Das Merkelzellkarzinom: Ätiopathogenese und Management

Zusammenfassung

Das Merkelzellkarzinom (MCC) ist ein seltenes Malignom mit neuroendokriner Differenzierung, an dem v. a. ältere und immunsupprimierte Patienten erkranken. Die Inzidenz des Tumors nimmt weiter zu; die Prognose ist mit einer 5-Jahres-Überlebensrate von 0 – 18 % im Stadium III und IV schlecht. Ein Zusammenhang mit dem Merkelzell-Polyoma-Virus oder einer vermehrten UV-Exposition gelten als gesichert. Das MCC präsentiert sich als solitärer, derber, kuppelförmiger, schnell wachsender Tumor. Die Diagnose wird mittels histologischer und immunhistochemischer Untersuchungen gestellt. 2017 wurde von der UICC eine neue Stadieneinteilung basierend auf der TNM-Klassifikation erstellt. Die Prognose ist stark abhängig vom Tumorstadium bei Erstdiagnose, weshalb entsprechende Staginguntersuchungen durchgeführt werden sollten. Therapeutisch steht, sofern möglich, die komplette Exzision des Tumors mit ausreichendem Sicherheitsabstand und ggf. die Exstirpation von Lymphknotenmetastasen im Vordergrund. Anschließend sollte eine Radiatio des Tumorbetts und der Lymphabflussbahnen erfolgen. In metastasierten Stadien hat sich in den letzten Jahren die Immuntherapie als Therapie der Wahl herauskristallisiert; die Chemotherapie spielt seitdem eine zunehmend geringere Rolle. So zeigten prospektive Studien mit Pembrolizumab vielversprechende Ergebnisse mit einer Ansprechrate von 56 % und einem progressionsfreien Überleben nach 6 Monaten von 67 %. Seit Oktober 2017 ist mit Avelumab, einem anti-PD-L1-Antikörper, die erste Immuntherapie zur Behandlung des metastasierten MCC in Deutschland zugelassen. Da die Therapie des metastasierten MCC trotz dieser innovativen Behandlungsansätze auch weiterhin als palliativ anzusehen ist, sollten frühzeitig zusätzlich palliative und psychoonkologische Therapiekonzepte miteinbezogen werden. Nach abgeschlossener Tumortherapie sollten regelmäßige Nachsorgeuntersuchungen erfolgen, um frühzeitig Rezidive oder Metastasen zu detektieren.

Abstract

Merkel cell carcinoma (MCC) is a rare malignant disease that is most commonly seen in elderly and immunosuppressed patients. The incidence has risen over the last few years and the prognosis is poor with 5-year survival rates between 0 – 18 % in stage III and IV. The Merkel cell polyoma virus and UV-exposition play a central role for the pathogenesis of MCC. It presents as a single, solid, dome-shaped and rapidly growing tumor. The diagnosis is verified by histologic and immunhistochemical examinations. In 2017 a new staging system based on the TNM-classification was released by the UICC. The prognosis depends on the stage at primary diagnosis. Wide excision of the tumor and, if required, of lymph node metastases is important. Surgery should always be followed by radiation of the tumor region and the draining lymphatic system. Over the last few years chemotherapy was replaced by immunotherapy as first line therapy in advanced stage MCC. In prospective studies pembrolizumab showed a response rate of 56 % with a progression-free survival of 67 %. In October 2017 the anti-PD-L1-antibody avelumab was the first immune checkpoint inhibitor approved for the treatment of advanced MCC in Germany. However, the prognosis is still poor and palliative and psychooncological services should be offered to the patients at an early stage. After treatment patients should undergo regular follow-up examinations.

