INTRODUCTION — Merkel cell carcinoma (MCC) is a rare, aggressive, cutaneous malignancy that predominantly affects older adults with light skin types and has a high propensity to metastasize.

The staging, treatment, and surveillance of MCC are discussed here. The clinical features and initial diagnosis of MCC are reviewed separately. (See "Pathogenesis, clinical features, and diagnosis of Merkel cell (neuroendocrine) carcinoma".)

STAGING SYSTEM — The eighth edition American Joint Committee on Cancer (AJCC) staging system provides important information for both management and prognosis of patients with MCC [1]. Prior to adoption of the AJCC staging system, the standard in the field, multiple other staging systems were used [2].

MCC staging is assigned based upon tumor, node, and metastasis assessment. These stages can be summarized as follows (table 1 and table 2):

●Stage I – Primary tumors ≤2 cm in maximum dimension (T1), without evidence of regional lymph node involvement.

●Stage II – Primary tumors >2 cm (T2 or T3) or a primary tumor with invasion into bone, muscle, fascia, or cartilage (T4), without evidence of lymph node involvement. Stage II is further divided into two subgroups based upon the size and depth of invasion of the primary tumor.

●Stage III – Any primary tumor with in-transit metastasis or regional lymph node disease. Pathologic stage III is divided into subgroups based upon the extent of in-transit or regional lymph node involvement.

●Stage IV – Metastasis beyond the regional lymph nodes, regardless of the status of the primary tumor and regional nodes.

PROGNOSTIC FACTORS — The extent of disease at presentation, which is represented by the American Joint Committee on Cancer (AJCC) staging system, is the single most important determinant of prognosis. Along with staging, several clinical and pathologic features independently affect prognosis. (See 'Surveillance after initial therapy' below and "Pathogenesis, clinical features, and diagnosis of Merkel cell (neuroendocrine) carcinoma", section on 'Pathogenesis'.)

Stage — Stage-specific recurrence rates, disease-specific survival, and overall survival (OS) vary between study cohorts. However, stage is consistently reported to be the most important prognostic factor [3-5].

An analysis of 9387 patients with MCC from the National Cancer Database (NCDB) provides more detailed information about the extent of disease and OS (figure 1A-C) [3]. Of note, disease-specific survival by stage was not evaluated in this study, so clinicians should be aware that, in the older population affected by MCC, a significant proportion of deaths captured by OS are not due to MCC.

●Local disease – At initial presentation, 65 percent of patients had local disease without evidence of regional lymph node involvement or metastatic disease. The five-year OS for these patients was 55.6 percent, and there was a progressive decrease in OS for those with a T1 (<2 cm), T2-3 (>2 to 5, >5 cm), and T4 (invasion of fascia or deeper tissues) primary lesion, with five-year OS rates of 55.8, 41.1, and 31.8 percent, respectively.

●Regional disease – At initial presentation, 26 percent of patients had regional lymph node involvement without disseminated metastatic disease. This group included those with occult disease (detected by sentinel lymph node (SLN) biopsy or regional lymph node dissection), those with clinically detected regional lymph node involvement, and those with in-transit metastases. The five-year OS for the entire group was 35.4 percent, 39.7 percent for patients with occult disease, 26.8 percent for those with clinically detected nodal disease, and 41.4 percent for those with in-transit disease.

Patients with lymph node metastasis and an unknown primary tumor constituted 3.6 percent of the total cohort. The five-year OS for unknown primary patients was 42.2 percent.

●Distant metastases – At initial presentation, approximately 8 percent of patients had distant metastatic disease. The five-year OS for these patients was 13.5 percent.

Positive Merkel cell polyomavirus status — The presence of the positive Merkel cell polyomavirus (MCPyV) antigen within the tumor is associated with a favorable prognosis, including improved disease-specific survival and reduced risk of recurrence [6-8]. Observational data supporting the prognostic utility of the MCPyV status are discussed separately [6,7]. (See "Pathogenesis, clinical features, and diagnosis of Merkel cell (neuroendocrine) carcinoma", section on 'Prognostic factors'.)

Other clinical and histologic factors — Clinical prognostic factors that are significantly favorable for OS, after adjustment for stage, include female sex, younger age at diagnosis, immune competence, and absence of comorbid conditions [9,10]. Inclusion of these factors could provide more precise prognostic information. A web-based individualized risk containing these risk factors is available.

INITIAL EVALUATION AND MANAGEMENT — Once a tumor biopsy has confirmed the diagnosis of MCC, the following evaluation and initial management are suggested. The diagnostic clinical and histopathologic features of a primary MCC tumor are discussed separately. (See "Pathogenesis, clinical features, and diagnosis of Merkel cell (neuroendocrine) carcinoma", section on 'Diagnosis'.)

Physical examination — The initial evaluation of a patient with MCC should include a complete examination of the skin and regional lymph nodes, with appropriate evaluation of any detected abnormalities. The clinical features of MCC are discussed separately. (See "Pathogenesis, clinical features, and diagnosis of Merkel cell (neuroendocrine) carcinoma", section on 'Clinical features'.)

Imaging — For initial imaging, we offer either positron emission tomography (PET) with fluorodeoxyglucose combined with either computed tomography (CT) or magnetic resonance imaging (MRI), or a CT of the chest, abdomen, and pelvis. MRI of the brain may be obtained if the patient is symptomatic to assess for the presence of central nervous system metastases. These imaging modalities are critical due to the metastatic potential of MCC and may influence subsequent management [11-14].

Imaging studies are strongly indicated if metastatic disease is suspected by physical examination. In addition, we offer baseline imaging to most patients to identify those with a higher stage of disease who would benefit from a different treatment approach. In one observational series, baseline imaging detected occult metastatic disease in 13 percent of patients who presented without suspicious physical examination findings (eg, palpable adenopathy) [15].

