Since the first description of the Merkel cell carcinoma by Cyril Toker in 1972, the number of studies has significantly increased over the last 4 decades. In this review, we will illustrate the historical background of the Merkel cell carcinoma beginning with the 19th century, the first description of the Merkel cell to the finding of the CK20 as a highly specific diagnostic marker and finally to the recently detected Merkel cell polyomavirus (MCPyV). Moreover, we will highlight the beginning of adjuvant therapeutic regimens with radiotherapy and chemotherapy and discuss the diagnostic work-up including imaging and histology of patients with Merkel cell carcinoma. Another very rapidly growing and interesting field of research is the development of patients' specific and tailored targeted therapy, in particular in patients with distant metastatic disease.

Inamaria Erovic

Boban M. Erovic

Merkel Cell Carcinoma: The Past, the Present, and the Future

Signal transducer and activator of transcription 3 (Stat3) is a cytoplasmic protein that is activated in response to cytokines and growth factors and acts as a transcription factor. Stat3 plays critical roles in various biological activities including cell proliferation, migration, and survival. Studies using keratinocyte-specific Stat3-deficient mice have revealed that Stat3 plays an important role in skin homeostasis including keratinocyte migration, wound healing, and hair follicle growth. Use of both constitutive and inducible keratinocyte-specific Stat3-deficient mouse models has demonstrated that Stat3 is required for both the initiation and promotion stages of multistage skin carcinogenesis. Further studies using a transgenic mouse model with a gain of function mutant of Stat3 (Stat3C) expressed in the basal layer of the epidermis revealed a novel role for Stat3 in skin tumor progression. Studies using similar Stat3-deficient and gain-of-function mouse models have indicated its similar roles in ultraviolet B (UVB) radiation-mediated skin carcinogenesis. This paper summarizes the use of these various mouse models for studying the role and underlying mechanisms for the function of Stat3 in skin carcinogenesis. Given its significant role throughout the skin carcinogenesis process, Stat3 is an attractive target for skin cancer prevention and treatment.

Everardo Macias

Dharanija Rao

John DiGiovanni

Role of Stat3 in Skin Carcinogenesis: Insights Gained from Relevant Mouse Models

Nowadays, oncogene-directed therapy and immunotherapy represent the two most promising avenues for patients with metastatic melanoma. The recent oncogene-directed therapeutic, vemurafenib, usually produces high level of tumor shrinkage and survival benefits in many patients with B-RA<svg style="vertical-align:-0.0pt;width:43.575001px;" id="M1" height="16.012501" version="1.1" viewBox="0 0 43.575001 16.012501" width="43.575001" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
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</svg> mutant melanomas, although the fast and high degrees of responses are likely short-lived. Conversely, the newly-approved immunotherapeutic, ipilimumab, produces durable responses in patients presenting CTLA-4 T-cell surface protein. Nevertheless, the possible synergy in combining these two therapeutic strategies primarily rely on the rational design of medical protocols (e.g., sequence and timing of agent administration; drug selectivity; compatibility of combined therapies i.e., adoptive T cell or agents, i.e., MEK inhibitor trametinib, PD-1 and PDL-1 blockers). Improved therapeutic protocols shall overcome therapeutic limitations such as the (i) tolerability and safety (i.e., minimal toxic side-effects); (ii) progression free survival (e.g., reduced relapse disease frequency); (iii) duration response (i.e., decreased drug resistance). Eventually, multidisciplinary approaches are still requested (e.g., genomics for personalized medicine, nanomedicine to overcome low free-drug bioavailability and targeting, systematic search of &#x201c;melanoma stem cells&#x201d; to enhance the prognosis and develop more valuable theranostics). In this paper, I will mainly present and discuss the latest and promising treatments for advanced cutaneous melanomas.

Farid Menaa

Latest Approved Therapies for Metastatic Melanoma: What Comes Next?

Exploitation of biological properties unique to cancer cells may provide a novel approach to overcome difficult challenges to the treatment of advanced melanoma. In order to develop melanoma-targeted chemothermoimmunotherapy, a melanogenesis substrate, N-propionyl-4-S-cysteaminylphenol (NPrCAP), sulfur-amine analogue of tyrosine, was conjugated with magnetite nanoparticles. NPrCAP was exploited from melanogenesis substrates, which are expected to be selectively incorporated into melanoma cells and produce highly reactive free radicals through reacting with tyrosinase, resulting in chemotherapeutic and immunotherapeutic effects by oxidative stress and apoptotic cell death. Magnetite nanoparticles were conjugated with NPrCAP to introduce thermotherapeutic and immunotherapeutic effects through nonapoptotic cell death and generation of heat shock protein (HSP) upon exposure to alternating magnetic field (AMF). During these therapeutic processes, NPrCAP was also expected to provide melanoma-targeted drug delivery system.

