Merkel Cell Carcinoma of the Skin: Deducing the Pattern of Spread from an International Aggregated Database of 949 Patients
Abstract
:1. Introduction
2. Materials and Methods
Statistical Analysis
3. Results
4. Discussion
- (a)
- After initial diagnosis, patients with primaries of any size should be referred without delay to experienced specialist(s) for definitive treatment, in a tertiary center if possible, since delay in surgery or postoperative radiotherapy was documented to be associated with worse outcome [31,32]. The Fred Hutchinson Cancer Center in Seattle reported on 124 MCC patients with a median time to initiate postoperative radiotherapy (ttPORT) of 41 days (range: 8–125 days) [31]. The median follow-up was 55 months. In total, 17 (14%) patients experienced a locoregional recurrence (LRR), 14 (82%) of which arose outside the radiation field. LRR at 5 years was increased for ttPORT > 8 weeks vs. ≤ 8 weeks, 28.0% vs. 9.2%, p = 0.006. There was an increase in the cumulative incidence of cancer-specific death with increasing ttPORT (Hazard Ratio = 1.14 per 1-week increase, p = 0.016) [31]. Readers should note that different cutoffs for surgical delays were used in the two above references [28,29,31,32], so currently there is no definite recommended guideline for the optimal time to start treatment. Surgeons are advised to perform wide local excision or Moh’s microsurgery to achieve negative margins but avoid extensive reconstructions that require a longer time to heal and hence delay radiotherapy initiation, as per the NCCN recommendations [21].
- (b)
- Multidisciplinary discussions of the best treatment options should be made on tumor boards. As combination therapy could have more side effects, a consideration of co-morbidities, performance status, and the available social support during and after the treatment for the patient is needed. Fine judgment is necessary to decide if the benefits outweigh the risks in elderly patients.
- (c)
- Clinicians should constantly update their knowledge by looking at websites such as merkelcell.org [33], Fred Hutchison Research Cancer Center [34], Memorial Sloan-Kettering Cancer Center [35], Cleveland Clinic [36], Mayo Clinic [37], the Skin Cancer Foundation [38], and NCCN (National Comprehensive Cancer Network guidelines [21]. More recently, retifanlimab has emerged as a notably effective treatment strategy, leading to US Food and Drug Administration Accelerated Approval for metastatic or recurrent locally advanced MCC based on the phase II POD1UM-201 study [39,40].
- (d)
- Enrollment in clinical trials is strongly encouraged. The results of the recent phase II study ADMEC-O could be confirmed with more trials to encourage clinicians to consider adopting adjuvant nivolumab into their clinical practice. Hypofractionated radiotherapy research is ongoing as well [41].
- (e)
- More research on cancer prevention and the development of treatment resistance should be performed in the future. An example is the study of tumor-associated macrophages (TAMs) in MCC, and the association of S100A8-expressing TAMs with resistance to anti-PD-L1 inhibitors (where PD-L1 stands for programmed death-ligand 1). Silk et al. commented that these data improve our understanding of why some tumors with brisk tumor-infiltrating lymphocytes do not respond to immunotherapy [42]. Another study on MCPyV+ metastatic MCCs treated with an intra-tumoral stimulator of interferon genes (STING) agonist (ADU-S100) plus intravenous anti-PD-1 antibody (spartalizumab) attained a durable objective response with the regression of both injected and non-injected lesions [43]. Eventually, a cancer vaccine may be possible [44].
