|Ahead of print publication
Merkel cell carcinoma in Turkey: A multicentric study
Fatih Yildiz1, Umut Demirci1, Ahmet Küçükarda2, Mahmut Büyüksimsek3, Teoman Sakalar4, Turkan Ozturk Topcu5, Ferit Aslan1, Gulnihal Tufan1, Ovgu Aydin6, Hande Turna7, Nalan Akgul Babacan8, Tugba Basoglu8, Bediz Kurt9, Birol Yildiz10, Tülay Eren11, Atike Gokcen Demiray12, Ozge Gumusay13, Cagatay Arslan14, Nuriye Özdemir15, Yuksel Urun16, Meltem Baykara17, Nedim Turan18, Mukremin Uysal19, Ahmet Bilici20, Halil Kavgaci5, İrfan Çiçin2, Saadettin Kilickap21, Semra Paydas3
1 Department of Medical Oncology, Dr. A. Y. Ankara Oncology Research and Education Hospital, University of Health Sciences, Yenimahalle, Ankara, Turkey
2 Department of Medical Oncology, Trakya University Faculty of Medicine, Edirne, Turkey
3 Department of Medical Oncology, Cukurova University Faculty of Medicine, Adana, Turkey
4 Department of Medical Oncology, Erciyes University Faculty of Medicine, Kayseri, Turkey
5 Department of Medical Oncology, Karadeniz Technical University Faculty of Medicine, Trabzon, Turkey
6 Department of Pathology, Istanbul University Cerrahpasa Medical Faculty, Istanbul, Turkey
7 Department of Medical Oncology, Istanbul University Cerrahpasa Medical Faculty, Istanbul, Turkey
8 Department of Medical Oncology, Marmara University Faculty of Medicine, Istanbul, Turkey
9 Department of Medical Oncology, Gazi University Faculty of Medicine, Ankara, Turkey
10 Department of Medical Oncology, Gulhane Education and Research Hospital, University of Health Sciences, Ankara, Turkey
11 Department of Medical Oncology, Diskapi Yildirim Beyazit Training and Research Hospital, Ankara, Turkey
12 Department of Medical Oncology, Faculty of Medicine, Pamukkale University, Denizli, Turkey
13 Department of Medical Oncology, Faculty of Medicine, Gaziosmanpasa University, Tokat, Turkey
14 Department of Medical Oncology, Medical Park Hospital, Izmir, Turkey
15 Department of Medical Oncology, Gazi University Faculty of Medicine, Ankara, Turkey
16 Department of Medical Oncology, Faculty of Medicine, Ankara University, Ankara, Turkey
17 Department of Medical Oncology, Sakarya University Training and Research Hospital, Sakarya, Turkey
18 Department of Medical Oncology, Dr. Lutfi Kirdar Kartal Education and Research Hospital, Istanbul, Turkey
19 Department of Medical Oncology, Faculty of Medicine, Afyon Kocatepe University, Afyon, Turkey
20 Department of Medical Oncology, Medipol University, Medical Faculty, Istanbul, Turkey
21 Department of Medical Oncology, Faculty of Medicine, Hacettepe University, Ankara, Turkey
|Date of Submission||05-Nov-2019|
|Date of Decision||23-May-2020|
|Date of Acceptance||18-Jun-2020|
|Date of Web Publication||03-Nov-2020|
Department of Medical Oncology, Dr. A. Y. Ankara Oncology Research and Education Hospital, University of Health Sciences, Yenimahalle, Ankara
Source of Support: None, Conflict of Interest: None
Background: Merkel cell carcinoma (MCC) is a rare but highly aggressive neuroendocrine carcinoma of the skin. In this study, we aimed to evaluate the clinicopathologic characteristics, treatment outcomes, and survival of MCC cases in Turkey.
Materials and Methods: The patients diagnosed with MCC between 1999 and 2018 at twenty different centers in Turkey were included in the study. Patient and tumor characteristics and adjuvant and metastatis treatment outcomes were analyzed retrospectively.
