Sentinel lymph node status and oncological outcomes of high-risk and low-risk cutaneous primary melanoma

Sentinel lymph node status and oncological outcomes of high-risk and low-risk cutaneous primary melanoma | 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 Sentinel lymph node status and oncological outcomes of high-risk and low-risk cutaneous primary melanoma Hesham S Mohamed, Micheal G Fadel, Michelle J Wilkinson, Olympia Hadjicosta, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8321644/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 13 Mar, 2026 Read the published version in World Journal of Surgical Oncology → Version 1 posted 12 You are reading this latest preprint version Abstract Introduction: Sentinel lymph node (SLN) status remains a key prognostic factor in melanoma. However, recent advances in immunotherapy have prompted debate over the necessity of Sentinel lymph node biopsy (SLNB). This study evaluates the impact of SLN on disease-free survival (DFS), recurrence, and staging in melanoma patients. Methods: A retrospective analysis was conducted on 300 patients with histologically confirmed cutaneous melanoma who underwent SLN biopsy between April 2018 and April 2023. Patients were classified as low-risk (T1–T3a) or high-risk (T3b–T4b). Clinical, pathological, and outcome data were analysed. Variables were compared using Mann-Whitney U test and Fisher’s exact test where appropriate. DFS and recurrence were evaluated relative to SLN status using Kaplan-Meier and log-rank test. Results: Median age was 60.7 years; 51.3% were female. SLN positivity was observed in 22% overall, significantly higher in high-risk patients (31.5% vs. 18.0%, P = 0.009). Recurrence occurred in 16%, more frequently in high-risk patients (31.5% vs. 9.5%). Median DFS was 1389 days; lower in high-risk patients (1141 vs. 1481 days, P < 0.001). SLN positivity correlated with reduced DFS (1168 vs. 1481 days, P = 0.056). Breslow thickness and mitotic index predicted recurrence. SLNB led to major reclassification of clinical stage, identifying Stage IIIC disease in 31.46%. of cases presumed Stage IIB/C. Conclusion: SLNB provides essential prognostic and staging information. Its omission risks misclassification and mismanagement, impacting survival predictions and treatment decisions. SLNB should remain a cornerstone of staging especially in high-risk melanoma, even in the evolving context of immunotherapy. Melanoma lymph node SLNB immunotherapy Surgery oncology Figures Figure 1 Figure 2 Figure 3 Introduction Melanoma is the most lethal form of skin cancer and its incidence is rapidly rising ( 1 ),( 2 ). The most important prognostic factors are Breslow thickness, ulceration, and sentinel lymph node (SLN) status ( 3 ),( 4 ),( 5 ). Sentinel lymph node biopsy (SLNB) allows for the detection of clinically and radiologically occult metastatic disease and has become standard of practice for staging lymph node basins in melanoma ( 6 ),( 7 ). Several predictive factors have been reported for SLNB positivity such as age, sex, primary tumour site, Breslow thickness, ulceration, mitotic index and lymphovascular invasion ( 8 ),( 9 ). The first Multicentre Selective Lymphadenectomy Trial (MSLT-I) compared the outcome of SLNB with nodal observation. This phase III clinical trial showed that SLN status was the most important prognostic factor and that patients who underwent SLNB had fewer nodal recurrences of melanoma than patients who underwent wide excision and nodal observation ( 10 – 12 ). However, SLNB is not without controversy regarding its therapeutic benefit and clinical utility in the setting of novel neoadjuvant-adjuvant strategies for early stage melanoma disease ( 13 ),( 14 ). In order to improve the estimation of the risk of regional nodal involvement and to improve decision-making on whether SLNB is required, several SLNB predictive tools have been developed. For example, the Melanoma Institute of Australia ( 15 ) Sentinel Node Metastasis Prediction Tool [ https://www.melanomarisk.org.au/SNLLand ] was established to estimate the risk of a positive SLNB using patient age and tumour characteristics, such as primary melanoma Breslow depth, histologic subtype, ulceration, mitotic rate, and lymphovascular invasion ( 16 ). Since the advent of the KEYNOTE-716 trial, and the CheckMate 76K there has been further debate with regard to the role of SLNB, the sequence of staging imaging and adjuvant immunotherapy, with some providers questioning the need for SLNB in certain cases ( 13 , 17 ). The recent UK National Institute for Health and Care Excellence (NICE) guidance recommend SLNB be performed followed by imaging staging in those with a positive SLNB, which would be consistent with entry criteria to these trials, and allow accurate staging, optimal locoregional control and afford the most accurate prediction of outcomes for patients having adjuvant therapy for proven high-risk stage II melanoma. There are significant risks of under-staging and overtreating patients in this group, with the potential for poor local control in undertreated nodal basins and increased nodal dissections. There is also the possibility of the underestimation of prognosis in patients with IIC melanoma, along with the long-term side-effects from adjuvant therapy in patients who could have avoided treatment. In this study, low-risk melanoma has been defined as T1, T2 and T3a, and high-risk melanoma has been defined here as T3b, T4a and T4b, congruent with patients who may be staged as Stage IIB-IIC post negative sentinel node biopsy, as per the KEYNOTE-716 trial. The aim of this study is to evaluate the ultimate SLN status, MIA score, and clinical stage as well as recurrence and disease-free survival (DFS) in a cohort of patients with potential “high-risk melanoma” at a reference melanoma centre. We also examined the impact of SLN status on DFS, and the impact of Breslow thickness and mitotic index on SLN status and recurrence. We aimed to define the clinical stage in our cohort of patients with potential high-risk melanoma, the nodal metastatic burden in these patients, prognosis, and consider the potential loss of prognostic information and local control if SLNB was omitted from their treatment. Methods Study design and participants All patients with histologically proven cutaneous melanoma undergoing SLNB at The Royal Marsden Hospital, London, were included in the study and retrospectively analysed including melanoma of the extremity, trunk, and the head and neck. Three hundred consecutive patients fitting the criteria were identified between April 2018 and April 2023. We divided patients into two groups based on AJCC 8th edition (according to Breslow thickness and ulceration): Group A - low-risk melanoma (T1, T2 and T3a), n = 211 and Group B - high-risk melanoma (T3b, T4a and T4b), n = 89. All patients had an injection of Tc-99 and single photon emission computed tomography/computed tomography (SPECT-CT) imaging preoperatively and either ICG or blue dye for SLN localisation intraoperatively. Data including age, gender, American Society of Anesthesiologists (ASA) physical status classification system, Breslow thickness (mm), mitotic index/mm 2 , ulceration, presence of satellite lesions, tumour type and anatomical location was recorded. Intraoperative results included SLN localisation and number of SLNs harvested. Lymph node positivity was recorded as well as mutation analysis where available: nodes were considered positive if there were any tumour cells within the node identified by histopathology assessment. Oncological outcomes were collected with length of