Merkel cell polyomavirus status — Baseline determination of Merkel cell polyomavirus (MCPyV) oncoprotein antibody titer can further assist with prognosis and subsequent detection of recurrent disease [8,16]. (See "Pathogenesis, clinical features, and diagnosis of Merkel cell (neuroendocrine) carcinoma", section on 'Prognostic factors' and "Pathogenesis, clinical features, and diagnosis of Merkel cell (neuroendocrine) carcinoma", section on 'Merkel cell polyomavirus serology' and 'Positive Merkel cell polyomavirus status' above.)

Approach to initial management — Based upon the initial evaluation, the approach to initial management of patients with MCC is dependent on the pathologic characteristics of the primary tumor and the presence of clinical evidence of lymph node or distant metastases.

●Clinically negative nodes – For patients with a biopsy-confirmed MCC and no clinical evidence of regional lymph node involvement, a sentinel lymph node (SLN) biopsy is generally indicated prior to, or in conjunction with, definitive local therapy. (See 'Clinically negative nodes' below.)

However, the role of SLN biopsy is less clear for lesions arising in the head and neck region, due to the variable lymphatic drainage of primary tumors in this region. (See 'Head and neck lesions' below.)

•Negative SLN biopsy – For patients with a negative SLN biopsy, an excision of the primary tumor is indicated. For patients in whom surgery is not technically feasible or for those who are not surgical candidates, radiation therapy (RT) to the primary tumor and nodal region is an alternative [17,18]. (See 'Primary tumor' below.)

•Positive SLN biopsy – For patients with a positive SLN biopsy, careful evaluation for occult metastatic disease is indicated. If no distant metastatic disease is detected, treatment of the primary tumor by excision and adjuvant RT and definitive treatment of regional lymph node basin by nodal dissection or definitive RT is indicated. However, performing both RT and nodal dissection of the lymph node basin is significantly morbid and does not improve control for SLN-positive disease [19]. (See 'Regional lymph nodes' below.)

•No SLN biopsy – For patients not undergoing SLN mapping and biopsy, adjuvant RT to the regional lymph nodes may be indicated. Adjuvant RT to the regional lymph nodes is a reasonable approach to avoid relapse as nodal evaluation is not performed. Without any elective regional lymph node treatment, at least 17 percent of patients with a primary tumor ≤1 cm will eventually develop nodal disease [20,21]. (See 'Adjuvant radiation therapy' below.)

●Clinically positive nodes – For patients with suspected clinical lymph node involvement, biopsy confirmation (fine needle aspirate, core needle biopsy, or excisional biopsy) is indicated.

•If the fine needle aspirate or core needle biopsy of the suspicious node is negative, an excisional nodal biopsy may be indicated [22].

•If the biopsy confirms the presence of nodal disease, patients should be carefully evaluated for the presence of metastatic disease. If there are no distant metastases detected, we recommend excision of the primary tumor and definitive therapy of the draining lymphatics. Treatment options include: (a) regional lymph node dissection, or (b) nodal excision followed by regional RT covering the intervening lymphatics if the RT field size is not too large or morbid. For very frail patients who cannot tolerate nodal excision even if carried out only with local anesthetic, definitive regional RT may be used instead, although local control will only be approximately 75 to 85 percent if clinically evident nodal disease is not surgically excised before RT [19,23-25]. (See 'Regional lymph nodes' below.)

•For patients who have completed a wide local excision of the primary tumor and a regional lymph node dissection, potential risk factors indicating the need for adjuvant RT to the primary site and/or involved node bed include the presence of a primary tumor ≥1 cm, positive or limited surgical resection margins, lymphovascular invasion, a head and neck primary, and an immunocompromised host. In addition, extracapsular extension of tumor outside the lymph node(s) or the involvement of multiple nodes are both associated with an increased risk of recurrence and are indications for adjuvant regional RT. Participation in a clinical trial of adjuvant immunotherapy, if available, may be offered to high-risk patients following the completion of surgery with or without RT of the regional lymph nodes. (See 'Adjuvant immunotherapy' below.)

●Metastatic disease – For patients with suspected disseminated disease after their initial evaluation, biopsy confirmation of the metastasis is indicated prior to systemic therapy. The treatment approach to metastatic disease is discussed below. (See 'Metastatic disease' below.)

LOCOREGIONAL DISEASE

Primary tumor — Surgery, rather than radiation therapy (RT), is preferred as the initial therapy of the primary tumor. However, given that adjuvant RT to the primary site is often indicated after excision, it is important to balance the extent of surgery and accompanied morbidity (eg, wound healing, cosmesis, and function).

Surgery — Wide excision of the primary MCC tumor is the standard initial management whenever possible [26,27]. A margin of at least 1 to 2 cm of normal-appearing skin is recommended. If the margins are close to or involved with tumors, postoperative RT is indicated to increase the probability of local disease control [16,26]. (See 'Adjuvant radiation therapy' below.)

Achieving wide negative margins with the initial excision is important for long-term disease control, especially if no adjuvant RT to the primary site is planned [17,28]. However, data are limited regarding the appropriate surgical margin size if postoperative RT will be delivered. Furthermore, critical information, such as sentinel lymph node (SLN) positivity, pathologic surgical margins, and lymphovascular invasion, is missing at the time of the surgery. As examples:

●In a retrospective observational study of 179 patients with MCC treated with curative intent, the addition of adjuvant RT to narrow excision (<10 mm margin) was associated with a reduction of local recurrence rates (25 versus 5 percent) and was also effective in the presence of microscopic positive margins. Irrespective of whether RT was used or not, the local recurrence rate was 7 percent when the margin size was >10 mm [28].