Results: The median age of totally 89 patients was 70 (26–93). The most common primary location was lower limbs (n = 29, 32.5%). Immunohistochemically, CK20 positivity was present in 59 patients (66.3%). Only two patients had secondary malignancy. The majority of the patients (n = 76, 85.4%) were diagnosed at the localized stage. Surgery was performed for all patients in the early stage, and adjuvant radiotherapy or/and chemotherapy was applied to 52.6% (n = 40) of nonmetastatic patients. The median follow-up was 29 months. Recurrence developed in 21 (27.6%) of the 76 patients who presented with local or regional disease. Two-year disease-free survival (DFS) was 68.1% and 5-year DFS was 62.0% for localized stage. The 5-year DFS was similar for patients receiving adjuvant treatment (chemotherapy, radiotherapy, or sequential chemoradiotherapy) and without adjuvant therapy (P > 0.05). Two-year overall survival in patients who presented with localized disease was 71.3% and 18.5% in metastatic patients (P < 0.001). In the metastatic stage, platinum/etoposide combination was the most preferred combination regimen. Median progression-free survival (PFS) in first-line chemotherapy was 7 months (95% confidence interval: 3.5–10.5 months; standart error: 1.78).
Conclusions: Although MCC is rare in Turkey, the incidence is increasing. Gender, CK20 status, tumor size, lymph node involvement, and adjuvant treatment were not associated with recurrence.
Keywords: CK20, merkel cell carcinoma, neuroendocrin carcinoma, skin carcinoma
|How to cite this URL:|
Yildiz F, Demirci U, Küçükarda A, Büyüksimsek M, Sakalar T, Topcu TO, Aslan F, Tufan G, Aydin O, Turna H, Babacan NA, Basoglu T, Kurt B, Yildiz B, Eren T, Demiray AG, Gumusay O, Arslan C, Özdemir N, Urun Y, Baykara M, Turan N, Uysal M, Bilici A, Kavgaci H, Çiçin &, Kilickap S, Paydas S. Merkel cell carcinoma in Turkey: A multicentric study. J Can Res Ther [Epub ahead of print] [cited 2021 Jun 22]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=299891
| > Introduction|| |
Merkel cell carcinoma (MCC) is a rare primary neuroendocrine carcinoma of the skin. It was first named as trabecular carcinoma of the skin in 1972 by Toker. Although the incidence of MCC in the United States was 0.7/100.000, there was a 95% increase in MCC cases between 2000 and 2013.
MCC is mainly seen in light-skinned and elderly people. Solid organ transplant recipients, HIV-infected individuals, patients with malignancy, and patients receiving immunosuppressive therapy are at higher risk for MCC.,,, The most accepted factors associated with the development of MCC are Merkel cell polyomavirus, exposure to ultraviolet radiation and immunosuppression.,
The most common primary location of MCC is head and neck.,,, While 65%–75% of the patients have localized disease, 16%–26% have regional lymph node involvement and 6%–8% have distant metastasis., Five-year overall survival rate is 60%–80% in the early stage and 11%–25% in patients with distant metastasis.,,
Responses with conventional chemotherapies for the treatment of advanced stage MCC are temporary. After understanding the immunogenicity of MCC over the past 10 years, treatment strategies have focused on immune modulators., Both the increase in incidence and achievements in immunotherapy have made MCC more remarkable.
In this study, we aimed to evaluate clinicopathologic characteristics, treatment outcomes, and survival of MCC cases in Turkey.
| > Materials and Methods|| |
This study was conducted by the Turkish Oncology Group with the participation of twenty institutions. Between 1999 and 2018, totally 89 patients with MCC were evaluated retrospectively.
Patient (sex, age at diagnosis, immunosuppression, and secondary malignancy) and tumor characteristics (anatomic location, size, nodal status, and immunohistochemical CK20 expression), treatment (adjuvant or metastatic setting) properties, and relaps or exitus status at last follow-up were investigated from the electronic registry system and patient files.
The patients were staged according to the 8th edition of the American Joint Committee.
Disease-free survival (DFS) was defined as the time from diagnosis to recurrence in localized disease, progression-free survival (PFS) was defined as the time from the beginning of treatment to progression in the metastatic stage, and OS was defined as the time from diagnosis to last control or death.
IBM Statistical Package for Social Sciences (SPSS®) v.23 (IBM Inc.; Armonk, NY, USA) software was used for data analysis.
The relationship between relapse and patient/tumor characteristics and adjuvant therapy was investigated by the univariate analysis.
Survival analyses were performed with Kaplan–Meier method, and the subgroups were compared with the log-rank test. A P < 0.05 was considered statistically significant.
| > Results|| |
The median age of totally 89 patients was 70 (26–93). The patients' characteristics are shown in [Table 1].
The most common primary location was lower limbs (n = 29, 32.5%). Majority of the patients (n = 76, 85.4%) had local or regional disease and 13 (14.6%) were in the metastatic stage. Eight patients (8.9%) were diagnosed between 1999 and 2008 and 91.1% (n = 81) were diagnosed in the past 10 years (2009–2018). Only two patients had secondary malignancy and they had used immunosuppressive therapy.