follow-up calculated from the date of surgery to the date of last follow-up or death. The MIA score was calculated using Sentinel Node Metastasis Risk Prediction Tool for individual patients in the high-risk melanoma group. Statistical analysis SLN detection parameters and oncological outcomes were compared between Group A and B with a median follow-up of two years. Data was processed using JASP software for descriptive and inferential statistics. The mean, median, standard deviation and range were calculated where applicable. Baseline characteristics and outcome variables were compared using Mann-Whitney U test for continuous variables, and Fisher’s exact test for categorical variables where appropriate (p values of ≤ 0.05 were considered statistically significant). Survival probability analysis was done using Kaplan-Meier curve and log-rank tests. Disease progression was defined as any recurrence or metastasis recorded from the date of surgery till the end of the follow-up. MIA prediction risks were compared to actual SLNB positivity using Hosmer–Lemeshow test and Brier score. This retrospective study was conducted using the Strengthening the Report of Observational Studies in Epidemiology ( 18 ) guidelines ( 19 ). Results Patient and melanoma characteristics The median age was 60.7 (10 - 91) years and 154 (51.3%) were female (Table 1). Two hundred and thirteen (71.0%) patients were ASA II or above. The most common subtypes of melanoma were superficial spreading (47.2%) and nodular (26.3%). The mean Breslow thickness was 2.6 mm (0.5 – 25 mm). Ninety patients (30.0%) had ulceration and 179 (59.7%) patients had mitosis ≥ 1 mm 2 with a mean value of 3.4 mm 2 across the cohort. One hundred and fifty-two patients (50.7%) had available mutation analysis with BRAF being positive in 59 (38.8%) of these patients. Patients with initial low-risk melanoma (Group A) n = 211 (T1=56, T2=116 and T3a=39). Patients with high-risk melanoma (Group B) were 89 with T3b = 36 (40.4%), T4a = 22 (24.7%) and T4b = 31 (34.8%). In total, 66 patients (22.0%) had positive SLNs and recurrence was recorded in 48 (16.0% of total cohort) patients. Adjuvant treatment was given in 78 (26.0%) patients (immunotherapy 54 (69.2%), small molecule markers/tyrosine kinase inhibitor 15 (19.2%), both in combination 6 (7.7%). Breslow thickness was statistically significant in both positivity of SLNB and recurrence with P value of 0.004 and 0.001 respectively. Mitotic index was found to be statistically significant in recurrence, however, not in SLNB positivity, P value = 0.001 and 0.127 respectively. Follow-up duration had a mean of 524 days (range, 7 - 2491 days). DFS was calculated across the sample and had a median of 1389 days (lower 1244, standard error (SE) 131.5, CI 95%) (Figure 1). Sentinel lymph node positivity was found to influence median DFS with SLNB negative median of 1481 days (lower 1389, SE 139, CI 95%) and SLNB positive median of 1168 days (lower 1064, SE 67, CI 95%), However it was not statistically significant with P value = 0.056. Oncological outcomes of high-risk versus low-risk melanoma Compared with patients in Group A, those in Group B were older (67 vs 61 years, p = 0.003) and had a higher mitotic rate (5 vs 1/mm², p < 0.001). Group B had more frequent ulceration of the primary tumour (75.3% vs 10.9%, p < 0.001), a higher rate of SLNB positivity (31.5% vs 18.0%, p = 0.009) and were more likely to receive adjuvant treatment (49.4% vs 16.1%, p < 0.001). At the end of follow up 171 patients were alive without recurrence in Group A (81%) with only 58 in group B (65%). Recurrence was recorded in 9.5% (20/211) in Group A with 31.5% (28/89) in Group B. Recurrence pattern were similar in both groups with nodal and distant metastasis constituting most of the recurrence, 2.3% and 4.3% in Group A, 10.1% and 16.8% in Group B, respectively. Median DFS for Group A and B were 1481 days (lower 1389, SE 138, CI 95%) and 1141 days (lower 980, SE 68, CI 95%), respectively (Figure 2). DFS was found to be statistically significant between the two groups (P value < 0.001). The mean predicted probability of SLN metastasis by the MIA score was 28.3%, compared with an observed positivity rate of 21.0%. Model discrimination was limited, with an AUC of 0.58 (95% CI, 0.41–0.75). Calibration analysis demonstrated systematic overestimation of risk across deciles, with most observed rates falling below the predicted values. The Hosmer–Lemeshow test was not statistically significant (χ²[8] = 13.49; p = 0.096), and the Brier score was 0.171, marginally higher than the baseline prevalence model (0.165). Fifty eight patients (65.2%) were alive without disease by the end of the follow-up period mean 630 days (15 - 1639). Clinical stage and prognostic value Clinical stage was recorded for the high-risk melanoma group (Table 2). Following SLNB, 37 patients (41.57%) were stage IIB, 24 patients (26.96%) were stage IIC, and 28 patients (31.46%) were stage IIIC. This translates into a 5-year survival rate of 87% for Stage IIB, 82% for Stage IIC and 69% for stage IIIC (20, 21) . Assuming clinical and radiological negative lymph node and omitting SLNB results, T3b (36) and T4a (22) patients will be staged as IIB (58 patient), which reflects a 56.76% increase than real-world data. T4b (31) will be staged as IIC which represent a 29.17% increase. These increases will be on the expense of zero patient staged as IIIC (Figure 3). Individual outcome of high-risk melanoma according to T stage T3b patients (n = 36) The mean MIA score was 24% (6 - 58), with positive SLNBs recorded in 13 cases (36.1%) (Table 3), Fourteen patients (38.8%) had adjuvant treatment (11 with positive SLNBs and 3 with negative SLNB). Adjuvant treatment given was mostly immunotherapy 78.5% (11 patients) with 2 patients receiving small molecule markers/TK inhibitors and 1 patient receiving both. Recurrence was observed in 10 patients (27.8%). Patients who received adjuvant therapy had a recurrence rate of 66% mainly in lymph nodes (n = 4) and in-transit (n = 4). Twenty-four patients were alive without disease (66.7%), with 12 patients had recorded recurrence two of which have died. T4a patients (n = 22) The mean MIA score was 27.1% (1-51), with positive SLNBs recorded in 8 cases (36%). Adjuvant treatment was given to 17 patients (77.2%) (8 had positive SLNBs and 9 had negative SLNBs). Adjuvant treatment given was predominantly immunotherapy 76.5% (13 patients) with 3 patients receiving small molecule markers/TK inhibitors and 1 patient receiving both. Recurrence was observed in six patients (27.2%), mainly distant recurrence (n = 5, 83.3% of recurrences). Ten patients were alive without disease (45.5%), and one patient (4.5%) with recurrence died. T4b patients (n = 31) Mean MIA score was 35.4% (18 - 71) with seven cases (22.5%) having positive SLNBs. Adjuvant treatment was given to 13 patients (41.9%) (five had positive SLNBs and 6 had negative SLNBs Adjuvant treatment given was mainly immunotherapy 69.2% (9 patients) with 2 patients receiving small molecule markers/TK inhibitors and 2 patients receiving both. Eighteen patients (58.1%) had no treatment. Recurrence was seen in 12 patients (38.7%), including distant and nodal recurrence (5 (41.7%) and 6 (50.0%), respectively). Nineteen patients were alive without disease (61%) and two patients (6.5%) died, both of which had recurrence. Discussion This retrospective study assessed DFS according to SLN status in patients with melanoma, and compared oncological outcomes in patients with low-risk compared to high-risk melanoma. Patients with SLN positivity had a reduced DFS than patients