Just 1 article describing a retrospective, single-center cohort study of 195 patients diagnosed with MCC between 1980 and 2007 mentioned the AEIOU acronym,12 which refers to Asymptomatic, Expanding rapidly, Immune suppression, Older than age 50, and UV-exposed site. Three or more of these features were found in 89% of MCCs in the cohort.

The expert opinion is that most MCCs are diagnosed on the basis of histopathologic not clinical features13 (level of evidence 4).

The AEIOU rule can be useful for diagnosing MCC. However, diagnostic suspicion based on clinical data only is the first option in just 1% of cases. A definitive diagnosis should always be established according to histopathologic findings (grade of recommendation C).

Immunohistochemical findings combined with conventional histopathologic features can help distinguish MCC from other tumors and guide prognosis, but clinical and pathologic findings must always be integrated.14–16 The most specific markers for MCC are the Cam 5.2 (a low-molecular–weight cytokeratin [CK]), CK20, and neurofilaments, particularly when perinuclear dot-like positivity is observed. MCCs typically express neuroendocrine markers such as synaptophysin, chromogranin, and CD56, which help distinguish these tumors from most non-neuroendocrine tumors. Negative staining for CK7 and thyroid transcription factor 1 helps rule out metastasis from small-cell carcinoma of the lung or other organs, while negative S-100 protein and common leukocyte antigen results rule out melanoma and lymphoma, respectively. Merkel cell polyomavirus, which is normally detected using the antibody CM2B4, is present in 70% to 80% of cases, and diffuse expression confirms diagnosis and indicates a better prognosis.17,18 Variations in immunohistochemical staining patterns have been described for MCC, but they are either less specific or are supported by lower levels of evidence (level of evidence 4).

Immunohistochemical staining should always be used as a complementary diagnostic technique in MCC. Positive staining with low-molecular–weight keratins showing a dot-like pattern is highly specific and is the minimum diagnostic requirement. The addition of CK7, CK20, and neurofilament stains to rule out metastasis from lung cancer, which is the main entity in the differential diagnosis, is highly recommendable. Expression of neuroendocrine markers is diagnostic. As some of these tumors are hybrid or may contain heterologous elements, detection of areas of squamous cell carcinoma or leiomyosarcoma cells does not rule out a diagnosis of MCC. Positive staining for Ber-EP4 is not uncommon in MCC and therefore this stain is not useful for distinguishing MCC from basal cell carcinoma. Correlation of clinical and pathologic findings is essential in MCC, as some tumors have unusual immunohistochemical profiles (grade of recommendation C).

No scientific studies have demonstrated that sentinel lymph node (SLN) biopsy alters survival in MCC. SLN status, however, is the strongest independent predictor of survival in this setting. Approximately one-third of patients with clinically node-negative disease have microscopic nodal disease. SLN biopsy therefore has an important role as a minimally invasive staging tool. Numerous studies have shown that pathologically negative lymph nodes (pN0) are associated with better survival compared with clinically negative lymph nodes(cN0)19–32 (level of evidence 5).

Although SLN biopsy has not been demonstrated to improve survival in MCC, it should be performed wherever possible in patients without clinically evident nodal disease (grade of recommendation D).

Most studies recommend performing SLN biopsy whenever possible, regardless of tumor size. Unlike in melanoma, there are no clinical (size, location) or pathologic (thickness, mitotic rate, lymphovascular invasion) predictors that help determine the need for SLN biopsy in MCC33–35 (level of evidence 4).

Tumor size should not influence decisions regarding whether or not to perform SLN biopsy (grade of recommendation C).

Imaging studies are recommended for the staging of MCC, but agreement is lacking on the best modalities. Some authors have recommended the use of simple chest radiography combined with other tests depending on clinical findings (chest and abdomen computed tomography [CT], brain magnetic resonance imaging, abdominal and lymph node ultrasound).36–39

Other studies have shown that positron emission tomography (PET)-CT scanning alters initial staging and treatment in 16% to 22% of cases and radiation therapy doses in 15%40–42 (level of recommendation 3a).

PET-CT scanning should be used for initial staging, particularly in patients with a high risk of distant metastasis (grade of recommendation B).

Retrospective observational studies have shown that radiation therapy can prevent recurrence and increase survival in MCC. In particular, a significant survival benefit has been observed for adjuvant radiation therapy in patients with stage i and ii disease.

In addition, a randomized controlled trial, which was stopped prematurely,43 and a meta-analysis44 of observational studies have shown that postoperative adjuvant radiation therapy reduces the risk of locoregional recurrence, although no evidence was found for altered survival (level of evidence 2a).

