A certain level of agreement concerning surgical excision as the treatment of choice in MCC has formed. The principal aim of surgery is to excise enough to ensure tumor-free margins given that incomplete excision is associated with recurrence.12 No consensus has emerged as to the ideal size of side margins, however. Most of the oldest studies recommended margins of 2to 3cm, including the muscle fascia or galea (Fig. 2).31–34 A lower recurrence rate has been reported when margins of 1to 3cm have been targeted.33 However, such large margins are not always feasible, especially if the tumor is located on the head. Nor has increased overall survival been demonstrated to depend on larger margins. More recent studies recommend less generous margins. Tai12 proposed 1-cm margins for tumors measuring less than 2cm but 2-cm margins for larger tumors. The guidelines of the National Comprehensive Cancer Network (NCCN) recommends tighter margins of 1to 2cm, followed by adjuvant irradiation of the tumor bed.

Figure 2.

A, Merkel cell carcinoma on the scalp. B, Wide excision of the tumor. C and D, Technique used for a sentinel lymph node biopsy in the preauricular region.

(0.27MB).

Some authors have proposed using Mohs micrographic surgery (Table 2), especially in areas where it is difficult to excise enough to obtain adequate margins, such as on the face and especially on the eyelid (Fig. 3).35,36 Boyeretal.37 studied a series of 45 cases treated with Mohs surgery followed or not by radiation, finding that a surgical margin of 1.67cm was necessary. If they had sought margins of 2or 3cm, 25% and 12% of the tumors, respectively, would have been inappropriately excised. Furthermore, nearly half the tumors required smaller margins of under 1cm, meaning that healthy tissue would have been removed unnecessarily if wider margins had been taken systematically. The experience of O’Connoretal.38 on using Mohs surgery in 12 patients was similar. Only 1 patient experienced local recurrence. In spite of such promising results, we find very few case series describing the treatment of MCCs with Mohs surgery.35–41 Therefore, we cannot say there is sufficient evidence to support a claim that this approach is more effective than traditional surgery with wider margins.

Figure 3.

Merkel cell carcinoma removed with Mohs surgery. A, Tumor on the eyelid. B, Surgical defect after Mohs surgery.

(0.12MB).

The frequency of local recurrence after surgery is high at between 27% and 32% when wide margins are taken, whereas frequencies as high as 70% to 89% have been reported in relation to smaller margins.42

MCC is a highly radiosensitive tumor and in spite of the lack of randomized controlled trials43 because of the low incidence of cases, there is a considerable body of literature supporting the usefulness of postoperative radiation in reducing local recurrence. The problem of lack of randomized trials, however, means that debate continues42 (Table 3).

Lewis et al.44 found that local tumors were better controlled when surgery was followed by radiation (12% recurrence) than with surgery alone (39%) in a meta-analysis of 1254 cases from 132 studies. Similarly, Huietal.45 showed that age, tumor size, and local irradiation were associated with rates of local recurrence but that only postoperative radiation remained a predictor on multivariate analysis. Therefore, once MCC tumors are removed, many hospitals irradiate the surgical bed and a wide margin surrounding it in the interest of reducing recurrence and increasing survival. Not all experts agree on the routine use of radiation, however. Only 17% were irradiated in the series of 251 patients reported by Allen et al.,15 who saw no effect of radiation on local recurrence: 10% recurred after radiation therapy vs 8% without it. They recommended local irradiation be used only when tumor-free margins cannot be obtained and when histologic staging of lymph nodes has not been possible. Clarketal.46 similarly concluded that patients with tumors smaller than 1cm in diameter and negative lymph nodes can be followed without radiation if closely watched. The NCCN at present recommends radiation after excision of tumors regardless of stage although it does not benefit certain patients who are considered to be at low risk.47 The criteria for inclusion in this group of low-risk patients are shown in Table 3.

Boyer et al.37 observed marginal recurrence of MCC in 4% of patients in a group treated with a combination of Mohs surgery and postoperative radiation as opposed to 0% in the group treated with surgery alone, but the difference was not significant. Gollardetal.,41 in contrast, did observe benefits of adjuvant irradiation.

In patients of advanced age with many concurrent conditions that contraindicate surgery, radiation therapy alone is considered a possible and effective treatment. Mortieretal.48 described their experience treating 9 patients considered inoperable for medical reasons who had clinically negative nodes; they were irradiated as the only treatment at a mean dose of 60Gy. No recurrence was seen after 3 years’ follow-up. Veness and Richards49 treated 43 patients exclusively with radiation, achieving local control of the field in 75% and a 2-year survival rate of 58%.49

Macroscopic tumors are irradiated with a local dose of 60to 66Gy. For microscopically observed disease, the dose is 56to 60Gy, and if the surgical margins are negative, 50to 56Gy. The tumor is usually exposed to fractionated doses of 1.8to 2Gy 5 times per week.