with a negative SLN status across our cohort, which is similar to other published findings. Holmberg et al. ( 22 ) presented a study where data was retrieved from a Swedish Melanoma Registry for patients with a diagnosis of primary invasive cutaneous melanoma. A total of 1,943 patients had a Breslow thickness greater than 4 mm (pT4). A positive SLN was found in 34% of cases, with a 5-year MSS of 71%. A statistical significant difference was found in MSS between patients with a positive SLN and those with a negative SLN for patients with stage T4a and T4b. This study verified that the outcome of SLNB continues to hold prognostic value for patients with thick (> 4 mm, stage pT4) melanoma. Their analysis also showed that age, Breslow thickness and ulceration status were significant independent predictors of MSS. High-risk melanoma was associated with higher rates of recurrence and a lower DFS compared to patients deemed to have low-risk melanoma. Rates of adjuvant treatment were also higher in patients with high-risk melanoma as expected. In our study, a significant number of patients had stage IIC and IIIC following SLNB, and that prognostic information would have been lost without lymph node staging. the MIA sentinel node risk prediction tool showed modest discrimination and evidence of miscalibration, tending to overestimate the true probability of nodal involvement. While the Hosmer–Lemeshow statistic did not indicate significant misfit, the calibration slope and Brier score suggest that predictions were less accurate than a simple prevalence-based estimate. These findings highlight the possibility of over-staging patients depending on prediction. Our findings also highlighted that DFS is reduced from T1 to T4b tumours, and it was evident that ulceration status and mitotic index are important histopathological features and is associated with higher rates of recurrence, which is consistent with other studies. Our findings also highlighted that DFS is reduced from T1 to T4b tumours, and it was evident that ulceration status and mitotic index are important histopathological features and is associated with higher rates of recurrence, which is consistent with other studies ( 23 ), ( 24 ),( 19 ). Gyorki et al. ( 25 ) carried out a study of 217 patients with primary T4 (> 4 mm) melanoma who had SLN performed. The median Breslow thickness was 6 mm, and there was a SLN positivity rate of 36% in this cohort of patients. Multivariable analysis revealed that SLN status was the most significant prognostic factor for overall survival, followed by primary tumour ulceration status. They reported a 5-year MSS of 57% in the cohort of patients with a Breslow thickness greater than 4 mm and SLN positivity. In addition, Han et al. ( 26 ) presented an analysis of 1,235 patients with pT4 melanomas from The Sentinel Lymph Node Working Group database, with a SLN positivity rate of 36% and 5-year MSS of 66%. The authors found that the single strongest prognostic factor for MSS was SLN status in all thickness groups, followed by tumour thickness, male gender, microsatellites and lymphovascular invasion. The NADINA trial recently reported its results for resectable, macroscopic, nodal stage III melanoma patients. It showed an increase in 12 months event-free survival (EFS) for the neoadjuvant arm -before therapeutic lymph node dissection plus adjuvant treatment, if there is no complete pathological response- compared to the adjuvant arm (EFS 83.7% vs 57.2%; P value < 0.0001). However, This was coupled with increased adverse events in the neoadjuvant arm 29.7% vs 14.7% for the adjuvant arm ( 27 ). Recently, a prediction model and nomogram has been developed, using a cohort of 4,071 patients, to potentially predict patient-specific risk probabilities for 5-year recurrence-free survival (RFS) and MSS( 28 ). The tool was based on sex, age, presence of ulceration, primary tumour location, histological subtype, Breslow thickness, sentinel node status, number of sentinel nodes removed, maximum diameter of the largest sentinel node metastasis, and Dewar classification. This tool may subsequently have significant implications for clinical decision-making when considering adjuvant treatments in patients with high-risk melanomas. The eighth edition AJCC published MSS probabilities for stages I, II and III on the basis of a multicentre database from 10 international centres with over 46,000 cases. The 5-year OS rate was calculated for stages IIB and IIC and reported as 87% and 82%, respectively. For stages III and IV, the 5-year OS rates were reported as 32%-93% and 34%-52%, respectively. Evaluation of three independent stage III melanoma cohorts revealed significantly less favourable survival rates than that presented in the eight edition ( 29 ) publication ( 29 ), and similar results were demonstrated for a stage III melanoma patient cohort from Germany and Sweden ( 20 , 30 ). It is clear that there is a difference in survival for patients with non-SLN metastases versus those with disease confined to the SLNs, and survival decreases as the number positive lymph nodes increases ( 31 – 34 ). There remains a substantial difference in prognosis between IIIA and IIIB–C patients, and therefore, accurate staging is therefore essential to determine which patients are at higher risk and would directly benefit from adjuvant therapy. Dedeilia et al. ( 35 ) performed a single-centre retrospective study analysing 92 patients with stage IIB or IIC melanoma. A Breslow thickness greater than 4 mm, a higher mitotic rate and an advanced T stage were found to have a negative impact on RFS. In our series, omitting a SNB would have understaged patients, depriving them and the treating team of useful prognostic information, with a potential difference in overall survival likely to be relevant to both parties. The KEYNOTE-716 study, a randomised, double-blind, phase 3 trial, showed a significantly longer RFS for patients with stage IIB/C melanoma receiving adjuvant PD-1 inhibition than for those receiving a placebo (hazards ratio 0.65; 95% CI 0.46–0.92), However this was only limited to patients with negative SLNB as an eligibility requirement ( 36 ). Accurate staging of high-risk melanoma patients with SLNB will provide a complete picture of patient prognosis and survival risks and can guide such decision making for treatment, for example, defining patients more likely to develop systemic disease without locoregional recurrence, with implications for adjuvant therapy and surveillance. Moreover, the more congruent the management approach is with the paradigm described, the better able to generalise and advise our patients on subsequent prognosis. It is important to consider what would occur in the high proportion of our patients with microscopic disease in their lymph node, if they had been treated with single agent “adjuvant” immunotherapy as per KEYNOTE-716 without sentinel node biopsy. We would reasonably expect a response and elimination of the metastatic melanoma in a significant proportion of patients, but even in the best case estimated of a 50% elimination of disease, 1:6 of our patients may have progressed, likely requiring a nodal disease, with attendant increased morbidity that could have been avoided by performing a sentinel node biopsy. Study limitations There are important limitations with this study that must be addressed. This was a single-institution, retrospective study with a relatively short follow-up period of two years. There were three patients with satellite lesions in our cohort in the high-risk melanoma group, this was not accounted for in the result