Best practices in surgical and nonsurgical management of head and neck Merkel cell carcinoma: An update

Abstract

Merkel cell carcinoma (MCC) is a rare, highly aggressive cutaneous neuroendocrine carcinoma. Controversy exists regarding optimal management of MCC as high‐quality randomized studies and clinical trials are limited, and physicians are bound to interpret highly heterogeneous, retrospective literature in their clinical practice. Furthermore, the rising incidence and notably poor prognosis of MCC urges the establishment of best practices for optimal management of the primary tumor and its metastases. Herein, we summarized the relevant evidence and provided an algorithm for decision‐making in MCC management based on the latest 2021 National Comprehensive Cancer Network guidelines. Additionally, we report current active MCC clinical trials in the United States. The initial management of MCC is dependent upon the pathology of the primary tumor and presence of metastatic disease. Patients with no clinical evidence of regional lymph node involvement generally require sentinel node biopsy (SLNB) while clinically node‐positive patients should undergo fine needle aspiration (FNA) or core biopsy and full imaging workup. If SLNB or FNA/core biopsy are positive, a multidisciplinary team should be assembled to discuss if additional node dissection or adjuvant therapy is necessary. Wide local excision is optimal for primary tumor management and SLNB remains the preferred staging and predictive tool in MCC. The management of MCC has progressively improved in the last decade, particularly due to the establishment of immunotherapy as a new treatment option in advanced MCC. Ongoing trials and prospective studies are needed to further establish the best practices for MCC management.

1. INTRODUCTION

Merkel cell carcinoma (MCC) is a rare, highly aggressive cutaneous neuroendocrine carcinoma with frequent locoregional recurrence and high mortality rates due to distant metastasis. ¹ , ² Relative to other cutaneous malignancies, the annual global incidence of MCC is low. However, its incidence is increasing each year, with the annual US incidence projected to rise to approximately 3250 cases per year in 2025. ³ This is likely due to longer life spans, advances in immunodiagnostic techniques, and increased reporting. MCC occurs predominantly in areas of sun‐damaged skin with the majority of cases in the head and neck region (53%). ⁴ Other known risk factors include Merkel cell polyomavirus, ultraviolet exposure, increasing age, male sex, and immunosuppression. ⁵ The aggressive nature of this tumor and challenges in management are depicted by rates as low as 50% for 5‐year survival in local disease and 14% for distant disease (though disease‐specific survival rates seem more favorable), highlighting the need for better treatment options. ⁵

Treatment for other types of skin cancer, such as melanoma, has greatly improved in the last decade, vastly impacting patient survival. ⁶ , ⁷ , ⁸ However, due to MCC's rare nature, high‐quality randomized studies are difficult to conduct and clinical trials on MCC alone are limited. MCC management (e.g., surgical margins, immunotherapy indications, radiation dose) therefore arises as an extrapolation of studies and trials based on other skin cancers. This has caused controversy regarding optimal management as physicians must interpret highly heterogeneous, retrospective literature to manage this disease, and often rely on their discretion when making treatment decisions in this life‐threatening disease. ⁹

Of note, the controversy regarding MCC treatment is highly linked to the uncertainty of the disease itself. MCC has been typically thought to arise from Merkel cells, located in the epidermis. However, recent research suggests it is possible that MCC arises from stem cells which eventually become Merkel cells. ¹⁰ Additionally, in 2008, Feng et al. implicated Merkel cell polyomavirus (MCPyV) infection in the pathogenesis of MCC, demonstrating that the virus integrates into the genome of MCC specimens, with approximately 66% to 80% of MCC specimens positive for MCPyV. ¹¹ The molecular mechanisms involved in the genesis of MCC are still not fully understood, which has raised questions regarding its pathogenesis, tumor microenvironment (TME), clinical behavior, and therapeutic strategies. ¹²

The rising incidence and notably poor prognosis of MCC urges the improvement of management, at both the primary tumor location and lymph node (LN) basin. This is particularly important in the head and neck region, as skin resection could represent an important functional and esthetic concern. Additionally, local management in the head and neck region is complex as it contains a rich and elaborate lymphatic network of more than 300 nodes, with their intermediate channels, making LN dissection notably complicated. ¹³ For the purpose of clarifying the best practices in the optimal management of head and neck MCC, we have summarized the relevant evidence, including the latest 2021 National Comprehensive Cancer Network (NCCN) guidelines, ¹⁴ systematic reviews, and meta‐analyses for MCC, and provided an algorithm for decision‐making in head and neck MCC management, as well as the latest updates on active MCC clinical trials.

2. METHODS

A comprehensive search was conducted in January 2022 across Ovid, PubMed, Web of Science, SCOPUS, and Cochrane Central Register of Controlled Trials (CENTRAL). The search strategy involved the use of MeSH terms as follows: (Merkel Cell Carcinoma”) OR (“Merkel” AND “skin cancer”) OR (“MCC”) AND (“Treatment”) OR (“Management”) AND (“Head and Neck”). No limits were imposed in any of our search queries. The search was executed by three authors (D. D. B., T. A. B., and A. S.) and a manual search of references followed to find relevant studies not identified in the electronic bibliographic search. Original articles written in English were included. Emphasis was made on systematic reviews and meta‐analyses, as these encompassed most high‐impact publications. In addition to the literature search, the authors reviewed the 2021 NCCN guidelines for MCC published on February 18, 2021. ¹⁴ Data obtained from the NCCN guidelines and other literature is summarized in a clinical decision‐making algorithm in this review.