●In a retrospective analysis of 188 patients with MCC, 48 were patients treated with surgery alone (all of whom had microscopically negative margins). Of those with surgical margins ≤1 cm, 20 percent (7 of 35 patients) developed a local recurrence, whereas none (0 of 13 patients) developed a local recurrence among those with margins >1.0 cm. In contrast, among 140 patients treated with adjuvant RT, local control was excellent for both large and small surgical margins, even among patients who had microscopically positive margins (1 percent local recurrence for both margin groups, n = 70 for both groups) [29].

Based upon the available data, our practice aims to select a surgical margin size that offers complete excision of disease yet is conservative enough to avoid significant delay in the initiation of adjuvant RT when it is indicated. Therefore, it is recommended that when adjuvant RT is planned, extensive tissue movement and grafting are avoided [22].

Mohs micrographic surgery can be offered where cosmetic outcomes are important, such as the face. If an SLN biopsy is to be carried out, it should be performed prior to Mohs surgery as the tumor excision site may interfere with a subsequent node biopsy [22]. With the Mohs approach, 100 percent of all major borders, including the deep margins, are evaluated histologically. However, adjuvant RT still has a role in preventing locoregional recurrences when Mohs surgery is used since MCC tends to recur beyond pathologically negative margins more often than other skin cancers [30-32].

Definitive radiation therapy — For patients in whom surgical resection is not technically feasible or who are medically unfit for surgery, definitive RT serves as an alternative treatment option [16,17,23,33]. Higher doses of radiation (60 to 66 Gy) are recommended if RT is used alone rather than in the adjuvant setting [16]. RT achieves an in-field disease control rate of only 75 to 85 percent, and systemic relapses are not rare [23,24].

The role of chemoradiotherapy versus RT alone is controversial, and there are no randomized trials comparing chemoradiotherapy with RT alone as the primary therapy for nonsurgical candidates. (See 'Adjuvant chemotherapy or chemoradiotherapy' below.)

Regional lymph nodes — Pathologic staging of lymph node status is important for both prognosis and treatment planning [34]. Optimal management of the regional lymphatics depends on whether there is clinical or pathologic evidence of MCC involvement as well as the size and pathologic characteristics of the primary tumor. The management approach of the regional lymph nodes is based upon retrospective series since there are no randomized trials that provide definitive guidance.

Clinically negative nodes — Most patients with a biopsy-proven MCC should have SLN mapping and biopsy, including immunohistochemistry [16,26].

However, some clinicians do not perform SLN mapping and biopsy when the primary tumor size is ≥2 cm, since RT is indicated due to the high risk of lymph node metastasis.

In addition, the role of SLN biopsy is less clear for patients with a lesion arising in the head and neck region since the lymphatic drainage from primary tumors in this region is highly variable to multiple nodal basins. If an SLN biopsy is not carried out, lymph nodes should usually be treated with prophylactic RT in higher-risk cases [16]. (See 'Head and neck lesions' below.)

The SLN mapping and biopsy should be performed prior to or in the same setting as the wide local excision because surgery may disrupt the lymphatic drainage from the primary tumor. This technique, which is widely used in patients with melanoma, is discussed separately. (See "Evaluation and treatment of regional lymph nodes in melanoma", section on 'Sentinel lymph node biopsy'.)

The results of the SLN biopsy provide important prognostic information and help guide further treatment. The impact on prognosis is illustrated by an analysis of 9387 patients with MCC from the National Cancer Database (NCDB) [3]. Patients with a negative SLN biopsy had improved five-year overall survival (OS) compared with those with a positive biopsy (55.6 versus 39.7 percent).

Approximately one-third of patients with clinically negative lymph nodes will have microscopic tumor involvement on pathologic examination [4]. However, a negative SLN biopsy does not preclude a subsequent regional recurrence. In an analysis of 721 patients, the false-negative rate for an SLN biopsy (as defined by a subsequent regional recurrence) was 17 percent [35]. Thus, adjuvant treatment to regional lymph nodes may rarely be indicated even after a negative SLN biopsy, depending upon the characteristics of the primary tumor or in high-risk situations such as an immunosuppressed patient. (See 'Adjuvant therapy' below.)

For patients with a negative SLN biopsy, adjuvant regional lymph node RT may be indicated if there is a high risk of recurrence due to anatomic, technical, or histologic factors (eg, previous wide local excision or immunohistochemistry evaluation of SLN biopsy was not performed). If none of these factors are present and the patient is compliant with follow-up and imaging, observation is appropriate after SLN biopsy.

If the SLN contains a tumor, regional lymph node dissection or definitive RT to the lymph node basin is indicated. However, performing both RT and nodal dissection is significantly morbid and does not improve control for SLN-positive disease [19]. For patients managed with a regional lymph node dissection, postoperative RT may be indicated, particularly in those with more extensive lymph node disease or extracapsular extension.

Clinically positive nodes — Patients with suspected lymph node involvement based upon clinical or radiographic findings require histologic confirmation of disease [16]. This may be obtained by a fine needle aspirate, core needle biopsy, or open biopsy.

If pathologic involvement of the regional nodes is confirmed, regional nodal therapy with surgery is indicated with or without postoperative RT. Excision of the clinically abnormal node followed by RT is supported by preliminary evidence [17]. Node dissection is recommended in the National Comprehensive Cancer Network guidelines. RT as the primary modality is an option in selected frail patients who cannot tolerate even nodal excision under local anesthetic [19,25].

The role of adjuvant RT following complete lymph node dissection has not been definitively established by randomized trials. However, multiple observational studies provide evidence that RT can decrease the rate of locoregional recurrence and improve OS [28,36-38]. Involvement of multiple lymph nodes or extracapsular extension of tumor outside the lymph node(s) is associated with an increased risk of recurrence and is an indication for adjuvant regional RT following lymph node dissection. The risks of node dissection plus RT include lymphoedema, fibrosis of the joints, and subsequent functional impairment. Therefore, despite retrospective studies showing decreased recurrence rates with adjuvant RT, clinical judgment is required to decide which patients can be followed without adjuvant RT after nodal dissection. In general, patients with clinically positive nodes have a five-year disease-specific survival of approximately 50 percent [39].