analysis. There was a lack of information regarding the mutation analysis along with the methods of recurrence detection. In addition, the lack of randomisation would have ultimately introduced some confounding factors which were not accounted for during the analysis. Patients were also managed with different treatment regimens rendering it difficult to make robust comparisons between the low-risk and high-risk melanoma groups. Conclusions Our retrospective study assessed the SLN status, recurrence and DFS in patients with low and high-risk melanoma. The high-risk melanoma group was associated with higher SLN positivity and recurrence rates, and with lower DFS. We also found differences between the mean MIA score and the actual SNB positivity in this study. Sentinel node biopsy remains a useful tool in the assessment and staging of patients with clinical high-risk primary melanoma. Accurate predictions of outcomes for an individual patient is necessary for individualisation of melanoma care. Declarations Ethics statement : All patient information, data collection and analysis were performed in compliance with the Royal Marsden Hospital research ethics committee guidelines. Availability of data statement: The data that support the findings of this study are available from the Royal Marsden hospital, but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are however available from the authors upon reasonable request and with permission of the Royal Marsden hospital. Consent for publication: Not applicable Funding This research didn’t receive funding Competing interests The authors declare that they have no competing interests Credit author statement H S M : study concepts, study design, data acquisition, quality control of data, data analysis and interpretation, statistical analysis, manuscript preparation, manuscript editing. M G F: study concepts, study design, data acquisition, quality control of data, data analysis and interpretation, statistical analysis, manuscript preparation, manuscript editing. 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Brown RE, Ross MI, Edwards MJ, Noyes RD, Reintgen DS, Hagendoorn LJ, et al. The prognostic significance of nonsentinel lymph node metastasis in melanoma. Ann Surg Oncol. 2010;17(12):3330–5. Jakub JW, Huebner M, Shivers S, Nobo C, Puleo C, Harmsen WS, et al. The number of lymph nodes involved with metastatic disease does not affect outcome in melanoma patients as long as all disease is confined to the sentinel lymph node. Ann Surg Oncol. 2009;16(8):2245–51. Dedeilia A, Lwin T, Li S, Tarantino G, Tunsiricharoengul S, Lawless A, et al. Factors Affecting Recurrence and Survival for Patients with High-Risk Stage II Melanoma. Ann Surg Oncol. 2024;31(4):2713–26. Luke JJ, Rutkowski P, Queirolo P, Del Vecchio M, Mackiewicz J, Chiarion-Sileni V, et al. Pembrolizumab versus placebo as adjuvant therapy in completely resected stage IIB or IIC melanoma (KEYNOTE-716): a randomised, double-blind, phase 3 trial. Lancet. 2022;399(10336):1718–29. Tables Table 1. Baseline characteristics of low-risk melanoma (Group A: T1, T2 and T3a) and high-risk melanoma (Group B: T3b, T4a and T4b). ASA, American Society of Anesthesiologists; SD, standard deviation; SLNB, sentinel lymph node biopsy. Characteristic Group A (n=211) Group B (n=89) p-value Age Years (median ± SD) 61 ± 14.7 67 ± 16.0 0.003 Gender – Female – Male 108 (51.2%) 103 (48.8%) 38 (42.7%) 51 (57.3%) 0.179 ASA – One – Two – Three – Unknown 57 (27.0%) 136 (64.5%) 13 (6.2%) 5 (2.4%) 24 (27.0%) 49 (55.1%) 15 (16.9%) 1 (1.1%) 0.029 Ulceration – Absent – Present – Unknown 175 (82.9%) 23 (10.9%) 13 (6.2%) 20 (22.5%) 67 (75.3%) 2 (2.2%) <0.001 Mitoses median ± SD 1 ± 3.2 5 ± 5.4 <0.001 SLNB – Negative – Positive – Unknown 170 (80.6%) 38 (18.0%) 3 (1.4%) 59 (66.3%) 28 (31.5%) 2 (2.2%) 0.029 Adjuvant treatment – Administered – Not administered 34 (16.1%) 177 (83.9%) 44 (49.4%) 45 (50.6%) <0.001 Location of melanoma – Head & neck – Trunk – Extremities 26 (12.3%) 72 (34.1%) 113 (53.5%) 18 (20.2%) 34 (38.2%) 37 (41.6%) 0.093 Table 2. Clinical stage prognostic information. Clinical stage refers to staging depending on clinical information without SLNB according to AJCC. Post SLNB stage refers to staging depending on clinical information with SLNB result according to AJCC. SLNB, sen T stage Clinical stage Post SLNB stage Stage n % Stage n % Stage n % T3b 36 40.45% IIB 58 65.17% IIB 37 41.57% T4a 22 24.72% IIC 24 26.97% T4b 31 34.83% IIC 31 34.83% IIIC 28 31.46% Table 3. The sentinel lymph node positivity, mean MIA score, adjuvant treatment, recurrence and disease-free survival percentage of patients in the high-risk melanoma group (T3b, T4a and T4b). MIA, Melanoma Institute Australia; SLNB, sentinel lymph node T3b (n=36) T4a (n=22) T4b (n=31) Mean MIA prediction 24.0% (6%-58%) 27.1% (1%-51%) 35.4% (18%-71%) Actual SLNB positivity 13 (36.1%) 8 (36.4%) 7 (22.5%) Adjuvant treatment 14 (38.8%) 17 (77.2%) 13 (41.9%) Recurrence recorded 10 (27.8%) 6 (27.2%) 12 (38.7%) Alive without disease recurrence 24 (66.7%) 10 (45.5%) 19 (61.3%) Additional Declarations No competing interests reported. Supplementary Files TablesforsubmissionWJSO.docx Cite Share Download PDF Status: Published Journal Publication published 13 Mar, 2026 Read the published version in World Journal of Surgical Oncology → Version 1 posted Editorial decision: Revision requested 30 Dec, 2025 Reviewers agreed at journal 29 Dec, 2025 Reviews received at journal 27 Dec, 2025 Reviewers agreed at journal 25 Dec, 2025 Reviews received at journal 22 Dec, 2025 Reviewers agreed at journal 22 Dec, 2025 Reviews received at journal 21 Dec, 2025 Reviewers agreed at journal 20 Dec, 2025 Reviewers invited by journal 20 Dec, 2025 Editor assigned by journal 13 Dec, 2025 Submission checks completed at journal 11 Dec, 2025 First submitted to journal 09 Dec, 2025 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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The most important prognostic factors are Breslow thickness, ulceration, and sentinel lymph node (SLN) status (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e),(\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e),(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). Sentinel lymph node biopsy (SLNB) allows for the detection of clinically and radiologically occult metastatic disease and has become standard of practice for staging lymph node basins in melanoma (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e),(\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). Several predictive factors have been reported for SLNB positivity such as age, sex, primary tumour site, Breslow thickness, ulceration, mitotic index and lymphovascular invasion (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e),(\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). The first Multicentre Selective Lymphadenectomy Trial (MSLT-I) compared the outcome of SLNB with nodal observation. This phase III clinical trial showed that SLN status was the most important prognostic factor and that patients who underwent SLNB had fewer nodal recurrences of melanoma than patients who underwent wide excision and nodal observation (\u003cspan additionalcitationids=\"CR11\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eHowever, SLNB is not without controversy regarding its therapeutic benefit and clinical utility in the setting of novel neoadjuvant-adjuvant strategies for early stage melanoma disease (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e),(\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). In order to improve the estimation of the risk of regional