A search for active clinical trials was conducted in ClinicalTrials.gov by one author (E. D.) on January 30, 2022, using the following filters: condition of disease (Merkel cell carcinoma), country (USA), age (18 years old or older), study type (interventional clinical trial), study phase (at least phase 2). The search included all active clinical trials currently recruiting and no filters were applied regarding sex or treatment offered.

3. RESULTS

The initial management of MCC is dependent upon the pathology of the primary tumor and the presence of clinical evidence of metastatic disease. ¹⁴ Diagnosis is usually confirmed with immunohistochemistry with a combination of neurofilament, CK‐20, CK7, and thyroid transcription factor‐1 stains. ⁵ For tumors with unclear immunohistochemistry, CAM 5.2, paired box 5, epithelial membrane antigen, MCV large T antigen, and CD56 staining can also be used for diagnosis. ⁵ Patients with biopsy‐confirmed MCC and no clinical evidence of regional LN involvement generally require sentinel lymph node biopsy (SLNB). Patients with clinical signs of LN involvement should undergo fine needle aspiration (FNA) or core biopsy and full imaging workup. If SLNB or FNA/core biopsy are positive, a multidisciplinary team should be assembled to discuss the course of action. This will usually involve node dissection or radiotherapy (RT) to the node basin and adjuvant therapy, which can include immunotherapy, RT, or chemotherapy. ¹⁴ However, increasing evidence suggests a higher local and distant disease control with immunotherapy and participation in clinical trials (Figure 1). ¹⁴ , ¹⁵ , ¹⁶

Figure 1.

Merkel cell carcinoma management algorithm based on the 2021 NCCN guidelines. CCPDMA, complete circumferential peripheral and deep margin assessment; MMS, Mohs micrographic surgery; NCCN, National Comprehensive Cancer Network; NME, narrow margin excision; WLE, wide local excision; RT, radiotherapy.

3.1. Surgical management of MCC

3.1.1. Primary tumor location management

As of now, the guidelines on all primary MCC resection margins are not well‐established. NCCN guidelines define surgical management of the primary tumor based on baseline risk factors (i.e., primary tumor >2 cm, chronic T‐cell immunosuppression, human immunodeficiency virus, chronic lymphocytic leukemia, solid organ transplant, head and neck primary site, and presence of lymphovascular invasion). ¹⁴ Patients with no baseline risk factors should undergo a wide local excision (WLE) reaching the muscle fascia with 1–2 cm margins of normal appearing skin. Those with at least one baseline risk factor (such as, head and neck as the primary site) should undergo narrow margin excision, which is defined as margins equal or less than 1.0 cm. ¹⁴ This can be done with wide local excision, Mohs micrographic surgery (MMS), or excision with complete circumferential peripheral and deep margin assessment, as long as they do not interfere with SLNB. ¹⁴ As the discussion of MMS applicability continues, surgeons are advised to send a debulked specimen of the central portion of the tumor for permanent vertical section microstaging if MMS is done. ¹⁴ If the patient is not a surgical candidate, the primary tumor and nodal region can be treated with RT, as MCC is highly radiosensitive. ¹⁴ , ¹⁷

3.1.2. Clinical lymph node involvement

Patients who present with clinical signs of LN involvement should undergo imaging studies and a biopsy of the lymphatic tissue with complete immunopanel. ¹⁴ Whole‐body positron emission tomography (PET) with computerized tomography (CT), magnetic resonance imaging (MRI), or chest/abdomen/pelvis CT with contrast (neck CT if the primary tumor is located on the head/neck; brain MRI if clinically suspicious for CNS involvement) may be useful to identify and quantify the progression and stage of the disease. ¹⁴ Lymphatic tissue biopsies should be taken through FNA, core needle biopsy, or excisional biopsy. ¹⁴

If biopsies are negative, observation of the nodal basin is suggested. Patients with high clinical suspicion or patients at high risk of disease progression (e.g., patients with primary lesions in the head and neck region) may be considered for RT to the nodal basin. ¹⁴ If the nodal biopsy is positive, most patients will undergo complete LN dissection (LND) and/or regional RT. ¹⁴ Of note, adjuvant RT after LND is generally not indicated for patients with a low tumor burden on SLNB and is only indicated for patients with multiple involved nodes. Treating the LN basin with both nodal dissection and definitive RT can increase morbidity and does not improve regional control rate or improve overall survival (OS). ¹⁴ , ¹⁸ If used, the recommended RT dose is 50–60 Gy. ¹⁴

Patients with clinical signs of metastasis should receive a multidisciplinary tumor board consultation focused on single or combined therapies, and participation in a clinical trial is preferred. When the disease is extensive or when other case‐specific circumstances are present, palliative care may be the most appropriate option for the patient. ¹⁴

3.1.3. No clinical lymph node involvement

If there is no evidence of metastatic disease, the patient should undergo excision of the primary tumor with SLNB since MCC exhibits a tendency for early locoregional metastasis. For patients who elect to forgo SLNB, WLE followed by adjuvant RT can be considered. As with many head and neck malignancies, both locoregional and distant nodal metastasis are associated with poor prognosis. ¹⁹ Therefore, the NCCN guidelines recommend SLNB, involving complete microscopic evaluation of the SLN(s) with hematoxylin and eosin (H&E) and at least one immunohistochemistry staining, such as CK20 and thyroid transcription factor‐1 (TTF1), AE1/3 keratin, neuroendocrine marker and/or Merkel cell polyomavirus T antigen (CM2B4), for all clinically node‐negative patients. ¹⁴

If the SLNB is positive, definitive treatment of the draining lymphatics should be done which may include regional LN dissection or nodal excision with regional RT, if high tumor burden. ¹⁴ , ¹⁸ Patients should be followed up with radiographic surveillance typically via diagnostic neck/chest/abdomen/pelvis CT with oral and intravenous (IV) contrast, and brain MRI. Available retrospective studies have not clarified the frequency of follow‐up surveillance or whether patients were believed to have no evidence of disease before follow‐up imaging.