The role of adjuvant immunotherapy is the subject of ongoing clinical trials. (See 'Adjuvant immunotherapy' below.)

For patients with a clinically positive lymph node that cannot be confirmed by appropriate pathologic examination (eg, confirmatory nodal biopsy is not feasible), we generally suggest RT to the primary tumor and draining lymph node basin. (See 'Adjuvant therapy' below.)

Special considerations

Head and neck lesions — Management of MCC arising in the head and neck region can present a unique problem because achieving an adequate wide resection in these patients is often particularly difficult and the lymphatic drainage from primary tumors in this region is highly variable [40-42]. MCCs arising in the head and neck appear to be associated with a worse prognosis than those arising in other sites [43].

Although there are no randomized trials in patients with MCC arising in the head and neck region, RT to the resection bed, in-transit lymphatics, and regional lymph nodes is generally recommended [16].

The benefit of adjuvant RT was reported in multiple studies. In an analysis of 46 low-risk head and neck MCC patients, the group that did not receive postoperative RT had a significantly higher risk of local recurrence (26 versus 0 percent) [44]. In another study of 4815 patients with MCC of the head and neck region, OS was significantly improved with postoperative RT compared with surgery alone (hazard ratio [HR] 0.80, 95% CI 0.70-0.92) [37].

Analyses of other large series and a review of the literature have also concluded that the inclusion of RT to the tumor bed and regional lymphatics as part of initial treatment improves local and regional tumor control [40-42,45].

The role of adjuvant chemoradiotherapy is uncertain and/or controversial. (See 'Adjuvant chemotherapy or chemoradiotherapy' below.)

Unknown primary — Among patients presenting with clinically detectable lymph nodes at the time of MCC diagnosis (stage IIIB), one-third to one-half of patients do not have an identifiable primary tumor [46]. In these cases, the primary tumor most likely regressed due to immune surveillance as these patients show markedly stronger immune responses across multiple parameters [46]. The concept that the MCC may have arisen within the node itself is unlikely as MCC tumor cells in the node have extensive ultraviolet-induced DNA mutations, strongly suggesting a cutaneous origin [46].

Observational series suggest that patients with an unknown primary, regional nodal disease and no evidence of distant metastases do significantly better (with approximately one-half the risk of disease progression) compared with those with a primary cutaneous site in addition to clinically positive lymph nodes [46-50].

As an example, an observational series of 321 patients with MCC included a subset of 38 patients (12 percent) who presented with an unknown primary, nodal disease and no evidence of distant metastases [50]. Among this cohort of patients, median recurrence-free survival was 35 months. Ten patients (26 percent) died, five of disease and five of other causes. Median OS was 104 months. This study did not have comparative data for patients with a known primary. However, in the 5371-patient NCDB, as shown in the figure (figure 1B), the median survival of node-positive patients with a known primary (pathologic IIIB) is around two years and is around 3.5 years for those with an unknown primary, almost double that of pathologic IIIB.

Management should be individualized based upon the specific pattern of disease presentation and should follow that for patients with an identifiable primary tumor and clinically positive lymph nodes or distant metastases. (See 'Clinically positive nodes' above and 'Metastatic disease' below.)

Adjuvant therapy — RT has an important role in treating occult lymph node disease or minimum residual tumors at the primary site in patients whose MCC is primarily managed with surgery. The role of systemic treatment (chemotherapy, immunotherapy) as part of a combined modality approach is not yet well established.

Adjuvant radiation therapy — Adjuvant RT is indicated in patients with any of the following risk factors: a primary tumor ≥1 cm in maximum dimension, a head and neck primary, positive or limited surgical resection margins, lymphovascular invasion, or an immunocompromised host. RT to the nodal basin is an option for patients with profound immunosuppression [51] or for those with a suspected false-negative SLN biopsy.

MCC is a radiosensitive malignancy. RT has been used as an adjuvant treatment after surgery to prevent recurrence in the primary tumor bed and regional lymphatics. Although there are no randomized trials supporting the role of adjuvant RT, multiple studies provide evidence that RT can decrease the rate of locoregional recurrence and improve OS [28,36-38].

The most extensive evidence supporting the role of adjuvant RT comes from an analysis of 6908 patients with MCC in the NCDB [38]. In the 4843 patients without evidence of lymph node involvement (stage I or II), adjuvant RT was associated with significantly improved OS (HR 0.71, 95% CI 0.64-0.80). In contrast, there was no improvement in OS observed in the 2065 patients with lymph node-positive (stage III) MCC (HR 0.98, 95% CI 0.86-1.12).

When RT is used as an adjuvant or definitive treatment, it is important to treat all regional lymphatics to avoid geographic miss since a recurrence in untreated regions may occur. Some providers use a 5 cm margin to cover the surgical bed for definitive or adjuvant RT [52,53]. As an example, the Trans Tasman Radiation Oncology Group (TROG) 96:07 study used a 3 to 5 cm margin, and the draining lymph nodes were treated in the same field as the primary if the nodal region was within 20 cm of the primary to reduce the risk of in-transit recurrence [54,55].

The RT dose required to treat either the primary tumor or regional lymph nodes is based upon the tumor burden [16]. Following a resection with negative margins, a total RT dose of 50 to 56 Gy is generally adequate for those at significant risk for residual subclinical disease. A dose of 56 to 60 Gy is recommended for those with microscopically positive resection margins, and a dose of 60 to 66 Gy is recommended for definitive treatment of those with grossly positive margins, an unresectable primary lesion, or unresectable regional lymph nodes.