• Literatur

• 1 Lemos BD. 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
• 2 Feng H. et al. Clonal integration of a polyomavirus in human Merkel cell carcinoma. Science 2008; 319: 1096-1100
• 3 Nghiem PT. et al. PD-1 Blockade with Pembrolizumab in Advanced Merkel-Cell Carcinoma. N Engl J Med 2016; 374: 2542-2552
• 4 Sauer CM. et al. [Merkel cell carcinoma: cutaneous manifestation of a highly malignant pre-/pro-B cell neoplasia?: Novel concept about the cellular origin of Merkel cell carcinoma]. Hautarzt 2017; 68: 204-210
• 5 Fitzgerald TL. et al. Dramatic Increase in the Incidence and Mortality from Merkel Cell Carcinoma in the United States. Am Surg 2015; 81: 802-806
• 6 Schadendorf D. et al. Merkel cell carcinoma: Epidemiology, prognosis, therapy and unmet medical needs. Eur J Cancer 2017; 71: 53-69
• 7 Heath M. et al. Clinical characteristics of Merkel cell carcinoma at diagnosis in 195 patients: the AEIOU features. J Am Acad Dermatol 2008; 58: 375-381
• 8 Agelli M. et al. The etiology and epidemiology of merkel cell carcinoma. Curr Probl Cancer 2010; 34: 14-37
• 9 Harms KL. 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
• 10 Jalilian C. et al. Clinical and dermoscopic characteristics of Merkel cell carcinoma. Br J Dermatol 2013; 169: 294-297
• 11 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
• 12 Fisher SG, Weber L, Carbone M. Cancer risk associated with simian virus 40 contaminated polio vaccine. Anticancer Res 1999; 19: 2173-2180
• 13 Houben R. et al. Merkel cell polyomavirus-infected Merkel cell carcinoma cells require expression of viral T antigens. J Virol 2010; 84: 7064-7072
• 14 Verhaegen ME. et al. Merkel Cell Polyomavirus Small T Antigen Initiates Merkel Cell Carcinoma-like Tumor Development in Mice. Cancer Res 2017; 77: 3151-3157
• 15 Shuda M. et al. T antigen mutations are a human tumor-specific signature for Merkel cell polyomavirus. Proc Natl Acad Sci U S A 2008; 105: 16272-16277
• 16 Gonzalez-Vela MD. et al. Shared Oncogenic Pathways Implicated in Both Virus-Positive and UV-Induced Merkel Cell Carcinomas. J Invest Dermatol 2017; 137: 197-206
• 17 Wong SQ. et al. UV-Associated Mutations Underlie the Etiology of MCV-Negative Merkel Cell Carcinomas. Cancer Res 2015; 75: 5228-5234
• 18 Hesbacher S. et al. RB1 is the crucial target of the Merkel cell polyomavirus Large T antigen in Merkel cell carcinoma cells. Oncotarget 2016; 7: 32956-32968
• 19 Verhaegen ME. et al. Merkel cell polyomavirus small T antigen is oncogenic in transgenic mice. J Invest Dermatol 2015; 135: 1415-1424
• 20 Becker JC. et al. Epidemiology, biology and therapy of Merkel cell carcinoma: conclusions from the EU project IMMOMEC. Cancer Immunol Immunother 2018; 67: 341-351
• 21 Foulongne V. et al. Merkel cell polyomavirus in cutaneous swabs. Emerg Infect Dis 2010; 16: 685-687
• 22 Tolstov YL. 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: 1250-1256
• 23 Tilling T, Moll I. Which are the cells of origin in merkel cell carcinoma?. J Skin Cancer 2012; 2012: 680410
• 24 Zur Hausen A. et al. Early B-cell differentiation in Merkel cell carcinomas: clues to cellular ancestry. Cancer Res 2013; 73: 4982-4987
• 25 Liu W. et al. Identifying the Target Cells and Mechanisms of Merkel Cell Polyomavirus Infection. Cell Host Microbe 2016; 19: 775-787
• 26 Union for International Cancer Control (uicc). Brierley JD, Gospodarowicz MK, Wittekind C, eds. TNM Classification of Malignant Tumours, 8th Edition. Wiley-Blackwell; 2017 8th Edition
• 27 Golan H. et al. FDG-PET imaging in Merkel cell carcinoma – value of head-to-toe scan. Nucl Med Rev Cent East Eur 2005; 8: 135-136
• 28 Tai P. A practical update of surgical management of merkel cell carcinoma of the skin. ISRN Surg 2013; 2013: 850797
• 29 Jouary T. et al. Adjuvant prophylactic regional radiotherapy versus observation in stage I Merkel cell carcinoma: a multicentric prospective randomized study. Ann Oncol 2012; 23: 1074-1080
• 30 Chen MM. et al. The role of adjuvant therapy in the management of head and neck merkel cell carcinoma: an analysis of 4815 patients. JAMA Otolaryngol Head Neck Surg 2015; 141: 137-141
• 31 Hasan S. et al. The role of postoperative radiation and chemoradiation in merkel cell carcinoma: a systematic review of the literature. Front Oncol 2013; 3: 276
• 32 Bhatia S. et al. Adjuvant Radiation Therapy and Chemotherapy in Merkel Cell Carcinoma: Survival Analyses of 6908 Cases From the National Cancer Data Base. J Natl Cancer Inst 2016; 108: pii: djw042
• 33 Mortier L. et al. Radiotherapy alone for primary Merkel cell carcinoma. Arch Dermatol 2003; 139: 1587-1590
• 34 Becker JC. et al. Merkel cell carcinoma. Nat Rev Dis Primers 2017; 3: 17077
• 35 D’Angelo SP. 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
• 36 Kaufman HL. 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
• 37 Tai PT. et al. Merkel cell carcinoma of the skin. J Cutan Med Surg 2000; 4: 186-195
• 38 Foote M. et al. Merkel cell carcinoma: the prognostic implications of an occult primary in stage IIIB (nodal) disease. J Am Acad Dermatol 2012; 67: 395-399
• 39 Fan K. et al. Circulating cell-free miR-375 as surrogate marker of tumor burden in Merkel cell carcinoma. Clin Cancer Res 2018; 24: 5873-5882