If SLNB is negative, observation is recommended. Nevertheless, due to the high risk of false‐negative SLNBs in the head and neck region, possibly resulting from aberrant LN drainage and frequent presence of multiple SLN basins, consideration should be taken to irradiate the nodal beds for subclinical disease. ¹⁴ While evidence for false negative SLNB is largely based on melanoma studies, little data exist describing predictors and outcomes of patients with MCC with false‐negative SLNB. The NCCN considers head and neck primary tumor location as risk factor alone, however history of primary tumor excision before SLNB and profound immunosuppression are also thought to be associated with false negativity. ¹⁴ , ²⁰

3.2. Nonsurgical treatment of MCC

3.2.1. Chemotherapy

MCC is widely considered a chemotherapy responsive tumor, with high response rates. ²¹ Traditionally, chemotherapy has only been used for the primary treatment of advanced MCC or as an adjuvant therapy. However, high‐quality clinical data on adjuvant systemic therapy are lacking and almost all the data concerning postoperative chemotherapy is combined with RT. Hence, the use of chemotherapy remains controversial as there are no sufficient clinical trials or retrospective studies of chemotherapy alone for its efficacy.

Neoadjuvant/adjuvant chemotherapy is not routinely recommended for regional disease as survival benefit has not been demonstrated. ²² , ²³ However, adjuvant chemotherapy could be used on a case‐by‐case basis, such as for palliative care or when patients have contraindications to immunotherapy. If used in selected cases, the NCCN panel recommends cisplatin or carboplatin, with or without etoposide. Postoperative chemoradiation may have a role in particularly high‐risk cases where residual disease is present after surgery. ¹⁴ Given the poor duration of response (DOR), significant toxicity, and ambiguous effects on OS, it is evident that alternative systemic therapies are necessary.

3.2.2. Radiation therapy

The use of adjuvant radiotherapy for MCC is controversial. NCCN states that RT should be considered as an adjunctive treatment measure except for very low‐risk features such as small tumors (<1 cm), a negative sentinel LN, non‐immunosuppressed state, or no evidence of lymphovascular disease. When RT is used as the main treatment and not as an adjuvant, higher doses are required (>50 Gy). ¹⁴ , ¹⁷ RT is effective in controlling the disease within the treatment field at a rate of roughly 80%, but systemic relapses do occur. Due to a lack of prospective comparative data, it is still unclear whether surgical management or RT is more effective as initial treatment for nodal MCC. Therefore, definitive RT for the primary tumor site is reserved only for patients that are not surgical candidates. ¹⁴

3.2.3. Immunotherapy

A systemic modality that has been explored with great success in treating advanced MCC is checkpoint immunotherapy, which is the preferred intervention in treating recurrent locally advanced, recurrent regional, and disseminated MCC. ¹⁴ The advent of immune checkpoint inhibitors (ICIs) has revolutionized cancer treatment as they promote the destruction of tumors by releasing immune checkpoint‐mediated suppression of the body's antitumoral T lymphocytes. Some immune checkpoint molecules inhibited by ICI's include programmed cell death protein 1 (PD‐1), programmed death‐ligand 1 (PD‐L1), and cytotoxic T‐lymphocyte associated protein 4 (CTLA‐4). ²⁴ Indeed, CD8⁺ T lymphocytes have been shown to be independently associated with improved MCC‐specific survival (Paulson, 2011). In addition, PD‐L1, an immune checkpoint molecule, is expressed in a majority of MCC tumors, has been shown to provide prognostic value in predicting OS. ²⁵ Finally, evidence from case reports indicated the efficacy of ICI's in treating MCC. ²⁶ , ²⁷ Multiple clinical trials discussed below have since demonstrated the efficacy of immunotherapy for MCC.

Avelumab, a PD‐L1 inhibitor, demonstrated an effective clinical response in part A of the JAVELIN Merkel 200, a multicenter, single‐group, open‐label, phase II clinical trial that enrolled 88 stage IV metastatic MCC patients refractory to at least one line of chemotherapy. Patients received avelumab infusions every 2 weeks until disease progression, unacceptable toxicity, or withdrawal. An objective response rate (ORR) of 31.8% was recorded, with 8 patients showing complete response (CR) and 20 showing partial response (PR) at a median follow‐up of 10.4 months. ²⁸ Subsequent studies demonstrated an ORR of 33% with 10 CR (11.4%) at a median follow‐up of 40.8 months. The median OS was 12.6 months, the 42‐month OS rate was 31%, and the median DOR was 40.5 months. ²⁹ , ³⁰ Treatment‐related adverse events (TRAEs) occurred in 62 patients (70%), with 4 (5%) reporting grade 3 TRAEs and no grade 4 TRAEs or treatment‐related deaths reported. This represents a favorable safety profile compared to the high incidence of toxicity‐related morbidity of chemotherapeutic treatments. Results from this study showed avelumab provides durable and long‐term survival responses in stage IV MCC patients and was FDA approved in March 2017 for the treatment of all patients, aged 12 and older, with metastatic MCC, regardless of treatment history. ³¹