Adjuvant chemotherapy or chemoradiotherapy — The role of chemotherapy, either alone or in combination with RT, as an adjuvant following surgery for locoregional therapy is uncertain and/or controversial.

Most studies are retrospective and were carried out prior to the introduction of immunotherapy. In addition, there are no randomized trials evaluating the efficacy of adjuvant chemotherapy or chemoradiotherapy in patients with MCC. Furthermore, there is concern about the immunosuppressive effects of chemotherapy. The immune system plays an important role in defense against MCC, based upon the increased incidence in immunosuppressed patients, association with Merkel cell polyomavirus (MCPyV), and reports of spontaneous regression. Data are as follows:

●The most extensive data regarding chemoradiotherapy derive from a retrospective study of 4815 patients with MCC of the head and neck region, based on the NCDB between 1998 and 2011 [37]. In this analysis, 1995 patients were managed with surgery alone, 2330 managed with postoperative RT, 393 managed with postoperative chemoradiotherapy, and 97 managed with postoperative chemotherapy alone. With a median survival of 3.4 years, postoperative chemoradiotherapy and RT both provided a survival benefit over surgery alone (HR 0.62, 95% CI 0.47-0.81, and HR 0.80, 95% CI 0.70-0.92, respectively). However, postoperative chemotherapy was associated with decreased OS (HR 1.74, 95% CI 1.10-2.75) when compared with surgery alone.

●Another large study from the NCDB included 6908 patients with MCC at all sites, including 2065 patients with stage III disease [38]. Neither adjuvant chemotherapy nor chemoradiotherapy was associated with statistically improved or worsened OS compared with patients treated without chemotherapy (stage I HR 0.79, 95% CI 0.60-1.05; stage II HR 1.14, 95% CI 0.89-1.45; stage III HR 0.97, 95% CI 0.85-1.12).

●In the prospective TROG 96:07 study, 53 patients were classified as being at high risk of recurrence based upon having a recurrence after initial therapy, positive regional lymph nodes, a primary tumor ≥1 cm, or gross residual disease after surgery [54,55]. Treatment consisted of RT (50 Gy in 25 fractions over five weeks) and synchronous carboplatin (area under the curve 4.5) plus etoposide (80 mg/m² intravenously on days 1 to 3) during weeks 1, 4, 7, and 10. With a median follow-up of 48 months, the three-year OS, locoregional control, and distant control rates were 76, 75, and 76 percent, respectively [55]. However, a comparison with historical controls suggested that chemotherapy did not affect OS compared with surgery plus RT without chemotherapy [54].

●Patients exposed to prior chemotherapy may have a lower response rate to immunotherapy. In the phase 2 JAVELIN Merkel 200 trial, the objective response rate to avelumab in patients previously treated with chemotherapy was lower than those who had received avelumab as first-line therapy (28 versus 62 percent) [56,57]. (See 'Avelumab' below.)

When carboplatin is being given during RT, a weekly regimen (area under the curve 2) may be a safer way to deliver synchronous chemotherapy [58]. This approach reduced the incidence of febrile neutropenia and grade 3 skin toxicity compared with the every-three-week regimen of carboplatin and etoposide used in the TROG 96:07 study [54].

In patients with metastatic disease, systemic chemotherapy has demonstrated high response rates but short duration of responses. The use of systemic chemotherapy in metastatic disease is discussed below. (See 'Metastatic disease' below.)

Adjuvant immunotherapy — In patients with resected MCC, there are limited data on the use of immunotherapy in the adjuvant setting. Adjuvant immunotherapy with checkpoint inhibitors is being evaluated in randomized trials. Enrollment in such a trial is encouraged when feasible.

Checkpoint inhibitor immunotherapy is now the preferred therapy for patients with metastatic MCC, and its use is discussed below. (See 'Metastatic disease' below.)

IS THERE A ROLE FOR NEOADJUVANT IMMUNOTHERAPY? — The role of neoadjuvant immunotherapy in the management of patients with MCC is not established and remains under investigation. Neoadjuvant immunotherapy may potentially decrease the extent of necessary surgery or the need for postoperative radiation therapy (RT) in patients with a good pathologic response. While preliminary data suggest pathologic complete response (pCR) in approximately one-half of patients [59], additional studies are required to confirm these results.

●Nivolumab – Nivolumab was evaluated in the neoadjuvant setting in a phase I/II study (Checkmate 358). In this study of 39 patients with resectable MCC, surgical resection specimens were obtained after two doses of nivolumab (240 mg on days 1 and 15) [59]. Among the 36 patients who underwent surgery, 17 patients (47 percent) achieved a pCR. Among 33 radiographically evaluable patients, 18 (55 percent) had tumor reductions greater than 30 percent. At a median follow-up of 20.3 months, recurrence-free survival significantly correlated with pCR and radiographic response at the time of surgery. No patient with a pCR had tumor relapse during observation.

SURVEILLANCE AFTER INITIAL THERAPY

Frequency of follow-up — Patients with MCC may benefit from frequent follow-up because of the high rate of recurrences. Follow-up should be individualized according to risk factors and potential therapeutic options.

The National Comprehensive Cancer Network guidelines recommend that patients should be followed every three to six months for three years and then every 6 to 12 months thereafter. Physical examination, with special emphasis on total-body skin examination and palpation of lymph nodes, is justified by the frequency of skin and nodal recurrences and the lack of expense or toxicity associated with such examinations.

Helpful data for deciding ongoing follow-up frequency after initial management are available in the form of stage-specific recurrence-free survival rates [60] and a web-based risk calculator tool.

Imaging studies — The use of imaging studies (eg, magnetic resonance imaging [MRI], computed tomography [CT]/positron emission tomography [PET]) should be based upon clinical indications [9,61]. Routine imaging should be considered for high-risk patients [16].

