{"paper_id":"d074ec86-9dc7-44ea-bfa3-70bbc6a0ad30","body_text":"General Health Versus Tumor Stage: Determinants of Survival in Merkel Cell Carcinoma Assessed by Sentinel Lymph Node Biopsy | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article General Health Versus Tumor Stage: Determinants of Survival in Merkel Cell Carcinoma Assessed by Sentinel Lymph Node Biopsy Thilo Gambichler, Ekaterina Heinzer, Nessr Abu Rached, Hans-Joachim Schulze, and 12 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8669831/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 28 Apr, 2026 Read the published version in Journal of Cancer Research and Clinical Oncology → Version 1 posted 7 You are reading this latest preprint version Abstract Purpose Overall survival (OS) of Merkel cell carcinoma (MCC) patient is strongly influenced by health. Sentinel lymph node biopsy (SLNB) is recommended for staging. We evaluated whether SLNB is associated with OS in clinically node-negative MCC and contrasted tumor factors with patient frailty. Methods STROBE-compliant cohort across eight centers in Germany (2004–2024). We included 271 primary stage I–II MCC; 167 underwent SLNB and 104 did not. The primary outcome was OS; disease-specific survival (DSS) and progression-free probability (PFP) were secondary. Kaplan–Meier and Cox models were used. Confounding by indication was addressed with 1:1 propensity score matching and sensitivity analyses. Results Patients receiving SLNB were younger (median 74 vs 82 years; p<.001) and less comorbid (Charlson 4 vs 5). Ten-year OS was 69.5% with SLNB versus 45.2% without (log-rank p < 0.0001); unadjusted HR 0.34 (95% CI 0.20–0.59). In the matched cohort, SLNB remained associated with lower all-cause mortality (HR 0.56, 95% CI 0.34–0.93; p = 0.024). DSS did not differ (HR 1.09, 95% CI 0.55–2.13; p = 0.81). For PFP, unadjusted curves favored SLNB (p = 0.0045), but the matched analysis was not significant (HR 0.53, 95% CI 0.23–1.26). Sensitivity analyses suggested benefit: overlap weighting HR 0.49 (95% CI 0.33–0.73; p = 0.00045) and a stage-restricted match HR 0.36 (95% CI 0.13–0.99; p = 0.048). Conclusions SLNB was associated with improved OS after adjustment, supporting its role in staging and risk stratification. The absence of DSS and matched PFP differences highlights the influence of overall health; residual confounding by indication cannot be excluded. Figures Figure 1 Figure 2 Figure 3 1. Introduction Merkel cell carcinoma (MCC) is a highly aggressive skin cancer with neuroendocrine differentiation. Its incidence among Whites living in the Northern hemisphere is approximately 0.7 per 100,000 person‑years and has risen steadily over recent decades. 1–3 MCC shows a marked propensity for regional and distant spread: up to one‑third of clinically node‑negative patients harbour occult nodal metastases at diagnosis. 3,4 Nodal status is the strongest predictor of recurrence and survival in primary MCC. 1,5 Accordingly, sentinel lymph node biopsy (SLNB) is recommended to improve staging accuracy in clinically node‑negative disease. 6 Early single‑centre and population‑based studies indicated that SLNB positivity identifies a subgroup at markedly higher risk for recurrence and disease‑specific mortality. 7–9 Meta‑analyses have reinforced the prognostic significance of sentinel node status, reporting pooled SLN positivity rates of 20–40% with worse outcomes among SLN‑positive patients. 10,11 Nevertheless, systematic reviews in non‑melanoma skin cancers highlight underutilization of SLNB and inconsistent adherence to guideline recommendations. 11,12 Most prior reports did not directly compare cohorts treated with SLNB to those in whom SLNB was omitted, limiting inference about whether the decision to perform SLNB itself is associated with long‑term outcomes. While SLNB is primarily a staging procedure that can guide adjuvant treatment, it could theoretically confer a direct prognostic benefit by removing micrometastatic disease or altering immune surveillance. However, any apparent survival advantage among patients undergoing SLNB may reflect selection bias: the decision to perform SLNB often favours younger patients with better performance status and fewer comorbidities. Disentangling a direct therapeutic effect from confounding by patient selection is therefore challenging in retrospective cohorts. To address this question, we conducted a retrospective multicentre analysis, reported in accordance with STROBE, explicitly incorporating tumour‑centric factors and available patient‑centric proxies (age and Charlson Comorbidity Index [CCI]) to compare survival and recurrence outcomes between patients who did and did not undergo SLNB. 16–21 By transparently acknowledging undocumented selection factors and focusing on measurable health indicators, we aim to inform a more differentiated, patient‑centred understanding of the role of SLNB in MCC. 2. Methods 2.1. Patients The study adhered to the STROBE guidelines ( Table 1suppl ). We performed a retrospective multicentre cohort study across eight skin cancer centres in North Rhine‑Westphalia, Germany (Bochum, Dortmund, Duisburg, Minden, Oberhausen, Hornheide [Münster], Unna, Wuppertal) covering the years 2004–2024. The protocol was approved by the institutional ethics review board (#16 5985), and the study was conducted in accordance with the Declaration of Helsinki. We included 271 consecutive patients with a primary diagnosis of MCC and an indication for SLNB per national guidelines (clinical stage I–II). Baseline staging comprised lymph‑node ultrasound, thoraco‑abdominal computed tomography, and cranial magnetic resonance imaging. SLNB was recommended for all patients in the absence of formal contraindications; however, 104 patients did not undergo SLNB, likely due to frailty, comorbidities, restricted life expectancy, or patient refusal. These reasons were not consistently recorded; consequently, beyond age and CCI we lacked comprehensive data to adjust for all patient‑ or physician‑driven selection factors. Clinical work‑up, treatment, and follow‑up were performed according to national guidelines. 3 2.2. Data collection and baseline variables Key baseline covariates are summarized in Table 1 . Age and sex were recorded at first presentation. Tumour stage was assigned per AJCC 8th edition immediately after SLNB for SLNB patients and at initial diagnosis for non‑SLNB patients. Comorbidities, including immunosuppression and other immunodeficiencies, were quantified using the CCI. Variables and survival outcomes were extracted by a dermatologist (E.H.) using each centre’s electronic health records, a predefined structured data collection form, and a data dictionary developed with a senior cons ultant dermatologist (T.G.). 2.3. SLNB procedure SLNB was performed predominantly under general anaesthesia. Lymphatic mapping was conducted by intradermal injection of technetium‑99m sulfur colloid adjacent to the tumour or biopsy site, followed by gamma imaging to identify draining basins. In select cases, intradermal blue dye was injected intraoperatively. Nodes appearing blue and/or exhibiting radioactivity greater than 10% of the ex vivo counts were excised as sentinel lymph nodes, as described by Wong et al. 6 Pathologic examination followed the recommendations by Su et al. 7 Immunohistochemical stains typically included cytokeratin‑20 (CK20) and/or pan‑cytokeratin. 3 2.4. Outcomes The primary outcome was overall survival (OS), defined from diagnosis to death from any cause; survivors were censored at last known contact. Disease‑specific survival (DSS) was defined as time from diagnosis to death due to MCC; deaths from other causes were treated as competing events, and survivors were censored at last follow‑up. Progression‑free probability (PFP) was defined as the Kaplan–Meier‑estimated probability of remaining free from the composite event (first MCC recurrence or death from any cause) up to time t and was reported at prespecified time points (e.g., 12, 24, and 60 months). For modelling and hypothesis testing, we analysed the corresponding time‑to‑event (time to first recurrence or death); deaths were counted as events. 2.5. Statistics Analyses were performed using MedCalc Software v22.014 (Ostend, Belgium) and R/RStudio (version 4.4.3; packages prodlim, survival, and optmatch). Sample size was determined a priori via Schoenfeld’s formula: assuming two‑sided α = 0.05, 80% power to detect HR = 2.0 for OS, equal SLNB/non‑SLNB allocation, and a 25% anticipated OS event rate, a minimum of 261 patients was required; our cohort of 271 thus afforded adequate power. Missing data for key outcomes led to case‑wise exclusion. Data distribution was assessed with the D’Agostino–Pearson test; non‑normal variables are reported as medians with ranges or interquartile ranges. Survival curves were estimated by Kaplan–Meier and compared by log‑rank test. Follow‑up time for OS, DSS, and the time‑to‑composite event underlying PFP was estimated by the reverse Kaplan–Meier method, with median follow‑up defined as the time point at which the reverse KM survival curve fell to 50%. Multivariable Cox proportional hazards models included age (continuous, HR per 10‑year increase), sex (male vs female), clinical stage (I vs II), CCI (continuous, HR per one‑point increase), SLNB performance (no vs yes), tumour localization, and adjuvant radiotherapy. The proportional hazards assumption was verified via Schoenfeld residuals and held for all covariates; ties were handled by the Breslow approximation (MedCalc default). For DSS, non‑MCC deaths were treated as competing events in a cause‑specific Cox model. To minimize residual confounding between SLNB and non‑SLNB groups, we performed propensity‑score matching (PSM) by estimating each patient’s propensity to undergo SLNB via logistic regression on age, sex, CCI, clinical AJCC stage (I vs II), tumour localization, and adjuvant radiotherapy. We then performed 1:1 nearest‑neighbour matching with a caliper of 0.05 on the propensity score. Matched pairs (85 SLNB vs 85 non‑SLNB) were used for univariable Cox regression analyses of OS, DSS, and the time‑to‑composite event; PFP was reported at fixed times. 