present by the time of the diagnosis. Since an immune checkpoint inhibitor therapy with avelumab was first approved for MCC in 2016, there has been considerable improvement in mean survival compared to cytostatic therapy; at the same time, there has been a reduction in serious treatment-associated adverse events. Other immune checkpoint inhibitors are currently still in clinical trials, with very promising initial results. Because of the complexity of the diagnosis, treatment, and prognosis, it is essential that MCC patients receive interdisciplinary care in a specialized center including consultation with a tumor review board.

Key words

immune checkpoint inhibitor - Merkel cell polyomavirus - PD-1 - PD-L1 - carcinoma of the eyelid

Publication History

Received: 30 June 2022

Accepted: 02 August 2022

Article published online:
11 November 2022

• References/Literatur

• 1 Heath M, Jaimes N, Lemos B. et al. Clinical characteristics of Merkel cell carcinoma at diagnosis in 195 patients: the AEIOU features. J Am Acad Dermatol 2008; 58: 375-381 DOI: 10.1016/j.jaad.2007.11.020.
• 2 Becker JC, Eigentler T, Frerich B. et al. S2k-Leitlinie Merkelzellkarzinom (MZK, MCC, neuroendokrines Karzinom der Haut) – Update 2018. J Dtsch Dermatol Ges 2019; 17: 562-577 DOI: 10.1111/ddg.13841_g.
• 3 Agelli M, Clegg LX. Epidemiology of primary Merkel cell carcinoma in the United States. J Am Acad Dermatol 2003; 49: 832-841 DOI: 10.1016/S0190-9622(03)02108-X.
• 4 Goessling W, McKee PH, Mayer RJ. Merkel cell carcinoma. J Clin Oncol 2002; 20: 588-598 DOI: 10.1200/JCO.2002.20.2.588.
• 5 Dika E, Pellegrini C, Lambertini M. et al. Merkel cell carcinoma: an updated overview of clinico-pathological aspects, molecular genetics and therapy. Eur J Dermatol 2021; 31: 691-701 DOI: 10.1684/ejd.2021.4170.
• 6 Becker JC, Stang A, zur Hausen A. et al. Epidemiology, biology and therapy of Merkel cell carcinoma: conclusions from the EU project IMMOMEC. Cancer Immunol Immunother 2018; 67: 341-351 DOI: 10.1007/s00262-017-2099-3.
• 7 Hoerster R, Schlaak M, Koch KR. et al. Merkel-Zell-Karzinom des Augenlids – eine häufig verkannte Diagnose: Klinische Aspekte und Behandlungsmethoden. Ophthalmologe 2017; 114: 134-139 DOI: 10.1007/s00347-016-0355-0.
• 8 Iuliano A, Tranfa F, Clemente L. et al. A case series of Merkel cell carcinoma of the eyelid: a rare entity often misdiagnosed. Orbit 2019; 38: 395-400 DOI: 10.1080/01676830.2018.1537291.
• 9 North VS, Habib LA, Yoon MK. Merkel cell carcinoma of the eyelid: A review. Surv Ophthalmol 2019; 64: 659-667 DOI: 10.1016/j.survophthal.2019.03.002.
• 10 Merritt H, Sniegowski MC, Esmaeli B. Merkel cell carcinoma of the eyelid and periocular region. Cancers (Basel) 2014; 6: 1128-1137 DOI: 10.3390/cancers6021128.
• 11 Schadendorf D, Lebbé C, zur Hausen A. et al. Merkel cell carcinoma: Epidemiology, prognosis, therapy and unmet medical needs. Eur J Cancer 2017; 71: 53-69 DOI: 10.1016/j.ejca.2016.10.022.
• 12 Hernandez LE, Mohsin N, Yaghi M. et al. Merkel cell carcinoma: An updated review of pathogenesis, diagnosis, and treatment options. Dermatol Ther 2022; 35: e15292 DOI: 10.1111/dth.15292.
• 13 Rokohl AC, Koch KR, Mor JM. et al. Personalisierte Medizin in der Behandlung von periokulären Tumoren: Zielgerichtete Therapien und der Einsatz von Immun-Checkpoint-Inhibitoren. Ophthalmologe 2020; 117: 521-527 DOI: 10.1007/s00347-019-01034-z.
