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Head and Neck Merkel Cell Carcinoma: A 12-Year Single Institutional Experience

  • C.M. Hurley
    Correspondence
    Correspondence: Mr Ciaran Hurley, MB BCh BAO MCh, MRCS, Specialist Registrar, Department of Plastic and Reconstructive Surgery, University Hospital Galway, Co. Galway, Republic of Ireland.
    Affiliations
    Department of Plastic & Reconstructive Surgery, University Hospital Galway, Galway, Ireland

    Royal College of Surgeons in Ireland, St. Stephen's Green, Dublin, Ireland
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  • D. ALNafisee
    Affiliations
    Department of Plastic & Reconstructive Surgery, University Hospital Galway, Galway, Ireland

    Royal College of Surgeons in Ireland, St. Stephen's Green, Dublin, Ireland
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  • D. Jones
    Affiliations
    Department of Plastic & Reconstructive Surgery, University Hospital Galway, Galway, Ireland

    Royal College of Surgeons in Ireland, St. Stephen's Green, Dublin, Ireland
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  • J.L. Kelly
    Affiliations
    Department of Plastic & Reconstructive Surgery, University Hospital Galway, Galway, Ireland

    Royal College of Surgeons in Ireland, St. Stephen's Green, Dublin, Ireland
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  • P.J. Regan
    Affiliations
    Department of Plastic & Reconstructive Surgery, University Hospital Galway, Galway, Ireland

    Royal College of Surgeons in Ireland, St. Stephen's Green, Dublin, Ireland
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  • A.J. Hussey
    Affiliations
    Department of Plastic & Reconstructive Surgery, University Hospital Galway, Galway, Ireland

    Royal College of Surgeons in Ireland, St. Stephen's Green, Dublin, Ireland
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  • N. McInerney
    Affiliations
    Department of Plastic & Reconstructive Surgery, University Hospital Galway, Galway, Ireland

    Royal College of Surgeons in Ireland, St. Stephen's Green, Dublin, Ireland
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Open AccessPublished:May 13, 2022DOI:https://doi.org/10.1016/j.jpra.2022.05.005

      Abstract

      Background

      Merkel cell carcinoma (MCC) is an aggressive malignancy of presumed neuroendocrine origin. Most case series of MCC are limited by low case numbers and are not specific to head and neck tumours. The purpose of this study was to provide a focused review of head and neck MCC diagnosis and management in a single Irish institution.

      Methods

      Patient's demographics, tumour characteristics, pathological diagnosis, surgical treatment, adjuvant treatment, subsequent management and clinical course were collected. Estimates of progression-free MCC survival rates were calculated by the Kaplan–Meier statistical model. A Pearson product-moment correlation coefficient examined the association between surgical margins and disease-free follow-up.

      Results

      In total, 11 patients were treated for head and neck MCC with a mean age of 79.6 years (range = 69–91 years). The mean average follow-up duration of patients was 18.3 months. Of the cohort, 18% (n=2) had a sentinel node biopsy (SLNB). A selective neck dissection was subsequently performed in 18% (n=2). In total, 72% (n=8) of patients received adjuvant radiotherapy. Median disease-specific survival was 15 months for the SLNB group and 17 months for the non-SLNB group, not statistically significant (p=0.23). There was no significant association between surgical margins and disease-free follow (p=0.65).

      Conclusions

      Our case series adds to a limited body of evidence of head and neck MCC. Surgery remains the treatment priority in localized disease, with an increasing role of SLNB for accurate prognostication and staging. Early management of stage I disease results in moderate long-term disease-free survivability.