3. Results 3.1. Baseline characteristics As shown in the flow diagram (Fig. 1 ), 271 patients with primary MCC were included; 167 (61.6%) underwent SLNB at diagnosis and 104 (38.4%) did not. Of the initial 326 patients, 55 were excluded due to missing data [survival data 36/55 (65.5%) and CCI data 11/55 (20%)] or misclassification [8/55 (14.5%)]. SLNB patients were significantly younger (median 74 vs 82 years; p < 0.0001) and had a lower comorbidity burden (median CCI 4 vs 5; p = 0.0009). Although guidelines recommend adjuvant radiotherapy irrespective of SLNB status, radiotherapy was administered more often in the SLNB cohort (72.5% vs 40.4%; p < 0.0001). 3.2. Relapse and mortality rates Overall, 56/271 patients (20.7%) experienced a disease relapse; 38/167 (22.8%) in the SLNB group and 18/104 (17.3%) in the non‑SLNB group (χ² = 1.16; p = 0.28). 3.3. Survival analyses Median time to the composite endpoint (first recurrence or death) was not reached in the SLNB group, as more than half of patients remained event‑free at last follow‑up. Kaplan–Meier curves demonstrated superior PFP in the SLNB group compared with the non‑SLNB group (log‑rank Z = − 2.84; p = 0.0045, Fig. 2 ). Corresponding PFP at 3, 5, and 10 years were 68.5% (95% CI 60.1–75.5), 61.5% (51.9–69.8), and 49.5% (36.9–60.9) in the SLNB cohort versus 53.5% (40.6–64.8), 39.2% (25.2–52.9), and not estimable in the non‑SLNB cohort ( Table 2 ). DSS did not differ significantly between groups by time‑to‑event analysis (HR 0.66; 95% CI 0.32–1.36; p = 0.26). Median OS was not reached in the SLNB group versus 57.6 months (95% CI 41.4–103.8) in the non‑SLNB group; 10‑year OS rates were 69.5% vs 45.2% (log‑rank χ² = 35.56; p < 0.0001; HR 0.34; 95% CI 0.20–0.59). Restricted mean survival time at 60 months was 51.8 months (95% CI 48.98–54.57) in the SLNB group vs 42.6 months (95% CI 37.20–48.05) in the non‑SLNB group, yielding an absolute gain of 9.2 months (95% CI 3.05–15.26; p = 0.0033). Among the 167 SLNB‑treated patients, 43 (25.7%) had a positive sentinel node, upstaging them to stage IIIA and identifying a high‑risk subgroup across survival endpoints. Stage IIIA had shorter OS compared to SLNB‑negative patients (log‑rank χ² = 7.25; p = 0.0071; HR 3.04; 95% CI 1.35–6.81), with a median OS of 82.0 months (95% CI 34.9–82.0) versus not reached for pathologically confirmed stage I/II (pI/pII). DSS was also inferior in stage IIIA (log‑rank χ² = 9.89; p = 0.0017; HR 4.56; 95% CI 1.77–11.73), with a median DSS of 82.0 months (95% CI 34.9–82.0) versus not reached in pI/pII. However, the shorter PFP in stage IIIA did not reach statistical significance (log‑rank χ² = 1.42; p = 0.23; HR 1.61; 95% CI 0.74–3.54). 3.4. Multivariable Cox regression We fitted multivariable Cox models for PFP, OS, and DSS incorporating age, sex, CCI, tumour localization and stage, SLNB performance, and adjuvant radiotherapy. Each full model significantly outperformed its null counterpart (PFP χ² = 28.72; OS χ² = 52.27; DSS χ² = 34.45; all p < 0.003). For PFP, higher CCI and tumour stage II were independently associated with earlier progression or death (CCI HR = 1.18; 95% CI 1.07–1.29; stage II vs I HR = 1.99; 95% CI 1.07–3.68). Age, sex, localization, adjuvant radiotherapy, and SLNB performance were not significant for PFP. For DSS, stage II carried a 3.54‑fold increased hazard (95% CI 1.22–10.3; p = 0.020) and age a 1.09‑fold increase (95% CI 1.021–1.16; p = 0.0092). Comorbidity, SLNB, sex, localization, and adjuvant radiotherapy lacked independent significance for DSS. For OS, comorbidity remained a key predictor (CCI HR = 1.17 per point; 95% CI 1.03–1.33; p = 0.014) alongside stage II (HR = 2.60; 95% CI 1.31–5.60; p = 0.007) and age (HR = 1.06; 95% CI 1.01–1.10; p = 0.0095). SLNB was not independently associated with OS after adjustment. Harrell’s C‑indices indicated good discrimination (OS 0.74; DSS 0.74; PFP 0.67). No covariate violated the proportional‑hazards assumption (all Schoenfeld p > 0.10). 3.5. Propensity‑matched and weighted analyses PSM yielded 85 well‑balanced pairs (absolute standardized differences < 0.20). In the matched cohort (Table 3 , Fig. 3 ), SLNB was associated with lower all‑cause mortality (OS HR = 0.56; 95% CI 0.34–0.93; p = 0.024), while DSS did not differ (HR = 1.09; 95% CI 0.55–2.13; p = 0.81). The time‑to‑composite event underlying PFP was not significantly different (HR non‑SLNB vs SLNB = 1.88; 95% CI 0.79–4.42; p = 0.15). Corresponding PFP values at 12/24/60 months in the matched set (caliper 0.05) were 74.8%/68.4%/60.5% (SLNB) vs 73.2%/63.2%/42.6% (non‑SLNB). Robustness checks confirmed the OS finding: with caliper 0.20 (matched N = 170) HR = 0.65 (95% CI 0.44–0.96; p = 0.03); with caliper 0.10 (matched N = 150) HR = 0.63 (95% CI 0.41–0.99; p = 0.04). In a stage I–II restricted match emphasizing common support (1:1, caliper 0.05; 52 pairs), pair‑stratified Cox showed a higher composite event hazard in non‑SLNB (HR = 2.80; 95% CI 1.01–7.77; p = 0.048). Overlap weighting achieved near‑perfect balance and indicated a lower composite event hazard with SLNB (HR = 0.49; 95% CI 0.33–0.73; p = 0.00045). 4. Discussion 4.1. Data and literature This multicentre cohort of clinically node‑negative MCC provides several insights into the role of SLNB. Consistent with prior reports, performance of SLNB was associated with a marked improvement in unadjusted overall survival (10‑year OS 69.5% vs 45.2%). 2,4,8,10,23–26 The survival advantage persisted, though attenuated, after propensity‑score matching. Interpreting this association requires caution. SLNB improves staging accuracy and facilitates risk‑adapted treatment, which may indirectly improve outcomes. Whether SLNB itself confers a direct therapeutic benefit by removing micrometastases remains unproven in MCC and has not been definitively established in melanoma. Our results are concordant with Delisle et al., who observed a 68% reduction in all‑cause mortality after SLNB (HR 0.32; 95% CI 0.23–0.45) in a propensity‑matched Canadian cohort, and with other series reporting improved OS without consistent DSS differences. 23–26 In our data, DSS did not differ significantly between SLNB and non‑SLNB across analyses (HR 1.09; 95% CI 0.55–2.13; p = 0.81), mirroring several prior studies. 23,27 SLN positivity (stage IIIA) identified a high‑risk subgroup across OS and DSS endpoints in our cohort, in line with established literature. Nevertheless, adjuvant radiotherapy was more frequent in the SLNB group (72.5% vs 40.4%), which may reflect enhanced risk stratification after pathological staging or indicate that the same clinical factors precluding SLNB also influenced the decision to omit radiotherapy. Non‑SLNB patients were also older and had more head‑and‑neck primaries, features historically linked to poorer prognosis. 29–32 Although PSM and overlap weighting improved balance, residual confounding remains possible and may partly account for the observed OS benefit. Overall, our data suggest that the principal advantage of SLNB is improved staging with downstream treatment selection rather than a demonstrated intrinsic effect on recurrence biology. The composite PFP endpoint favoured SLNB in unadjusted analyses; in the primary matched analysis it was neutral overall but showed benefit in the stage‑restricted match and in the overlap‑weighted estimand. No adjustments for multiplicity were applied, and inferences should be regarded as exploratory. We prioritized estimation with effect sizes and uncertainty intervals over strict hypothesis testing. Kaplan–Meier curves were visually inspected for late separation and crossing hazards. Schoenfeld residual plots showed no meaningful departures from proportionality on visual review. Event adjudication relied on clinical documentation and imaging reports available in the electronic record. The analytic code and data dictionary are available on request to support reproducibility. The participating centres spanned urban and regional catchment areas, supporting external validity within our healthcare system. Future work should incorporate patient‑reported outcomes to complement survival‑based endpoints. 4.2. Limitations and strengths This study has several limitations. Its retrospective design introduces selection bias and precludes causal inference. MCPyV status was not uniformly assessed, limiting analyses by viral aetiology. Key confounders such as performance status, detailed comorbidity beyond the CCI, and socioeconomic factors were not captured. Follow‑up schedules varied across centres, potentially underestimating late recurrences. Documentation of the rationale for omitting SLNB was incomplete, limiting adjustment for selection factors. Nevertheless, the study has notable strengths. The relatively large, multicentre setting bolstered statistical power despite MCC’s rarity and enhanced generalizability. Data abstraction followed a centralized, standardized process with STROBE‑conformant reporting to ensure transparency and reproducibility. We prespecified a composite definition for PFP and complemented the primary matched analysis with overlap weighting and stage‑restricted sensitivity analyses to probe robustness. Model performance was summarized with Harrell’s C‑indices, and no proportional‑hazards violations were detected. Conclusions In this multicentre cohort of clinical stage I–II MCC, SLNB was associated with substantially better unadjusted overall survival, and this association persisted after propensity‑score matching, albeit attenuated. For PFP (composite) and DSS, the primary 1:1 matched analysis did not show statistically significant differences, although unadjusted PFP curves favoured SLNB and sensitivity analyses (overlap weighting and a stage‑restricted match) suggested a lower hazard of progression or death with SLNB. Multivariable models identified comorbidity (CCI), tumour stage II, and age as the principal determinants of outcome; SLNB itself was not independently prognostic after adjustment. We hypothesize that the decision to proceed with SLNB—arrived at through shared decision‑making—serves as a surrogate for patient fitness in addition to tumour staging and thus tracks with overall survival. Future prospective work should standardize SLNB decision criteria, ensure balanced adjuvant treatment across groups, capture performance status and patient preferences, and predefine composite endpoints