In the Cancer Immunotherapy Trials Network‐09/KEYNOTE‐017, a phase II, multicenter clinical trial, a total of 50 patients with unresectable locally advanced (14%) or metastatic (86%) MCC received pembrolizumab, an anti‐PD‐1 ICI. Results from the first two updates ³² , ³³ led to FDA approval of pembrolizumab for locally advanced or metastatic MCC. In the most recent study update, ³² patients were followed up for a median of 31.8 months, representing the longest available follow‐up for a first‐line anti‐PD‐1 or anti‐PD‐L1 therapy in MCC. An ORR of 58%, with 15 (30%) CR and 14 (28%) PR, was recorded. In addition, a median progression‐free survival (PFS) of 16.8 months, a 3‐year PFS of 39.1%, and an estimated 3‐year OS of 59.4% were also observed. While a median DOR was not reached, most responses were durable, with 73% persisting at 3 years. TRAEs were observed in 49 (98%) patients, with grade 3 or 4 TRAEs occurring in 15 (30%) patients, and a single treatment‐related death was reported. These results indicate that pembrolizumab provides promise as an effective first‐line systemic treatment, with a high response rate and durability, in treating patients with locally advanced or metastatic MCC. Based on these results, in December 2018, pembrolizumab was approved for adult and pediatric patients with recurrent locally advanced or metastatic MCC.

As a result, the NCCN guidelines recommend both avelumab and pembrolizumab as a preferred intervention for disseminated disease if clinical trial enrollment is not feasible. Furthermore, the NCCN guidelines consider the use of pembrolizumab for recurrent locally advanced and recurrent regional MCC if curative surgery and curative RT are not feasible (NCCN 2021 Guidelines). However, it is important to note that there is no data available to support the adjuvant application of immunotherapy outside of a clinical trial. ¹⁴ When treatment is not possible with avelumab or pembrolizumab (FDA approved), nivolumab (not FDA approved), a PD‐1 ICI, should be considered. In the CheckMate 358 trial, the 22 advanced MCC patients who received nivolumab and were evaluable for response reported an ORR of 68% with ongoing response in 87% of those patients. Notably, responses occurred in 71% of treatment naïve patients and in 63% of patients with 1 or 2 prior systemic therapies indicating nivolumab's potential as a first‐ or second‐line therapy in advanced MCC. TRAEs occurred in 68% of patients with grade 3 or 4 TRAEs occurring in 20% of patients.

TRAE patterns associated with avelumab, pembrolizumab, and nivolumab are consistent with prior observations across cancer indications. ³⁴ Grade 3 or higher TRAEs appear to be lower in avelumab treated MCC compared to pembrolizumab or nivolumab treated MCC, possibly owing to the presence of additional checkpoint signaling from PD‐L2 in avelumab treatment. A direct comparison between the overall activity and toxicity of avelumab, pembrolizumab, and nivolumab can only be accurately assessed through future clinical trials. Currently, the effects of nivolumab (NCT02196961), nivolumab plus RT or ipilimumab (NCT03798639), avelumab (NCT03271372, NCT04291885), and pembrolizumab (NCT03712605) are being evaluated in active clinical trials.

3.2.4. Neoadjuvant immunotherapy

Neoadjuvant immunotherapy also holds promise in promoting long term surgical outcomes by enhancing the detection and destruction of micrometastases, which are the source of postoperative relapse. ³⁵ Administering immunotherapy before surgery may allow for improved priming of immune cells against the larger antigen load provided by the primary tumor, especially with regard to highly immunogenic tumors like MCC. While neoadjuvant immunotherapy approaches for resectable MCC are not typically utilized in clinical practice, some clinical trials suggest a potential future role for immunotherapy in this setting. Within the CheckMate 358 study, an evaluation of 36 patients with stage IIA‐IV resectable MCC who were provided neoadjuvant nivolumab doses for approximately 4 weeks before surgery reported 17 (47.2%) patients who achieved a pathologic complete response (pCR) and 18 (54.5%) of the 33 radiographically evaluable patients had tumor reductions greater or equal to 30%. ³⁵ In all patients, 24‐month RFS and OS were 68.5% and 79.4%, respectively. TRAEs occurred in 18 (46.2%) of patients, with 3 (7.7%) experiencing grade 3 or 4 TRAEs. These results demonstrate nivolumab's potential as a tolerable neoadjuvant capable of inducing radiographic tumor regressions and pCRs in resectable MCC patients. Additional actively recruiting clinical trials will provide further information regarding the efficacy of neoadjuvant immunotherapy for MCC. One trial (NCT04975152) is investigating the safety and effectiveness of neoadjuvant Cemiplimab, an anti‐PD‐1 ICI, in treating stage I‐II MCC. Another trial (NCT04869137) is investigating the role of neoadjuvant pembrolizumab plus levatinib in MCC based on evidence suggesting that this drug combination produces a greater reduction in tumor volume and enhanced immunomodulatory effects compared to either therapy alone. ³⁶ Thus, it is clear that immunotherapy in neoadjuvant and adjuvant settings will continue to make advancements in the field of MCC.