      Keywords

      Introduction

      Merkel cell carcinoma (MCC), also termed cutaneous neuroendocrine carcinoma, is a rare yet aggressive tumour of neuroendocrine cell origin that commonly presents in the head and neck region.
      • Jalilian C
      • Chamberlain AJ
      • Haskett M
      • et al.
      Clinical and dermoscopic characteristics of Merkel cell carcinoma.
      First described in 1972, it is characterized by a high incidence of local recurrence and regional and distant metastasis.
      • Toker C.
      Trabecular carcinoma of the skin.
      Despite its increasing incidence, MCC remains atypical and, as a result, poorly characterized.
      • Fritsch VA
      • Camp ER
      • Lentsch EJ.
      Sentinel lymph node status in Merkel cell carcinoma of the head and neck: not a predictor of survival.
      The diagnosis of MCC is rarely clinically suspected because the primary tumour often lacks predictable characteristics and is often asymtomatic.
      • Bichakjian CK
      • Olencki T
      • Aasi SZ
      • et al.
      Merkel Cell Carcinoma, Version 1.2018, NCCN Clinical Practice Guidelines in Oncology.
      The primary manifestation for the disease includes a rapidly growing, red or purple painless nodule.
      • Müller-Richter UDA
      • Gesierich A
      • Kübler AC
      • Hartmann S
      • Brands RC.
      Merkel Cell Carcinoma of the Head and Neck: Recommendations for Diagnostics and Treatment.
      Increasing age, immunosuppression, ultraviolet light, male sex and the Merkel cell polyomavirus are independent risk factors for developing MCC.
      • Jalilian C
      • Chamberlain AJ
      • Haskett M
      • et al.
      Clinical and dermoscopic characteristics of Merkel cell carcinoma.
      ,
      • Feng H
      • Shuda M
      • Chang Y
      • Moore PS.
      Clonal integration of a polyomavirus in human Merkel cell carcinoma.
      The current management of stage I-II disease includes surgical excision with wide margins with adjuvant post-operative radiotherapy in most cases.
      • Bichakjian CK
      • Olencki T
      • Aasi SZ
      • et al.
      Merkel Cell Carcinoma, Version 1.2018, NCCN Clinical Practice Guidelines in Oncology.
      ,
      • Müller-Richter UDA
      • Gesierich A
      • Kübler AC
      • Hartmann S
      • Brands RC.
      Merkel Cell Carcinoma of the Head and Neck: Recommendations for Diagnostics and Treatment.
      The role of sentinel node biopsy (SLNB) in the management of MCC remains unclear. Evidence suggests that SLNB negativity is a strong predictor of longer disease-free survival and overall survival.
      • Servy A
      • Maubec E
      • Sugier PE
      • et al.
      Merkel cell carcinoma: value of sentinel lymph-node status and adjuvant radiation therapy.
      ,
      • Feldmeyer L
      • Hudgens CW
      • Ray-Lyons G
      • et al.
      Density, Distribution, and Composition of Immune Infiltrates Correlate with Survival in Merkel Cell Carcinoma.
      Conversely, others suggest no prognostic value of SLNB.
      • Fritsch VA
      • Camp ER
      • Lentsch EJ.
      Sentinel lymph node status in Merkel cell carcinoma of the head and neck: not a predictor of survival.
      ,
      • Sims JR
      • Grotz TE
      • Pockaj BA
      • et al.
      Sentinel lymph node biopsy in Merkel cell carcinoma: The Mayo Clinic experience of 150 patients.
      MCC of the head and neck may require distinct review from MCC in other anatomic locations.
      • Fritsch VA
      • Camp ER
      • Lentsch EJ.
      Sentinel lymph node status in Merkel cell carcinoma of the head and neck: not a predictor of survival.
      Head and neck MCCs are complicated by complex draining patterns and aggressive tumour characteristics.
      • Fritsch VA
      • Camp ER
      • Lentsch EJ.
      Sentinel lymph node status in Merkel cell carcinoma of the head and neck: not a predictor of survival.
      • Bichakjian CK
      • Olencki T
      • Aasi SZ
      • et al.
      Merkel Cell Carcinoma, Version 1.2018, NCCN Clinical Practice Guidelines in Oncology.
      • Müller-Richter UDA
      • Gesierich A
      • Kübler AC
      • Hartmann S
      • Brands RC.
      Merkel Cell Carcinoma of the Head and Neck: Recommendations for Diagnostics and Treatment.
      ,
      • Morand G
      • Vital D
      • Pézier T
      • et al.
      Merkel cell carcinoma of the head and neck: a single institutional experience.
      ,
      • Brissett AE
      • Olsen KD
      • Kasperbauer JL
      • et al.
      Merkel cell carcinoma of the head and neck: a retrospective case series.
      Nonetheless, the current MCC management guideline from the National Comprehensive Cancer Network (NCCN) recommends a diagnostic SLNB for all clinically node-negative patients who are fit for surgery.
      • Bichakjian CK
      • Olencki T
      • Aasi SZ
      • et al.
      Merkel Cell Carcinoma, Version 1.2018, NCCN Clinical Practice Guidelines in Oncology.
      Most case series of MCC are limited by low case numbers and are not specific to head and neck tumours. The purpose of this study was to provide a focused review of head and neck MCC diagnosis and management in a single Irish institution.

      Methods

      Patient selection

      The study was approved by our local institutional ethics review committee. All head and neck MCC patients from 2008 to 2020 were retrospectively identified via the ‘Hospital Inpatient Enquiry Department’ system, a prospectively maintained coded database of patient diagnosis. This was cross-referenced with the institutions’ ‘Tumour Database’ histopathological archive system. Any diagnosis of MCC above the clavicle was included. All patient data were collected and stored anonymously in an encrypted database in Microsoft Excel (Microsoft Corp., Redmond, WA, USA). The patient's demographics, tumour characteristics, pathological diagnosis, surgical treatment, adjuvant treatment, subsequent management and clinical course were collected. Tumours were staged via the latest American Joint Committee on Cancer (AJCC) system.
      • Harms KL
      • Healy MA
      • Nghiem P
      • et al.
      Analysis of Prognostic Factors from 9387 Merkel Cell Carcinoma Cases Forms the Basis for the New 8th Edition AJCC Staging System.

      Statistics

      Statistical analysis was carried out using SPSS version 18 (SPSS Inc., Chicago, IL, USA), with alpha values <0.05 indicating statistical significance. Estimates of progression-free MCC survival rates were calculated by the Kaplan–Meier statistical model. The progression of disease was defined as the regional or metastatic spread of MCC. A Pearson product-moment correlation coefficient was conducted to examine the association between surgical margins and disease-free follow-up.