and estimands to disentangle staging benefits from selection effects. Residual confounding by indication cannot be excluded. All tests were two‑sided and p values < 0.05 were considered statistically significant. Confidence intervals were calculated at the 95% level throughout the manuscript. Reverse Kaplan–Meier was used to estimate median follow‑up for each endpoint. Censoring was administrative and independent of the outcomes to the best of our knowledge. Nearest‑neighbour matching used a caliper on the logit of the propensity score to reduce residual bias. Overlap weighting targeted the average treatment effect in the overlap population and yielded excellent covariate balance. Harrell’s C‑index was used to summarize discrimination for time‑to‑event models. Analyses were cross‑checked by two investigators to minimize transcription or coding errors. Radiotherapy decisions were made by multidisciplinary tumour boards according to national guidance. No subgroup analyses were performed beyond those prespecified for matching and overlap weighting. Declarations Ethic statement: This study was conducted according to the declaration of Helsinki and followed a protocol approved by the institutional ethics review board of the Ruhr-University Bochum (#16-5985). Data Availability Statement: The data that support the findings of this study are available from the corresponding author upon reasonable request. Funding sources . None Conflict of interest : T.G. has received speakers and/or advisory board honoraria from BMS, Sanofi-Genzyme, MSD, Novartis Pharma, Roche, UCB, Abbvie, Almirall, Janssen, Lilly, Pfizer, Pierre Fabre, Merck-Serono, outside the submitted work. N.A. received funding, travel support and/or personal honoraria for lectures from Novartis Pharma, JanssenCilag GmbH, Recordati Rare Diseases Germany GmbH, UCB Pharma, Almirall Hermal GmbH, Bristol-Myers Squibb (BMS) and Johnson & Johnson that were independent of the work submitted. R.G. has received honoraria for lectures/advisory boards from BMS, MSD, Novartis, Merck Serono, Almirall Hermal, SUN Pharma, Sanofi/Regeneron, Pierre Fabre, Immunocore, Janssen, Incyte and Delcath and has received research funding from Amgen, Merck Serono, SUN Pharma, Sanofi/Regeneron, Almirall Hermal, Kyowa Kirin, and Recordati as well as congress participation supported by SUN Pharma and Pierre Fabre, all outside of the submitted work. J.C.B is receiving speaker’s bureau honoraria from Amgen, Incyte Merck-Serono and Regeneron is a paid consultant/advisory board member for Merck-Serono, Incyte, 4SC and Regeneron. His group receives research grants from Regeneron, Merck Serono, and Alcedis. L.S. has received speakers and/or advisory board honoraria from UCB, BMS, Sun-Pharma, MSD, and Novartis. The other authors report no conflicts or competing interests. Acknowledgment: The data of this study is part of the doctoral thesis of Ekaterina Heinzer. *Corresponding author. Prof. Dr. T. 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J Dermatol 40(5):374–379 Song Y, Azari FS, Tang R, Shannon AB, Miura JT, Fraker DL, Karakousis GC (2021) Patterns of Metastasis in Merkel Cell Carcinoma. Ann Surg Oncol 28(1):519–529 Smith FO, Yue B, Marzban SS, Walls BL, Carr M, Jackson RS, Puleo CA, Padhya T, Cruse CW, Gonzalez RJ, Sarnaik AA, Schell MJ, DeConti RC, Messina JL, Sondak VK, Zager JS (2015) Both tumor depth and diameter are predictive of sentinel lymph node status and survival in Merkel cell carcinoma. Cancer 121(18):3252–3260. 10.1002/cncr.29452 Lamb EP, Shaw FR, Fleming MD (2018) Investigation of the Diagnostic Precision and Utility of Sentinel Lymph Node Biopsy in the Treatment of Patients with Merkel Cell Carcinoma. Am Surg 84(5):e173–e175 Ma KL, Sharon CE, Tortorello GN, Perry NJ, Keele LJ, Lukens JN, Karakousis GC, Miura JT (2023) Radiation, Lymph Node Dissection, or Both: Management of Lymph Node Micrometastases from Merkel Cell Carcinoma. Ann Surg Oncol 30(7):4345–4355 Jacobs D, Olino K, Park HS, Clune J, Cheraghlou S, Girardi M, Burtness B, Kluger H, Judson BL (2021) Primary Treatment Selection for Clinically Node-Negative Merkel Cell Carcinoma of the Head and Neck. Otolaryngol Head Neck Surg 164(6):1214–1221 Erstine EM, Tetzlaff MT, Jia X, Aung PP, Prieto VG, Funchain P, Gastman BR, Billings SD, Ko JS (2019) Prognostic Significance of Nonsolid Microscopic Metastasis in Merkel Cell Carcinoma Sentinel Lymph Nodes. Am J Surg Pathol 43(7):907–919 Jenkins LN, Howle JR, Veness MJ (2019) Sentinel lymph node biopsy in clinically node-negative Merkel cell carcinoma: the Westmead Hospital experience. ANZ J Surg 89(5):520–523 Okła B, Moser T, Scheftel J et al (2020) Tissue-resident memory T cells in tumor immunity and immunotherapy. J Exp Med 217(2):e20191826 Fulop T, Larbi A, Pawelec G et al (2014) Immunosenescence and cancer. Curr Opin Immunol 29:105–111 Butala J, Markovic SN, Mesko T et al (2021) Impact of tumor-infiltrating lymphocytes and Merkel cell polyomavirus status on prognosis in Merkel cell carcinoma. Clin Cancer Res 27(14):3515–3523 Harms KL, Iyer JG, Schrama D et al (2021) Virus-positive Merkel cell carcinoma is an independent prognostic factor. Clin Cancer Res 27(9):2494–2504 Fransen MF, Schoonderwoerd MJ, Knopf P et al (2018) Surgical disruption of lymphatic pathways modulates PD-1/PD-L1 expression and T-cell trafficking in the tumor microenvironment. Cancer Immunol Res 6(11):1281–1292 Tables Tables are available in the Supplementary Files section. Additional Declarations Competing interest reported. T.G. has received speakers and/or advisory board honoraria from BMS, Sanofi-Genzyme, MSD, Novartis Pharma, Roche, UCB, Abbvie, Almirall, Janssen, Lilly, Pfizer, Pierre Fabre, Merck-Serono, outside the submitted work. N.A. received funding, travel support and/or personal honoraria for lectures from Novartis Pharma, JanssenCilag GmbH, Recordati Rare Diseases Germany GmbH, UCB Pharma, Almirall Hermal GmbH, Bristol-Myers Squibb (BMS) and Johnson & Johnson that were independent of the work submitted. R.G. has received honoraria for lectures/advisory boards from BMS, MSD, Novartis, Merck Serono, Almirall Hermal, SUN Pharma, Sanofi/Regeneron, Pierre Fabre, Immunocore, Janssen, Incyte and Delcath and has received research funding from Amgen, Merck Serono, SUN Pharma, Sanofi/Regeneron, Almirall Hermal, Kyowa Kirin, and Recordati as well as congress participation supported by SUN Pharma and Pierre Fabre, all outside of the submitted work. J.C.B is receiving speaker’s bureau honoraria from Amgen, Incyte Merck-Serono and Regeneron is a paid consultant/advisory board member for Merck-Serono, Incyte, 4SC and Regeneron. His group receives research grants from Regeneron, Merck Serono, and Alcedis. L.S. has received speakers and/or advisory board honoraria from UCB, BMS, Sun-Pharma, MSD, and Novartis. The other authors report no conflicts or competing interests. Supplementary Files STROBEchecklistcompleted.docx Tables.docx Cite Share Download PDF Status: Published Journal Publication published 28 Apr, 2026 Read the published version in Journal of Cancer Research and Clinical Oncology → Version 1 posted Editorial decision: Revision requested 06 Apr, 2026 Reviews received at journal 06 Apr, 2026 Reviewers agreed at journal 25 Mar, 2026 Reviewers invited by journal 25 Mar, 2026 Editor assigned by journal 24 Mar, 2026 Submission checks completed at journal 24 Mar, 2026 First submitted to journal 18 Mar, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {\"props\":{\"pageProps\":{\"initialData\":{\"identity\":\"rs-8669831\",\"acceptedTermsAndConditions\":true,\"allowDirectSubmit\":false,\"archivedVersions\":[],\"articleType\":\"Research Article\",\"associatedPublications\":[],\"authors\":[{\"id\":612374255,\"identity\":\"cadbefa7-9bb4-44fd-8689-09ee343ecff1\",\"order_by\":0,\"name\":\"Thilo Gambichler\",\"email\":\"data:image/png;base64,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\",\"orcid\":\"\",\"institution\":\"\",\"correspondingAuthor\":true,\"prefix\":\"\",\"firstName\":\"Thilo\",\"middleName\":\"\",\"lastName\":\"Gambichler\",\"suffix\":\"\"},{\"id\":612374256,\"identity\":\"c4616abf-20be-482d-b00f-aab2311ea9e7\",\"order_by\":1,\"name\":\"Ekaterina Heinzer\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Ekaterina\",\"middleName\":\"\",\"lastName\":\"Heinzer\",\"suffix\":\"\"},{\"id\":612374257,\"identity\":\"a3d414a2-21fb-4558-bac1-059fb33535b4\",\"order_by\":2,\"name\":\"Nessr Abu Rached\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Nessr\",\"middleName\":\"Abu\",\"lastName\":\"Rached\",\"suffix\":\"\"},{\"id\":612374258,\"identity\":\"edeed96b-28e3-4488-94b6-49eda361ec68\",\"order_by\":3,\"name\":\"Hans-Joachim Schulze\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Hans-Joachim\",\"middleName\":\"\",\"lastName\":\"Schulze\",\"suffix\":\"\"},{\"id\":612374259,\"identity\":\"5c589541-660c-42da-8f0a-c500c86c5796\",\"order_by\":4,\"name\":\"Kirsten Noah\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Kirsten\",\"middleName\":\"\",\"lastName\":\"Noah\",\"suffix\":\"\"},{\"id\":612374260,\"identity\":\"fe73d2c1-31fc-4801-85f4-0a1d36349990\",\"order_by\":5,\"name\":\"Silke C. 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Weyer-Fahlbusch\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Sera\",\"middleName\":\"S.\",\"lastName\":\"Weyer-Fahlbusch\",\"suffix\":\"\"},{\"id\":612374266,\"identity\":\"c10b2a71-dba7-47c4-b4b6-84e05c3a867a\",\"order_by\":11,\"name\":\"Alexander Kreuter\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Alexander\",\"middleName\":\"\",\"lastName\":\"Kreuter\",\"suffix\":\"\"},{\"id\":612374267,\"identity\":\"4c139797-7f48-45d5-8163-1c3de10f03d4\",\"order_by\":12,\"name\":\"Julia Hyun\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Julia\",\"middleName\":\"\",\"lastName\":\"Hyun\",\"suffix\":\"\"},{\"id\":612374268,\"identity\":\"ba5d2a74-48a4-45b6-b661-16714033fc49\",\"order_by\":13,\"name\":\"Valentina L. Müller\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Valentina\",\"middleName\":\"L.\",\"lastName\":\"Müller\",\"suffix\":\"\"},{\"id\":612374269,\"identity\":\"0ad31c2f-0b33-4ad0-9c3c-5be255359e8e\",\"order_by\":14,\"name\":\"Rosanna Auer\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Rosanna\",\"middleName\":\"\",\"lastName\":\"Auer\",\"suffix\":\"\"},{\"id\":612374270,\"identity\":\"bb86f951-c584-4105-9389-b43ce2a9a56a\",\"order_by\":15,\"name\":\"Jürghen C. Becker\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Jürghen\",\"middleName\":\"C.