• 14 Jaeger T, Ring J, Andres C. Histological, immunohistological, and clinical features of Merkel cell carcinoma in correlation to Merkel cell polyomavirus status. J Skin Cancer 2012; 2012: 983421 DOI: 10.1155/2012/983421.
• 15 Becker JC, Kauczok CS, Ugurel S. et al. Merkel cell carcinoma: molecular pathogenesis, clinical features and therapy. J Dtsch Dermatol Ges 2008; 6: 709-719 DOI: 10.1111/j.1610-0387.2008.06830.x.
• 16 Hauschild A, Garbe C. Kurzleitlinie – Kutanes neuroendokrines Karzinom (Merkelzell-Karzinom). J Dtsch Dermatol Ges 2006; 4: 508-510 DOI: 10.1111/j.1610-0387.2006.05890.x.
• 17 Smith FO, Yue B, Marzban SS. et al. Both tumor depth and diameter are predictive of sentinel lymph node status and survival in Merkel cell carcinoma. Cancer 2015; 121: 3252-3260 DOI: 10.1002/cncr.29452.
• 18 Farooq Baba PU, Rasool Z, Younas Khan I. et al. Merkel Cell Carcinoma: From Pathobiology to Clinical Management. Biology (Basel) 2021; 10: 1293 DOI: 10.3390/biology10121293.
• 19 Barksdale SK. Advances in Merkel cell carcinoma from a pathologistʼs perspective. Pathology 2017; 49: 568-574 DOI: 10.1016/j.pathol.2017.07.003.
• 20 Kleffner F, Schürholz J, Burckhardt S. et al. Merkel-Zell-Karzinom. Hautarzt 2014; 65: 823-830 DOI: 10.1007/s00105-014-2854-8.
• 21 Harms PW. Update on Merkel Cell Carcinoma. Clin Lab Med 2017; 37: 485-501 DOI: 10.1016/j.cll.2017.05.004.
• 22 Oram CW, Bartus CL, Purcell SM. Merkel cell carcinoma: a review. Cutis 2016; 97: 290-295
• 23 Alexandrov LB, Nik-Zainal S, Wedge DC. et al. Signatures of mutational processes in human cancer. Nature 2013; 500: 415-421 DOI: 10.1038/nature12477.
• 24 Ricci C, Righi A, Ambrosi F. et al. Prognostic Impact of MCPyV and TIL Subtyping in Merkel Cell Carcinoma: Evidence from a Large European Cohort of 95 Patients. Endocr Pathol 2020; 31: 21-32 DOI: 10.1007/s12022-019-09601-5.
• 25 Harms KL, Healy MA, Nghiem P. et al. Analysis of Prognostic Factors from 9387 Merkel Cell Carcinoma Cases Forms the Basis for the New 8th Edition AJCC Staging System. Ann Surg Oncol 2016; 23: 3564-3571 DOI: 10.1245/s10434-016-5266-4.
• 26 Herbert HM, Sun MT, Selva D. et al. Merkel cell carcinoma of the eyelid: management and prognosis. JAMA Ophthalmol 2014; 132: 197-204 DOI: 10.1001/jamaophthalmol.2013.6077.
• 27 National Comprehensive Cancer Network (NCCN). National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: Merkel cell Carcinoma. Im Internet (Stand: 27.06.2022): https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1444
• 28 Gunaratne DA, Howle JR, Veness MJ. Sentinel lymph node biopsy in Merkel cell carcinoma: a 15-year institutional experience and statistical analysis of 721 reported cases. Br J Dermatol 2016; 174: 273-281 DOI: 10.1111/bjd.14240.
• 29 [Anonym] Stadieneinteilung nach TNM gemäß der 8. Ausgabe AJCC Klassifikation. Im Internet (Stand: 28.06.2022): https://www.awmf.org/fileadmin/user_upload/Leitlinien/032_D_Krebsgesellschaft/032-023t2_S2k_Merkelzellkarzinom_2018-12.pdf
• 30 Ng L, Beer TW, Murray K. Vascular density has prognostic value in Merkel cell carcinoma. Am J Dermatopathol 2008; 30: 442-445 DOI: 10.1097/DAD.0b013e318172364d.
• 31 Beer TW, Ng LB, Murray K. Mast cells have prognostic value in Merkel cell carcinoma. Am J Dermatopathol 2008; 30: 27-30 DOI: 10.1097/DAD.0b013e31815c932a.