- (f)
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
ADMEC-O | Adjuvant immunotherapy with nivolumab versus observation |
ADT | Androgen deprivation therapy |
CK | Cytokeratin |
CSS | Cause-specific survival |
CT | Computerized tomography |
DFS | Disease-free survival |
DMs | Distant metastases |
LNMs | Lymph node metastases |
LRR | Locoregional recurrence |
MCC | Merkel cell carcinoma |
NCDB | National Cancer Database |
OS | National Comprehensive Cancer Network |
NCCN | Overall survival |
PD-L1 | Programmed death-ligand 1 |
PET | Positron emission tomography |
PFS | Progression-free survival |
SEER | Surveillance, Epidemiology, and End Results (SEER) program |
SLNB | Sentinel lymph node biopsy |
STING | Stimulator of interferon genes |
TAMs | Tumor-associated macrophages |
ttPORT | Time to initiate postoperative radiotherapy |
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Aggregated data from | Saskatchewan (Canada) | 13 (16%) | |||
Alberta (Canada) | 17 (22%) | ||||
London, Ontario (Canada) | 15 (19%) | ||||
Windsor/Ontario, Canada | 5 (6%) | ||||
Amiens (France) | 9 (11%) | ||||
Westmead, New South Wales (Australia) | 20 (25%) | ||||
Baseline characteristics | Age: | median 78 (range: 47–95) years | |||
Sex: | 29 males and 50 females | ||||
Size of primary tumor: | median 2.5 (range: 0.2–17) cm | ||||
Initial stages | Local | Nodal | Distant metastases | Unknown | |
Clinical | 42 (53%) | 28 (35%) | 8 (10%) | 1 (1%) | |
Pathological | 35 (44%) | 35 (44%) | 8 (10%) | 1 (1%) | |
Primary site | Head and neck | 35 (44%) | |||
Limb (upper or lower) | 23 (29%) | ||||
Trunk | 13 (16%) | ||||
Unknown primary, presented with nodes only | 8 (10%) | ||||
Timing of nodal metastases (patient number = 47) | Before distant metastases diagnosis | 31/47 (66%) | |||
Within 1 month of distant metastases diagnosis | 10/47 (21%) | ||||
After distant metastases diagnosis | 1/47 (2%) | ||||
Unknown time relative to distant metastases | 5/47 (11%) |
Treatment of localized disease at presentation (patient number = 43) | Surgery | 24/43 (56%) |
Surgery + Radiotherapy | 11/43 (26%) | |
Surgery + Chemotherapy | 1/43 (2%) | |
Radiotherapy alone | 4/43 (9%) | |
Radiotherapy + Chemotherapy | 1/43 (2%) | |
None | 2/43 (5%) | |
Treatment of nodal metastases at presentation (patient number = 28) | Surgery | 6/28 (21%) |
Surgery + Radiotherapy | 7/28 (25%) | |
Surgery + Radiotherapy + Chemotherapy | 2/28 (7%) | |
Radiotherapy alone | 13/28 (46%) | |
Treatment of distant metastases at presentation (patient number = 8) | Radiotherapy + Chemotherapy | 3/8 (38%) |
Chemotherapy alone | 2/8 (25%) | |
None | 3/8 (38%) | |
Final vital status | Alive | 8/79 (10%) |
Dead | 71/79 (90%) | |
Cause of death among those expired (patient number = 71) | Merkel cell carcinoma | 65/71 (92%) |
Intercurrent disease | 6/71 (8%) |
Variable | Hazard Ratio | (95% Confidence Interval) | p Values | |
---|---|---|---|---|
Age: | 60 | Reference variable | ||
70 | 0.90 | (0.64–1.26) | 0.50 | |
80 | 1.06 | (0.66–1.68) | 0.82 | |
90 | 1.75 | (0.89–3.46) | 0.11 | |
Sex: | Male | 0.87 | (0.54–1.42) | 0.59 |
Female | Reference variable | |||
Chemotherapy: | Yes | 0.56 | (0.19–1.62) | 0.29 |
No | Reference variable | |||
Clinical stage: | Localized disease | 2.53 | (1.21–5.28) | 0.013 |
Primary ≤1 cm | Reference variable | |||
Primary >1 cm | 1.32 | (0.61–2.89) | 0.49 | |
Nodal metastases | 3.27 | (1.85–5.78) | <0.001 | |
Distant metastases | 21.42 | (7.15–64.21) | <0.001 | |
Previous irradiation: | Yes | 2.95 | (0.90–9.61) | 0.073 |
No | Reference variable |
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Tai, P.; Joseph, K.; Prajapati, V.H.; Jones Thachuthara, A.; Lian, J.; Assouline, A.; Yu, E.; Veness, M. Merkel Cell Carcinoma of the Skin: Deducing the Pattern of Spread from an International Aggregated Database of 949 Patients. Curr. Oncol. 2025, 32, 211. https://doi.org/10.3390/curroncol32040211
Tai P, Joseph K, Prajapati VH, Jones Thachuthara A, Lian J, Assouline A, Yu E, Veness M. Merkel Cell Carcinoma of the Skin: Deducing the Pattern of Spread from an International Aggregated Database of 949 Patients. Current Oncology. 2025; 32(4):211. https://doi.org/10.3390/curroncol32040211
Chicago/Turabian StyleTai, Patricia, Kurian Joseph, Vimal H. Prajapati, Aoife Jones Thachuthara, Jidong Lian, Avi Assouline, Edward Yu, and Michael Veness. 2025. "Merkel Cell Carcinoma of the Skin: Deducing the Pattern of Spread from an International Aggregated Database of 949 Patients" Current Oncology 32, no. 4: 211. https://doi.org/10.3390/curroncol32040211
APA StyleTai, P., Joseph, K., Prajapati, V. H., Jones Thachuthara, A., Lian, J., Assouline, A., Yu, E., & Veness, M. (2025). Merkel Cell Carcinoma of the Skin: Deducing the Pattern of Spread from an International Aggregated Database of 949 Patients. Current Oncology, 32(4), 211. https://doi.org/10.3390/curroncol32040211