\",\"lastName\":\"Becker\",\"suffix\":\"\"}],\"badges\":[],\"createdAt\":\"2026-01-22 12:41:55\",\"currentVersionCode\":1,\"declarations\":\"\",\"doi\":\"10.21203/rs.3.rs-8669831/v1\",\"doiUrl\":\"https://doi.org/10.21203/rs.3.rs-8669831/v1\",\"draftVersion\":[],\"editorialEvents\":[{\"content\":\"https://doi.org/10.1007/s00432-026-06485-x\",\"type\":\"published\",\"date\":\"2026-04-28T15:58:02+00:00\"}],\"editorialNote\":\"\",\"failedWorkflow\":false,\"files\":[{\"id\":105728315,\"identity\":\"223c4de5-5080-4e73-b716-60512ff4860b\",\"added_by\":\"auto\",\"created_at\":\"2026-03-30 11:11:25\",\"extension\":\"jpg\",\"order_by\":1,\"title\":\"Figure 1\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":678461,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eFlow diagram of patient inclusion. Of 326 Merkel cell carcinoma patients screened across eight tertiary skin cancer centers (2004–2024), 55 were excluded due to missing data [survival data 36/55 (65.5%) and CCI data 11/55 (20%)] or misclassification [8/55 (14.5%)], yielding 271 patients for analysis with 167 in the SLNB group and 104 in the non-SLNB group.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"Figure1new.jpg\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-8669831/v1/8b945d575335198654b0b7df.jpg\"},{\"id\":105641386,\"identity\":\"f5b96181-cb91-4a39-a452-d71332554f10\",\"added_by\":\"auto\",\"created_at\":\"2026-03-28 16:29:13\",\"extension\":\"jpg\",\"order_by\":2,\"title\":\"Figure 2\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":151438,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eProgression‑free probability (PFP), disease‑specific survival (DSS) and overall survival (OS) in patients with Merkel cell carcinoma stratified by sentinel lymph node biopsy (SLNB) performance. (a) \\u003cem\\u003ePFP (composite: recurrence or death).\\u003c/em\\u003e The median time to the composite event was not reachedin the SLNB group, whereas it was 57.6 months (IQR 24.3–93.5)in the non‑SLNB group; log‑rank Z = –2.84, p = 0.0045; Cox HR (SLNB vs non‑SLNB = 0.55 (95 % CI 0.36–0.84). PFP at 12/24/60 months:82.0 %/72.3 %/62.6 % (SLNB) vs 71.5 %/63.8 %/49.2 % (non‑SLNB). (b) \\u003cem\\u003eDSS.\\u003c/em\\u003e Median DSS was 35.4 months (IQR 16.9–62.7) in SLNB vs 10.9 months in non‑SLNB; log‑rank p = 0.26; HR = 0.66 (95 % CI 0.32–1.36). (c) \\u003cem\\u003eOS.\\u003c/em\\u003e Median OS was not reached in SLNB vs 57.6 months (95 % CI 41.4–103.8)in non‑SLNB; 10‑year OS 69.5 % vs 45.2 %; log‑rank χ² = 35.56 (df = 1), p \\u0026lt; 0.0001; adjusted HR = 0.34 (95 % CI 0.20–0.59). Solid line = SLNB (n = 167), dashed line = non‑SLNB (n = 104); tick marks indicate censored observations. Numbers at risk are shown below the x‑axis.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"Figure2new.jpg\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-8669831/v1/e7467870c75290884d462673.jpg\"},{\"id\":105728443,\"identity\":\"b637b30a-0375-4064-a0bb-d0a97307c97f\",\"added_by\":\"auto\",\"created_at\":\"2026-03-30 11:11:55\",\"extension\":\"jpg\",\"order_by\":3,\"title\":\"Figure 3\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":724718,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eForest plot of hazard ratios (HRs) comparing sentinel lymph node biopsy (SLNB) vs non‑SLNB in the 1:1 propensity‑score‑matched cohort. Points show HRs on a log scale; horizontal lines indicate 95% confidence intervals; the vertical dashed line at HR = 1 denotes no effect. Progression‑free probability (composite: recurrence or death): HR 0.53 (95% CI 0.23–1.26), p = 0.15. Disease‑specific survival: HR 1.09 (95% CI 0.55–2.13), p = 0.81. Overall survival: HR 0.56 (95% CI 0.34–0.93), p = 0.02. All p‑values two‑sided; Cox models stratified by matched pair (Breslow ties).\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"Figure3.jpg\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-8669831/v1/ea1ce3a72a87db29fa0f1174.jpg\"},{\"id\":108438933,\"identity\":\"1d21fc55-8de2-4fe0-b1f9-3d8d0cfc81f4\",\"added_by\":\"auto\",\"created_at\":\"2026-05-04 16:11:44\",\"extension\":\"pdf\",\"order_by\":0,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"manuscript-pdf\",\"size\":1761438,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"manuscript.pdf\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-8669831/v1/9d35d188-1a5a-4e1f-a596-98d814310189.pdf\"},{\"id\":105728882,\"identity\":\"d90aa06c-886b-4676-88ef-aba71c90450b\",\"added_by\":\"auto\",\"created_at\":\"2026-03-30 11:12:57\",\"extension\":\"docx\",\"order_by\":1,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"supplement\",\"size\":32580,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"STROBEchecklistcompleted.docx\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-8669831/v1/0f203716bf8f03867e240581.docx\"},{\"id\":105641391,\"identity\":\"cbc72eee-0079-410e-9de8-bfea43d889ff\",\"added_by\":\"auto\",\"created_at\":\"2026-03-28 16:29:13\",\"extension\":\"docx\",\"order_by\":2,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"supplement\",\"size\":21532,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"Tables.docx\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-8669831/v1/73e7f01f5565550cfc4748e0.docx\"}],\"financialInterests\":\"Competing interest reported. T.G. has received speakers and/or advisory board honoraria from BMS, Sanofi-Genzyme, MSD, Novartis Pharma, Roche, UCB, Abbvie, Almirall, Janssen, Lilly, Pfizer, Pierre Fabre, Merck-Serono, outside the submitted work. N.A. received funding, travel support and/or personal honoraria for lectures from Novartis Pharma, JanssenCilag GmbH, Recordati Rare Diseases Germany GmbH, UCB Pharma, Almirall Hermal GmbH, Bristol-Myers Squibb (BMS) and Johnson \\u0026 Johnson that were independent of the work submitted. R.G. has received honoraria for lectures/advisory boards from BMS, MSD, Novartis, Merck Serono, Almirall Hermal, SUN Pharma, Sanofi/Regeneron, Pierre Fabre, Immunocore, Janssen, Incyte and Delcath and has received research funding from Amgen, Merck Serono, SUN Pharma, Sanofi/Regeneron, Almirall Hermal, Kyowa Kirin, and Recordati as well as congress participation supported by SUN Pharma and Pierre Fabre, all outside of the submitted work. J.C.B is receiving speaker’s bureau honoraria from Amgen, Incyte Merck-Serono and Regeneron is a paid consultant/advisory board member for Merck-Serono, Incyte, 4SC and Regeneron. His group receives research grants from Regeneron, Merck Serono, and Alcedis. L.S. has received speakers and/or advisory board honoraria from UCB, BMS, Sun-Pharma, MSD, and Novartis. The other authors report no conflicts or competing interests.\",\"formattedTitle\":\"General Health Versus Tumor Stage: Determinants of Survival in Merkel Cell Carcinoma Assessed by Sentinel Lymph Node Biopsy\",\"fulltext\":[{\"header\":\"1. Introduction\",\"content\":\"\\u003cp\\u003eMerkel cell carcinoma (MCC) is a highly aggressive skin cancer with neuroendocrine differentiation. Its incidence among Whites living in the Northern hemisphere is approximately 0.7 per 100,000 person‑years and has risen steadily over recent decades. \\u003csup\\u003e1\\u0026ndash;3\\u003c/sup\\u003e MCC shows a marked propensity for regional and distant spread: up to one‑third of clinically node‑negative patients harbour occult nodal metastases at diagnosis. \\u003csup\\u003e3,4\\u003c/sup\\u003e Nodal status is the strongest predictor of recurrence and survival in primary MCC. \\u003csup\\u003e1,5\\u003c/sup\\u003e Accordingly, sentinel lymph node biopsy (SLNB) is recommended to improve staging accuracy in clinically node‑negative disease. \\u003csup\\u003e6\\u003c/sup\\u003e Early single‑centre and population‑based studies indicated that SLNB positivity identifies a subgroup at markedly higher risk for recurrence and disease‑specific mortality. \\u003csup\\u003e7\\u0026ndash;9\\u003c/sup\\u003e Meta‑analyses have reinforced the prognostic significance of sentinel node status, reporting pooled SLN positivity rates of 20\\u0026ndash;40% with worse outcomes among SLN‑positive patients. \\u003csup\\u003e10,11\\u003c/sup\\u003e Nevertheless, systematic reviews in non‑melanoma skin cancers highlight underutilization of SLNB and inconsistent adherence to guideline recommendations. \\u003csup\\u003e11,12\\u003c/sup\\u003e Most prior reports did not directly compare cohorts treated with SLNB to those in whom SLNB was omitted, limiting inference about whether the decision to perform SLNB itself is associated with long‑term outcomes. While SLNB is primarily a staging procedure that can guide adjuvant treatment, it could theoretically confer a direct prognostic benefit by removing micrometastatic disease or altering immune surveillance. However, any apparent survival advantage among patients undergoing SLNB may reflect selection bias: the decision to perform SLNB often favours younger patients with better performance status and fewer comorbidities. Disentangling a direct therapeutic effect from confounding by patient selection is therefore challenging in retrospective cohorts. To address this question, we conducted a retrospective multicentre analysis, reported in accordance with STROBE, explicitly incorporating tumour‑centric factors and available patient‑centric proxies (age and Charlson Comorbidity Index [CCI]) to compare survival and recurrence outcomes between patients who did and did not undergo SLNB. \\u003csup\\u003e16\\u0026ndash;21\\u003c/sup\\u003e By transparently acknowledging undocumented selection factors and focusing on measurable health indicators, we aim to inform a more differentiated, patient‑centred understanding of the role of SLNB in MCC.