• 32 Llombart B, Monteagudo C, López-Guerrero JA. et al. Clinicopathological and immunohistochemical analysis of 20 cases of Merkel cell carcinoma in search of prognostic markers. Histopathology 2005; 46: 622-634 DOI: 10.1111/j.1365-2559.2005.02158.x.
• 33 Husein-ElAhmed H, Ramos-Pleguezuelos F, Ruiz-Molina I. et al. Histological Features, p53, c-Kit, and Poliomavirus Status and Impact on Survival in Merkel Cell Carcinoma Patients. Am J Dermatopathol 2016; 38: 571-579 DOI: 10.1097/DAD.0000000000000573.
• 34 Peters 3rd GB, Meyer DR, Shields JA. et al. Management and prognosis of Merkel cell carcinoma of the eyelid. Ophthalmology 2001; 108: 1575-1579 DOI: 10.1016/s0161-6420(01)00701-1.
• 35 Danesh MJ, Menge TD, Helliwell L. et al. Adherence to the National Comprehensive Cancer Network Criteria of Complete Circumferential Peripheral and Deep Margin Assessment in Treatment of High-Risk Basal and Squamous Cell Carcinoma. Dermatol Surg 2020; 46: 1473-1480 DOI: 10.1097/DSS.0000000000002354.
• 36 Flohil SC, van Lee CB, Beisenherz J. et al. Mohs micrographic surgery of rare cutaneous tumours. J Eur Acad Dermatol Venereol 2017; 31: 1285-1288 DOI: 10.1111/jdv.14079.
• 37 Colunga A, Pulliam T, Nghiem P. Merkel Cell Carcinoma in the Age of Immunotherapy: Facts and Hopes. Clin Cancer Res 2018; 24: 2035-2043 DOI: 10.1158/1078-0432.CCR-17-0439.
• 38 Villani A, Fabbrocini G, Costa C. et al. Merkel Cell Carcinoma: Therapeutic Update and Emerging Therapies. Dermatol Ther (Heidelb) 2019; 9: 209-222 DOI: 10.1007/s13555-019-0288-z.
• 39 Iyer JG, Blom A, Doumani R. et al. Response rates and durability of chemotherapy among 62 patients with metastatic Merkel cell carcinoma. Cancer Med 2016; 5: 2294-2301 DOI: 10.1002/cam4.815.
• 40 Kaufman HL, Russell JS, Hamid O. et al. Updated efficacy of avelumab in patients with previously treated metastatic Merkel cell carcinoma after ≥ 1 year of follow-up: JAVELIN Merkel 200, a phase 2 clinical trial. J Immunother Cancer 2018; 6: 7 DOI: 10.1186/s40425-017-0310-x.
• 41 Bhatia S, Afanasiev O, Nghiem P. Immunobiology of Merkel cell carcinoma: implications for immunotherapy of a polyomavirus-associated cancer. Curr Oncol Rep 2011; 13: 488-497 DOI: 10.1007/s11912-011-0197-5.
• 42 Afanasiev OK, Yelistratova L, Miller N. 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: 5351-5360 DOI: 10.1158/1078-0432.CCR-13-0035.
• 43 Dowlatshahi M, Huang V, Gehad AE. 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 Invest Dermatol 2013; 133: 1879-1889 DOI: 10.1038/jid.2013.75.
• 44 Trillium Krebsmedizin. PD-L1-Immunhistochemie und ihre Bedeutung: Momentaufnahme einer rasanten Entwicklung. Im Internet (Stand: 27.06.2022): https://www.trillium.de/zeitschriften/trillium-krebsmedizin/ausgaben-2017/heft-32017/pd-l1-immunhistochemie-und-ihre-bedeutung-momentaufnahme-einer-rasanten-entwicklung-teaser/pd-l1-immunhistochemie-und-ihre-bedeutung-momentaufnahme-einer-rasanten-entwicklung.html
• 45 Lebbe C, Becker JC, Grob JJ. et al. Diagnosis and treatment of Merkel Cell Carcinoma. European consensus-based interdisciplinary guideline. Eur J Cancer 2015; 51: 2396-2403 DOI: 10.1016/j.ejca.2015.06.131.
• 46 Kaufman HL, Hunger M, Hennessy M. et al. Nonprogression with avelumab treatment associated with gains in quality of life in metastatic Merkel cell carcinoma. Future Oncol 2018; 14: 255-266 DOI: 10.2217/fon-2017-0470.