3.2.5. Immunotherapy versus chemotherapy

Data from non‐randomized trials have shown response rates are improved with PD‐1/PD‐L1 blockade compared to cytotoxic therapy in patients with MCC. ¹³ However, the safety profiles and indications of checkpoint immunotherapy are significantly different from cytotoxic therapies, and careful consideration of contraindications to checkpoint immunotherapy as well as the detection and management of TRAEs is necessary. For patients with contraindications, or who have demonstrated a lack of durable response to checkpoint immunotherapy cytotoxic therapies may be considered. However, because cytotoxic therapies are highly toxic and unlikely to offer lasting clinical benefit for patients with disseminated MCC, careful clinical judgment must be used to ensure they are prescribed at appropriate times.

3.2.6. New directions

There has been considerable work in identifying further treatment options in MCC patients for whom adjuvant checkpoint inhibitors alone have proven ineffective. One potential direction involves the usage of combination ipilimumab/nivolumab (IPI/NIVO) in anti‐PD‐(L)1 refractory MCC patients. A retrospective study conducted in Germany observed responses to IPI/NIVO in three out of five anti‐PD‐L1 treatment refractory patients, without grade II or III IRAEs. ³⁷ In addition, a recently publishedrandomized, open label, phase 2 clinical trial (NCT03071406) enrolled advanced stage MCC patients who were either treatment naïve or had received prior anti‐PD‐1 or anti‐PD‐L1 monotherapy to study the effects of IPI/NIVO with or without stereotactic body radiation therapy (SBRT). ³⁸ The primary endpoint was the ORR (proportion of patients with a CR or PR) in all randomly assigned patients receiving at least one dose of IPI/NIVO. Amongst 50 total patients across both IPI/NIVO and IPI/NIVO + SBRT groups, with a median follow up of 14.6 months, 22 of 22 (100%) ICI naïve patients had an OR, with 9 of 22 (41%) achieving a CR. In patients with a prior ICI treatment, 8 of 26 (31%) had an OR, with 4 of 26 (15%) experiencing a CR. Grade 3 or 4 TRAE's occurred in 10 of 25 (40%) patients in the IPI/NIVO group and 8 of 25 (32%) in the IPI/NIVO + SBRT group. There were no significant improvements in efficacy with the addition of SBRT to IPI/NIVO. Importantly, even though no clinical benefit was observed with SBRT addition to ICI therapy, this randomized trial represents the first prospective study to determine that combination IPI/NIVO provides a manageable safety profile, high ORR, and durable responses as a first‐line therapy for advanced MCC. Additionally, clinical benefit was observed with IPI/NIVO for patients who had received prior ICI, thus combination IPI/NIVO may be an effective therapy for ICI treatment refractory advanced MCC. Another direction for checkpoint inhibitor refractory MCC patients involves the utilization of epigenetic modifiers such as histone deacetylase inhibitors (HDACis) to increase the immunogenicity of the TME. HDACis have previously been shown to enhance MHCI expression, ³⁹ improve T cell infiltration to the TME, ⁴⁰ and decrease immunosuppressive regulatory T cell (T‐reg) activity. ⁴¹ The MERKLIN2 study (NCT04393753) is a phase II trial investigating the selective class I HDACi domatinostat in combination with avelumab for advanced unresectable/metastatic MCC patients who have progressed on prior anti‐PD‐(L)1 therapy.

Other alternatives involve the usage of MDM2 inhibitors. Specifically, in MCPyV positive MCC, the MCPyV small T antigen activates MDM2 expression, inhibiting p53, a known tumor suppressor. A recent in vitro and in vivo study demonstrated the role of MDM2 inhibitors as potent suppressors of MCC by stabilizing the p53 response. ⁴² A current phase 1b/2 clinical trial (NCT03787602) seeks to evaluate the effectiveness of navtemadlin, an MDM2 inhibitor, for patients who have failed prior anti‐PD‐(L)1 treatment, or in combination with avelumab in anti‐PD‐(L)1 treatment naïve patients. A recent update demonstrated a 25% confirmed ORR, 38% confirmed + unconfirmed ORR, and a 63% disease control rate for patients receiving 180 mg for 5 days on/23 days off. ⁴³ Additionally, one responder achieved a complete metabolic remission by PET/CT after 2 years on treatment. Thus, the upregulation of p53 in MCPyV positive MCC patients who have failed anti‐PD‐(L)1 therapy is an exciting therapeutic strategy.

3.3. Follow‐up

Clinical and radiological surveillance is the most common follow‐up modality in MCC. The NCCN guidelines recommend that patients should be followed every 3–6 months for 3 years and then every 6–12 months thereafter. Physical examination, should emphasize on total‐body skin examination and palpation of lymph nodes, and routine imaging should be considered for high‐risk patients.

Studies have validated a MCPyV antibody (MCPyV‐Ab) test, also known as the AMERK test, as a useful clinical marker for both prognostication and ongoing surveillance. In a prospective cohort study, it was found that over 50% of MCC patients had MCPyV‐oncoprotein antibodies, and only 1% of non‐MCC patients had the antibodies. Additionally, an increasing titer had a 66% positive predictive value for clinically evident recurrence and a decreasing titer had a negative predictive value of 97%. ⁴⁴ The NCCN guidelines describe a potential role for the AMERK test but no detailed guidelines aside from suggestions are available. Clinicians should use baseline MCPyV oncoprotein antibody titers for stratification of newly diagnosed MCC patients into higher risk seronegative and lower risk seropositive cohorts for initial workup of the disease. This risk stratification could potentially prompt more aggressive treatment or surveillance that could result in the detection of early recurrence and survival advantage. Some authors have suggested to perform the AMERK test every 3 months while the patient remains at risk for MCC recurrence (typically up to approximately 5 years). If the titer increases more than 30% from the previous value, an imaging study is warranted to evaluate possible recurrence. ⁴⁵

It is noteworthy that AMERK's true application in promoting management for survival advantage or increasing response rates following (re)‐institution of therapy is still unproven. In this manner, NCCN guidelines suggest clinical trial enrollment, if available, to be assured that all patients receive best supportive care depending on the disease and case‐specific circumstances. Moreover, palliative care alone may be the most appropriate option for some patients, as seen in the NCCN Guidelines for Palliative Care.