\\u003c/p\\u003e\"},{\"header\":\"2. Methods\",\"content\":\"\\u003cdiv id=\\\"Sec3\\\" class=\\\"Section2\\\"\\u003e\\n \\u003ch2\\u003e2.1. Patients\\u003c/h2\\u003e\\n \\u003cp\\u003eThe study adhered to the STROBE guidelines (\\u003cstrong\\u003eTable\\u0026nbsp;1suppl\\u003c/strong\\u003e). We performed a retrospective multicentre cohort study across eight skin cancer centres in North Rhine‑Westphalia, Germany (Bochum, Dortmund, Duisburg, Minden, Oberhausen, Hornheide [M\\u0026uuml;nster], Unna, Wuppertal) covering the years 2004\\u0026ndash;2024. The protocol was approved by the institutional ethics review board (#16 5985), and the study was conducted in accordance with the Declaration of Helsinki. We included 271 consecutive patients with a primary diagnosis of MCC and an indication for SLNB per national guidelines (clinical stage I\\u0026ndash;II). Baseline staging comprised lymph‑node ultrasound, thoraco‑abdominal computed tomography, and cranial magnetic resonance imaging. SLNB was recommended for all patients in the absence of formal contraindications; however, 104 patients did not undergo SLNB, likely due to frailty, comorbidities, restricted life expectancy, or patient refusal. These reasons were not consistently recorded; consequently, beyond age and CCI we lacked comprehensive data to adjust for all patient‑ or physician‑driven selection factors. Clinical work‑up, treatment, and follow‑up were performed according to national guidelines. \\u003csup\\u003e3\\u003c/sup\\u003e\\u003c/p\\u003e\\n\\u003c/div\\u003e\\n\\u003cdiv id=\\\"Sec4\\\" class=\\\"Section2\\\"\\u003e\\n \\u003ch2\\u003e2.2. Data collection and baseline variables\\u003c/h2\\u003e\\n \\u003cp\\u003eKey baseline covariates are summarized in Table \\u003cspan refid=\\\"Tab1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e. Age and sex were recorded at first presentation. Tumour stage was assigned per AJCC 8th edition immediately after SLNB for SLNB patients and at initial diagnosis for non‑SLNB patients. Comorbidities, including immunosuppression and other immunodeficiencies, were quantified using the CCI. Variables and survival outcomes were extracted by a dermatologist (E.H.) using each centre\\u0026rsquo;s electronic health records, a predefined structured data collection form, and a data dictionary developed with a senior cons\\u003c/p\\u003e\\n \\u003cp\\u003eultant dermatologist (T.G.).\\u003c/p\\u003e\\n\\u003c/div\\u003e\\n\\u003cdiv id=\\\"Sec5\\\" class=\\\"Section2\\\"\\u003e\\n \\u003ch2\\u003e2.3. SLNB procedure\\u003c/h2\\u003e\\n \\u003cp\\u003eSLNB was performed predominantly under general anaesthesia. Lymphatic mapping was conducted by intradermal injection of technetium‑99m sulfur colloid adjacent to the tumour or biopsy site, followed by gamma imaging to identify draining basins. In select cases, intradermal blue dye was injected intraoperatively. Nodes appearing blue and/or exhibiting radioactivity greater than 10% of the ex vivo counts were excised as sentinel lymph nodes, as described by Wong et al. \\u003csup\\u003e6\\u003c/sup\\u003e Pathologic examination followed the recommendations by Su et al. \\u003csup\\u003e7\\u003c/sup\\u003e Immunohistochemical stains typically included cytokeratin‑20 (CK20) and/or pan‑cytokeratin. \\u003csup\\u003e3\\u003c/sup\\u003e\\u003c/p\\u003e\\n\\u003c/div\\u003e\\n\\u003cdiv id=\\\"Sec6\\\" class=\\\"Section2\\\"\\u003e\\n \\u003ch2\\u003e2.4. Outcomes\\u003c/h2\\u003e\\n \\u003cp\\u003eThe primary outcome was overall survival (OS), defined from diagnosis to death from any cause; survivors were censored at last known contact. Disease‑specific survival (DSS) was defined as time from diagnosis to death due to MCC; deaths from other causes were treated as competing events, and survivors were censored at last follow‑up. Progression‑free probability (PFP) was defined as the Kaplan\\u0026ndash;Meier‑estimated probability of remaining free from the composite event (first MCC recurrence or death from any cause) up to time t and was reported at prespecified time points (e.g., 12, 24, and 60 months). For modelling and hypothesis testing, we analysed the corresponding time‑to‑event (time to first recurrence or death); deaths were counted as events.\\u003c/p\\u003e\\n\\u003c/div\\u003e\\n\\u003cdiv id=\\\"Sec7\\\" class=\\\"Section2\\\"\\u003e\\n \\u003ch2\\u003e2.5. Statistics\\u003c/h2\\u003e\\n \\u003cp\\u003eAnalyses were performed using MedCalc Software v22.014 (Ostend, Belgium) and R/RStudio (version 4.4.3; packages prodlim, survival, and optmatch). Sample size was determined a priori via Schoenfeld\\u0026rsquo;s formula: assuming two‑sided \\u0026alpha;\\u0026thinsp;=\\u0026thinsp;0.05, 80% power to detect HR\\u0026thinsp;=\\u0026thinsp;2.0 for OS, equal SLNB/non‑SLNB allocation, and a 25% anticipated OS event rate, a minimum of 261 patients was required; our cohort of 271 thus afforded adequate power. Missing data for key outcomes led to case‑wise exclusion. Data distribution was assessed with the D\\u0026rsquo;Agostino\\u0026ndash;Pearson test; non‑normal variables are reported as medians with ranges or interquartile ranges. Survival curves were estimated by Kaplan\\u0026ndash;Meier and compared by log‑rank test. Follow‑up time for OS, DSS, and the time‑to‑composite event underlying PFP was estimated by the reverse Kaplan\\u0026ndash;Meier method, with median follow‑up defined as the time point at which the reverse KM survival curve fell to 50%. Multivariable Cox proportional hazards models included age (continuous, HR per 10‑year increase), sex (male vs female), clinical stage (I vs II), CCI (continuous, HR per one‑point increase), SLNB performance (no vs yes), tumour localization, and adjuvant radiotherapy. The proportional hazards assumption was verified via Schoenfeld residuals and held for all covariates; ties were handled by the Breslow approximation (MedCalc default). For DSS, non‑MCC deaths were treated as competing events in a cause‑specific Cox model. To minimize residual confounding between SLNB and non‑SLNB groups, we performed propensity‑score matching (PSM) by estimating each patient\\u0026rsquo;s propensity to undergo SLNB via logistic regression on age, sex, CCI, clinical AJCC stage (I vs II), tumour localization, and adjuvant radiotherapy. We then performed 1:1 nearest‑neighbour matching with a caliper of 0.05 on the propensity score. Matched pairs (85 SLNB vs 85 non‑SLNB) were used for univariable Cox regression analyses of OS, DSS, and the time‑to‑composite event; PFP was reported at fixed times.\\u003c/p\\u003e\\n\\u003c/div\\u003e\"},{\"header\":\"3. Results\",\"content\":\"\\u003cdiv id=\\\"Sec9\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003e3.1. Baseline characteristics\\u003c/h2\\u003e \\u003cp\\u003eAs shown in the flow diagram (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e), 271 patients with primary MCC were included; 167 (61.6%) underwent SLNB at diagnosis and 104 (38.4%) did not. Of the initial 326 patients, 55 were excluded due to missing data [survival data 36/55 (65.5%) and CCI data 11/55 (20%)] or misclassification [8/55 (14.5%)]. SLNB patients were significantly younger (median 74 vs 82 years; p\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.0001) and had a lower comorbidity burden (median CCI 4 vs 5; p\\u0026thinsp;=\\u0026thinsp;0.0009). Although guidelines recommend adjuvant radiotherapy irrespective of SLNB status, radiotherapy was administered more often in the SLNB cohort (72.5% vs 40.4%; p\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.0001).\\u003c/p\\u003e \\u003cp\\u003e \\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec10\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003e3.2. Relapse and mortality rates\\u003c/h2\\u003e \\u003cp\\u003eOverall, 56/271 patients (20.7%) experienced a disease relapse; 38/167 (22.8%) in the SLNB group and 18/104 (17.3%) in the non‑SLNB group (χ\\u0026sup2; = 1.16; p\\u0026thinsp;=\\u0026thinsp;0.28).\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec11\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003e3.3. Survival analyses\\u003c/h2\\u003e \\u003cp\\u003eMedian time to the composite endpoint (first recurrence or death) was not reached in the SLNB group, as more than half of patients remained event‑free at last follow‑up. Kaplan\\u0026ndash;Meier curves demonstrated superior PFP in the SLNB group compared with the non‑SLNB group (log‑rank Z = \\u0026minus;\\u0026thinsp;2.84; p\\u0026thinsp;=\\u0026thinsp;0.0045, Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig2\\\" class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003e). Corresponding PFP at 3, 5, and 10 years were 68.5% (95% CI 60.1\\u0026ndash;75.5), 61.5% (51.9\\u0026ndash;69.8), and 49.5% (36.9\\u0026ndash;60.9) in the SLNB cohort versus 53.5% (40.6\\u0026ndash;64.8), 39.2% (25.2\\u0026ndash;52.9), and not estimable in the non‑SLNB cohort (\\u003cb\\u003eTable\\u0026nbsp;2\\u003c/b\\u003e). DSS did not differ significantly between groups by time‑to‑event analysis (HR 0.66; 95% CI 0.32\\u0026ndash;1.36; p\\u0026thinsp;=\\u0026thinsp;0.26). Median OS was not reached in the SLNB group versus 57.6 months (95% CI 41.4\\u0026ndash;103.8) in the non‑SLNB group; 10‑year OS rates were 69.5% vs 45.2% (log‑rank χ\\u0026sup2; = 35.56; p\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.0001; HR 0.34; 95% CI 0.20\\u0026ndash;0.59). Restricted mean survival time at 60 months was 51.8 months (95% CI 48.98\\u0026ndash;54.57) in the SLNB group vs 42.6 months (95% CI 37.20\\u0026ndash;48.05) in the non‑SLNB group, yielding an absolute gain of 9.2 months (95% CI 3.05\\u0026ndash;15.26; p\\u0026thinsp;=\\u0026thinsp;0.0033). Among the 167 SLNB‑treated patients, 43 (25.7%) had a positive sentinel node, upstaging them to stage IIIA and identifying a high‑risk subgroup across survival endpoints. Stage IIIA had shorter OS compared to SLNB‑negative patients (log‑rank χ\\u0026sup2; = 7.25; p\\u0026thinsp;=\\u0026thinsp;0.0071; HR 3.04; 95% CI 1.35\\u0026ndash;6.81), with a median OS of 82.0 months (95% CI 34.9\\u0026ndash;82.0) versus not reached for pathologically confirmed stage I/II (pI/pII). DSS was also inferior in stage IIIA (log‑rank χ\\u0026sup2; = 9.89; p\\u0026thinsp;=\\u0026thinsp;0.0017; HR 4.56; 95% CI 1.77\\u0026ndash;11.73), with a median DSS of 82.0 months (95% CI 34.9\\u0026ndash;82.0) versus not reached in pI/pII. However, the shorter PFP in stage IIIA did not reach statistical significance (log‑rank χ\\u0026sup2; = 1.42; p\\u0026thinsp;=\\u0026thinsp;0.23; HR 1.61; 95% CI 0.74\\u0026ndash;3.54).