      Results

      Patient and Tumour Characteristics

      Between 2008 and 2020, eleven patients were treated for head and neck MCC in our institution. Of these, eight were male, and three were female. The mean age of the cohort was 79.6 years (range = 69–91 years). Six tumours were on the cheek, and one on the forehead, brow, upper eyelid, upper lip and scalp. The size of the tumours ranged from 5 mm to 20 mm in their widest diameter (range = 5mm–20mm). The mean average follow-up duration was 18.3 months (range = 3–72 months). In total, 36.4% (n=4) patients had a recurrence at a mean time of 12.25 months (range = 8–17 months). Of these, two patients developed distant metastatic MCC. The distribution of the primary lesions, patient-associated demographics and their management is listed in Table 1.
      Table 1Summary of patient characteristics.
      PatientSex/agePrimary tumourlocationStage at presentationSurgical treatmentWider excisionmargin (cm)ReconstructionSLNBxLNDAdjuvant therapyProgression-free follow-upPrognosis
      1M/78Brow (L)IWLE1.5FTSGNoNoRad13 monthsNo recurrence
      2M/82Cheek (L)IWLE2ClosureNoNoRad8 monthsDistant Metastasis
      3M/72Cheek (L)IWLE2ClosureYesYesRad + chemo15 monthsDistant metastasis
      4M/84Upper eyelid (L)IWLE2Local flapNoNoRad + chemo9 monthsRegional recurrence
      5M/69Forehead (R)IWLE1FTSGNoNoNo46 monthsAlive, NED
      6M/79Cheek (R)IWLE1ClosureNoNoNo17 monthsLocal recurrence
      7F/79Upper LipIWLE1ClosureNoNoRad6 monthsNo recurrence
      8F/91Cheek (L)IIIBWLE2Local flapYesYesRad + chemo72 monthsNo recurrence
      9F/77Cheek (L)IWLE1FTSGNoNoRad3 monthsNo recurrence
      10M/85Cheek (R)IWLE1ClosureNoNoNo6 monthsNo recurrence
      11M/84ScalpIWLE2Local flapNoNoRad7 monthsNo recurrence
      Abbreviations: WLE = wide local excision; FTSG = full-thickness skin graft; SLNBx = sentinel lymph node biopsy; LND = lymph node dissection; Rad = radiation therapy; chemo = chemotherapy; NED = no evidence of disease.

      Surgical Treatment and Reconstruction

      The index biopsy was performed by a plastic surgeon in 73% of cases (n=8). The other three cases were referred from general surgeons in a tertiary centre. Of these, 18% (n=2) were excisions, and 9% (n=1) was a punch biopsy. All patients had a further wider excision with a mean margin of 1.14 cm (mean = 0.6–2 cm). After wider excision, five were closed primarily, three with a local flap, and three with a full-thickness skin graft. A Pearson product-moment correlation coefficient revealed no significant association between surgical margins and disease-free follow-up (p=0.65).

      Regional Lymph Nodes

      Of the cohort, 18% (n=2) had an SLNB. One node was identified in each SLNB. The mean size of the nodes was 8 mm in the widest diameter (range = 7–9 mm). Both of these were positive for MCC with H&E and CK-20 immunostaining. A selective neck dissection was subsequently performed in 18% (n=2). One demonstrated 18 nodes, 7 of which MCC was observed. Another had 15 nodes, 7 of which were positive for MCC. There were no associated complications with each SLNB.

      Adjuvant Radiotherapy

      In total, 72% (n=8) of patients received adjuvant radiotherapy. Of these, 54% (n=6) had radiotherapy after the wider excision as adjuvant therapy. An additional 18% (n=2) had radiotherapy for treatment for recurrent disease. One patient died from unrelated illness awaiting adjuvant radiotherapy.

      Prognosis

      The median disease-free follow-up for all patients was 17 months (range = 3–46 months). A Kaplan–Meier graph in Figure 1 summarizes the effect of SLNB on estimated disease-specific survival (DSS). SLNB had an effect on the DSS time compared to those that did not have an SLNB as part of primary management. The median DSS was 17 months. Median DDS was 15 months for the SLNB group and 17 months for the non-SLNB group, but this was not statistically significant (p=0.23). One patient developed local recurrence at the primary tumour scar, and one patient developed regional progression. Distant metastasis developed in two patients.
      Figure 1
      Figure 1Kaplan–Meier curve demonstrating MCC-specific disease-free survival according to sentinel lymph node procedure.

      Case Series

      Case 1

      A 78-year-old Caucasian man had an excisional biopsy of a tan keratotic nodule on his left brow demonstrating MCC on a background history of malignant melanoma. The lesion measured 20 × 13.5 mm in size, and perineural and lymphovascular invasion was present. Peripheral and deep margins were clear. A follow-up wider excision of 1 cm was performed, and the defect was reconstructed with a full-thickness skin graft. He had radiotherapy to the surgical bed and is disease free for 13 months post-operative.

      Case 2

      An 82-year-old gentleman had an excision of a pearly white lesion of his left cheek. The histopathology demonstrated a 14 mm MCC with perineural invasion with extensively positive deep margins. He had a further wider excision of 1 cm. Eight months later, he presented with recurrent local disease involving the left lower eyelid and medial canthus. This was resected and reconstructed with a full-thickness skin graft. He remained disease free for 8 months. Subsequent imaging demonstrated regional lymph node involvement and a 5 mm lung metastasis. He received 60 Gy of radiotherapy to the tumour site and regional lymph nodes. However, he died of metastatic disease 2 months after completing radiotherapy.

      Case 3

      A 72-year-old gentleman was referred with a red, raised nodular lesion on his left cheek. Excisional biopsy demonstrated a 12 mm MCC with negative radial and deep margins. He had a subsequent wider excision of 2 cm. A sentinel lymph node biopsy of one 9 × 7 × 6 mm node was negative for metastatic disease. He had 54 Gy of radiotherapy delivered to the tumour bed. He was disease free, until he developed regional recurrence in the neck at 15 months post-operative. A CT scan demonstrated large lobulated masses in the left submandibular area indicative of regional lymph node involvement. A PET CT demonstrated no distant metastasis. He had a selective neck dissection which identified 18 lymph nodes, nine of which were positive for MCC. He had one cycle of cisplatin and oral etoposide followed by 50Gy of radiotherapy to the involved regional lymph nodes and is disease free to date.