Merkel cell polyomavirus serology — We suggest that the Merkel cell polyomavirus (MCPyV) oncoprotein antibody test be performed every three months while the patient remains at risk for MCC recurrence (typically up to approximately five years). If the titer increases more than 30 percent from the previous value, an imaging study is warranted to evaluate possible recurrence. (See "Pathogenesis, clinical features, and diagnosis of Merkel cell (neuroendocrine) carcinoma", section on 'Merkel cell polyomavirus serology'.)

Changes in the titer of antibodies that recognize MCPyV oncoproteins reflect alterations in a patient's MCC tumor burden [62-66]. As such, this test can be a useful component of ongoing surveillance for seropositive patients. A rising titer can be an early indicator of recurrence. Additionally, for patients who do not have recurrent disease, titers are expected to decrease significantly within three months of successful treatment of MCC [8]. A combination of the MCPyV oncoprotein antibody test and imaging studies can help guide surveillance.

In an analysis of 260 patients with MCC who had a positive MCPyV oncoprotein antibody test, the positive predictive value of recurrence was 99 percent (eg, fraction of patients with rising titers that had or soon developed clinically evident MCC recurrence) and the negative predictive value was 99 percent (eg, fraction of patients with stable or declining titers who did not have detectable recurrent disease) [67].

Secondary malignancies — MCC is associated with an increased incidence of other skin cancers, particularly hematologic malignancies that are associated with immunosuppression. Patients with treated MCC who are under surveillance should also be evaluated for the potential development of such secondary malignancies (eg, on physical examination). (See "Pathogenesis, clinical features, and diagnosis of Merkel cell (neuroendocrine) carcinoma", section on 'Epidemiology'.)

RECURRENT DISEASE — Following initial therapy, MCC has a 20 to 75 percent chance of recurrence, depending on stage at diagnosis [68]. In one literature review, the reported local recurrence rate was 29 percent; nodal or distant disease recurrence rates were 50 and 25 percent, respectively [9,61]. Patients with an initial nodal recurrence had a significantly higher chance of developing subsequent distant metastases than those without a nodal recurrence.

●Local recurrences – Local recurrences usually occur within one year of initial therapy, with a median time to recurrence of four months (range one to nine months) [9,39,61,69]. Patients with locoregional recurrence should be carefully reevaluated to rule out disseminated disease. Although isolated locoregional recurrences are associated with a relatively poor prognosis, some patients with disease limited to locoregional sites can be salvaged with multimodal therapy. The impact of a local recurrence on survival is controversial [70,71].

●Nodal recurrences – The median time to develop a clinically detectable nodal recurrence after resection of the primary lesion is seven to eight months. Among patients with nodal involvement, either at presentation or at recurrence, 11 to 66 percent die of their disease within five years [72-74]. As with local recurrences, multimodal approaches have been associated with improved outcome following a nodal recurrence. In a literature review of 661 patients, median overall survival (OS) was 27 months (range 1 to 216 months) among those who received salvage treatments for recurrent disease [9,61]. Combined modality therapy (surgery, radiation therapy [RT], and/or systemic therapy) is associated with the best salvage potential [72,75,76].

METASTATIC DISEASE — For patients with metastatic disease, biopsy confirmation of the metastasis is often indicated. Clinical factors that should be taken into account when deciding treatment course include sites of disease involvement, age, comorbidities, and patient preferences. A clinical trial of systemic therapy is preferred whenever possible.

Immunotherapy — Checkpoint inhibitor immunotherapy is the preferred initial treatment approach for patients with advanced MCC without absolute contraindications to such therapy [22,77]. (See "Toxicities associated with checkpoint inhibitor immunotherapy".)

In patients with advanced or metastatic MCC, we suggest initial treatment with a programmed cell death ligand 1 (PD-L1)-blocking agent (avelumab) or programmed cell death protein 1 (PD-1) inhibitor-based immunotherapy (pembrolizumab, nivolumab), rather than chemotherapy, as immunotherapy has a greater capacity to induce clinically meaningful, durable responses in such patients. The US Food and Drug Administration has approved avelumab and pembrolizumab to treat patients with advanced or metastatic MCC, irrespective of prior therapy.

Avelumab — Avelumab is a monoclonal antibody that binds to PD-L1.

●In the international, multicenter, phase II JAVELIN Merkel 200 trial part A, 88 patients were treated with avelumab (10 mg/kg every two weeks) [56,78,79]. All patients had received prior cytotoxic chemotherapy, and 40 percent had received two or more lines of chemotherapy. With a minimum follow-up of two years (median 29.2 months), there were 29 objective responses (33 percent), including 10 complete responses (11 percent). The two-year progression-free survival rate was 26 percent, and the two-year overall survival (OS) rate was 36 percent. In this trial, avelumab was associated with infusion-related adverse reactions in 17 percent of patients; all were grade 1 or 2. Premedication with acetaminophen and an antihistamine is recommended prior to the first four infusions and subsequently as needed [80]. There were no grade 4 or 5 treatment-related adverse events in the JAVELIN Merkel 200 trial. Only 4 of 88 patients (5 percent) had grade 3 adverse events. (See "Toxicities associated with checkpoint inhibitor immunotherapy".)

●The role of avelumab in MCC is also supported by preliminary results from part B of the JAVELIN Merkel 200 study in 29 previously untreated patients [57]. In a preplanned analysis with a median follow-up of five months, the objective response rate was 62 percent. In responding patients, 83 percent had a durable response for at least six months. No treatment-related deaths or grade 4 adverse events occurred.