\\u003c/p\\u003e \\u003cp\\u003e \\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec12\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003e3.4. Multivariable Cox regression\\u003c/h2\\u003e \\u003cp\\u003e We fitted multivariable Cox models for PFP, OS, and DSS incorporating age, sex, CCI, tumour localization and stage, SLNB performance, and adjuvant radiotherapy. Each full model significantly outperformed its null counterpart (PFP χ\\u0026sup2; = 28.72; OS χ\\u0026sup2; = 52.27; DSS χ\\u0026sup2; = 34.45; all p\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.003). For PFP, higher CCI and tumour stage II were independently associated with earlier progression or death (CCI HR\\u0026thinsp;=\\u0026thinsp;1.18; 95% CI 1.07\\u0026ndash;1.29; stage II vs I HR\\u0026thinsp;=\\u0026thinsp;1.99; 95% CI 1.07\\u0026ndash;3.68). Age, sex, localization, adjuvant radiotherapy, and SLNB performance were not significant for PFP. For DSS, stage II carried a 3.54‑fold increased hazard (95% CI 1.22\\u0026ndash;10.3; p\\u0026thinsp;=\\u0026thinsp;0.020) and age a 1.09‑fold increase (95% CI 1.021\\u0026ndash;1.16; p\\u0026thinsp;=\\u0026thinsp;0.0092). Comorbidity, SLNB, sex, localization, and adjuvant radiotherapy lacked independent significance for DSS. For OS, comorbidity remained a key predictor (CCI HR\\u0026thinsp;=\\u0026thinsp;1.17 per point; 95% CI 1.03\\u0026ndash;1.33; p\\u0026thinsp;=\\u0026thinsp;0.014) alongside stage II (HR\\u0026thinsp;=\\u0026thinsp;2.60; 95% CI 1.31\\u0026ndash;5.60; p\\u0026thinsp;=\\u0026thinsp;0.007) and age (HR\\u0026thinsp;=\\u0026thinsp;1.06; 95% CI 1.01\\u0026ndash;1.10; p\\u0026thinsp;=\\u0026thinsp;0.0095). SLNB was not independently associated with OS after adjustment. Harrell\\u0026rsquo;s C‑indices indicated good discrimination (OS 0.74; DSS 0.74; PFP 0.67). No covariate violated the proportional‑hazards assumption (all Schoenfeld p\\u0026thinsp;\\u0026gt;\\u0026thinsp;0.10).\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec13\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003e3.5. Propensity‑matched and weighted analyses\\u003c/h2\\u003e \\u003cp\\u003ePSM yielded 85 well‑balanced pairs (absolute standardized differences\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.20). In the matched cohort (Table\\u0026nbsp;\\u003cspan refid=\\\"Tab2\\\" class=\\\"InternalRef\\\"\\u003e3\\u003c/span\\u003e, Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig3\\\" class=\\\"InternalRef\\\"\\u003e3\\u003c/span\\u003e), SLNB was associated with lower all‑cause mortality (OS HR\\u0026thinsp;=\\u0026thinsp;0.56; 95% CI 0.34\\u0026ndash;0.93; p\\u0026thinsp;=\\u0026thinsp;0.024), while DSS did not differ (HR\\u0026thinsp;=\\u0026thinsp;1.09; 95% CI 0.55\\u0026ndash;2.13; p\\u0026thinsp;=\\u0026thinsp;0.81). The time‑to‑composite event underlying PFP was not significantly different (HR non‑SLNB vs SLNB\\u0026thinsp;=\\u0026thinsp;1.88; 95% CI 0.79\\u0026ndash;4.42; p\\u0026thinsp;=\\u0026thinsp;0.15). Corresponding PFP values at 12/24/60 months in the matched set (caliper 0.05) were 74.8%/68.4%/60.5% (SLNB) vs 73.2%/63.2%/42.6% (non‑SLNB). Robustness checks confirmed the OS finding: with caliper 0.20 (matched N\\u0026thinsp;=\\u0026thinsp;170) HR\\u0026thinsp;=\\u0026thinsp;0.65 (95% CI 0.44\\u0026ndash;0.96; p\\u0026thinsp;=\\u0026thinsp;0.03); with caliper 0.10 (matched N\\u0026thinsp;=\\u0026thinsp;150) HR\\u0026thinsp;=\\u0026thinsp;0.63 (95% CI 0.41\\u0026ndash;0.99; p\\u0026thinsp;=\\u0026thinsp;0.04). In a stage I\\u0026ndash;II restricted match emphasizing common support (1:1, caliper 0.05; 52 pairs), pair‑stratified Cox showed a higher composite event hazard in non‑SLNB (HR\\u0026thinsp;=\\u0026thinsp;2.80; 95% CI 1.01\\u0026ndash;7.77; p\\u0026thinsp;=\\u0026thinsp;0.048). Overlap weighting achieved near‑perfect balance and indicated a lower composite event hazard with SLNB (HR\\u0026thinsp;=\\u0026thinsp;0.49; 95% CI 0.33\\u0026ndash;0.73; p\\u0026thinsp;=\\u0026thinsp;0.00045).\\u003c/p\\u003e \"},{\"header\":\"4. Discussion\",\"content\":\"\\u003cdiv id=\\\"Sec15\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003e4.1. Data and literature\\u003c/h2\\u003e \\u003cp\\u003eThis multicentre cohort of clinically node‑negative MCC provides several insights into the role of SLNB. Consistent with prior reports, performance of SLNB was associated with a marked improvement in unadjusted overall survival (10‑year OS 69.5% vs 45.2%). \\u003csup\\u003e2,4,8,10,23–26\\u003c/sup\\u003e The survival advantage persisted, though attenuated, after propensity‑score matching. Interpreting this association requires caution. SLNB improves staging accuracy and facilitates risk‑adapted treatment, which may indirectly improve outcomes. Whether SLNB itself confers a direct therapeutic benefit by removing micrometastases remains unproven in MCC and has not been definitively established in melanoma. Our results are concordant with Delisle et al., who observed a 68% reduction in all‑cause mortality after SLNB (HR 0.32; 95% CI 0.23–0.45) in a propensity‑matched Canadian cohort, and with other series reporting improved OS without consistent DSS differences. \\u003csup\\u003e23–26\\u003c/sup\\u003e In our data, DSS did not differ significantly between SLNB and non‑SLNB across analyses (HR 1.09; 95% CI 0.55–2.13; p = 0.81), mirroring several prior studies. \\u003csup\\u003e23,27\\u003c/sup\\u003e SLN positivity (stage IIIA) identified a high‑risk subgroup across OS and DSS endpoints in our cohort, in line with established literature. Nevertheless, adjuvant radiotherapy was more frequent in the SLNB group (72.5% vs 40.4%), which may reflect enhanced risk stratification after pathological staging or indicate that the same clinical factors precluding SLNB also influenced the decision to omit radiotherapy. Non‑SLNB patients were also older and had more head‑and‑neck primaries, features historically linked to poorer prognosis. \\u003csup\\u003e29–32\\u003c/sup\\u003e Although PSM and overlap weighting improved balance, residual confounding remains possible and may partly account for the observed OS benefit. Overall, our data suggest that the principal advantage of SLNB is improved staging with downstream treatment selection rather than a demonstrated intrinsic effect on recurrence biology. The composite PFP endpoint favoured SLNB in unadjusted analyses; in the primary matched analysis it was neutral overall but showed benefit in the stage‑restricted match and in the overlap‑weighted estimand. No adjustments for multiplicity were applied, and inferences should be regarded as exploratory. We prioritized estimation with effect sizes and uncertainty intervals over strict hypothesis testing. Kaplan–Meier curves were visually inspected for late separation and crossing hazards. Schoenfeld residual plots showed no meaningful departures from proportionality on visual review. Event adjudication relied on clinical documentation and imaging reports available in the electronic record. The analytic code and data dictionary are available on request to support reproducibility. The participating centres spanned urban and regional catchment areas, supporting external validity within our healthcare system. Future work should incorporate patient‑reported outcomes to complement survival‑based endpoints.\\u003c/p\\u003e \\u003c/div\\u003e \\u003cdiv id=\\\"Sec16\\\" class=\\\"Section2\\\"\\u003e \\u003ch2\\u003e4.2. Limitations and strengths\\u003c/h2\\u003e \\u003cp\\u003eThis study has several limitations. Its retrospective design introduces selection bias and precludes causal inference. MCPyV status was not uniformly assessed, limiting analyses by viral aetiology. Key confounders such as performance status, detailed comorbidity beyond the CCI, and socioeconomic factors were not captured. Follow‑up schedules varied across centres, potentially underestimating late recurrences. Documentation of the rationale for omitting SLNB was incomplete, limiting adjustment for selection factors. Nevertheless, the study has notable strengths. The relatively large, multicentre setting bolstered statistical power despite MCC’s rarity and enhanced generalizability. Data abstraction followed a centralized, standardized process with STROBE‑conformant reporting to ensure transparency and reproducibility. We prespecified a composite definition for PFP and complemented the primary matched analysis with overlap weighting and stage‑restricted sensitivity analyses to probe robustness. Model performance was summarized with Harrell’s C‑indices, and no proportional‑hazards violations were detected.\\u003c/p\\u003e \\u003c/div\\u003e \"},{\"header\":\"Conclusions\",\"content\":\"\\u003cp\\u003eIn this multicentre cohort of clinical stage I–II MCC, SLNB was associated with substantially better unadjusted overall survival, and this association persisted after propensity‑score matching, albeit attenuated. For PFP (composite) and DSS, the primary 1:1 matched analysis did not show statistically significant differences, although unadjusted PFP curves favoured SLNB and sensitivity analyses (overlap weighting and a stage‑restricted match) suggested a lower hazard of progression or death with SLNB. Multivariable models identified comorbidity (CCI), tumour stage II, and age as the principal determinants of outcome; SLNB itself was not independently prognostic after adjustment. We hypothesize that the decision to proceed with SLNB—arrived at through shared decision‑making—serves as a surrogate for patient fitness in addition to tumour staging and thus tracks with overall survival. Future prospective work should standardize SLNB decision criteria, ensure balanced adjuvant treatment across groups, capture performance status and patient preferences, and predefine composite endpoints and estimands to disentangle staging benefits from selection effects. Residual confounding by indication cannot be excluded. All tests were two‑sided and p values \\u0026lt; 0.05 were considered statistically significant. Confidence intervals were calculated at the 95% level throughout the manuscript. Reverse Kaplan–Meier was used to estimate median follow‑up for each endpoint. Censoring was administrative and independent of the outcomes to the best of our knowledge. Nearest‑neighbour matching used a caliper on the logit of the propensity score to reduce residual bias. Overlap weighting targeted the average treatment effect in the overlap population and yielded excellent covariate balance. Harrell’s C‑index was used to summarize discrimination for time‑to‑event models. Analyses were cross‑checked by two investigators to minimize transcription or coding errors. Radiotherapy decisions were made by multidisciplinary tumour boards according to national guidance. No subgroup analyses were performed beyond those prespecified for matching and overlap weighting.