      Case 4

      An 84-year-old male was referred with a recurrence of an MCC of his left upper eyelid. A wider excision of 2 cm was performed, and the defect was reconstructed with a cervicofacial flap. She received 66 Gy of radiotherapy to the tumour site. A CT brain, thorax abdomen and pelvis identified no metastatic disease. However, she presented with metastatic disease 9 months later and was commenced on systemic carboplatin and oral etoposide. She died 11 months later due to complications of chronic lymphoid leukaemia.

      Case 5

      A 60-year-old gentleman presented with a slow-growing ulcerating nodule on his right forehead in March 2016. An excisional biopsy demonstrated a fully excised 12 × 10 × 6 mm irregularly shaped MCC, and a wider excision of 1 cm was reconstructed with a full-thickness skin graft. He received no radiotherapy and is disease free for 46 months later.

      Case 6

      A 79-year-old male was referred from a peripheral hospital with a MCC over the site of a previous basal cell carcinoma on his right cheek. A wider excision of 1 cm was performed to muscle and closed primarily. Following this, 17 months later, he presented with two subcutaneous nodules adjacent to the previous scar. A fine-needle aspiration of the nodules was positive for MCC. He was treated with radical radiation therapy and concomitant cisplatin and etoposide, which was discontinued due to his declining performance status. The patient died due to unrelated heart disease.

      Case 7

      A 79-year-old female was referred with a 5 × 5 mm dark papule on her upper lip present for 8 months. An excisional biopsy demonstrated an MCC with negative peripheral and deep margins. A wider excision of 1 cm was performed and closed primarily. She is currently undergoing radiotherapy treatment to the tumour site.

      Case 8

      A 91-year-old female presented with 15 × 14 mm MCC on her left. A wider excision of 2 cm was performed, and the defect was reconstructed with a local flap. Her investigative CT scan demonstrated probable metastatic disease in the left submandibular region, and she subsequently had a left neck SLNB. One 7 × 7 × 7 mm node was positive for MCC, and she had a completion lymphadenectomy. Post-operatively, she had 60 Gy to the tumour bed and regional lymph nodes and had two cycles of systemic cisplatin. At 6 years post-operative, she demonstrated no recurrence and died of an unrelated causes.

      Case 9

      A 77-year-old female was referred from a tertiary hospital with a punch biopsy confirmed MCC of the left cheek. One month later, a wider excision of 1 cm was performed demonstrating a 20 × 17 mm MCC. She died of unrelated illness while waiting for scheduled radiotherapy.

      Case 10

      An 85-year-old male was referred from a tertiary hospital with a rapidly growing pearly nodule over the site of a previous BCC excision on the right cheek. An excisional biopsy in the referring centre demonstrated MCC. A wider excision of 1 cm was performed to muscle, and the defect was closed primarily. The patient died from unrelated causes at 6 months post-operative.

      Case 11

      An 84-year-old gentleman presented with a slow-growing ulcerating tumour on the vertex of his scalp. An excisional biopsy confirmed the diagnosis of MCC without perineural or lymphovascular invasion. A wider excision of 2 cm was performed, and the defect was resurfaced with a local transposition flap. A CT brain and PET CT were negative for metastatic disease. He is currently awaiting radiotherapy to the tumour site.

      Discussion

      The incidence of head and neck MCC has steadily risen over the last decade.
      • Paulson KG
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      • Vandeven NA
      • et al.
      Merkel cell carcinoma: Current US incidence and projected increases based on changing demographics.
      As the Western population ages, its incremental increase is above that of melanoma and all solid tumours.
      • Morand G
      • Vital D
      • Pézier T
      • et al.
      Merkel cell carcinoma of the head and neck: a single institutional experience.
      ,
      • Paulson KG
      • Park SY
      • Vandeven NA
      • et al.
      Merkel cell carcinoma: Current US incidence and projected increases based on changing demographics.
      The head and neck are the most common location of a primary MCC.
      • Fritsch VA
      • Camp ER
      • Lentsch EJ.
      Sentinel lymph node status in Merkel cell carcinoma of the head and neck: not a predictor of survival.
      ,
      • Morand G
      • Vital D
      • Pézier T
      • et al.
      Merkel cell carcinoma of the head and neck: a single institutional experience.
      ,
      • Lee YW
      • Bae YC
      • Nam SB
      • Bae SH
      • Kim HS.
      Merkel cell carcinoma: A series of seven cases.
      ,
      • Akhtar S
      • Oza KK
      • Wright J.
      Merkel cell carcinoma: report of 10 cases and review of the literature.
      The head and neck MCC has the propensity for loco-regional recurrence, and early microscopic spread to regional nodal basins, and distant metastasis which makes it challenging to treat.
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      • Iyer JG
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      Pathologic nodal evaluation improves prognostic accuracy in Merkel cell carcinoma: analysis of 5823 cases as the basis of the first consensus staging system.
      Reported rates of disease-associated 5-year mortality are as high as 46%.
      • Müller-Richter UDA
      • Gesierich A
      • Kübler AC
      • Hartmann S
      • Brands RC.
      Merkel Cell Carcinoma of the Head and Neck: Recommendations for Diagnostics and Treatment.
      The presence of conflicting staging systems has complicated the management of MCC, and the single most important measure of recurrence and metastasis is the stage at diagnosis.
      • Harms KL
      • Healy MA
      • Nghiem P
      • et al.
      Analysis of Prognostic Factors from 9387 Merkel Cell Carcinoma Cases Forms the Basis for the New 8th Edition AJCC Staging System.
      However, treatment guidelines are not well defined, predominantly due to the rarity of the tumour, which prohibits clinical trials.
      • Akhtar S
      • Oza KK
      • Wright J.
      Merkel cell carcinoma: report of 10 cases and review of the literature.
      Nonetheless, the mainstay of head and neck MCC management is dependent on accurate histopathological interpretation, micro-staging of the primary lesion, surgery, and radiotherapy.
      • Bichakjian CK
      • Olencki T
      • Aasi SZ
      • et al.
      Merkel Cell Carcinoma, Version 1.2018, NCCN Clinical Practice Guidelines in Oncology.