4. DISCUSSION

MCC management remains complex and requires a multidisciplinary team in most cases. When treating the primary tumor, WLE is most commonly performed with a minimum margin size of 1 cm. However, the ideal method of excision and surgical margin assessment has not been clearly established, and current recommendation of 1–2 cm margins may be unreliable. A retrospective review conducted at our institution found that despite the resection margins meeting or exceeding NCCN recommendations, the surgical margin was positive in 57% of the patients, and 92% of those were positive at the deep margin. ⁴⁶ Many studies have shown survival is worse in the setting of residual tumor on surgical margins, with positive margins widely reported in 3.7%–57% of patients with MCC. ⁴⁷ , ⁴⁸ , ⁴⁹ Conversely, Allen et al. found no difference in local recurrence between patients with resection margins smaller than 1 cm (9%) and patients with resection margins 1 cm or wider (10%) (p = 0.83). ⁵⁰ However, they did find head and neck tumor location was associated with a higher 5‐year DSS by univariate analysis. This is particularly important in the setting of wider margins being associated with more frequent skin graft or flap reconstruction for definitive closure in head and neck region (p = 0.025), as demonstrated by Doepker et al. ⁵¹ Perez et al. later confirmed these finding in a single institution study comparing margin widths of 1, 1.1–1.9, and 2 cm or more, with only 34.1% of patients undergoing a resection margin of 2 cm or more having primary closure of their wounds. They also found no difference in local recurrence, OS, or disease‐specific survival (DSS) between the patients with a 1‐cm resection margin for primary MCC and the patients with larger resection margins, with a median follow‐up period was 21 months. However, they did not distinguish between anatomical regions. ⁵²

RT after resection has shown improvements in both locoregional control and OS. ⁵³ , ⁵⁴ , ⁵⁵ In a series of 171 patients, Strom et al. found that postoperative RT improved both 3‐year locoregional control (79.5% for RT vs. 59.1% for no RT; p = 0.004) and 3‐year OS (79.4% for RT vs. 59.6% for no RT; p = 0.03). ⁵⁴ Conversely, a retrospective study with 6156 patients with localized MCC who underwent surgical resection showed that patients with excision margins of 1.0 cm or smaller who received adjuvant RT experienced OS rates similar to that of patients with larger excision margins who did not receive radiotherapy. Interestingly, and in line with previous studies, they found the combination of excision margins larger than 1.0 cm with adjuvant RT was associated with the highest OS. ⁵⁶ However, discussion whether larger resection margins are necessary when frequently administering postoperative RT to the primary tumor bed after resection is ongoing. Due to heterogeneity of the outcomes reported in the literature, surgeons typically use their discretion when selecting margin width in an attempt to maximize outcomes while minimizing morbidity. Thus, alternative options for tumor resection should be further explored and considered in MCC. As an alternative to conventionally fractionated, postoperative radiation therapy, Cook et al. reported preliminary data suggesting that 8‐Gy single‐fraction radiation therapy could offer a potential to treat the primary site for localized head and neck MCC stages I‐II. However, larger studies are needed to identify which patients with MCC may benefit from abbreviated versus protracted postoperative radiation therapy. ⁵⁷

MMS for MCC has the advantage of complete histologic control over deep and peripheral margins, while sparing normal tissue. It is especially indicated in narrow margin excision in the setting of head and neck MCC, because with WLE it is not always possible to maintain the function and appearance of facial features. ¹ In addition, for head and neck MCC's, WLE is often problematic because the resection itself is surgically challenging and lymphatic drainage is variable. ⁵⁸ Though studies have shown MMS to have OS outcomes comparable to WLE for early‐stage T1 and T2 primary MCC tumors of the head and neck region, ⁴⁷ further comparative studies are necessary to confirm its overall utility in head and neck MCC when compared to narrow margin local excision. Though there is ongoing discussion concerning the strength of studies supporting the use of MSS for MCC, the recurrence rates of MCC after MMS have been reported from 5%–22%, compared to 25%–40% after WLE with negative margins. ⁵⁹ , ⁶⁰ , ⁶¹ , ⁶²

In head and neck MCC, recurrence rates as high as 77% have been reported. ⁶³ McEvoy et al. found the risk of recurrence in the first year after diagnosis was high and related to stage: 11% for pathologic stage I, 33% for pathologic stage IIA/IIB, 30% for stage IIIA, 45% for pathologic stage IIIB, and 58% for pathologic stage IV. Additionally, at 5 years, 80% of patients with pathologic stage I cancer were without recurrence versus 28% of patients with stage IV. For all stages, the highest risk of recurrence occurred 1–3 years after initial treatment, and 94% of recurrences occurred within the first 3 years after initial treatment. ⁶⁴ The American Joint Cancer Commission 8th edition (AJCC8) database also reported that the expected 5‐year OS for localized disease (stages 1 and 2) was 50.6% and decreased with increasing tumor size. ⁶⁵ Harms et al. later confirmed that increasing tumor size, and hence increasing tumor (T) stage, was predictive of survival. ⁶⁶ However, other studies from high‐volume referral centers have reported contradictory results, calling into question the dependability of the AJCC system for estimating prognosis. ⁶⁷ Of note, the ALCC8 lacked adjustment for age‐ or sex‐matched life expectancy in the OS analysis, which is significant for a disease in which peak incidence occurs at advanced age. Because AJCC staging systems are widely used by clinicians to prognosticate for patients, acknowledging its limitations and questioning the accuracy and reliability of the prognostic information in these systems is essential. ⁶⁷