Pembrolizumab — Pembrolizumab is a monoclonal antibody that binds to PD-1. In a phase II study, 50 patients who were systemic therapy-naïve were treated with pembrolizumab (2 mg/kg every three weeks) for up to two years [81,82]. Overall, 43 patients had stage IV disease and seven had stage III unresectable disease. At a median follow-up of 14.9 months, objective responses were observed in 28 of 50 evaluable patients (56 percent), which included 12 complete responses and 16 partial responses. Responses were durable, with 85 percent of responders remaining in remission at one year and 79 percent in remission at two years. OS rates at one, two, and three years were 72, 69, and 64 percent, respectively. There was no statistically significant difference in response rate or duration of response in patients whether or not tumors were positive for the Merkel cell polyomavirus (MCPyV) or based upon PD-L1 expression.

Nivolumab — Nivolumab is a monoclonal antibody that binds to PD-1. In a phase I/II study, 25 patients who were treatment-naïve or who had received one to two prior systemic chemotherapies were treated with nivolumab (240 mg every two weeks) [83]. In the 22 response-evaluable patients, the overall response rate was 68 percent, with ongoing responses in 13 of 15 patients (87 percent). At three months, progression-free survival and OS rates were 82 and 92 percent, respectively. Responses occurred in 71 percent of treatment-naïve patients and in 63 percent of patients with one to two prior systemic therapies, in both virus-positive and virus-negative tumors.

Other agents (ipilimumab) — Due to limited evidence on efficacy and safety, we do not offer the cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) inhibitor ipilimumab monotherapy as a first-line treatment for metastatic MCC. Data are as follows:

●The efficacy of ipilimumab monotherapy for MCC was initially studied in the adjuvant setting. In a randomized phase II study, compared with observation, ipilimumab did not improve disease-free survival and worsened toxicity. Given the lack of efficacy of ipilimumab with the pronounced toxicity, enrollment for the trial was discontinued [84].

●For patients with metastatic MCC, ipilimumab monotherapy has not been studied in a trial, but one small case series reports efficacy of ipilimumab monotherapy in metastatic MCC [85].

●For those with advanced disease that has progressed through anti-PD-1 therapy, one retrospective case series reported the efficacy of ipilimumab alone or in combination with an anti-PD-1 agent. Among the 13 patients evaluated, objective responses were seen in four patients (31 percent) [86].

Chemotherapy — Chemotherapy retains a role in the treatment of patients who do not respond to or relapse after immunotherapy or in those patients in whom immunotherapy is contraindicated. (See "Toxicities associated with checkpoint inhibitor immunotherapy", section on 'Preexisting autoimmune disease'.)

There are no randomized trials or prospective studies of chemotherapy in patients with distant metastases. Carboplatin plus etoposide is generally the initial treatment option, and weekly carboplatin (area under the curve 2.0) has been used to reduce toxicity [58]. Cyclophosphamide plus doxorubicin and vincristine is an alternative. Alternative regimens and second-line therapies are patterned after those used in small cell carcinoma of the lung. (See "Extensive-stage small cell lung cancer: Initial management", section on 'Rationale for addition of immune checkpoint inhibitors to chemotherapy' and "Treatment of refractory and relapsed small cell lung cancer".)

The most extensive results of chemotherapy come from a retrospectively analyzed series of 103 patients with distant metastases [61]. Patients were treated with a wide range of chemotherapy regimens (59 percent); the median duration for complete responses and partial responses was six and three months, respectively.

The impact of systemic chemotherapy on survival in patients with metastatic MCC is unclear; however, relapse-free survival averages only three months from the time of initiating therapy [87]. Furthermore, despite a relatively high response rate, cisplatin-based chemotherapy is toxic, especially in this relatively older adult population, and multiple treatment-related deaths have been reported [61].

Palliative treatment — For patients with metastatic disease that is symptomatic or nonresponsive to systemic therapy, options include local treatment of the symptomatic primary tumor and/or regional nodes with surgery or radiation therapy (RT). This approach is useful in a palliative setting as well. If impending organ damage is suspected (eg, spinal cord compression or superior vena cava obstruction), RT should be initiated promptly.

RT is a particularly effective modality as MCC is a radiosensitive tumor. The dose is typically delivered in multiple (between 5 and 20) fractions. One palliative option that has been reported to be well tolerated for symptomatic tumor masses is single-fraction radiotherapy. In a retrospective analysis of 93 tumors treated with single-fraction radiotherapy, objective response rate was 94 percent with complete responses in 45 percent [88]. Other palliative RT options such as brachytherapy have been reported as well [89].

EXPERIMENTAL APPROACHES — Newer approaches to advanced disease are required, given that checkpoint inhibitor immunotherapy only provides a durable benefit in approximately one-half of patients and chemotherapy offers short durations of response. Patients should be enrolled in clinical studies whenever possible.

●Pazopanib – The tyrosine kinase inhibitor pazopanib has activity against metastatic MCC in at least one report [90]. In a phase II trial (UKMCC-01), pazopanib demonstrated clinical benefit in 9 of 16 patients with metastatic MCC (56 percent): 3 of 16 with partial responses and 6 of 16 with stable disease [91,92].

●Somatostatin receptor-based therapy – Like other neuroendocrine tumors, MCC possesses receptors for somatostatin. These receptors can be demonstrated in vivo by somatostatin receptor-based diagnostic imaging (indium-111 pentetreotide single-photon emission computed tomography [SPECT; OctreoScan] or gallium Ga-68 DOTATATE positron emission tomography [PET] scanning) [93-97]. Peptide receptor radionuclide therapy with lutetium-177 isotope has been successfully used in other neuroendocrine tumors, and MCC also responds to the lutetium treatment [97,98].