Improved overall survival has been observed in patients treated with postoperative radiation therapy, particularly in those with a primary tumor larger than 2cm.45 One retrospective study published in 2013, however, renewed doubts about the value of radiation therapy in MCC, as it found an increase in overall but not disease-specific survival46 (level of evidence 2b).

In the absence of data from large, prospective, randomized studies, it would appear reasonable to contemplate the use of radiation therapy in patients with high-risk factors for recurrence, namely, immunosuppression, large tumors, aggressive histologic patterns, and lymphovascular invasion (level of evidence 2b).

Radiation therapy can be omitted at the site of small primary tumors (<1cm) excised with wide negative margins in patients without risk factors, such as lymphovascular invasion and immunosuppression.7

Nonetheless, and unless there is evidence indicating otherwise, adjuvant radiation therapy to the surgical bed should always be considered following the excision of a tumor with a diameter of 2cm or more without clear margins. Radiation therapy should be administered as soon as possible, as delayed intervention can negatively affect prognosis (grade of recommendation B).

Just 1 randomized clinical trial has compared observation versus adjuvant regional radiation therapy to the tumor bed following the surgical treatment of stage I MMC.43 The trial, however, was stopped prematurely due to a decrease in recruitment because of the growing use of SLN biopsy. Eighty-three patients, nonetheless, were recruited. While radiation therapy did not improve overall survival, it was associated with a significant reduction in the risk of regional recurrence (0% vs 16.7%).

All the guidelines consulted recommend SLN biopsy in this situation, followed by radiation therapy or lymph node dissection if the result is positive.

Radiation therapy is only recommended as a stand-alone treatment for patients who are not candidates for SLN biopsy (contraindication, surgical problems, or refusal to undergo the procedure) or for lymph node regions where sentinel lymph nodes are difficult to identify (level of evidence 3b).

In patients with MCC and clinically negative nodes, SLN biopsy should be performed whenever possible and be followed by lymph node dissection if the result is positive.

Regional radiotherapy is recommended in the following cases:

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  Patients who did not undergo SLN biopsy with enlarged lymph nodes or with clinically negative nodes and a risk of subclinical disease.

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  Patients with a negative SLN biopsy result that is very likely to be a false negative because of tumor location (head and neck), previous wide excision, or other technical problems.

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  Patients with a positive SLN biopsy who did not undergo lymph node dissection.

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  Patients who underwent lymph node dissection but had multiple affected lymph nodes or extracapsular extension (grade of recommendation B).

No scientific studies have analyzed optimal follow-up intervals following MCC treatment.

MCC has a high risk of local and nodal recurrence and distant metastasis. Risk of recurrence is mainly determined by stage at diagnosis and is higher in the first 2 to 3 years after treatment of the primary tumor.47–50 Most guidelines therefore recommend close observation for the first 2 to 3 years. The minimum follow-up time is 5 years, but lifetime monitoring is recommended (level of evidence 5).

There is no evidence to support any particular follow-up schedules after treatment of a primary MCC.

Several factors should be considered when deciding on follow-up intervals and duration: risk of recurrence, disease stage, age, immunosuppression, treatment received (clear or involved margins, use of radiation therapy or not), patient anxiety levels, physician preferences, and resources available.

Follow-up should be more intensive, i.e., with more frequent visits, for the first 2 to 3 years and longer in patients with more advanced disease or a higher risk of recurrence. Depending on these factors, follow-up visits should be scheduled at intervals of 1 to 6 months for the first 2 to 3 years and thereafter at intervals of 6 to 12 months. Patients should be monitored for at least 5 years and annually thereafter (grade of recommendation D).

No studies have established the most effective exploratory techniques for monitoring patients with MCC.

All the guidelines recommend a full skin and lymph node examination at each visit accompanied by imaging studies depending on the findings of this examination and the patient's history. Some guidelines do, however, recommend routine ultrasound examination of regional lymph nodes. However, even in high-risk cases, imaging studies should be tailored to the individual, as not all patients are candidates for additional treatment and it is not clear whether early detection of metastasis improves prognosis.41,51

Recent studies have described the value of serial measurements of capsid protein and Merkel cell polyomavirus oncogene antibody titers, although these results are still controversial52–54 (level of evidence 4).

Physical examination of the full skin surface, the area around the primary tumor, and superficial lymph nodes should be performed at each visit.

As there is a lack of consensus on which tests should be ordered at different clinical stages and follow-up visits, the need for routine imaging and serology testing should be determined by local skin tumor committees depending on the resources available. If there are clinical manifestations of recurrence, appropriate imaging studies should be ordered to reassess stage. PET-CT offers greater sensitivity than CT and is considered useful for detecting subclinical disease (grade of recommendation, C).