nodal involvement and to improve decision-making on whether SLNB is required, several SLNB predictive tools have been developed. For example, the Melanoma Institute of Australia (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e) Sentinel Node Metastasis Prediction Tool [\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.melanomarisk.org.au/SNLLand\u003c/span\u003e\u003cspan address=\"https://www.melanomarisk.org.au/SNLLand\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e] was established to estimate the risk of a positive SLNB using patient age and tumour characteristics, such as primary melanoma Breslow depth, histologic subtype, ulceration, mitotic rate, and lymphovascular invasion (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eSince the advent of the KEYNOTE-716 trial, and the CheckMate 76K there has been further debate with regard to the role of SLNB, the sequence of staging imaging and adjuvant immunotherapy, with some providers questioning the need for SLNB in certain cases (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). The recent UK National Institute for Health and Care Excellence (NICE) guidance recommend SLNB be performed followed by imaging staging in those with a positive SLNB, which would be consistent with entry criteria to these trials, and allow accurate staging, optimal locoregional control and afford the most accurate prediction of outcomes for patients having adjuvant therapy for proven high-risk stage II melanoma. There are significant risks of under-staging and overtreating patients in this group, with the potential for poor local control in undertreated nodal basins and increased nodal dissections. There is also the possibility of the underestimation of prognosis in patients with IIC melanoma, along with the long-term side-effects from adjuvant therapy in patients who could have avoided treatment.\u003c/p\u003e \u003cp\u003eIn this study, low-risk melanoma has been defined as T1, T2 and T3a, and high-risk melanoma has been defined here as T3b, T4a and T4b, congruent with patients who may be staged as Stage IIB-IIC post negative sentinel node biopsy, as per the KEYNOTE-716 trial. The aim of this study is to evaluate the ultimate SLN status, MIA score, and clinical stage as well as recurrence and disease-free survival (DFS) in a cohort of patients with potential \u0026ldquo;high-risk melanoma\u0026rdquo; at a reference melanoma centre. We also examined the impact of SLN status on DFS, and the impact of Breslow thickness and mitotic index on SLN status and recurrence. We aimed to define the clinical stage in our cohort of patients with potential high-risk melanoma, the nodal metastatic burden in these patients, prognosis, and consider the potential loss of prognostic information and local control if SLNB was omitted from their treatment.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design and participants\u003c/h2\u003e \u003cp\u003eAll patients with histologically proven cutaneous melanoma undergoing SLNB at The Royal Marsden Hospital, London, were included in the study and retrospectively analysed including melanoma of the extremity, trunk, and the head and neck. Three hundred consecutive patients fitting the criteria were identified between April 2018 and April 2023. We divided patients into two groups based on AJCC 8th edition (according to Breslow thickness and ulceration): Group A - low-risk melanoma (T1, T2 and T3a), n\u0026thinsp;=\u0026thinsp;211 and Group B - high-risk melanoma (T3b, T4a and T4b), n\u0026thinsp;=\u0026thinsp;89. All patients had an injection of Tc-99 and single photon emission computed tomography/computed tomography (SPECT-CT) imaging preoperatively and either ICG or blue dye for SLN localisation intraoperatively.\u003c/p\u003e \u003cp\u003eData including age, gender, American Society of Anesthesiologists (ASA) physical status classification system, Breslow thickness (mm), mitotic index/mm\u003csup\u003e2\u003c/sup\u003e, ulceration, presence of satellite lesions, tumour type and anatomical location was recorded. Intraoperative results included SLN localisation and number of SLNs harvested. Lymph node positivity was recorded as well as mutation analysis where available: nodes were considered positive if there were any tumour cells within the node identified by histopathology assessment. Oncological outcomes were collected with length of follow-up calculated from the date of surgery to the date of last follow-up or death. The MIA score was calculated using Sentinel Node Metastasis Risk Prediction Tool for individual patients in the high-risk melanoma group.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eSLN detection parameters and oncological outcomes were compared between Group A and B with a median follow-up of two years. Data was processed using JASP software for descriptive and inferential statistics. The mean, median, standard deviation and range were calculated where applicable. Baseline characteristics and outcome variables were compared using Mann-Whitney U test for continuous variables, and Fisher\u0026rsquo;s exact test for categorical variables where appropriate (p values of \u0026le;\u0026thinsp;0.05 were considered statistically significant). Survival probability analysis was done using Kaplan-Meier curve and log-rank tests. Disease progression was defined as any recurrence or metastasis recorded from the date of surgery till the end of the follow-up. MIA prediction risks were compared to actual SLNB positivity using Hosmer\u0026ndash;Lemeshow test and Brier score.\u003c/p\u003e \u003cp\u003eThis retrospective study was conducted using the Strengthening the Report of Observational Studies in Epidemiology (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e) guidelines (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003ePatient and melanoma characteristics\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe median age was 60.7 (10 - 91) years and 154 (51.3%) were female (Table 1). Two hundred and thirteen (71.0%) patients were ASA II or above. The most common subtypes of melanoma were superficial spreading (47.2%) and nodular (26.3%). The mean Breslow thickness was 2.6 mm (0.5 – 25 mm). Ninety patients (30.0%) had ulceration and 179 (59.7%) patients had mitosis ≥ 1 mm\u003csup\u003e2\u0026nbsp;\u003c/sup\u003ewith a mean value of 3.4 mm\u003csup\u003e2\u003c/sup\u003e across the cohort. One hundred and fifty-two patients (50.7%) had available mutation analysis with BRAF being positive in 59 (38.8%) of these patients. Patients with initial low-risk melanoma (Group A) n = 211 (T1=56, T2=116 and T3a=39). Patients with high-risk melanoma (Group B) were 89 with T3b = 36 (40.4%), T4a = 22 (24.7%) and T4b = 31 (34.8%).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn total, 66 patients (22.0%) had positive SLNs and recurrence was recorded in 48 (16.0% of total cohort) patients. Adjuvant treatment was given in 78 (26.0%) patients (immunotherapy 54 (69.2%), small molecule markers/tyrosine kinase inhibitor 15 (19.2%), both in combination 6 (7.7%). Breslow thickness was statistically significant in both positivity of SLNB and recurrence with P value of 0.004 and 0.001 respectively. Mitotic index was found to be statistically significant in recurrence, however, not in SLNB positivity, P value = 0.001 and 0.127 respectively. Follow-up duration had a mean of 524 days (range, 7 - 2491 days). DFS was calculated across the sample and had a median of 1389 days (lower 1244, standard error (SE) 131.5, CI 95%) (Figure 1). Sentinel lymph node positivity was found to influence median DFS with SLNB negative median of 1481 days (lower 1389, SE 139, CI 95%) and SLNB positive median of 1168 days (lower 1064, SE 67, CI 95%), However it was not statistically significant with P value = 0.056.