Merkel cell carcinoma (MCC) is a neuroendocrine neoplasia formerly called ‘trabecular carcinoma of the skin’ but then renamed following the observation that tumor cells closely resemble Merkel cells. Merkel cells are reliably identified through the expression of several markers, such as cytokeratin (CK) 8, 18 and 20, mechanosensitive ion channels, neuropeptides and presynaptic machinery components . MCC cells express the same markers, and the development of immunostaining techniques has improved disease identification [2▪▪].
Although rare, MCC is a rapidly progressing disease and until recently, available therapeutic approaches led to poor prognosis, with 5-year overall survival (OS) rates of only 40% . This article reviews current knowledge on MCC and its treatment, with a focus on recent advancements.
MCC is a relatively rare disease, roughly 50 times less frequent than melanoma, with reported incidences of 0.6 cases/100 000 person-years in the United States (US), 1.6/100 000 in Australia and 0.3/100 000 in Sweden, between 2006 and 2012 [4▪▪]. However, an ascending trend over time was noted for several countries [5▪]; for instance, in the United States, an increase of 95% in the number of MCC cases was reported during 2000–2013, leading to an incidence of 0.7/100 000 person-years in 2013, with further escalation predicted by 2025 [6▪]. The observed increase in incidence is best explained by the improvements in the diagnosis techniques used (particularly, the use of CK-20 immunohistochemistry), but might be also paralleling ageing of the global population, as the disease is more frequent in the elderly.
The main cause of MCC, accounting for more than 80% of cases, is a mutated form of the Merkel cell polyoma virus (MCPyV). The virus is widely spread among the general population, and a recent study evaluating seroprevalence of human polyomaviruses in blood donors showed an overall prevalence of 81.9% for MCPyV . Moreover, MCPyV DNA was previously identified in around 3% of tested serum samples from 196 healthy blood donors [8▪▪], suggesting the possibility that transfusion is a way of infection. The nonmutated form of the virus is, nevertheless, innocuous and infection does not cause any symptoms in healthy individuals.
MCPyV-positive (MCPyV+) MCC tumors consistently express two major viral proteins, the large T (LT) and small T (ST) antigens. MCPyV is considered as an MCC trigger in most cases and is clearly associated with the disease. The underlying mechanism is still under investigation, but considerable advances have been made over the last 2 years. Co-expression of ST and the atonal basic helix–loop–helix transcription factor 1 (ATOH-1) was shown to lead to the growth of epidermis-derived MCC-like tumors in mice [9▪]. Epigenetic deregulation mediated by polycomb repressive complex 2 (PRC2) was also linked to the pathogenesis of MCPyV+ MCC, by investigating immunohistochemical expression of the H3K27me3 marker . Binding of ST to the MYC homolog MYCL and the EP400 histone acetyltransferase and chromatin remodeling complex was also shown to activate gene expression, which contributes to MCC-tumorigenesis . MCPyV ST expression enhances cell dissociation, through a process, which implicates the cellular sheddases (A disintegrin and metalloproteinase 10 and 17 proteins) in cellular transformation and metastasis . Cellular chloride channels  and Rho-GTPase-induced filopodium formation  have also been shown to be upregulated by MCPyV ST and contribute to cell motility. Other findings suggest that MCPyV survives in the host by impairing the innate immune response through binding of ST to nuclear factor kappa B transcriptors, involving an interaction between ST and the regulatory sub-unit 1 of protein phosphatase4 .
For MCPyV-negative (MCPyV−) MCC, incidence is strongly associated with ultraviolet (UV) exposure, but an increased somatic UV-mediated mutation rate is needed to reach oncogenesis of the same severity as that driven by MCPyV positivity [16▪]. In Australia, the country with the highest incidence of the disease, most MCCs are in fact MCPyV− [5▪], indicating UV radiation mutagenesis as the etiologic factor for MCC. MCPyV− MCC can be reliably detected by immunostaining with an anti-CM2B4 antibody and has been shown to have a higher risk of progression and death compared with MCPyV+ MCC .
Regardless of MCC cause, the cellular origin of the tumor remains unknown. Although the involvement of Merkel cell precursors has been proposed [4▪▪], the Merkel cells themselves are unlikely candidates, as they do not undergo cell division and MCC cells are highly dividing cells. Moreover, many molecular markers are expressed differently in Merkel cells and MCC cells, and many markers expressed by tumor cells are not expressed by Merkel cells [18▪▪]. Following an analysis of genetic and virology studies up to date, Sunshine et al. [18▪▪] suggested that MCPyV+ and MCPyV− MCC cells might have different origin, with the former deriving from dermal fibroblast and the latter from epidermal keratinocytes.