\\u003c/p\\u003e\"},{\"header\":\"Declarations\",\"content\":\"\\u003cp\\u003e\\u003cstrong\\u003eEthic statement: \\u003c/strong\\u003eThis study was conducted according to the declaration of Helsinki and followed a protocol approved by the institutional ethics review board of the Ruhr-University Bochum (#16-5985).\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eData Availability Statement: \\u003c/strong\\u003eThe data that support the findings of this study are available from the corresponding author upon reasonable request.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eFunding sources\\u003c/strong\\u003e. None\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eConflict of interest\\u003c/strong\\u003e: T.G. has received speakers and/or advisory board honoraria from BMS, Sanofi-Genzyme, MSD, Novartis Pharma, Roche, UCB, Abbvie, Almirall, Janssen, Lilly, Pfizer, Pierre Fabre, Merck-Serono, outside the submitted work. N.A. received funding, travel support and/or personal honoraria for lectures from Novartis Pharma, JanssenCilag GmbH, Recordati Rare Diseases Germany GmbH, UCB Pharma, Almirall Hermal GmbH, Bristol-Myers Squibb (BMS) and Johnson \\u0026amp; Johnson that were independent of the work submitted. \\u003cstrong\\u003eR.G. has received\\u003c/strong\\u003e honoraria for lectures/advisory boards from BMS, MSD, Novartis, Merck Serono, Almirall Hermal, SUN Pharma, Sanofi/Regeneron, Pierre Fabre, Immunocore, Janssen, Incyte and Delcath and has received research funding from Amgen, Merck Serono, SUN Pharma, Sanofi/Regeneron, Almirall Hermal, Kyowa Kirin, and Recordati as well as congress participation supported by SUN Pharma and Pierre Fabre, all outside of the submitted work. J.C.B is receiving speaker\\u0026rsquo;s bureau honoraria from Amgen, Incyte Merck-Serono and Regeneron is a paid consultant/advisory board member for Merck-Serono, Incyte, 4SC and Regeneron. His group receives research grants from Regeneron, Merck Serono, and Alcedis. L.S. has received speakers and/or advisory board honoraria from UCB, BMS, Sun-Pharma, MSD, and Novartis. The other authors report no conflicts or competing interests. \\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eAcknowledgment:\\u003c/strong\\u003e The data of this study is part of the doctoral thesis of Ekaterina Heinzer.\\u003c/p\\u003e\\n\\u003cp\\u003e*Corresponding author. Prof. Dr. T. Gambichler: thilo.gambichler@klinikumdo.de\\u003c/p\\u003e\"},{\"header\":\"References\",\"content\":\"\\u003col\\u003e\\u003cli\\u003e\\u003cspan\\u003eLugowska I, Becker JC, Ascierto PA, Veness M, Blom A, Lebbe C, Migliano E, Hamming-Vrieze O, Goebeler M, Kneitz H, Nathan P, Rutkowski P, Slowinska M, Schadendorf D, Piulats JM, Petrelli F, van Akkooi ACJ, Berruti A (2024) ESMO Guidelines Committee. Electronic address: clinicalguidelines@esmo.org. Merkel-cell carcinoma: ESMO-EURACAN Clinical Practice Guideline for diagnosis, treatment and follow-up. ESMO Open 9(5):102977\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eLodde GC, Leiter U, Gesierich A, Eigentler T, Hauschild A, Pf\\u0026ouml;hler C, Gambichler T, Herbst R, Meier F, Hassel JC, Mei\\u0026szlig; F, Mohr P, Terheyden P, Nikolakis G, Hecht M, Stang A, Dalkoohi M, Galetzka W, Ugurel S, Becker JC (2025) Clinical course of Merkel cell carcinoma: A DeCOG multicenter study of 1049 patients. Eur J Cancer 221:115406\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eBecker JC, Beer AJ, DeTemple VK, Eigentler T, Flaig M, Gambichler T, Grabbe S, H\\u0026ouml;ller U, Klumpp B, Lang S, Pf\\u0026ouml;hler C, Posch C, Prasad V, Schlattmann P, Schneider-Burrus S, Ter-Nedden J, Terheyden P, Thoms K, Vordermark D, Ugurel S (2023) S2k Guideline \\u0026ndash; Merkel cell carcinoma (MCC, neuroendocrine carcinoma of the skin) \\u0026ndash; Update 2022. J Dtsch Dermatol Ges 21(3):305\\u0026ndash;320\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eShafique N, Ertmann E, Vargas GM, Farooq MS, Gimotty PA, Karakousis GC, Miura JT High rates of sentinel lymph node positivity across all age groups in Merkel cell carcinoma. J Am Acad Dermatol 2025 Apr 20:S0190-9622(25)00665-6.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eAmerican Joint Committee on Cancer (2017) AJCC Cancer Staging Handbook. Merkel Cell Carcinoma. Springer, New York, NY, USA\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eWong SL, Balch CM, Hurley P, Agarwala SS, Akhurst TJ, Cochran A, Cormier JN, Gorman M, Kim TY, McMasters KM, Noyes RD, Schuchter LM, Valsecchi ME, Weaver DL, Lyman GH (2012) American Society of Clinical Oncology; Society of Surgical Oncology. Sentinel lymph node biopsy for melanoma: American Society of Clinical Oncology and Society of Surgical Oncology joint clinical practice guideline. J Clin Oncol 30(23):2912\\u0026ndash;2918\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eSu LD, Lowe L, Bradford CR, Yahanda AI, Johnson TM, Sondak VK (2002) Immunostaining for cytokeratin 20 improves detection of micrometastatic Merkel cell carcinoma in sentinel lymph nodes. J Am Acad Dermatol 46(5):661\\u0026ndash;666\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eKo JS, Prieto VG, Elson PJ, Vilain RE, Pulitzer MP, Scolyer RA, Reynolds JP, Piliang MP, Ernstoff MS, Gastman BR, Billings SD (2016) Histological pattern of Merkel cell carcinoma sentinel lymph node metastasis improves stratification of Stage III patients. Mod Pathol 29(2):122\\u0026ndash;130\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eConic RRZ, Ko J, Saridakis S, Damiani G, Funchain P, Vidimos A, Gastman BR (2019) Sentinel lymph node biopsy in Merkel cell carcinoma: Predictors of sentinel lymph node positivity and association with overall survival. J Am Acad Dermatol 81(2):364\\u0026ndash;372\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eSadeghi R, Adinehpoor Z, Maleki M, Fallahi B, Giovanella L, Treglia G (2014) Prognostic significance of sentinel lymph node mapping in Merkel cell carcinoma: systematic review and meta-analysis of prognostic studies. Biomed Res Int 2014:489536\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eBorgognoni L, Susini P, Gerlini G, Brandani P, Giannotti V, Sestini S (2024) Sentinel Lymph Node Biopsy: Is There a Role in Non-Melanoma Skin Cancer? A Systematic Review. Cancers (Basel) 16(24):4279\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eLewis DJ, Fathy RA, Nugent S, Etzkorn JR, Sobanko JF, Shin TM, Giordano CN, McMurray SL, Walker JL, Zhang J, Miller CJ, Higgins HW 2 (2023) Sentinel lymph node biopsy in Merkel cell carcinoma: Rates and predictors of compliance with the National Comprehensive Cancer Network guidelines. J Am Acad Dermatol 88(2):448\\u0026ndash;450\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eNan Tie E, Kok DL (2022) Merkel cell carcinoma: is sentinel lymph node biopsy crucial? Intern Med J 52(2):330\\u0026ndash;331\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eLambert J, Marrel A, D\\u0026rsquo;Angelo SP, Burgess MA, Chmielowski B, Fazio N, Gambichler T, Grob JJ, Lebb\\u0026eacute; C, Robert C, Russell J, G\\u0026uuml;zel G, Bharmal M (2020) Patient Experiences with Avelumab in Treatment-Na\\u0026iuml;ve Metastatic Merkel Cell Carcinoma: Longitudinal Qualitative Interview Findings from JAVELIN Merkel 200, a Registrational Clinical Trial. Patient 13(4):457\\u0026ndash;467\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eStraker RJ 3rd, Sharon CE, Fraker DL, Karakousis GC, Miura JT (2022) Contemporary Analysis of Sentinel Lymph Node Biopsy Performance Among Patients with Clinically Localized Merkel Cell Carcinoma. Ann Surg Oncol 29(12):7261\\u0026ndash;7264\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eScampa M, Kalbermatten DF, Oranges CM (2023) Demographic and Clinicopathological Factors as Predictors of Lymph Node Metastasis in Merkel Cell Carcinoma: A Population-Based Analysis. J Clin Med 12(5):1813\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eVordermark D, H\\u0026ouml;ller U (2023) The role of radiotherapy in the updated German S2k guideline for management of Merkel cell carcinoma. Strahlenther Onkol 199(5):433\\u0026ndash;435\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eAlexander NA, Schaub SK, Goff PH, Hippe DS, Park SY, Lachance K, Bierma M, Liao JJ, Apisarnthanarax S, Bhatia S, Tseng YD, Nghiem PT, Parvathaneni U (2024) Increased risk of recurrence and disease-specific death following delayed postoperative radiation for Merkel cell carcinoma. J Am Acad Dermatol 90(2):261\\u0026ndash;268\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003ePalencia R, Sandhu A, Webb S, Blaikie T, Bharmal M (2021) Systematic literature review of current treatments for stage I-III Merkel cell carcinoma. Future Oncol. ;17(34):4813\\u0026ndash;4822. Tam K, St\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eJohn MA (2022) Is Radiation, Sentinel Lymph Node Biopsy, or Neck Dissection Beneficial for the Node Negative Neck in Merkel Cell Carcinoma? Laryngoscope 132(6):1142\\u0026ndash;1143\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003ePerez MC, Oliver DE, Weitman ES, Boulware D, Messina JL, Torres-Roca J, Cruse CW, Gonzalez RJ, Sarnaik AA, Sondak VK, Wuthrick EJ, Harrison LB, Zager JS (2019) Management of Sentinel Lymph Node Metastasis in Merkel Cell Carcinoma: Completion Lymphadenectomy, Radiation, or Both? Ann Surg Oncol 26(2):379\\u0026ndash;385\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eKanakopoulos D, Lacey H, Payne A, Houlihan M, Riyat H, Wheelan R, Cubitt J, Totty JP (2024) The Role of Sentinel Lymph Node Biopsy in the Management of Merkel Cell Carcinoma: A Systematic Review and Meta-analysis. Plast Reconstr Surg Glob Open 12(4):e5760\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eDelisle ME, Dingley B, Apte S et al (2022) Sentinel lymph node biopsy in Merkel cell carcinoma: a multi-institutional study from the Pan-Canadian Merkel Cell Collaborative. J Clini Oncol 40(16 Supplement 1):9583\\u0026ndash;9583\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eHarounian JA, Molin N, Galloway TJ, Ridge D, Bauman J, Farma J, Reddy S, Lango MN (2021) Effect of Sentinel Lymph Node Biopsy and LVI on Merkel Cell Carcinoma Prognosis and Treatment. Laryngoscope 131(3):E828\\u0026ndash;E835\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eSattler E, Geimer T, Sick I, Flaig MJ, Ruzicka T, Berking C, Kunte C (2013) Sentinel lymph node in Merkel cell carcinoma: to biopsy or not to biopsy? J Dermatol 40(5):374\\u0026ndash;379\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eSong Y, Azari FS, Tang R, Shannon AB, Miura JT, Fraker DL, Karakousis GC (2021) Patterns of Metastasis in Merkel Cell Carcinoma. Ann Surg Oncol 28(1):519\\u0026ndash;529\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eSmith FO, Yue B, Marzban SS, Walls BL, Carr M, Jackson RS, Puleo CA, Padhya T, Cruse CW, Gonzalez RJ, Sarnaik AA, Schell MJ, DeConti RC, Messina JL, Sondak VK, Zager JS (2015) Both tumor depth and diameter are predictive of sentinel lymph node status and survival in Merkel cell carcinoma. 