All patients in the localized stage were R0 resected. Forty patients (52.6% of localized stage patients) received adjuvant therapy. Adjuvant therapy and relapse status according to the stages are shown in [Table 2].
The median follow-up for all patients was 29 months (32 months for stage I, II, and III patients and 14 months for stage IV patients). Distant metastasis developed as a first recurrence in 14 (18.4%) and local recurrence developed in 7 (9.2%) of the 76 patients who presented with local or regional disease. Two-year DFS was 68.1% and 5-year DFS was 62% for localized stage. The 5-year DFS for patients receiving adjuvant chemotherapy or sequential chemoradiotherapy was 72.0%, 50.6% for adjuvant radiotherapy, and 62.2% for patients without adjuvant therapy [P > 0.05; [Figure 1].
Two-year survival in patients who presented with local or regional disease was 71.3% and 18.5% in metastatic patients [P < 0.001; [Figure 2]. Median OS at the metastatic stage was 14.8 months (1.8–36.2 months; 95% confidence interval [CI]: 8.2–21.4, standard error: 3.3).
|Figure 2: Overall survival according to the localized or advanced (metastatic) stage|
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Univariate analyses of DFS and OS are shown in [Table 3]. Gender, CK20 status, tumor size, lymph node involvement, and adjuvant treatment were not associated with recurrence. Only age was associated with OS.
|Table 3: Univariate analysis of overall survival and disease-free survival|
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In the metastatic setting, sisplatin or carboplatin and etoposid combination was the most preferred chemotherapy agents. Median PFS was 7 months for first-line treatment (2.3–11.4; 95% CI; 3.5–10.5, standart error: 1.7). In second-line therapy, six patients were treated with vincristine/doxorubicin/cyclophosphamide combination and two patients with avelumab.
| > Discussion|| |
MCC is a rare but highly aggressive skin carcinoma. The incidence is increasing gradually. Most of the previous studies included European and American patients, and this is one of the rare retrospective analyses performed in our region. In this study, we aimed to evaluate the clinicopathological features and survival of MCC in Turkey retrospectively.
MCC mainly affects elderly. Previous studies which were conducted in different geographies such as the USA, Europe, and China, reported that the median age of MCC patients was between 65 and 81 years.,,,, Similarly, the median age of the patients was 70 years in our study.
The most common anatomic location of MCC is head and neck in the Scandinavian countries, while the extremity and head-and-neck region are equally common in the USA.,,,,, In some European countries such as Italy, MCC is seen in extremities more commonly. In more than half of the patients in our study, MCC lesions were located in the extremity. We think that these differences might be related to ethnic and geographical factors.
The increase in the incidence of MCC in almost all of the recent studies is remarkable. During 2000–2013, 95% increase in MCC cases was reported in the USA. The epidemiological studies conducted in different countries such as France, the Netherlands, and Sweden showed that approximately 2-fold increase was observed in MCC cases in the last decade.,, Remarkably, 89.4% of the patients in our study were diagnosed in the past 10 years (2000–2018) and 10.6% were diagnosed in previous years (1999–2008). The main reason for this increase in the incidence was thought to be the use of immunohistochemical tests such as CK20. In addition, the increase in HIV positivity, other malignancies, and the use of immunosuppressive treatment are other factors for the increase in the incidence of MCC worldwide.
The efficacy of adjuvant therapy in resected MCC is controversial. Adjuvant radiotherapy has been reported to significantly reduce local recurrence in most retrospective studies including meta-analyses.,,, However, there are also reports that adjuvant radiotherapy did not reduce recurrence.,, There is no randomized study of the efficacy of adjuvant chemotherapy or chemoradiotherapy in MCC. In a retrospective analysis of approximately 7000 patients, neither adjuvant chemotherapy nor chemoradiotherapy had an effect on OS. In other studies with fewer patients, adjuvant chemotherapy had no positive effect on relapse and OS., In our study, 27.6% of the patients in the early stage had relapsed. Patients who received adjuvant chemotherapy or chemoradiotherapy had better 5-year DFS than those who received radiotherapy or did not receive adjuvant therapy numerically, but this difference was not statistically significant. Adjuvant treatment decisions were not similar among the participating centers included in our study. While adjuvant treatment was applied to some of the patients in stage I, some of the high-risk patients in stage III did not receive adjuvant therapy. Therefore, we could not conclude a definite conclusion about the efficacy of adjuvant therapy in this study.