Kowichi Jimbow

Yasue Ishii-Osai

Shosuke Ito

Yasuaki Tamura

Akira Ito

Akihiro Yoneta

Takafumi Kamiya

Toshiharu Yamashita

Hiroyuki Honda

Kazumasa Wakamatsu

Katsutoshi Murase

Satoshi Nohara

Eiichi Nakayama

Takeo Hasegawa

Itsuo Yamamoto

Takeshi Kobayashi

Melanoma-Targeted Chemothermotherapy and In Situ Peptide Immunotherapy through HSP Production by Using Melanogenesis Substrate, NPrCAP, and Magnetite Nanoparticles

The management of lymph nodes in nonmelanoma skin cancer patients is currently still debated. 
Merkel cell carcinoma (MCC), squamous cell carcinoma (SCC), pigmented epithelioid melanocytoma (PEM), and other rare skin neoplasms have a well-known risk to spread to regional lymph nodes. The use of sentinel lymph node biopsy (SLNB) could be a promising procedure to assess this risk in clinically N0 patients. Metastatic SNs have been observed in 4.5&#x2013;28&#x25; SCC (according to risk factors), in 9&#x2013;42&#x25; MCC, and in 14&#x2013;57&#x25; PEM. We observed overall 30.8&#x25; positive SNs in 13 consecutive patients operated for high-risk nonmelanoma skin cancer between 2002 and 2011 in our institution. These high rates support recommendation to implement SLNB for nonmelanoma skin cancer especially for SCC patients. Completion lymph node dissection following positive SNs is also a matter of discussion especially in PEM. It must be remembered that a definitive survival benefit of SLNB in melanoma patients has not been proven yet. However, because of its low morbidity when compared to empiric elective lymph node dissection or radiation therapy of lymphatic basins, SLNB has allowed sparing a lot of morbidity and could therefore be used in nonmelanoma skin cancer patients, even though a significant impact on survival has not been demonstrated.

Marie-Laure Matthey-Gi&#xe8;

Ariane Boubaker

Igor Letovanec

Nicolas Demartines

Maurice Matter

Sentinel Lymph Node Biopsy in Nonmelanoma Skin Cancer Patients

Merkel cell carcinoma (MCC) is a rare neuroendocrine skin tumor that typically occurs in elderly, immunosuppressed patients. Infection with Merkel cell virus (MCV) and immunosuppression play an important role in the development of MCC. Different staging systems make it difficult to compare the existing clinical data. Furthermore, there predominantly exist single case reports and case series, but no randomized controlled trials. However, it is necessary to develop further therapy options because MCC tends to grow rapidly and metastasizes early. In the metastatic disease, therapeutic attempts were made with various chemotherapeutic combination regimens. Because of the high toxicity of these combinations, especially those established in SCLC, and regarding the unsatisfying results, the challenge is to balance the pros and cons of chemotherapy individually and carefully. Up to now, emerging new therapy options as molecular-targeted agents, for example, pazopanib, imatinib, or somatostatin analogues as well as immunologicals, for example, imiquimod and interferons, also showed less success concerning the disease-free response rates. According to the literature, neither chemotherapy nor molecular-targeted agents or immunotherapeutic strategies have shown promising effects in the therapy of the metastatic disease of MCC so far. There is a great demand for randomized controlled studies and a need for an MCC registry and multicenter clinical trials due to the tumors curiosity.

Laura Desch

Rainer Kunstfeld

Merkel Cell Carcinoma: Chemotherapy and Emerging New Therapeutic Options

Merkel cell carcinoma (MCC) is a rare, aggressive neuroendocrine tumor of the skin with a mortality rate of approximately 25&#x25; (Peloschek et al., 2010). Accurate assessment of nodal involvement in patients with MCC predicts significantly overall outcome (Smith et al., 2012 and Ortin-Perez et al., 2007). Due to the rarity of this highly aggressive disease, only a few imaging reports on MCC were published, and subsequently still to date no accepted imaging algorithm for MCC is available. For primary staging of MCC, general recommendations have included ultrasonography, chest X-ray CT, and MRI, but recent articles show that the use of sentinel node and FDG-PET/PET-CT is gaining more and more importance.