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eOncological outcomes of high-risk versus low-risk melanoma\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCompared with patients in Group A, those in Group B were older (67 vs 61 years, p = 0.003) and had a higher mitotic rate (5 vs 1/mm², p \u0026lt; 0.001). Group B had more frequent ulceration of the primary tumour (75.3% vs 10.9%, p \u0026lt; 0.001), a higher rate of SLNB positivity (31.5% vs 18.0%, p = 0.009) and were more likely to receive adjuvant treatment (49.4% vs 16.1%, p \u0026lt; 0.001). At the end of follow up 171 patients were alive without recurrence in Group A (81%) with only 58 in group B (65%). Recurrence was recorded in 9.5% (20/211) in Group A with 31.5% (28/89) in Group B. Recurrence pattern were similar in both groups with nodal and distant metastasis constituting most of the recurrence, 2.3% and 4.3% in Group A, 10.1% and 16.8% in Group B, respectively. Median DFS for Group A and B were 1481 days (lower 1389, SE 138, CI 95%) and 1141 days (lower 980, SE 68, CI 95%), respectively (Figure 2). DFS was found to be statistically significant between the two groups (P value \u0026lt; 0.001).\u003c/p\u003e\n\u003cp\u003eThe mean predicted probability of SLN metastasis by the MIA score was 28.3%, compared with an observed positivity rate of 21.0%. Model discrimination was limited, with an AUC of 0.58 (95% CI, 0.41–0.75). Calibration analysis demonstrated systematic overestimation of risk across deciles, with most observed rates falling below the predicted values. The Hosmer–Lemeshow test was not statistically significant (χ²[8] = 13.49; p = 0.096), and the Brier score was 0.171, marginally higher than the baseline prevalence model (0.165). Fifty eight patients (65.2%) were alive without disease by the end of the follow-up period mean 630 days (15 - 1639).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eClinical stage and prognostic value\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eClinical stage was recorded for the high-risk melanoma group (Table 2). Following SLNB, 37 patients (41.57%) were stage IIB, 24 patients (26.96%) were stage IIC, and 28 patients (31.46%) were stage IIIC. This translates into a 5-year survival rate of 87% for Stage IIB, 82% for Stage IIC and 69% for stage IIIC (20, 21) . Assuming clinical and radiological negative lymph node and omitting SLNB results, T3b (36) and T4a (22) patients will be staged as IIB (58 patient), which reflects a 56.76% increase than real-world data. T4b (31) will be staged as IIC which represent a 29.17% increase. These increases will be on the expense of zero patient staged as IIIC (Figure 3).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eIndividual outcome of high-risk melanoma according to T stage\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eT3b patients (n = 36)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe mean MIA score was 24% (6 - 58), with positive SLNBs recorded in 13 cases (36.1%) (Table 3), Fourteen patients (38.8%) had adjuvant treatment (11 with positive SLNBs and 3 with negative SLNB). Adjuvant treatment given was mostly immunotherapy 78.5% (11 patients) with 2 patients receiving small molecule markers/TK inhibitors and 1 patient receiving both. Recurrence was observed in 10 patients (27.8%). Patients who received adjuvant therapy had a recurrence rate of 66% mainly in lymph nodes (n = 4) and in-transit (n = 4). Twenty-four patients were alive without disease (66.7%), with 12 patients had recorded recurrence two of which have died.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eT4a patients (n = 22)\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe mean MIA score was 27.1% (1-51), with positive SLNBs recorded in 8 cases (36%). Adjuvant treatment was given to 17 patients (77.2%) (8 had positive SLNBs and 9 had negative SLNBs). Adjuvant treatment given was predominantly immunotherapy 76.5% (13 patients) with 3 patients receiving small molecule markers/TK inhibitors and 1 patient receiving both. Recurrence was observed in six patients (27.2%), mainly distant recurrence (n = 5, 83.3% of recurrences). Ten patients were alive without disease (45.5%), and one patient (4.5%) with recurrence died.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eT4b patients (n = 31)\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMean MIA score was 35.4% (18 - 71) with seven cases (22.5%) having positive SLNBs. Adjuvant treatment was given to 13 patients (41.9%) (five had positive SLNBs and 6 had negative SLNBs Adjuvant treatment given was mainly immunotherapy 69.2% (9 patients) with 2 patients receiving small molecule markers/TK inhibitors and 2 patients receiving both. Eighteen patients (58.1%) had no treatment. Recurrence was seen in 12 patients (38.7%), including distant and nodal recurrence (5 (41.7%) and 6 (50.0%), respectively). Nineteen patients were alive without disease (61%) and two patients (6.5%) died, both of which had recurrence. \u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis retrospective study assessed DFS according to SLN status in patients with melanoma, and compared oncological outcomes in patients with low-risk compared to high-risk melanoma. Patients with SLN positivity had a reduced DFS than patients with a negative SLN status across our cohort, which is similar to other published findings. Holmberg et al. (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e) presented a study where data was retrieved from a Swedish Melanoma Registry for patients with a diagnosis of primary invasive cutaneous melanoma. A total of 1,943 patients had a Breslow thickness greater than 4 mm (pT4). A positive SLN was found in 34% of cases, with a 5-year MSS of 71%. A statistical significant difference was found in MSS between patients with a positive SLN and those with a negative SLN for patients with stage T4a and T4b. This study verified that the outcome of SLNB continues to hold prognostic value for patients with thick (\u0026gt;\u0026thinsp;4 mm, stage pT4) melanoma. Their analysis also showed that age, Breslow thickness and ulceration status were significant independent predictors of MSS. High-risk melanoma was associated with higher rates of recurrence and a lower DFS compared to patients deemed to have low-risk melanoma. Rates of adjuvant treatment were also higher in patients with high-risk melanoma as expected. In our study, a significant number of patients had stage IIC and IIIC following SLNB, and that prognostic information would have been lost without lymph node staging. the MIA sentinel node risk prediction tool showed modest discrimination and evidence of miscalibration, tending to overestimate the true probability of nodal involvement. While the Hosmer\u0026ndash;Lemeshow statistic did not indicate significant misfit, the calibration slope and Brier score suggest that predictions were less accurate than a simple prevalence-based estimate. These findings highlight the possibility of over-staging patients depending on prediction. Our findings also highlighted that DFS is reduced from T1 to T4b tumours, and it was evident that ulceration status and mitotic index are important histopathological features and is associated with higher rates of recurrence, which is consistent with other studies. Our findings also highlighted that DFS is reduced from T1 to T4b tumours, and it was evident that ulceration status and mitotic index are important histopathological features and is associated