A large retrospective analysis of 8044 patients revealed that tumor diameter and lymph node involvement were associated with survival. In other large series, patients with small tumor size and no lymph node involvement were reported to have the longest survival group. It was observed that tumor diameter, lymph node status, immunohistochemical CK20 positivity, primary location, and gender had no effect on recurrence and OS in our study. OS decreased as the age at diagnosis increased in our series. It is not correct to make a clear conclusion on this issue because of the low number of patients and heterogeneity of patient characteristics.
Our study had some limitations. First, our study was retrospective and this restricted us from accessing some data of some patients such as immunohistochemical CK20 status. Second, our study group was not homogeneous; therefore, we could not evaluate the benefit of adjuvant treatment. However, according to the best of our knowledge, this study is the largest analysis of MCC outside the USA and Europe. We believe that the multicentric study of this rare disease is very valuable in understanding the clinicopathological features of patients in our region.
| > Conclusions|| |
MCC is a very rare aggressive carcinoma. The incidence and mortality of MCC increase with age. The benefit of adjuvant therapy in early stage is not clear; prospective studies are needed on this subject.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| > References|| |
Xue Y, Thakuria M. Merkel Cell Carcinoma Review. Hematol Oncol Clin North Am 2019;33:39-52.
Harms PW, Harms KL, Moore PS, DeCaprio JA, Nghiem P, Wong MK, et al
. The biology and treatment of Merkel cell carcinoma: Current understanding and research priorities. Nat Rev Clin Oncol 2018;15:763-76.
Paulson KG, Park SY, Vandeven NA, Lachance K, Thomas H, Chapuis AG, et al
. Merkel cell carcinoma: Current US incidence and projected increases based on changing demographics. J Am Acad Dermatol 2018;78:457-6300.
Albores-Saavedra J, Batich K, Chable-Montero F, Sagy N, Schwartz AM, Henson DE. Merkel cell carcinoma demographics, morphology, and survival based on 3870 cases: A population based study. J Cutan Pathol 2010;37:20-7.
Clarke CA, Robbins HA, Tatalovich Z, Lynch CF, Pawlish KS, Finch JL, et al
. Risk of merkel cell carcinoma after solid organ transplantation. J Natl Cancer Inst 2015;107:dju382.
Tadmor T, Aviv A, Polliack A. Merkel cell carcinoma, chronic lymphocytic leukemia and other lymphoproliferative disorders: An old bond with possible new viral ties. Ann Oncol 2011;22:250-6.
Engels EA, Frisch M, Goedert JJ, Biggar RJ, Miller RW. Merkel cell carcinoma and HIV infection. Lancet 2002;359:497-8.
Howard RA, Dores GM, Curtis RE, Anderson WF, Travis LB. Merkel cell carcinoma and multiple primary cancers. Cancer Epidemiol Biomarkers Prev 2006;15:1545-9.
Goon PK, Greenberg DC, Igali L, Levell NJ. Merkel cell carcinoma: Rising incidence in the east of England. J Eur Acad Dermatol Venereol 2016;30:2052-5.
Rastrelli M, Ferrazzi B, Cavallin F, Chiarion Sileni V, Pigozzo J, Fabozzi A, et al
. Prognostic factors in merkel cell carcinoma: A retrospective single-center study in 90 patients. Cancers (Basel) 2018;10:350.
Liang E, Brower JV, Rice SR, Buehler DG, Saha S, Kimple RJ. Merkel Cell Carcinoma Analysis of Outcomes: A 30-Year Experience. PLoS One 2015;10:e0129476.
Reichgelt BA, Visser O. Epidemiology and survival of Merkel cell carcinoma in the Netherlands. A population-based study of 808 cases in 1993-2007. Eur J Cancer 2011;47:579-85.
Harms KL, Healy MA, Nghiem P, Sober AJ, Johnson TM, Bichakjian CK, 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;23:3564-71.
Allen PJ, Bowne WB, Jaques DP, Brennan MF, Busam K, Coit DG. Merkel cell carcinoma: Prognosis and treatment of patients from a single institution. J Clin Oncol 2005;23:2300-9.
Youlden DR, Soyer HP, Youl PH, Fritschi L, Baade PD. Incidence and survival for Merkel cell carcinoma in Queensland, Australia, 1993-2010. JAMA Dermatol 2014;150:864-72.