      Surgical Management

      Early wide excision remains the primary treatment of MCC.
      • Bichakjian CK
      • Olencki T
      • Aasi SZ
      • et al.
      Merkel Cell Carcinoma, Version 1.2018, NCCN Clinical Practice Guidelines in Oncology.
      There are no randomized controlled trials of excision margins and disease-specific control.
      • Morand G
      • Vital D
      • Pézier T
      • et al.
      Merkel cell carcinoma of the head and neck: a single institutional experience.
      ,
      • Akhtar S
      • Oza KK
      • Wright J.
      Merkel cell carcinoma: report of 10 cases and review of the literature.
      ,
      • Kokoska ER
      • Kokoska MS
      • Collins BT
      • Stapleton DR
      • Wade TP.
      Early aggressive treatment for Merkel cell carcinoma improves outcome.
      Excision to fascia with a negative lateral margin of at least 2 to 3 cm is preferred.
      • Bichakjian CK
      • Olencki T
      • Aasi SZ
      • et al.
      Merkel Cell Carcinoma, Version 1.2018, NCCN Clinical Practice Guidelines in Oncology.
      ,
      • Akhtar S
      • Oza KK
      • Wright J.
      Merkel cell carcinoma: report of 10 cases and review of the literature.
      However, previous studies have shown little effect on recurrence-free survival with wider margins.
      • Morand G
      • Vital D
      • Pézier T
      • et al.
      Merkel cell carcinoma of the head and neck: a single institutional experience.
      Obtaining wide clear margins can be challenging in the head and neck with cosmetic and functional impairment.
      • Müller-Richter UDA
      • Gesierich A
      • Kübler AC
      • Hartmann S
      • Brands RC.
      Merkel Cell Carcinoma of the Head and Neck: Recommendations for Diagnostics and Treatment.
      As this tumour has a tendency to extensive vertical growth, some advocate the use of Mohs micrographic surgery.
      • Kokoska ER
      • Kokoska MS
      • Collins BT
      • Stapleton DR
      • Wade TP.
      Early aggressive treatment for Merkel cell carcinoma improves outcome.
      The benefits of Mohs include the preservation of normal tissues of important anatomical regions.
      • O'Connor WJ
      • Roenigk RK
      • Brodland DG.
      Merkel cell carcinoma. Comparison of Mohs micrographic surgery and wide excision in eighty-six patients.
      However, head and neck trial numbers including Mohs excision remain low.
      • Morand G
      • Vital D
      • Pézier T
      • et al.
      Merkel cell carcinoma of the head and neck: a single institutional experience.
      ,
      • Brissett AE
      • Olsen KD
      • Kasperbauer JL
      • et al.
      Merkel cell carcinoma of the head and neck: a retrospective case series.
      ,
      • Kline L
      • Coldiron B.
      Mohs Micrographic Surgery for the Treatment of Merkel Cell Carcinoma.
      O'Connor et al. found Mohs superior in local control to standard surgical excision, but suggested the adjunct use of radiotherapy in these patients.
      • O'Connor WJ
      • Roenigk RK
      • Brodland DG.
      Merkel cell carcinoma. Comparison of Mohs micrographic surgery and wide excision in eighty-six patients.
      MCC has been shown to spread in a non-contiguous manner, and the risk of recurrence post-Mohs surgery is substantially higher if no radiotherapy is delivered.
      • O'Connor WJ
      • Roenigk RK
      • Brodland DG.
      Merkel cell carcinoma. Comparison of Mohs micrographic surgery and wide excision in eighty-six patients.
      In our case series, there was no significant survival benefit demonstrated with wider surgical margins. This finding is demonstrated by other authors’ experience with head and neck MCC.
      • Morand G
      • Vital D
      • Pézier T
      • et al.
      Merkel cell carcinoma of the head and neck: a single institutional experience.
      ,
      • Brissett AE
      • Olsen KD
      • Kasperbauer JL
      • et al.
      Merkel cell carcinoma of the head and neck: a retrospective case series.
      ,
      • Kokoska ER
      • Kokoska MS
      • Collins BT
      • Stapleton DR
      • Wade TP.
      Early aggressive treatment for Merkel cell carcinoma improves outcome.
      ,
      • Gillenwater AM
      • Hessel AC
      • Morrison WH
      • et al.
      Merkel cell carcinoma of the head and neck: effect of surgical excision and radiation on recurrence and survival.
      Unfortunately, many case series to date have not reported data on margin and survival benefit.
      • Fritsch VA
      • Camp ER
      • Lentsch EJ.
      Sentinel lymph node status in Merkel cell carcinoma of the head and neck: not a predictor of survival.
      ,
      • Schmalbach CE
      • Lowe L
      • Teknos TN
      • Johnson TM
      • Bradford CR.
      Reliability of sentinel lymph node biopsy for regional staging of head and neck Merkel cell carcinoma.
      Surgery alone was used in several of our cases. It has been well documented that surgery alone can be sufficient in low-risk MCC tumours.
      • Fields RC
      • Busam KJ
      • Chou JF
      • et al.
      Recurrence after complete resection and selective use of adjuvant therapy for stage I through III Merkel cell carcinoma.
      ,
      • Frohm ML
      • Griffith KA
      • Harms KL
      • et al.
      Recurrence and Survival in Patients With Merkel Cell Carcinoma Undergoing Surgery Without Adjuvant Radiation Therapy to the Primary Site.
      Radiotherapy may not be needed if the tumour is less than 2 cm in size, wide excision margins have been achieved, and no other high-risk histological features.
      • Fields RC
      • Busam KJ
      • Chou JF
      • et al.
      Recurrence after complete resection and selective use of adjuvant therapy for stage I through III Merkel cell carcinoma.
      ,
      • Frohm ML
      • Griffith KA
      • Harms KL
      • et al.
      Recurrence and Survival in Patients With Merkel Cell Carcinoma Undergoing Surgery Without Adjuvant Radiation Therapy to the Primary Site.
      However, if any of the high-risk factors are present, selective adjuvant radiotherapy should be considered.
      • Bichakjian CK
      • Olencki T
      • Aasi SZ
      • et al.
      Merkel Cell Carcinoma, Version 1.2018, NCCN Clinical Practice Guidelines in Oncology.
      ,
      • Fields RC
      • Busam KJ
      • Chou JF
      • et al.
      Recurrence after complete resection and selective use of adjuvant therapy for stage I through III Merkel cell carcinoma.
      ,
      • Frohm ML
      • Griffith KA
      • Harms KL
      • et al.
      Recurrence and Survival in Patients With Merkel Cell Carcinoma Undergoing Surgery Without Adjuvant Radiation Therapy to the Primary Site.