• 47 Kaufman HL, Russell J, Hamid O. et al. Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial. Lancet Oncol 2016; 17: 1374-1385 DOI: 10.1016/S1470-2045(16)30364-3.
• 48 DʼAngelo SP, Russell J, Lebbé C. et al. Efficacy and Safety of First-line Avelumab Treatment in Patients With Stage IV Metastatic Merkel Cell Carcinoma: A Preplanned Interim Analysis of a Clinical Trial. JAMA Oncol 2018; 4: e180077 DOI: 10.1001/jamaoncol.2018.0077.
• 49 Deutsche Gesellschaft für Hämatologie und medizinische Onkologie (DGHO). Stellungnahme zur Nutzenbewertung gemäß § 35a SGB V Avelumab, veröffentlicht am 1. Juli 2020, Vorgangsnummer 2020-04-01-D-534. IQWiG Bericht Nr. 93. Im Internet (Stand: 12.09.2022): https://www.dgho.de/publikationen/stellungnahmen/fruehe-nutzenbewertung/avelumab/avelumab-merkelzellkarzinom-stellungnahme-20200722.pdf
• 50 Nghiem PT, Bhatia S, Lipson EJ. et al. PD-1 Blockade with Pembrolizumab in Advanced Merkel-Cell Carcinoma. N Engl J Med 2016; 374: 2542-2552 DOI: 10.1056/NEJMoa1603702.
• 51 Nghiem P, Bhatia S, Lipson EJ. et al. Three-year survival, correlates and salvage therapies in patients receiving first-line pembrolizumab for advanced Merkel cell carcinoma. J Immunother Cancer 2021; 9: e002478 DOI: 10.1136/jitc-2021-002478.
• 52 Nghiem P, Bhatia S, Lipson EJ. 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 DOI: 10.1200/JCO.18.01896.
• 53 Topalian SL, Bhatia S, Amin A. et al. Neoadjuvant Nivolumab for Patients With Resectable Merkel Cell Carcinoma in the CheckMate 358 Trial. J Clin Oncol 2020; 38: 2476-2487 DOI: 10.1200/JCO.20.00201.
• 54 Ferris RL, Spanos WC, Leidner R. et al. Neoadjuvant nivolumab for patients with resectable HPV-positive and HPV-negative squamous cell carcinomas of the head and neck in the CheckMate 358 trial. J Immunother Cancer 2021; 9: e002568 DOI: 10.1136/jitc-2021-002568.
• 55 Glutsch V, Kneitz H, Gesierich A. et al. Activity of ipilimumab plus nivolumab in avelumab-refractory Merkel cell carcinoma. Cancer Immunol Immunother 2021; 70: 2087-2093 DOI: 10.1007/s00262-020-02832-0.
• 56 Strom T, Carr M, Zager JS. et al. Radiation Therapy is Associated with Improved Outcomes in Merkel Cell Carcinoma. Ann Surg Oncol 2016; 23: 3572-3578 DOI: 10.1245/s10434-016-5293-1.
• 57 Strom T, Naghavi AO, Messina JL. et al. Improved local and regional control with radiotherapy for Merkel cell carcinoma of the head and neck. Head Neck 2017; 39: 48-55 DOI: 10.1002/hed.24527.
• 58 Eisemann N, Jansen L, Castro FA. et al. Survival with nonmelanoma skin cancer in Germany. Br J Dermatol 2016; 174: 778-785 DOI: 10.1111/bjd.14352.
• 59 Fields RC, Busam KJ, Chou JF. et al. Five hundred patients with Merkel cell carcinoma evaluated at a single institution. Ann Surg 2011; 254: 465-473 discussion 473–475 DOI: 10.1097/SLA.0b013e31822c5fc1.
• 60 Girschik J, Thorn K, Beer TW. et al. Merkel cell carcinoma in Western Australia: a population-based study of incidence and survival. Br J Dermatol 2011; 165: 1051-1057 DOI: 10.1111/j.1365-2133.2011.10493.x.
• 61 Sridharan V, Muralidhar V, Margalit DN. et al. Merkel Cell Carcinoma: A Population Analysis on Survival. J Natl Compr Canc Netw 2016; 14: 1247-1257 DOI: 10.6004/jnccn.2016.0134.
• 62 van der Zwan JM, Trama A, Otter R. et al. Rare neuroendocrine tumours: results of the surveillance of rare cancers in Europe project. Eur J Cancer 2013; 49: 2565-2578 DOI: 10.1016/j.ejca.2013.02.029.