Iyer JG, Blom A, Doumani R, Lewis C, Tarabadkar ES, Anderson A, et al
. Response rates and durability of chemotherapy among 62 patients with metastatic Merkel cell carcinoma. Cancer Med 2016;5:2294-301.
Nghiem PT, Bhatia S, Lipson EJ, Kudchadkar RR, Miller NJ, Annamalai L, et al
. PD-1 blockade with pembrolizumab in advanced merkel-cell carcinoma. N Engl J Med 2016;374:2542-52.
Baker M, Cordes L, Brownell I. Avelumab: A new standard for treating metastatic Merkel cell carcinoma. Expert Rev Anticancer Ther 2018;18:319-26.
Voelker R. Why merkel cell cancer is garnering more attention. JAMA 2018;320:18-20.
Song PI, Liang H, Wei WQ, Jiang YQ, Smith JS, Qiao YL. The clinical profile of Merkel cell carcinoma in mainland China. Int J Dermatol 2012;51:1054-9.
Kieny A, Cribier B, Meyer N, Velten M, Jégu J, Lipsker D. Epidemiology of Merkel cell carcinoma. A population-based study from 1985 to 2013, in northeastern of France. Int J Cancer 2019;144:741-5.
Santamaria-Barria JA, Boland GM, Yeap BY, Nardi V, Dias-Santagata D, Cusack JC Jr. Merkel cell carcinoma: 30-year experience from a single institution. Ann Surg Oncol 2013;20:1365-73.
Zaar O, Gillstedt M, Lindelöf B, Wennberg-Larkö AM, Paoli J. Merkel cell carcinoma incidence is increasing in Sweden. J Eur Acad Dermatol Venereol 2016;30:1708-13.
Kaae J, Hansen AV, Biggar RJ, Boyd HA, Moore PS, Wohlfahrt J, et al
. Merkel cell carcinoma: Incidence, mortality, and risk of other cancers. J Natl Cancer Inst 2010;102:793-801.
Kukko H, Böhling T, Koljonen V, Tukiainen E, Haglund C, Pokhrel A, et al
. Merkel cell carcinoma-a population-based epidemiological study in Finland with a clinical series of 181 cases. Eur J Cancer 2012;48:737-42.
Fondain M, Dereure O, Uhry Z, Guizard AV, Woronoff AS, Colonna M, et al
. Merkel cell carcinoma in France: A registries-based, comprehensive epidemiological survey. J Eur Acad Dermatol Venereol 2018;32:1292-6.
Medina-Franco H, Urist MM, Fiveash J, Heslin MJ, Bland KI, Beenken SW. Multimodality treatment of Merkel cell carcinoma: Case series and literature review of 1024 cases. Ann Surg Oncol 2001;8:204-8.
Lewis KG, Weinstock MA, Weaver AL, Otley CC. Adjuvant local irradiation for Merkel cell carcinoma. Arch Dermatol 2006;142:693-700.
Fields RC, Busam KJ, Chou JF, Panageas KS, Pulitzer MP, Allen PJ, et al
. Recurrence after complete resection and selective use of adjuvant therapy for stage I through III Merkel cell carcinoma. Cancer 2012;118:3311-20.
Villani A, Fabbrocini G, Costa C, Carmela Annunziata M, Scalvenzi M. Merkel cell carcinoma: Therapeutic update and emerging therapies. Dermatol Ther (Heidelb) 2019;9:209-22.
Boyer JD, Zitelli JA, Brodland DG, D'Angelo G. Local control of primary Merkel cell carcinoma: Review of 45 cases treated with Mohs micrographic surgery with and without adjuvant radiation. J Am Acad Dermatol 2002;47:885-92.
Vargo JA, Ghareeb ER, Balasubramani GK, Beriwal S. Adjuvant radiation therapy and chemotherapy in merkel cell carcinoma: Survival analyses of 6908 cases from the national cancer data base. J Natl Cancer Inst 2017;109:10.
Poulsen MG, Rischin D, Porter I, Walpole E, Harvey J, Hamilton C, et al
. Does chemotherapy improve survival in high-risk stage I and II Merkel cell carcinoma of the skin? Int J Radiat Oncol Biol Phys 2006;64:114-9.
Iyer JG, Storer BE, Paulson KG, Lemos B, Phillips JL, Bichakjian CK, et al
. Relationships among primary tumor size, number of involved nodes, and survival for 8044 cases of Merkel cell carcinoma. J Am Acad Dermatol 2014;70:637-43.
Lemos BD, Storer BE, Iyer JG, Phillips JL, Bichakjian CK, Fang LC, 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;63:751-61.
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]