Advanced age is associated with an increased risk of developing MCC, and the mean age at diagnosis is over 73 years in both women and men . MCC in pediatric patients and young adults is extremely rare. A retrospective study in the United States covering 27 105 incident MCC cases between 2001 and 2015 estimated that not only 0.07% of patients were aged less than 30 years but also pointed out that the disease is more likely to be diagnosed at advanced stages in pediatric and young adult patients .
MCC has previously been reported as more frequent in men, although sex-specific incidences tend to vary from one region to another and over time, as shown by an analysis of 11 576 MCC cases from 20 countries covering the 1990–2007 time period [5▪]. A recent registry-based study in France showed that 56.9% of cases occurred in women .
Individuals with white skin pigmentation, sustained exposure to sun or UV light or history of other skin cancers [4▪▪] are at higher risk of MCC. Immunodeficiency has also long been identified as a risk factor for MCC [2▪▪,4▪▪]. Recent reports have shown that individuals with a history of chronic inflammatory disorders [22▪] and organ transplant recipients [23▪,24,25] are at higher risk of MCC.
MCC presents as a painless, rapidly growing, solitary, firm nodule or plaque that is red – pink or blue – violaceous in color. The most frequent locations for the primary tumor are the head and neck in more than 50% of cases [26,27], followed by the lower limbs and upper extremities, together accounting for more than 80% of the tumors, in body regions exposed to UV light . The trunk , the eyelid [30,31▪▪] and oral/genital mucosa [32,33] are also possible sites, albeit rarely reported, in less than 16% of patients, whereas in up to 15% of cases, the primary lesion is not identified . Although MCC typically involves the dermis, rare instances of strictly intraepidermal tumors have also been reported [34,35] and a recent case of pure nodal MCC has recently been described . Laterality has been previously reported in MCC and a recent study in German patients found a statistically significant left-side localization of tumors, underlining that the explanation of this finding likely goes beyond asymmetrical UV exposure .
The ‘AEIOU’ acronym was developed by Heath et al. and is frequently used in the diagnosis of MCC. It stands for the clinical features: asymptomatic/lack of tenderness, expanding rapidly, immune suppression, older than 50 years and UV-exposed/fair skin. Virtually all cases of MCC present with at least three of these features .
DIAGNOSIS: HISTOLOGY, IMMUNOHISTOCHEMICAL AND MOLECULAR MARKERS
In clinical practice, sufficient diagnosis of MCC relies on a characteristic histopathological analysis of a biopsy sample with a positive result for CK-20 immunostaining and negative for TTF-1, in order to differentiate the tumor from other neoplasms and cancer types [2▪▪,38] (Table 1). However, CK-20 expression has been previously reported to be negative in 5–10% of MCC cases. Neurofilament expression has recently been proposed as a superior differentiator between MCC and small cell neuroendocrine carcinomas, with neurofilament and CK-20 specificity of 96.7 and 59.0%, respectively, in discriminating between the two tumor types . Diffuse CD56 expression and patchy CK-5/6 positivity can also be used to differentiate MCC from basal cell carcinoma . Special AT-rich sequence-binding protein 2, neurofilament and MCPyV DNA detection have been recently proposed as sensitive additional markers for MCC diagnosis, allowing to distinguish CK20-negative MCC from other neuroendocrine cancers [41▪▪]. Positivity for MCPyV can also be determined with specific markers against LT and ST antigens. The use of other markers continues to be investigated [10,13,29,42–50].
Complete skin and lymph nodal clinical examination, together with hematoxylin and eosin staining of tumor samples and a full immunopanel are recommended prior to diagnosis, whereas imaging studies are required postdiagnosis [2▪▪].
Knowledge of the morphology of MCC tumors by other noninvasive methods, such as nonreflectance confocal microscopy [51▪], dermoscopy [52▪] and ultrasound  continues to be improved.
Age over 60 years, male sex, head/neck localization of the primary tumor, disease stage at diagnosis have already been established as being associated with worse MCC outcomes [4▪▪,19,54,55▪▪] and these data continue to be confirmed by recent reports. Table 2 summarizes large retrospective and prospective studies conducted in real-world settings, published within the last 2 years and reporting on MCC outcomes and prognostic factors.