      Radiotherapy

      The NCCN Clinical Practice Guidelines in Oncology for MCC recommends selective use of adjuvant local radiotherapy, and its definite use in all nodal disease.
      • Bichakjian CK
      • Olencki T
      • Aasi SZ
      • et al.
      Merkel Cell Carcinoma, Version 1.2018, NCCN Clinical Practice Guidelines in Oncology.
      However, no level one evidence currently guides this application.
      • Bichakjian CK
      • Olencki T
      • Aasi SZ
      • et al.
      Merkel Cell Carcinoma, Version 1.2018, NCCN Clinical Practice Guidelines in Oncology.
      ,
      • Fields RC
      • Busam KJ
      • Chou JF
      • et al.
      Recurrence after complete resection and selective use of adjuvant therapy for stage I through III Merkel cell carcinoma.
      In the largest cohort study to date, Bhatia et al. demonstrated an overall survival benefit with surgery combined with adjuvant radiotherapy in stage I-II MCC.
      • Bhatia S
      • Storer BE
      • Iyer JG
      • et al.
      Adjuvant Radiation Therapy and Chemotherapy in Merkel Cell Carcinoma: Survival Analyses of 6908 Cases From the National Cancer Data Base.
      Similarly, Lewis et al. report an increase overall survival in all stages with surgery combined with radiotherapy.
      • Lewis KG
      • Weinstock MA
      • Weaver AL
      • Otley CC.
      Adjuvant local irradiation for Merkel cell carcinoma.
      These findings have been questioned by smaller cohort studies, advocating selective use in high-risk tumours.
      • Fields RC
      • Busam KJ
      • Chou JF
      • et al.
      Recurrence after complete resection and selective use of adjuvant therapy for stage I through III Merkel cell carcinoma.
      ,
      • Frohm ML
      • Griffith KA
      • Harms KL
      • et al.
      Recurrence and Survival in Patients With Merkel Cell Carcinoma Undergoing Surgery Without Adjuvant Radiation Therapy to the Primary Site.
      Fields et al. examined the pattern of recurrence in 364 patients who underwent surgery with or without adjuvant treatment for stages I through III MCC.
      • Fields RC
      • Busam KJ
      • Chou JF
      • et al.
      Recurrence after complete resection and selective use of adjuvant therapy for stage I through III Merkel cell carcinoma.
      Patients with stage I-IIIA MCC and clinically negative lymph nodes had a low recurrence rate with adequate surgery and selective use of adjuvant radiotherapy for high-risk tumours.
      • Fields RC
      • Busam KJ
      • Chou JF
      • et al.
      Recurrence after complete resection and selective use of adjuvant therapy for stage I through III Merkel cell carcinoma.
      On the other hand, patients with clinically positive lymph nodes and stage IIIB MCC had significantly higher recurrence rates with the same treatment.
      • Fields RC
      • Busam KJ
      • Chou JF
      • et al.
      Recurrence after complete resection and selective use of adjuvant therapy for stage I through III Merkel cell carcinoma.
      Assessing the value of adjuvant radiotherapy specifically in the head and neck clinical context remains difficult.
      • Bichakjian CK
      • Olencki T
      • Aasi SZ
      • et al.
      Merkel Cell Carcinoma, Version 1.2018, NCCN Clinical Practice Guidelines in Oncology.
      Specific retrospective evaluation of the benefit of radiotherapy in head and neck MCC has been demontrated.
      • Morand G
      • Vital D
      • Pézier T
      • et al.
      Merkel cell carcinoma of the head and neck: a single institutional experience.
      ,
      • Clark JR
      • Veness MJ
      • Gilbert R
      • O'Brien CJ
      • Gullane PJ.
      Merkel cell carcinoma of the head and neck: is adjuvant radiotherapy necessary?.
      ,
      • Veness MJ
      • Morgan GJ
      • Gebski V.
      Adjuvant locoregional radiotherapy as best practice in patients with Merkel cell carcinoma of the head and neck.
      Clark et al. report that combination therapy was associated with improvement in local and regional control and disease-free survival in stage II and III MCC of the head and neck.
      • Clark JR
      • Veness MJ
      • Gilbert R
      • O'Brien CJ
      • Gullane PJ.
      Merkel cell carcinoma of the head and neck: is adjuvant radiotherapy necessary?.
      Similarly, Veness et al. substantiate its use in all stages of head and neck disease, with high rates of locoregional relapse in its absence.
      • Veness MJ
      • Morgan GJ
      • Gebski V.
      Adjuvant locoregional radiotherapy as best practice in patients with Merkel cell carcinoma of the head and neck.
      This trend was comparably demonstrated in smaller reported case series institutional experiences.
      • Morand G
      • Vital D
      • Pézier T
      • et al.
      Merkel cell carcinoma of the head and neck: a single institutional experience.
      Overall, our institutions’ experience supports the NCCN practice guidelines.
      • Bichakjian CK
      • Olencki T
      • Aasi SZ
      • et al.
      Merkel Cell Carcinoma, Version 1.2018, NCCN Clinical Practice Guidelines in Oncology.