Besides T stage, regional nodal involvement (corresponding to the N stage) determines cancer stage and, therefore, management. Results from retrospective studies consistently show that MCC prognosis worsens with increasing nodal involvement. Additionally, head and neck MCC in particular is associated with higher locoregional metastasis and distant node metastasis, which corresponds with poorer DSS. Therefore, management of the nodal basin should always be considered when treating MCC, especially in cases of head and neck involvement. ¹⁴

For patients with clinically occult disease, SLNB is currently the most reliable predictor of survival, although controversy remains on the prognostic value of SLN status. A study conducted at our institution identified patients who underwent SLNB (38.5%, [n = 1174]) had better survival (1.64 ± 0.64 vs. 1.37 ± 0.72 years, p < 0.001) than those who did not receive SLNB (61.5%, [n = 1874]). In addition, 2‐year survival was 81% (95% confidence interval [CI], 78%–85%) for patients who received SLNB and was 54% (95% CI, 51%–58%) for those who did not. ⁶⁸ This study also showed subgroups of patients were at higher risk for SLNB positivity; patients with MCC on the trunk versus the extremity; immunosuppressed versus not immunosuppressed; diffusely infiltrative MCC growth type versus circumscribed/nodular MCC growth type; and presence of tumor infiltrating lymphocytes (TIL) or lymphovascular invasion may (LVI) versus no presence of TIL or LVI. Comorbidities, male sex, clinical diameter, and transection did not affect SLN positivity. ⁶⁸ A study conducted by Straker et al. looked at the predictors of false negative SLNB in MCC and concluded males sex, age above 75 years, and LVI may be at increased risk for false negative SLNB, arguing increased nodal surveillance following negative SLNB in these high‐risk patients may aid in early identification of regional nodal recurrences. ²⁰

Furthermore, variations in the application of SLNB techniques have led to differences in successful SLN identification, which have been reflected in the reported regional relapse rates in patients with negative SLNB, ranging from 5% to 12% with corresponding false‐negative rates between 17% and 21%. ⁶⁹ , ⁷⁰ , ⁷¹ Nevertheless, SLNB has proven to detect occult metastasis in approximately one‐third of patients who are clinically node‐negative. Large retrospective studies or meta‐analyses of SLNB in patients with clinically node‐negative localized MCC have reported rates of SLN positivity ranging from 30% to 38%, ⁶⁹ , ⁷⁰ , ⁷¹ , ⁷² proving SLNB is a crucial step in disease management.

ICG is a widely used clinical fluorescent dye and has been proven useful in SLN identification in melanoma, breast, and other cancers. ⁷³ , ⁷⁴ A recent study at our institution reported ICG fluorescence had a higher node localization rate than vital blue dye (89.6% vs. 63.6%) in clinically node‐negative MCC patients undergoing SLNB with lymphoscintigraphy. Blue dye or gamma probe alone did not identify any unique positive SLNs. ⁷⁵ This highlights the importance of utilizing two modalities when performing SLNB and suggests ICG‐based fluorescence may be able to identify nodes that would have been otherwise missed when using gamma probe only.

Though NCCN recommendations do not call for baseline imaging for clinically node negative patients, some experts recommend baseline cross‐sectional imaging such as CT, PET‐CT, or MRI. ⁷⁶ , ⁷⁷ In a study of 584 MCC patients with cutaneous primary tumor, baseline imaging, and no evident distant metastasis, patients that were clinically node negative showed a rate of occult metastatic MCC at a rate of 13%, suggesting that baseline imaging may be helpful in both clinically node positive and negative patients. ⁷⁷ Radiological surveillance, however, is recommended for all patients due to the high recurrence rate of MCC. The AMERK test, although rising in clinical value and application, can only be utilized for MCPyV positive MCC. For patients with UV light induced MCC, cell free circulating tumor DNA (ctDNA) may serve as a potential alternative tool for prognostication and treatment response prediction for MCC. Prior studies have demonstrated ctDNA as a predictor of MCC treatment response, ⁷⁸ as well as a sensitive biomarker of residual disease and relapse after treatment. ⁷⁹ Further work is necessary to elucidate the prognostic role of ctDNA in MCC management.