As expected, OS rates in MCC patients depend on the size of the primary tumor at diagnosis: 5-year OS rates of 55.8, 41.1 and 31.8% have been reported for T1 (≤2 cm), T2/T3 (>2 to ≤5 cm/>5 cm) and T4 (primary tumor invading fascia, muscle, cartilage or bone) categories, respectively [87▪▪]. This analysis was carried out in 9000 patients and constituted the basis of the new American Joint Committee on Cancer staging system. The new system requires clinical or pathological designation, as the diagnosis type leads to differences in predicted MCC recurrence and survival. Patients with nodal disease but unknown primary tumor are also staged differently from those with visible primary tumors. According to the current stages, stages I (tumor ≤2 cm), IIA (tumor >2 cm) and IIB (tumor invading bone, muscle, fascia or cartilage) have no nodal disease or distant metastasis. Stages III, IIIA (which distinguishes pathologically unknown/known primary tumors) and IIIB require the presence of positive node, but involve no distant metastasis, whereas stage IV includes distant metastases with or without regional node involvement . The potential value of novel imaging techniques in the diagnosis and staging of MCC continues to be evaluated. Sentinel lymph node biopsy (SLNB) can be improved with better preoperative imaging techniques. A recent study comparing the routinely used planar lymphoscintigraphy to single-photon emission computed tomography/computed tomography (SPECT/CT) has shown the latter to allow the identification of additional hot spots in almost 50% of patients with cutaneous malignancies. However, in 6.8% of patients, additional spots not identified in SPECT/CT were detected by lymphoscintigraphy, suggesting that the two techniques should be used together . In a prospective study conducted in Australia, fluorine-18 fluorodeoxyglucose PET (18-FDG PET)/CT was recently shown to have high sensitivity and specificity in the staging of MCC. Pretreatment staging influenced treatment decision by allowing for the upstaging of the disease in 25.9% of MCC patients . 68-Ga-somatostatin analog PET/CT has been shown to have a similar diagnosis performance . 18-FDG PET/CT has also been used to monitor response of metastatic MMC to immunotherapy .
Immunosuppression is also associated with decreased survival in MCC patients  and a recent study also showed that the type of immunosuppression (chronic lymphocytic leukemia, other hematologic malignancies, solid organ transplant, autoimmune disease and HIV-acquired deficiency syndrome) leads to significantly different MCC-specific survival and OS [58▪▪].
UPDATES IN MERKEL CELL CARCINOMA TREATMENT
Surgery remains the first therapeutic option in the treatment of primary tumors, with recommended resection margins of 1–2 cm [94▪]. Mohs micrographic surgery is also performed and has been shown to be noninferior to wide local excision in several recent studies [77,79,80]. Adjuvant radiotherapy is also indicated (50 Gy and >10 Gy on tumor bed) [4▪▪,38], with the radiation dose impacting the OS of MCC patients [74,75▪▪,95]. When surgical resection is not feasible, definitive radiotherapy can be used as an alternative first-line treatment of MCC, and 5-year OS rates of 40% have been reported with this technique . However, the use of radiotherapy alone has recently been shown to have poorer outcomes than the standard-of-care surgical intervention, with the surgery improving median and even long-term survival compared with radiotherapy alone. In a retrospective study conducted in 2454 MCC patients in the United States, who received either surgery or radiotherapy as primary treatment, stage I/II disease patients who underwent surgery showed median OS of 76 months (versus 25 months in those under radiotherapy). In stage III patients, median OS was 30 and 15 months in the surgery and radiotherapy groups, respectively . Of note, immunosuppressed patients have a lower response to radiotherapy compared with immunocompetent MCC patients, as shown by significantly inferior recurrence-free survival (2-year: 30% in immunosuppressed versus 57% in immunocompetent; 5-year: 29 versus 48%), higher rates of local recurrence (2-year: 25 versus 12%; 5-year: 27 versus 13%) and lower OS (2-year: 53 versus 82%; 5-year: 38 versus 63%) [81▪▪]. A recent systematic review evaluating radiotherapy treatment for inoperable MCC tumors concluded that adjuvant doses of 50–55 Gy might be optimal for head/neck tumors . Other recent studies reporting on the predictive value of therapeutic options in MCC are included in Table 2 .