      Role of Sentinel Lymph Node Biopsy

      MCC of the head and neck has a high propensity to metastasise to the lymph nodes, and recent attention has been focused on the use of SLNB.
      • Mehrany K
      • Otley CC
      • Weenig RH
      • et al.
      A meta-analysis of the prognostic significance of sentinel lymph node status in Merkel cell carcinoma.
      Accurate staging is required for appropriate treatment planning and development of clinical trials in head and neck MCC.
      • Fritsch VA
      • Camp ER
      • Lentsch EJ.
      Sentinel lymph node status in Merkel cell carcinoma of the head and neck: not a predictor of survival.
      It has been demonstrated that approximately one-third of MCC patients who only undergo clinical nodal evaluation are under-staged due to the presence of occult microscopic nodal involvement.
      • Lemos BD
      • Storer BE
      • Iyer JG
      • et al.
      Pathologic nodal evaluation improves prognostic accuracy in Merkel cell carcinoma: analysis of 5823 cases as the basis of the first consensus staging system.
      Sentinel node status has a significant prognostication value, with nodal positivity reflecting high rates of recurrence or metastasis.
      • Mehrany K
      • Otley CC
      • Weenig RH
      • et al.
      A meta-analysis of the prognostic significance of sentinel lymph node status in Merkel cell carcinoma.
      Conversely, sentinel node negativity may be associated with a significant survival advantage.
      • Kachare SD
      • Wong JH
      • Vohra NA
      • Zervos EE
      • Fitzgerald TL.
      Sentinel lymph node biopsy is associated with improved survival in Merkel cell carcinoma.
      The role of sentinel lymph node biopsy may extend with therapeutic benefit in recurrence protection and progression.
      • Bichakjian CK
      • Olencki T
      • Aasi SZ
      • et al.
      Merkel Cell Carcinoma, Version 1.2018, NCCN Clinical Practice Guidelines in Oncology.
      Kachare et al. report a small, but significant, DSS in patients who underwent SLNB compared to those who opted for nodal observation only.
      • Kachare SD
      • Wong JH
      • Vohra NA
      • Zervos EE
      • Fitzgerald TL.
      Sentinel lymph node biopsy is associated with improved survival in Merkel cell carcinoma.
      Similarly, Kaae et al. report a survival benefit in the SLNB arm of a retrospective review in comparison with those who did not have an SLNB.
      • Kaae J
      • Hansen AV
      • Biggar RJ
      • et al.
      Merkel cell carcinoma: incidence, mortality, and risk of other cancers.
      However, the prognostic significance of sentinel node status may be different in head and neck MCC compared with other anatomical sites. Lentsch et al. report no predictive survival benefit with sentinel node status in MCC specific to the head and neck.
      • Fritsch VA
      • Camp ER
      • Lentsch EJ.
      Sentinel lymph node status in Merkel cell carcinoma of the head and neck: not a predictor of survival.
      However, these findings should be interpreted with caution due to the limitations of their recurrence data.
      • Fritsch VA
      • Camp ER
      • Lentsch EJ.
      Sentinel lymph node status in Merkel cell carcinoma of the head and neck: not a predictor of survival.
      Our institutions’ experience of SLNB in head and neck MCC reflects the tumours rarity. Unfortunately, reported case series of head and neck MCC are similar.
      • Morand G
      • Vital D
      • Pézier T
      • et al.
      Merkel cell carcinoma of the head and neck: a single institutional experience.
      ,
      • Brissett AE
      • Olsen KD
      • Kasperbauer JL
      • et al.
      Merkel cell carcinoma of the head and neck: a retrospective case series.
      ,
      • Lee YW
      • Bae YC
      • Nam SB
      • Bae SH
      • Kim HS.
      Merkel cell carcinoma: A series of seven cases.
      ,
      • Schmalbach CE
      • Lowe L
      • Teknos TN
      • Johnson TM
      • Bradford CR.
      Reliability of sentinel lymph node biopsy for regional staging of head and neck Merkel cell carcinoma.
      ,
      • Pan D
      • Narayan D
      • Ariyan S.
      Merkel cell carcinoma: five case reports using sentinel lymph node biopsy and a review of 110 new cases.
      ,
      • Papadiochos I
      • Patrikidou A
      • Patsatsi A
      • et al.
      Head and neck Merkel cell carcinoma: a retrospective case series and critical literature review with emphasis on treatment and prognosis.
      However, the overall trend demonstrates SLNB as a safe and reliable technique for the staging of MCC of the head and neck. Therefore, as per the NCCN guideline, SLNB should be recommended for all patients with clinically node-negative head and neck MCC who are fit for surgery.
      • Bichakjian CK
      • Olencki T
      • Aasi SZ
      • et al.
      Merkel Cell Carcinoma, Version 1.2018, NCCN Clinical Practice Guidelines in Oncology.