MCC metastasis to the lymph nodes occurs often and early, in around 30% of patients on average (range, 15% to 66%) at diagnosis,50,51 and in 79% over the course of disease.52 Approximately a third of MCC patients with clinically palpable but radiologically negative lymph nodes are found to have microscopically detectable lymphadenopathy.53 Because of these findings, an initial SLNB is recommended (Table 2, Fig. 1). Although SLNB in tumors smaller than 1cm was questioned for some time,54 most authors now opt to do the procedure regardless of size (Fig. 1). Thus, a retrospective study of 8044 MCCs found that a 14% risk of lymph node involvement in tumors measuring 0.5cm rose to 25% risk in tumors measuring 1.7cm and to 36% in tumors of more than 6cm.55 They also noted that the number of affected lymph nodes on diagnosis predicted survival (0 nodes, 76% 5-year survival; 1 node, 50%; 2 nodes, 47%; 3–5 nodes, 42%; ≥6 nodes, 24%). Biopsy results, therefore, could be useful for managing cases.

Because wide resection can alter the drainage of the primary tumor, SLNB should be done at the same time the tumor is excised, starting with the nodes.30

A 30% rate of false negatives in SLNB decreases to 22% when immunohistochemical analysis is used.56 Suetal.57 reported the highest diagnostic sensitivity and specificity for MCC micrometastasis to the lymph nodes was achieved when they used anti-CK20 antibody immunostaining.

A problem that emerges when managing an MCC tumor on the head or neck is the low predictability of the pattern of lymph drainage in these locations. According to some authors, drainage does not coincide with what is expected in 34% to 84% of these patients, increasing the risk of false negatives; furthermore bilateral drainage has been found in up to 10% of cases.58,59 In contrast, others have reported seeing unexpected drainage pathways in only 14% of cases.60 SLNB is technically more complex in the head and neck because it is more difficult to visualize lymphatic drainage by lymphoscintigraphy in this part of the body, where the potentially affected nodes are very close to the site of tracer injection. In addition, SLNB in the head and neck is associated with more complications because the nodes are not always easy to access (e.g., the parenchyma of the parotid gland), thus increasing risk of serious injury.

Patients with positive biopsy results should undergo complete lymph node dissection or receive adjuvant radiation therapy of the nodal basin. Dissection is the treatment of choice, but radiation has also been used successfully in patients at high risk of complications of surgery61 (Tables 2 and 3). Radiation has been shown to be as effective as surgery in controlling subclinical disease.62

Excision of palpable nodes combined with irradiation of the basin has been recommended when multiple or massive node involvement or extracapsular spread might be present,63 although some authors have found that radiotherapy alone controls disease as well as surgery.64

If it is decided not to perform SLNB in MCC, the nodal basin should be irradiated as a precautionary measure (Tables 2 and 3, Fig. 1).

When nodal irradiation is chosen (elective, adjuvant, or radical) all stations in the region of drainage should be included.65,66

The treatment of metastatic MCC relies mainly on chemotherapy, but surgery or radiation therapy may also be used.67

MCC responds to a great range of chemotherapies. Drugs used to treat small cell lung cancer are the ones most often used in MCC.68 The regimens that give the best results combine cisplatin, or carboplatin, with etoposide or use topotecan in monotherapy. The combination of cyclophosphamide (or epirubicin) and vincristine is also given but is more toxic. The level of evidence supporting these therapies is low (2A), but as MCC is highly chemosensitive, treatment usually leads to a satisfactory partial or complete response. The effect, however, is short-term: in most cases and the disease progresses, recurring within 4 to 15 months.69 It must be emphasized that there is no clear evidence that chemotherapy prolongs survival.70,71 Furthermore, a mortality rate of 7.7% has been attributed to chemotherapy-related toxicity.72 Therefore, the decision to provide adjuvant or palliative treatment of this type, particularly in older or immunocompromised patients, should be grounded in the clinical judgement of a multidisciplinary team.

Surprisingly good outcomes have been reported in isolated cases of MCC treated with c-kit inhibitors in recent years.73 Although CD117 expression was detected by immunohistochemistry in 95% of MCC tumors in one series, mutations on the c-kit receptor could not be demonstrated.74 While the receptor is expressed in MCC, therefore, it is not activated. Disease progressed in most patients in a series of 23 cases when 400mg/d of imatinib was given; a partial response was observed in only 1 patient.21 In another trial, disease only became stable in a single patient given imitinib.75 The use of imatinib is therefore not recommended at present.

Some interesting treatment approaches that take into the account the relationship between MCC and MCPyV are under study in vitro or in vivo. An approach that includes antiviral agents might prove useful in treating this tumor in the future.

Furthermore, MCC, like melanoma, might logically respond to immune therapy for several reasons: the incidence is higher, and prognosis worse, in immunocompromised patients; MCC is known to regress spontaneously; an intense CD8 inflammatory infiltrate is associated with a better prognosis, as is the lack of a primary skin tumor; and MCPyV has been found in the genome of tumor cells and its presence is associated with a better prognosis. It is interesting, therefore, that various pharmacologic pathways are now being explored in patients with metastasis. Therapies under study are the anti-PD-L1 drug pembrolizumab, anti-PD-1, anti-CTLA-4 (ipilimumab), and the interleukin 12 gene plus a plasmid DNA vaccine. Clinical trials with these new candidate approaches will clarify whether any offer new benefits.

The authors declare that no experiments were performed on humans or animals for this investigation.

The authors declare that they followed their hospitals’ regulations regarding the publication of patient information and that written informed consent for voluntary participation was obtained for all patients.

The authors declare that no private patient data appear in this article.