While surgical tumor excision and nodal removal are key steps in MCC treatment, systemic therapies are also commonly utilized for later stage MCC patients. Chemotherapy has been used to treat advanced MCC, alone or as an adjuvant therapy (often combined with RT), with response rates greater than 60%. ⁸⁰ , ⁸¹ Despite the high response rate to chemotherapy, controversy remains regarding its use in MCC, as there are no sufficient clinical trials to prove its efficacy, TRAEs are common, and durability of response is low. A retrospective study that examined 62 patients with metastatic MCC treated with chemotherapy found that while response rate to first‐line chemotherapy was 55%, the median DOR was only 85 days, suggesting a nondurable response of metastatic MCC to first‐line chemotherapy. ⁸² Amongst all patients, the median PFS was also only 3 months. A systematic literature review further demonstrated that chemotherapy provides a short DOR (less than 8 months) associated with significant toxicities for patients with metastatic MCC in both first‐ and second‐line settings. ⁸³ The short DOR is indicative of the ability of MCC cells to quickly develop resistance to chemotherapeutic modalities. Previous retrospective studies have even reported a decreased OS in patients who received adjuvant chemotherapy compared to those who did not, ⁵⁰ or to those who received either surgery alone or adjuvant RT. ⁸⁴ While adjuvant chemotherapy is no longer commonly utilized for MCC, some results report that adjuvant chemoradiation provides a significant improvement in OS compared to adjuvant RT alone for patients who have positive margins, primary tumor size greater than 3 cm, and male sex. ⁸⁴ These results suggest that there is a possible role for adjuvant chemoradiation in some high‐risk patients.

While adjuvant chemotherapy does not provide strong, durable responses in treating MCC, certain types of systemic adjuvant immunotherapy have proven effective on this front. MCC has consistently been associated with immune system activation even before the discovery of the Merkel cell polyomavirus (MCPyV). ⁸⁵ , ⁸⁶ , ⁸⁷ Currently, it is thought that the majority of MCCs (up to 80%) are associated with the MCPyV, with the remainder due to UV light‐induced mutations. ⁸⁸ Both pathogenic pathways involve immune system activation due to either the cellular expression of MCPyV oncoproteins following infection, or the generation of neoantigens from UV light‐induced DNA damage. ⁸⁹ Previously discussed clinical trials have demonstrated the efficacy of FDA‐approved therapies such as avelumab and pembrolizumab in treating advanced MCC. While not yet FDA‐approved, Nivolumab, a PD‐1 inhibitor has also shown efficacy in treating advanced MCC. Most recently, combination IPI/NIVO has also demonstrated clinical efficacy as a first line for advanced MCC. ³⁸

Although checkpoint inhibitors have advanced treatment of MCC, some patients do not respond to the treatment. Thus, identifying biomarkers of responsiveness to immunotherapy will be important in improving treatment stratification in MCC. One study observed absence of immunosuppression, predominance of central memory CD8⁺ T cells among TILs, and a limited number of tumor affected organs as markers associated with response to anti‐PD‐(L)1 therapy. ⁹⁰ Other studies have demonstrated a role for ctDNA as a predictor of response to therapy. ⁷⁹ In addition, identifying alternative treatments for checkpoint inhibitor refractory patients also remains an active area of research. As previously mentioned, various therapies such as anti‐MDM2, anti‐HDACi, and combination IPI/NIVO have been explored for anti‐PD‐(L)1 refractory patients. One report showed results demonstrating that combinatorial sequential immune checkpoint blocking agents can activate antitumor immunity in patients for whom anti‐PD‐1/L1 alone is insufficient. Tumor regressions have been seen after sequencing PD‐1‐ and PD‐L1‐blocking antibodies and appeared to potentially have nonredundant anticancer properties in an individual patient. ⁹¹ As previously described, a recently completed clinical trial reported clinical response following combination IPI/NIVO in advanced MCC patients who were treatment refractory to ICI monotherapy. Further results from additional studies will continue to improve our understanding of MCC treatments and allow for optimal care to be provided.

5. CONCLUSION

The establishment of optimal management guidelines for rare malignancies such as MCC requires the incorporation of data from studies of similar malignancies to aid in creating optimal treatment protocols, as sufficient patient recruitment is often limited. Despite these challenges, the management of MCC has progressively improved in the last decade, particularly due to the availability of immunotherapy as a new treatment option. Overall, treatment is primarily dependent on accurate histopathologic interpretation and microstaging of the primary lesion. WLE or MMS are recommended in most cases and SLNB remains the preferred staging and predictive tool in MCC. In advanced disease, involvement in a clinical trial is always preferred. Ongoing trials and prospective studies are needed to further establish the best practices for MCC management (Table 1).

Table 1.

Active clinical trials for Merkel cell carcinoma in the United States

Abbreviations: IMT, iImmunotherapy; RT, radiotherapy. TR, Targeted therapy.

AUTHOR CONTRIBUTIONS

Daniela Duarte‐Bateman: Conceptualization (lead); investigation (lead); writing–original draft preparation (lead). Alan Shen: Investigation (lead); writing– original draft (lead). Taylor Bullock: Methodology (lead); investigation (supporting); writing–review and editing (supporting). Payam Sadeghi: writing–review and editing (equal). Joseph M. Escandón: Writing–original draft (supporting); writing–review and editing (lead). Eliska Dedkova: Methodology (supporting); visualization (lead); investigation (supporting); writing–review and editing (equal). Brian R. Gastman: Conceptualization (equal); writing–review and editing (equal); supervision (lead).

CONFLICT OF INTEREST

The corresponding author is a principal investigator in various clinical trials, including MCC trials. This research did not receive any specific grant from funding agencies in the public, commercial, or not‐for‐profit sectors.

Duarte‐Bateman D, Shen A, Bullock T, et al. Best practices in surgical and nonsurgical management of head and neck Merkel cell carcinoma: an update. Molecular Carcinogenesis. 2023;62:101‐112. 10.1002/mc.23483

DATA AVAILABILITY STATEMENT

Data sharing not applicable to this article as no data sets were generated or analyzed during the current study.