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Ann Surg Oncol 30(7):4345\\u0026ndash;4355\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eJacobs D, Olino K, Park HS, Clune J, Cheraghlou S, Girardi M, Burtness B, Kluger H, Judson BL (2021) Primary Treatment Selection for Clinically Node-Negative Merkel Cell Carcinoma of the Head and Neck. Otolaryngol Head Neck Surg 164(6):1214\\u0026ndash;1221\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eErstine EM, Tetzlaff MT, Jia X, Aung PP, Prieto VG, Funchain P, Gastman BR, Billings SD, Ko JS (2019) Prognostic Significance of Nonsolid Microscopic Metastasis in Merkel Cell Carcinoma Sentinel Lymph Nodes. Am J Surg Pathol 43(7):907\\u0026ndash;919\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eJenkins LN, Howle JR, Veness MJ (2019) Sentinel lymph node biopsy in clinically node-negative Merkel cell carcinoma: the Westmead Hospital experience. ANZ J Surg 89(5):520\\u0026ndash;523\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eOkła B, Moser T, Scheftel J et al (2020) Tissue-resident memory T cells in tumor immunity and immunotherapy. J Exp Med 217(2):e20191826\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eFulop T, Larbi A, Pawelec G et al (2014) Immunosenescence and cancer. Curr Opin Immunol 29:105\\u0026ndash;111\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eButala J, Markovic SN, Mesko T et al (2021) Impact of tumor-infiltrating lymphocytes and Merkel cell polyomavirus status on prognosis in Merkel cell carcinoma. Clin Cancer Res 27(14):3515\\u0026ndash;3523\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eHarms KL, Iyer JG, Schrama D et al (2021) Virus-positive Merkel cell carcinoma is an independent prognostic factor. Clin Cancer Res 27(9):2494\\u0026ndash;2504\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eFransen MF, Schoonderwoerd MJ, Knopf P et al (2018) Surgical disruption of lymphatic pathways modulates PD-1/PD-L1 expression and T-cell trafficking in the tumor microenvironment. Cancer Immunol Res 6(11):1281\\u0026ndash;1292\\u003c/span\\u003e\\u003c/li\\u003e\\u003c/ol\\u003e\"},{\"header\":\"Tables\",\"content\":\"\\u003cp\\u003eTables are available in the Supplementary Files section.\\u003c/p\\u003e\\n\"}],\"fulltextSource\":\"\",\"fullText\":\"\",\"funders\":[],\"hasAdminPriorityOnWorkflow\":false,\"hasManuscriptDocX\":true,\"hasOptedInToPreprint\":true,\"hasPassedJournalQc\":\"\",\"hasAnyPriority\":false,\"hideJournal\":false,\"highlight\":\"\",\"institution\":\"\",\"isAcceptedByJournal\":true,\"isAuthorSuppliedPdf\":false,\"isDeskRejected\":\"\",\"isHiddenFromSearch\":false,\"isInQc\":false,\"isInWorkflow\":false,\"isPdf\":false,\"isPdfUpToDate\":true,\"isWithdrawnOrRetracted\":false,\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"journal-of-cancer-research-and-clinical-oncology\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":false,\"externalIdentity\":\"jocr\",\"sideBox\":\"Learn more about [Journal of Cancer Research and Clinical Oncology](https://www.springer.com/journal/432)\",\"snPcode\":\"432\",\"submissionUrl\":\"https://submission.nature.com/new-submission/432/3\",\"title\":\"Journal of Cancer Research and Clinical Oncology\",\"twitterHandle\":\"\",\"acdcEnabled\":true,\"dfaEnabled\":true,\"editorialSystem\":\"em\",\"reportingPortfolio\":\"Springer Hybrid\",\"inReviewEnabled\":true,\"inReviewRevisionsEnabled\":false},\"keywords\":\"\",\"lastPublishedDoi\":\"10.21203/rs.3.rs-8669831/v1\",\"lastPublishedDoiUrl\":\"https://doi.org/10.21203/rs.3.rs-8669831/v1\",\"license\":{\"name\":\"CC BY 4.0\",\"url\":\"https://creativecommons.org/licenses/by/4.0/\"},\"manuscriptAbstract\":\"\\u003ch2\\u003ePurpose\\u003c/h2\\u003e \\u003cp\\u003eOverall survival (OS) of Merkel cell carcinoma (MCC) patient is strongly influenced by health. Sentinel lymph node biopsy (SLNB) is recommended for staging. We evaluated whether SLNB is associated with OS in clinically node-negative MCC and contrasted tumor factors with patient frailty.\\u003c/p\\u003e\\u003ch2\\u003eMethods\\u003c/h2\\u003e \\u003cp\\u003eSTROBE-compliant cohort across eight centers in Germany (2004\\u0026ndash;2024). We included 271 primary stage I\\u0026ndash;II MCC; 167 underwent SLNB and 104 did not. The primary outcome was OS; disease-specific survival (DSS) and progression-free probability (PFP) were secondary. Kaplan\\u0026ndash;Meier and Cox models were used. Confounding by indication was addressed with 1:1 propensity score matching and sensitivity analyses.\\u003c/p\\u003e\\u003ch2\\u003eResults\\u003c/h2\\u003e \\u003cp\\u003ePatients receiving SLNB were younger (median 74 vs 82 years; p\\u0026lt;.001) and less comorbid (Charlson 4 vs 5). Ten-year OS was 69.5% with SLNB versus 45.2% without (log-rank p\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.0001); unadjusted HR 0.34 (95% CI 0.20\\u0026ndash;0.59). In the matched cohort, SLNB remained associated with lower all-cause mortality (HR 0.56, 95% CI 0.34\\u0026ndash;0.93; p\\u0026thinsp;=\\u0026thinsp;0.024). DSS did not differ (HR 1.09, 95% CI 0.55\\u0026ndash;2.13; p\\u0026thinsp;=\\u0026thinsp;0.81). For PFP, unadjusted curves favored SLNB (p\\u0026thinsp;=\\u0026thinsp;0.0045), but the matched analysis was not significant (HR 0.53, 95% CI 0.23\\u0026ndash;1.26). Sensitivity analyses suggested benefit: overlap weighting HR 0.49 (95% CI 0.33\\u0026ndash;0.73; p\\u0026thinsp;=\\u0026thinsp;0.00045) and a stage-restricted match HR 0.36 (95% CI 0.13\\u0026ndash;0.99; p\\u0026thinsp;=\\u0026thinsp;0.048).\\u003c/p\\u003e\\u003ch2\\u003eConclusions\\u003c/h2\\u003e \\u003cp\\u003eSLNB was associated with improved OS after adjustment, supporting its role in staging and risk stratification. The absence of DSS and matched PFP differences highlights the influence of overall health; residual confounding by indication cannot be excluded.\\u003c/p\\u003e\",\"manuscriptTitle\":\"General Health Versus Tumor Stage: Determinants of Survival in Merkel Cell Carcinoma Assessed by Sentinel Lymph Node Biopsy\",\"msid\":\"\",\"msnumber\":\"\",\"nonDraftVersions\":[{\"code\":1,\"date\":\"2026-03-28 16:29:08\",\"doi\":\"10.21203/rs.3.rs-8669831/v1\",\"editorialEvents\":[{\"type\":\"communityComments\",\"content\":0},{\"type\":\"decision\",\"content\":\"Revision requested\",\"date\":\"2026-04-06T18:46:12+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"editorInvitedReview\",\"content\":\"\",\"date\":\"2026-04-06T17:43:51+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"reviewerAgreed\",\"content\":\"310610327059474819414679520346965129159\",\"date\":\"2026-03-25T19:25:27+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"reviewersInvited\",\"content\":\"\",\"date\":\"2026-03-25T13:01:31+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"editorAssigned\",\"content\":\"\",\"date\":\"2026-03-24T12:19:31+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"checksComplete\",\"content\":\"\",\"date\":\"2026-03-24T08:45:06+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"submitted\",\"content\":\"Journal of Cancer Research and Clinical Oncology\",\"date\":\"2026-03-18T10:07:06+00:00\",\"index\":\"\",\"fulltext\":\"\"}],\"status\":\"published\",\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"journal-of-cancer-research-and-clinical-oncology\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":false,\"externalIdentity\":\"jocr\",\"sideBox\":\"Learn more about [Journal of Cancer Research and Clinical Oncology](https://www.springer.com/journal/432)\",\"snPcode\":\"432\",\"submissionUrl\":\"https://submission.nature.com/new-submission/432/3\",\"title\":\"Journal of Cancer Research and Clinical Oncology\",\"twitterHandle\":\"\",\"acdcEnabled\":true,\"dfaEnabled\":true,\"editorialSystem\":\"em\",\"reportingPortfolio\":\"Springer Hybrid\",\"inReviewEnabled\":true,\"inReviewRevisionsEnabled\":false}}],\"origin\":\"\",\"ownerIdentity\":\"42a5362c-7c40-4933-b65c-72f83a8911cb\",\"owner\":[],\"postedDate\":\"March 28th, 2026\",\"published\":true,\"recentEditorialEvents\":[],\"rejectedJournal\":[],\"revision\":\"\",\"amendment\":\"\",\"status\":\"published-in-journal\",\"subjectAreas\":[],\"tags\":[],\"updatedAt\":\"2026-05-04T16:11:39+00:00\",\"versionOfRecord\":{\"articleIdentity\":\"rs-8669831\",\"link\":\"https://doi.org/10.1007/s00432-026-06485-x\",\"journal\":{\"identity\":\"journal-of-cancer-research-and-clinical-oncology\",\"isVorOnly\":false,\"title\":\"Journal of Cancer Research and Clinical Oncology\"},\"publishedOn\":\"2026-04-28 15:58:02\",\"publishedOnDateReadable\":\"April 28th, 2026\"},\"versionCreatedAt\":\"2026-03-28 16:29:08\",\"video\":\"\",\"vorDoi\":\"10.1007/s00432-026-06485-x\",\"vorDoiUrl\":\"https://doi.org/10.1007/s00432-026-06485-x\",\"workflowStages\":[]},\"version\":\"v1\",\"identity\":\"rs-8669831\",\"journalConfig\":\"researchsquare\"},\"__N_SSP\":true},\"page\":\"/article/[identity]/[[...version]]\",\"query\":{\"redirect\":\"/article/rs-8669831\",\"identity\":\"rs-8669831\",\"version\":[\"v1\"]},\"buildId\":\"XKTyCvWXoU3ODBz1xrDgd\",\"isFallback\":false,\"isExperimentalCompile\":false,\"dynamicIds\":[84888],\"gssp\":true,\"scriptLoader\":[]}","source_license":"CC-BY-4.0","license_restricted":false}