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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.
Department of Plastic & Reconstructive Surgery, University Hospital Galway, Galway, IrelandRoyal College of Surgeons in Ireland, St. Stephen's Green, Dublin, Ireland
Department of Plastic & Reconstructive Surgery, University Hospital Galway, Galway, IrelandRoyal College of Surgeons in Ireland, St. Stephen's Green, Dublin, Ireland
Department of Plastic & Reconstructive Surgery, University Hospital Galway, Galway, IrelandRoyal College of Surgeons in Ireland, St. Stephen's Green, Dublin, Ireland
Department of Plastic & Reconstructive Surgery, University Hospital Galway, Galway, IrelandRoyal College of Surgeons in Ireland, St. Stephen's Green, Dublin, Ireland
Department of Plastic & Reconstructive Surgery, University Hospital Galway, Galway, IrelandRoyal College of Surgeons in Ireland, St. Stephen's Green, Dublin, Ireland
Department of Plastic & Reconstructive Surgery, University Hospital Galway, Galway, IrelandRoyal College of Surgeons in Ireland, St. Stephen's Green, Dublin, Ireland
Department of Plastic & Reconstructive Surgery, University Hospital Galway, Galway, IrelandRoyal College of Surgeons in Ireland, St. Stephen's Green, Dublin, Ireland
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.
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.
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.
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.
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.
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.
Patient
Sex/age
Primary tumourlocation
Stage at presentation
Surgical treatment
Wider excisionmargin (cm)
Reconstruction
SLNBx
LND
Adjuvant therapy
Progression-free follow-up
Prognosis
1
M/78
Brow (L)
I
WLE
1.5
FTSG
No
No
Rad
13 months
No recurrence
2
M/82
Cheek (L)
I
WLE
2
Closure
No
No
Rad
8 months
Distant Metastasis
3
M/72
Cheek (L)
I
WLE
2
Closure
Yes
Yes
Rad + chemo
15 months
Distant metastasis
4
M/84
Upper eyelid (L)
I
WLE
2
Local flap
No
No
Rad + chemo
9 months
Regional recurrence
5
M/69
Forehead (R)
I
WLE
1
FTSG
No
No
No
46 months
Alive, NED
6
M/79
Cheek (R)
I
WLE
1
Closure
No
No
No
17 months
Local recurrence
7
F/79
Upper Lip
I
WLE
1
Closure
No
No
Rad
6 months
No recurrence
8
F/91
Cheek (L)
IIIB
WLE
2
Local flap
Yes
Yes
Rad + chemo
72 months
No recurrence
9
F/77
Cheek (L)
I
WLE
1
FTSG
No
No
Rad
3 months
No recurrence
10
M/85
Cheek (R)
I
WLE
1
Closure
No
No
No
6 months
No recurrence
11
M/84
Scalp
I
WLE
2
Local flap
No
No
Rad
7 months
No 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.
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 1Kaplan–Meier curve demonstrating MCC-specific disease-free survival according to sentinel lymph node procedure.
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.
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.
Pathologic nodal evaluation improves prognostic accuracy in Merkel cell carcinoma: analysis of 5823 cases as the basis of the first consensus staging system.
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.
Nonetheless, the mainstay of head and neck MCC management is dependent on accurate histopathological interpretation, micro-staging of the primary lesion, surgery, and radiotherapy.
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.
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.
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.
The NCCN Clinical Practice Guidelines in Oncology for MCC recommends selective use of adjuvant local radiotherapy, and its definite use in all nodal disease.
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.
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.
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.
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.
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.
Pathologic nodal evaluation improves prognostic accuracy in Merkel cell carcinoma: analysis of 5823 cases as the basis of the first consensus staging system.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
References
Jalilian C
Chamberlain AJ
Haskett M
et al.
Clinical and dermoscopic characteristics of Merkel cell carcinoma.
Pathologic nodal evaluation improves prognostic accuracy in Merkel cell carcinoma: analysis of 5823 cases as the basis of the first consensus staging system.
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.
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.
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