      Systemic Therapy

      High-quality clinical data on the delivery of post-operative systemic agents for head and neck MCC is lacking.
      • Bichakjian CK
      • Olencki T
      • Aasi SZ
      • et al.
      Merkel Cell Carcinoma, Version 1.2018, NCCN Clinical Practice Guidelines in Oncology.
      The majority of available data is pooled from retrospective reviews of a variety of stages, concomitant therapies, anatomical locations, and different systemic agents. In the largest review to date, Chen et al. concluded that chemoradiation increased overall survivability in addition to surgery, but chemotherapy alone had the opposite effect.
      • Chen MM
      • Roman SA
      • Sosa JA
      • BL Judson
      The role of adjuvant therapy in the management of head and neck merkel cell carcinoma: an analysis of 4815 patients.
      This suggests that although chemotherapy as a post-operative monotherapy is likely to be unsuccessful, there may be a role for chemoradiotherapy in high-risk cases. Due to the lack of evidence for increased survival, associated morbidity, and rapid development of resistance, its routine use remains unsupported.
      • Garneski KM
      • Nghiem P.
      Merkel cell carcinoma adjuvant therapy: current data support radiation but not chemotherapy.
      ,
      • Iyer JG
      • Blom A
      • Doumani R
      • et al.
      Response rate and durability of chemotherapy for metastatic Merkel cell carcinoma among 62 patients.
      Our own institutions most common systemic treatment of metastatic or palliative disease is cisplatin or carboplatin with or without etoposide, which is consistent with current conventions.
      • Bichakjian CK
      • Olencki T
      • Aasi SZ
      • et al.
      Merkel Cell Carcinoma, Version 1.2018, NCCN Clinical Practice Guidelines in Oncology.
      ,
      • Brissett AE
      • Olsen KD
      • Kasperbauer JL
      • et al.
      Merkel cell carcinoma of the head and neck: a retrospective case series.
      ,
      • Akhtar S
      • Oza KK
      • Wright J.
      Merkel cell carcinoma: report of 10 cases and review of the literature.
      ,
      • Papadiochos I
      • Patrikidou A
      • Patsatsi A
      • et al.
      Head and neck Merkel cell carcinoma: a retrospective case series and critical literature review with emphasis on treatment and prognosis.
      ,
      • McAfee WJ
      • Morris CG
      • Mendenhall CM
      • et al.
      Merkel cell carcinoma: treatment and outcomes.
      However, no established treatment based on validated evidence has been determined to date.
      • Müller-Richter UDA
      • Gesierich A
      • Kübler AC
      • Hartmann S
      • Brands RC.
      Merkel Cell Carcinoma of the Head and Neck: Recommendations for Diagnostics and Treatment.
      Emerging data on targeted therapies for MCC is promising.
      • Müller-Richter UDA
      • Gesierich A
      • Kübler AC
      • Hartmann S
      • Brands RC.
      Merkel Cell Carcinoma of the Head and Neck: Recommendations for Diagnostics and Treatment.
      The PD-1 antibody pembrolizumab and the PD-L1 antibody avelumab have been shown to induce partial and complete remission in advanced MCC.
      • Nghiem PT
      • Bhatia S
      • Lipson EJ
      • et al.
      PD-1 Blockade with Pembrolizumab in Advanced Merkel-Cell Carcinoma.
      Both virus-positive and virus-negative tumours were shown to be immunogenic and susceptible to therapy. Ongoing trails continue to support the success of avelumab monotherapy in patients with distant MCC.
      • Kaufman HL
      • Russell JS
      • Hamid O
      • et al.
      Updated efficacy of avelumab in patients with previously treated metastatic Merkel cell carcinoma after ≥1 year of follow-up: JAVELIN Merkel 200, a phase 2 clinical trial.
      ,
      • SP D'Angelo
      • Russell J
      • Lebbé C
      • et al.
      Efficacy and Safety of First-line Avelumab Treatment in Patients With Stage IV Metastatic Merkel Cell Carcinoma: A Preplanned Interim Analysis of a Clinical Trial.
      These results suggest that immune checkpoint inhibitors may have a role in the first-line management of advanced disease. Although there are no randomized comparative trials that demonstrate the superiority of checkpoint immunotherapies over chemotherapy, they may provide more longevity in response.
      • Bichakjian CK
      • Olencki T
      • Aasi SZ
      • et al.
      Merkel Cell Carcinoma, Version 1.2018, NCCN Clinical Practice Guidelines in Oncology.

      Conclusions

      MCC of the head and neck remains a rare and aggressive disease entity with diagnostic and treatment challenges. The results of our retrospective review should be interpreted with caution due to the limited cohort. However, our case series adds to a sparse body of evidence of head and neck MCC. Surgery remains the treatment priority in localized disease, with an increasing role of SLNB for accurate prognostication and staging. Early management of stage I disease results in moderate long-term disease-free survivability. Radiotherapy is recommended for high-risk tumours. Clear recommendations on the use of systemic therapies are lacking, but prospective trials are promising.

      Conflict of Interest

      The authors have no conflict of interest to disclose.

      Funding

      This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

      Patient Consent

      The authors of this paper received written informed consent from the patients for the publication of these cases.

      Ethical Approval

      Ethical approval was waived by the local review board due to the study design of this audit.

      Acknowledgements

      The authors of this paper have no acknowledgements to make.

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