Determining the degree/extent of lymph node disease in MCC patient is crucial. The most important independent predictor of distant involvement in MCC is lymph node status [2▪▪]; therefore, after histological diagnosis, SLNB is recommended in the management of all MCC patients to identify subclinical nodal extension . SLN positivity is reported for 30–38% of MCC tumors, but results of studies evaluating the prognostic value of SLN are still conflicting [2▪▪], with a recent study indicating no statistical differences in the disease-free survival of SLN-positive and SLN-negative patients [78▪].
Clinically positive nodes should also be managed with a combination of surgical interventions and radiotherapy of the primary tumor, followed by therapeutic lymph node dissection. As the benefit of lymph node area radiotherapy is considered to be limited to local disease control, this approach should be discussed on a case-by-case basis. Enrollment of patients in clinical trials is strongly recommended [2▪▪,38].
Unresectable metastatic MCC had no established curative treatment until recently. Chemotherapy (most often a combination of cisplatin and etoposide) or monotherapies using anthracyclines, liposomal anthracyclines or etoposide are recommended, along with best supportive care and strong support towards clinical trials assessing immunotherapeutic and targeted therapy approaches . However, as real-world evidence continues to accumulate, it indicates that metastatic MCC tumor response to chemotherapy as first-line or second-line treatment is transient. In a systematic literature review, Nghiem et al. [97▪] report objective response rates (ORRs) of 20–61% after chemotherapy, with improved outcomes in first-line versus second-line settings, and a duration of response (DOR) of 8 months or less among responders. In a retrospective European study including immunocompetent and immunosuppressed patients having received at least two lines of therapy, an ORR of 8.8% and median DOR of 1.9 months were observed; these outcomes were improved when only the immunocompetent population was considered .
The poor outcomes observed with chemotherapy reflect a medical need for metastatic MCC patients. Over the last decade, immunotherapy emerged as a viable therapeutic alternative for MCC, as a direct conclusion of several lines of evidence. First, the association between immunosuppression and poorer disease prognosis lead to the identification of MCC as an immunogenic cancer. Second, early observations that patients with high CD8 T-cell infiltration into MCC tumors had improved outcomes compared with those with sparse infiltration (100 versus 60% MCC-specific survival) suggested a potential role of CD8 T cells in the tumor environment . Third, the presence of MCPyV-specific CD8 T cells and MCC-infiltrating lymphocytes were later correlated with expression of programmed cell death-ligand 1 (PD-L1) . Fourth, MCPyV-negative MCCs also harbor more tumor neoantigens than other types of cancer for which therapy using immune checkpoint inhibitors (CPIs) have been approved, such as melanoma or nonsmall cell lung cancers [100▪▪]. Taken together, these findings suggested that increased immune function would favor positive MCC outcomes and that therapies targeting the programmed cell death protein 1 (PD1)/PD-L1 immune checkpoint blockade would be effective in the treatment of the disease.
Several CPIs have been evaluated in clinical trials for treatment of MCC. The rapid advances in this field over the last decade culminated with the approval of avelumab, a human IgG1 anti-PD-L1 monoclonal antibody, for use as second-line treatment of metastatic MCC in individuals 12 years of age or older in the United States  and adults in Europe . Avelumab also received a marketing authorization in Australia in 2018  and in Japan. Approval was based on the results of an open-label, single-arm, multicenter phase II clinical trial (JAVELIN Merkel 200, NCT02155647), in which 88 adult patients with metastatic MCC previously treated with chemotherapy received 10 mg/kg avelumab intravenously every 2 weeks [104▪▪]. After at least 1 year of follow-up, ORRs were 33.0%, with 11.4 and 21.6% of patients achieving complete and partial responses, respectively. Median OS was 12.9 months [105▪▪], exceeding by far historical OS outcomes achieved with other second-line therapies (Table 3). Metastatic MCC nonprogression following treatment with avelumab was associated with improved health-related quality of life [106▪▪]. Avelumab is also currently being evaluated in first-line settings, in a multicenter, single-arm, open-label clinical trial (JAVELIN 200 Merkel part B) in MCC patients, receiving 10 mg/kg every 2 weeks until confirmed disease progression and results from an interim analysis are available [107▪▪]. Over a median follow-up of 5.1 months, the ORR was 62.1%, and treatment was generally well tolerated [107▪▪]. The study is still ongoing.