Elisabeth Enzenhofer

Philipp Ubl

Christian Czerny

Imaging in Patients with Merkel Cell Carcinoma

Background. The goal of this paper is to review contemporary multidisciplinary treatment with reference to Merkel cell carcinoma. Management of this rare but highly aggressive skin cancer is a complex undertaking that necessitates an understanding of its etiology, epidemiology, clinical presentation, and the coordinated work of several clinical specializations. Recent Findings. The contemporary literature employs a multidisciplinary approach to achieve the best patient's treatment. Conclusion. This paper presents an algorithm for contemporary management for the rare and aggressive Merkel cell carcinoma. Multidisciplinary approach in a tumor center provides high-quality care for patients with Merkel cell carcinoma.

Sven Schneider

Dietmar Thurnher

Merkel Cell Carcinoma: Interdisciplinary Management of a Rare Disease

There is a need for effective &#x201c;broad spectrum&#x201d; therapies for metastatic melanoma which would be suitable for all patients. The objectives of Phase Ia/Ib studies were to evaluate the safety, pharmacokinetics, dosimetry, and antitumor activity of 188Re-6D2, a 188-Rhenium-labeled antibody to melanin. Stage IIIC/IV metastatic melanoma (MM) patients who failed standard therapies were enrolled in both studies. In Phase Ia, 10&#x2009;mCi 188Re-6D2 were given while unlabeled antibody preload was escalated. In Phase Ib, the dose of 188Re-6D2 was escalated to 54&#x2009;mCi. SPECT/CT revealed 188Re-6D2 uptake in melanoma metastases. The mean effective half-life of 188Re-6D2 was 12.4&#x2009;h. Transient HAMA was observed in 9 patients. Six patients met the RECIST criteria for stable disease at 6 weeks. Two patients had durable disease stabilization for 14 weeks and one for 22 weeks. Median overall survival was 13 months with no dose-limiting toxicities. The data demonstrate that 188Re-6D2 was well tolerated, localized in melanoma metastases, and had antitumor activity, thus warranting its further investigation in patients with metastatic melanoma.

M. Klein

M. Lotem

T. Peretz

S. T. Zwas

S. Mizrachi

Y. Liberman

R. Chisin

J. Schachter

I. G. Ron

G. Iosilevsky

J. A. Kennedy

E. Revskaya

A. W. de Kater

E. Banaga

V. Klutzaritz

N. Friedmann

E. Galun

G. L. DeNardo

S. J. DeNardo

A. Casadevall

E. Dadachova

G. B. Thornton

Safety and Efficacy of 188-Rhenium-Labeled Antibody to Melanin in Patients with Metastatic Melanoma

Merkel cell carcinoma (MCC) is a rare cutaneous malignancy occurring mostly in older immunocompromized Caucasian males. A growing incidence of MCC has been reported in epidemiological studies. Treatment of MCC usually consists of surgical excision, pathological lymph node evaluation, and adjuvant radiotherapy. This paper reports the experience of a single tertiary center institution with 17 head and neck Merkel cell carcinoma patients. Median followup for the cohort was 37.5 months. After five years, recurrence-free survival, disease specific survival, and overall survival were 85&#x25;, 90&#x25;, and 83&#x25;, respectively. Our limited data support the use of adjuvant radiotherapy. We also report two cases of MCC located at the vestibule of the nose and two cases of spontaneous regression after diagnostic biopsy. About 40&#x25; of our patients were referred to our center for surgical revision and pathological lymph node evaluation. Increased awareness of MCC and an interdisciplinary approach are essential in the management of MCC.

G. Morand

D. Vital

T. P&#xe9;zier

D. Holzmann

M. Roessle

A. Cozzio

G. F. Huber

Merkel Cell Carcinoma of the Head and Neck: A Single Institutional Experience

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Journal of Skin Cancer publishes clinical and translational research on the detection, diagnosis, prevention, and treatment of skin malignancies.

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Journal of Skin Cancer - Table of contents 2013

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Journal of Skin Cancer publishes clinical and translational research on the detection, diagnosis, prevention, and treatment of skin malignancies.

Journal of Skin Cancer