Somatostatin analogs (octreotide and lanreotide) have been studied in MCC [93-96,99]. As an example, in one case report, a patient with metastatic MCC had a complete response to treatment with octreotide after receptors were demonstrated using indium-111 pentetreotide [96]. In another study of patients whose metastatic MCC was treated with somatostatin analogs, among seven patients who had a response-evaluable target lesion, three patients (43 percent) experienced progression-free survival of more than 120 days (median 237 days). This is a favorable outcome compared with historical data of chemotherapy, with median progression-free survival of approximately 90 days [87]. (See "Metastatic well-differentiated gastroenteropancreatic neuroendocrine tumors: Presentation, prognosis, imaging, and biochemical monitoring", section on 'Somatostatin receptor-based imaging techniques' and "Metastatic well-differentiated gastrointestinal neuroendocrine (carcinoid) tumors: Systemic therapy options to control tumor growth", section on 'Radiolabeled somatostatin analogs'.)

SUMMARY AND RECOMMENDATIONS

●Prognostic factors for Merkel cell carcinoma (MCC) – MCC is an aggressive cutaneous malignancy that has a high propensity for regional spread via the lymphatics and for distant metastasis. Prognostic factors include stage, Merkel cell polyomavirus (MCPyV) status, and immune competence, among other clinical factors. A multidisciplinary consultation at a center with significant MCC expertise, including dermatology, medical oncology, radiation oncology, and surgery, is in the best interest of the patient. (See 'Prognostic factors' above.)

●Initial evaluation and management – For a patient with a biopsy-confirmed cutaneous MCC, the initial evaluation should focus on determining whether there is clinical evidence of lymph node involvement or distant metastasis. Baseline determination of Merkel virus oncoprotein antibody titer can assist with prognosis and subsequent detection of recurrent disease. Imaging studies are important because of the metastatic potential of this cancer. (See 'Initial evaluation and management' above.)

●Indications for sentinel lymph node (SLN) biopsy – For patients without evidence of regional lymph node or distant metastases, SLN mapping and biopsy are generally indicated to rule out occult disease. (See 'Approach to initial management' above and 'Clinically negative nodes' above.)

•Positive SLN biopsy – For patients with a positive SLN biopsy, careful evaluation for occult metastatic disease is indicated (including appropriate imaging if not already done). If no distant metastatic disease is detected, treatment of the regional lymph node basin is indicated with either nodal dissection or definitive radiation therapy (RT). Adjuvant RT is offered after node dissection for multiple nodal involvement or extranodal extension.

●Surgery – For patients without regional lymphatic or distant metastases, we suggest excision of the primary lesion with a margin of 1 to 2 cm as a component of initial treatment (Grade 2C). (See 'Primary tumor' above and 'Surgery' above.)

•Adjuvant radiation – For patients who undergo surgical resection and are at high risk for local or regional recurrence, we suggest adjuvant RT, rather than observation (Grade 2C). High-risk factors include a primary tumor ≥1 cm in maximum dimension, positive or limited surgical resection margins, lymphovascular invasion, or an immunocompromised host. Adjuvant nodal RT is indicated if there is a high risk of anatomic, technical, or histologic failure (previous wide local excision, immunohistochemistry of the SLN not performed). (See 'Adjuvant therapy' above.)

•For patients not at high risk for locoregional recurrence, observation may be an alternative to adjuvant RT following surgery.

●Definitive RT – For patients who are not surgical candidates or for those in whom wide excision of the primary tumor is not feasible, definitive RT is an alternative to surgery. (See 'Primary tumor' above and 'Definitive radiation therapy' above.)

●Clinical lymph node involvement – For patients suspected to have regional lymph node involvement based upon clinical evaluation, biopsy confirmation (fine needle aspirate, core biopsy, or excisional biopsy) is necessary. (See 'Approach to initial management' above and 'Regional lymph nodes' above and 'Clinically positive nodes' above.)

•If regional lymph node disease is pathologically confirmed and there is no evidence of distant metastasis, we suggest definitive surgery (Grade 2C). Adjuvant RT may also be indicated. (See 'Clinically positive nodes' above and 'Adjuvant radiation therapy' above.)

•If regional lymph node disease cannot be confirmed by appropriate pathologic examination (eg, confirmatory nodal biopsy is not feasible), we suggest adjuvant RT to the suspicious node (Grade 2C).

•Patients at high risk for recurrence following definitive therapy of the primary tumor and regional lymph nodes should be considered for enrollment in formal clinical trials. (See 'Adjuvant immunotherapy' above.)

●Surveillance – Following initial definitive therapy, patients with MCC should have frequent follow-up due to the high incidence of recurrent disease and evolving options for effective therapy. Decisions regarding follow-up frequency after initial management can be informed by accurate risk data for a given patient, via a web-based risk calculator tool. (See 'Surveillance after initial therapy' above.)

●Recurrent locoregional disease – Patients with an isolated locoregional recurrence should be carefully reevaluated to definitively exclude the presence of disseminated disease. If no distant metastases are identified, patients should be treated with an individualized multimodality salvage treatment. (See 'Recurrent disease' above.)

●Initial management of metastatic disease (immunotherapy) – For patients with metastatic disease, we suggest initial treatment with a programmed cell death ligand 1 (PD-L1)-blocking agent (avelumab) or programmed cell death protein 1 (PD-1) inhibitor-based immunotherapy (pembrolizumab, nivolumab) rather than chemotherapy (Grade 2C). Whenever possible, patients with advanced MCC should be referred for participation in PD-1/PD-L1 inhibitor-based immunotherapy trials. (See 'Metastatic disease' above and 'Immunotherapy' above.)

●Subsequent management of metastatic disease – For patients with metastatic disease who progress on or are not candidates for checkpoint inhibitor immunotherapy, systemic chemotherapy may provide palliative benefit, although its impact on overall survival (OS) is uncertain. Most contemporary experience has used a regimen of a platinum (cisplatin, carboplatin) plus etoposide, as is used in small cell carcinoma of the lung. (See 'Chemotherapy' above and "Extensive-stage small cell lung cancer: Initial management", section on 'Initial treatment'.)