Another CPI, the humanized IgG4 anti-PD1 monoclonal antibody pembrolizumab, was also evaluated as first-line treatment in a single-arm, multicenter, phase II, single-arm study (NCT02267603), in which 26 patients with metastatic MCC received 2 mg/kg pembrolizumab every 3 weeks [108▪▪]. Over a median follow-up of 8.3 months, the ORR was 56% and increased to 62% in patients with MCPyV-positive MCC and the DOR ranged from 2.2 to 9.7 months [108▪▪] (Table 3). An additional assessment in this study showed that tumors from patients responding to pembrolizumab treatment showed higher densities of PD1 and PDL1-expressing cells when compared with nonresponders, whereas no significant correlation between CD8 T-cell density and clinical response was observed [110▪▪]. The National Comprehensive Cancer Network recommendations currently include the use of pembrolizumab as a systemic therapy option in patients with metastatic MCC [2▪▪].
Nivolumab, a human IgG4 anti-PD1 antibody, also shows clinical activity in MCC patients. In an open-label, single-arm, multicenter phase I/II study (CheckMate358, NCT02488759), among 25 patients with metastatic MCC who received 240 mg/kg nivolumab, the ORR was 68% over 6.5 months of follow-up with higher responses observed in treatment-naïve than in previously treated MCC patients. The 3-month progression-free survival and OS rates were high and treatment was well tolerated  (Table 3). The study is ongoing and includes cohorts in which the antibody is administered in combination with other therapies.
More than 20 clinical trials investigating immunotherapy alone or in combination with other therapies are ongoing on, in recruiting phase, and are evaluating several immunotherapeutic agents, which could eventually constitute a viable, decisive option in the treatment of MCC. A pilot study assessing the intratumoral administration of G100 – a toll-like receptor 4 – with or without surgery/radiation therapy, has already shown promising results in both neoadjuvant and metastatic settings . Talimogene laherparepvec has already received an indication for advanced melanoma and is currently evaluated for MCC in clinical trial settings (NCT02819843). However, its use as first-line therapy for surgically incurable MCC has recently been reported. Intratumorally administered talimogene laherparepvec led to a regression of tumors and prevented new locoregional and distant metastasis for 6–11 months . In a phase I clinical trial evaluating utomilumab (an agonistic monoclonal antibody), an overall ORR of 13.3% was observed in patients with MCC, including a complete and a partial response [113▪]. However, carbozantinib did not show any activity and was poorly tolerated by patients with platinum failure, recurrent/metastatic MCC .
Recent studies also propose activated protein kinase Cε , tropomyosin receptor kinase A , indoleamine 2,3-dioxygenase 1, tryptophan 2,3-dioxygenase 2 and aryl hydrocarbon receptor expression , or CCL17/TARC and its receptor CCR4 , vascular endothelial growth factor A inhibition  or blockade of CD33 [118▪] as potential targets of future therapeutic strategies.
The treatment of MCC, a rare but severe and aggressive disease, is complicated by immunosuppression and poor response to chemotherapy and radiotherapy. However, knowledge continues to accumulate on immunohistochemical and molecular markers associated with MCC, and recent advances in imaging techniques facilitate diagnosis and identification of factors with predictive value for the disease outcome. The development of anti-PD1 and anti-PDL1 immunotherapeutics, leading to the approval of avelumab for treatment of metastatic MCC in several countries, represents a breakthrough in the field and begins to cover an unmet medical need. Nevertheless, alternative therapies are still needed for patients not responding to currently approved treatment options and future trials should consider administration of CPIs in combination/sequence with chemotherapy, immunotherapies or targeted therapies, as well as evaluation in adjuvant setting.
The authors thank Petronela M. Petrar, PhD (XPE Pharma & Science) for medical writing services.
Financial support and sponsorship
The development of this publication was financially supported by Merck KGaA, Darmstadt, Germany, as part of an alliance between Merck KGaA, Darmstadt, Germany and Pfizer, Inc. New-York, through an independent medical writing grant. The views and opinions described in this publication do not necessarily reflect those of the grantor.
Conflicts of interest
V.d.M. has been part of advisory board from Sanofi, MSD and received unrestricted educational grant from ABVIE, JANSSEN
C.L. has been part of advisory board from Sanofi, MSD, BMS, Roche, Amgen, Merck, Novartis, Pierre Fabre.
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