with higher rates of recurrence, which is consistent with other studies (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e), (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e),(\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eGyorki et al. (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e) carried out a study of 217 patients with primary T4 (\u0026gt;\u0026thinsp;4 mm) melanoma who had SLN performed. The median Breslow thickness was 6 mm, and there was a SLN positivity rate of 36% in this cohort of patients. Multivariable analysis revealed that SLN status was the most significant prognostic factor for overall survival, followed by primary tumour ulceration status. They reported a 5-year MSS of 57% in the cohort of patients with a Breslow thickness greater than 4 mm and SLN positivity. In addition, Han et al. (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e) presented an analysis of 1,235 patients with pT4 melanomas from The Sentinel Lymph Node Working Group database, with a SLN positivity rate of 36% and 5-year MSS of 66%. The authors found that the single strongest prognostic factor for MSS was SLN status in all thickness groups, followed by tumour thickness, male gender, microsatellites and lymphovascular invasion. The NADINA trial recently reported its results for resectable, macroscopic, nodal stage III melanoma patients. It showed an increase in 12 months event-free survival (EFS) for the neoadjuvant arm -before therapeutic lymph node dissection plus adjuvant treatment, if there is no complete pathological response- compared to the adjuvant arm (EFS 83.7% vs 57.2%; P value\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). However, This was coupled with increased adverse events in the neoadjuvant arm 29.7% vs 14.7% for the adjuvant arm (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e). Recently, a prediction model and nomogram has been developed, using a cohort of 4,071 patients, to potentially predict patient-specific risk probabilities for 5-year recurrence-free survival (RFS) and MSS(\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e). The tool was based on sex, age, presence of ulceration, primary tumour location, histological subtype, Breslow thickness, sentinel node status, number of sentinel nodes removed, maximum diameter of the largest sentinel node metastasis, and Dewar classification. This tool may subsequently have significant implications for clinical decision-making when considering adjuvant treatments in patients with high-risk melanomas.\u003c/p\u003e \u003cp\u003eThe eighth edition AJCC published MSS probabilities for stages I, II and III on the basis of a multicentre database from 10 international centres with over 46,000 cases. The 5-year OS rate was calculated for stages IIB and IIC and reported as 87% and 82%, respectively. For stages III and IV, the 5-year OS rates were reported as 32%-93% and 34%-52%, respectively. Evaluation of three independent stage III melanoma cohorts revealed significantly less favourable survival rates than that presented in the eight edition (\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e) publication (\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e), and similar results were demonstrated for a stage III melanoma patient cohort from Germany and Sweden (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e). It is clear that there is a difference in survival for patients with non-SLN metastases versus those with disease confined to the SLNs, and survival decreases as the number positive lymph nodes increases (\u003cspan additionalcitationids=\"CR32 CR33\" citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e). There remains a substantial difference in prognosis between IIIA and IIIB\u0026ndash;C patients, and therefore, accurate staging is therefore essential to determine which patients are at higher risk and would directly benefit from adjuvant therapy. Dedeilia et al. (\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e) performed a single-centre retrospective study analysing 92 patients with stage IIB or IIC melanoma. A Breslow thickness greater than 4 mm, a higher mitotic rate and an advanced T stage were found to have a negative impact on RFS. In our series, omitting a SNB would have understaged patients, depriving them and the treating team of useful prognostic information, with a potential difference in overall survival likely to be relevant to both parties.\u003c/p\u003e \u003cp\u003eThe KEYNOTE-716 study, a randomised, double-blind, phase 3 trial, showed a significantly longer RFS for patients with stage IIB/C melanoma receiving adjuvant PD-1 inhibition than for those receiving a placebo (hazards ratio 0.65; 95% CI 0.46\u0026ndash;0.92), However this was only limited to patients with negative SLNB as an eligibility requirement (\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e). Accurate staging of high-risk melanoma patients with SLNB will provide a complete picture of patient prognosis and survival risks and can guide such decision making for treatment, for example, defining patients more likely to develop systemic disease without locoregional recurrence, with implications for adjuvant therapy and surveillance. Moreover, the more congruent the management approach is with the paradigm described, the better able to generalise and advise our patients on subsequent prognosis.\u003c/p\u003e \u003cp\u003eIt is important to consider what would occur in the high proportion of our patients with microscopic disease in their lymph node, if they had been treated with single agent \u0026ldquo;adjuvant\u0026rdquo; immunotherapy as per KEYNOTE-716 without sentinel node biopsy. We would reasonably expect a response and elimination of the metastatic melanoma in a significant proportion of patients, but even in the best case estimated of a 50% elimination of disease, 1:6 of our patients may have progressed, likely requiring a nodal disease, with attendant increased morbidity that could have been avoided by performing a sentinel node biopsy.\u003c/p\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eStudy limitations\u003c/h2\u003e \u003cp\u003eThere are important limitations with this study that must be addressed. This was a single-institution, retrospective study with a relatively short follow-up period of two years. There were three patients with satellite lesions in our cohort in the high-risk melanoma group, this was not accounted for in the result analysis. There was a lack of information regarding the mutation analysis along with the methods of recurrence detection. In addition, the lack of randomisation would have ultimately introduced some confounding factors which were not accounted for during the analysis. Patients were also managed with different treatment regimens rendering it difficult to make robust comparisons between the low-risk and high-risk melanoma groups.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusions","content":"\u003cp\u003eOur retrospective study assessed the SLN status, recurrence and DFS in patients with low and high-risk melanoma. The high-risk melanoma group was associated with higher SLN positivity and recurrence rates, and with lower DFS. We also found differences between the mean MIA score and the actual SNB positivity in this study. Sentinel node biopsy remains a useful tool in the assessment and staging of patients with clinical high-risk primary melanoma. Accurate predictions of outcomes for an individual patient is necessary for individualisation of melanoma care.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics statement\u003c/strong\u003e:\u003c/p\u003e\n\u003cp\u003eAll patient information, data collection and analysis were performed in compliance with the Royal Marsden Hospital research ethics committee guidelines.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data statement:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data that support the findings of this study are available from the Royal Marsden hospital, but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are however available from the authors upon reasonable request and with permission of the Royal Marsden hospital.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research didn’t receive funding\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCredit author statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eH S M\u003c/strong\u003e\u003cstrong\u003e:\u0026nbsp;\u003c/strong\u003estudy concepts, study design, data acquisition, quality control of data, data analysis and interpretation, statistical analysis, manuscript preparation, manuscript editing.\u003cstrong\u003e\u0026nbsp;M G F:\u0026nbsp;\u003c/strong\u003estudy concepts, study design, data acquisition, quality control of data, data analysis and interpretation, statistical analysis, manuscript preparation, manuscript editing.\u0026nbsp;\u003cstrong\u003eM J W\u003c/strong\u003e\u003cstrong\u003e:\u003c/strong\u003e data analysis and interpretation, manuscript preparation, manuscript editing.\u0026nbsp;\u003cstrong\u003eO H:\u0026nbsp;\u003c/strong\u003edata analysis and interpretation, manuscript editing, manuscript review.\u003cstrong\u003e\u0026nbsp;J W:\u003c/strong\u003e data analysis and interpretation, manuscript editing, manuscript review.\u003cstrong\u003e\u0026nbsp;K P:\u0026nbsp;\u003c/strong\u003emanuscript editing, manuscript review. \u003cstrong\u003eA J H:\u0026nbsp;\u003c/strong\u003emanuscript editing, manuscript review. \u003cstrong\u003eM J S:\u0026nbsp;\u003c/strong\u003eStudy concepts, study design, data acquisition, quality control of data, data analysis and interpretation, statistical analysis, manuscript editing, manuscript review.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSaginala K, Barsouk A, Aluru JS, Rawla P, Barsouk A. Epidemiol Melanoma Med Sci (Basel). 2021;9(4).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNurla LA, Forsea AM. Melanoma epidemiology in Europe: what is new? Ital J Dermatol Venerol. 2024;159(2):128\u0026ndash;34.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eValsecchi ME, Silbermins D, de Rosa N, Wong SL, Lyman GH. Lymphatic mapping and sentinel lymph node biopsy in patients with melanoma: a meta-analysis. J Clin Oncol. 2011;29(11):1479\u0026ndash;87.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSpeijers MJ, Bastiaannet E, Sloot S, Suurmeijer AJ, Hoekstra HJ. Tumor mitotic rate added to the equation: melanoma prognostic factors changed? a single-institution database study on the prognostic value of tumor mitotic rate for sentinel lymph node status and survival of cutaneous melanoma patients. Ann Surg Oncol. 2015;22(9):2978\u0026ndash;87.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSmithson SL, Pan Y, Mar V. Differing trends in thickness and survival between nodular and non-nodular primary cutaneous melanoma in Victoria, Australia. Med J Aust. 2015;203(1):20.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRughani MG, Swan MC, Adams TS, Middleton MR, Ramcharan RN, Pay A, et al. Sentinel lymph node biopsy in melanoma: The Oxford ten year clinical experience. J Plast Reconstr Aesthet Surg. 2011;64(10):1284\u0026ndash;90.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePeach H, Board R, Cook M, Corrie P, Ellis S, Geh J, et al. Current role of sentinel lymph node biopsy in the management of cutaneous melanoma: A UK consensus statement. J Plast Reconstr Aesthet Surg. 2020;73(1):36\u0026ndash;42.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWhite RL Jr., Ayers GD, Stell VH, Ding S, Gershenwald JE, Salo JC, et al. Factors predictive of the status of sentinel lymph nodes in melanoma patients from a large multicenter database. Ann Surg Oncol. 2011;18(13):3593\u0026ndash;600.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJeremic J, Radenovic K, Jurisic M, Sudecki B, Marinkovic M, Mihaljevic J et al. Primary Melanoma Histopathologic Predictors of Sentinel Lymph Node Positivity: A Proposed Scoring System for Risk Assessment and Patient Selection in a Clinical Setting. Med (Kaunas). 2023;59(11).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMorton DL, Cochran AJ, Thompson JF, Elashoff R, Essner R, Glass EC, et al. Sentinel node biopsy for early-stage melanoma: accuracy and morbidity in MSLT-I, an international multicenter trial. Ann Surg. 2005;242(3):302\u0026ndash;11. discussion 11\u0026thinsp;\u0026ndash;\u0026thinsp;3.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMorton DL, Thompson JF, Cochran AJ, Mozzillo N, Elashoff R, Essner R, et al. Sentinel-node biopsy or nodal observation in melanoma. N Engl J Med. 2006;355(13):1307\u0026ndash;17.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMorton DL, Thompson JF, Cochran AJ, Mozzillo N, Nieweg OE, Roses DF, et al. Final trial report of sentinel-node biopsy versus nodal observation in melanoma. N Engl J Med. 2014;370(7):599\u0026ndash;609.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLong GV, Luke JJ, Khattak MA, de la Cruz Merino L, Del Vecchio M, Rutkowski P, et al. Pembrolizumab versus placebo as adjuvant therapy in resected stage IIB or IIC melanoma (KEYNOTE-716): distant metastasis-free survival results of a multicentre, double-blind, randomised, phase 3 trial. Lancet Oncol. 2022;23(11):1378\u0026ndash;88.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePatel SP, Othus M, Chen Y, Wright GP Jr., Yost KJ, Hyngstrom JR, et al. Neoadjuvant-Adjuvant or Adjuvant-Only Pembrolizumab in Advanced Melanoma. N Engl J Med. 2023;388(9):813\u0026ndash;23.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003e(MIA) MIoA. Sentinel Node Metastasis Prediction Tool 2024 [Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.melanomarisk.org.au/SNLLand\u003c/span\u003e\u003cspan address=\"https://www.melanomarisk.org.au/SNLLand\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMaddineni S, Dizon MP, Muralidharan V, Young LA, Sunwoo JB, Baik FM, et al. Validation of the Melanoma Institute of Australia's Sentinel Lymph Node Biopsy Risk Prediction Tool for Cutaneous Melanoma. Ann Surg Oncol. 2024;31(4):2737\u0026ndash;46.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKirkwood JM, Del Vecchio M, Weber J, Hoeller C, Grob JJ, Mohr P, et al. Adjuvant nivolumab in resected stage IIB/C melanoma: primary results from the randomized, phase 3 CheckMate 76K trial. Nat Med. 2023;29(11):2835\u0026ndash;43.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVandenbroucke JP, von Elm E, Altman DG, Gotzsche PC, Mulrow CD, Pocock SJ, et al. Strengthening the Reporting of Observational Studies in Epidemiology (STROBE): explanation and elaboration. Epidemiology. 2007;18(6):805\u0026ndash;35.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003evon Schuckmann LA, Hughes MCB, Ghiasvand R, Malt M, van der Pols JC, Beesley VL, et al. Risk of Melanoma Recurrence After Diagnosis of a High-Risk Primary Tumor. JAMA Dermatol. 2019;155(6):688\u0026ndash;93.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKanaki T, Stang A, Gutzmer R, Zimmer L, Chorti E, Sucker A, et al. Impact of American Joint Committee on Cancer 8th edition classification on staging and survival of patients with melanoma. Eur J Cancer. 2019;119:18\u0026ndash;29.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eUK Mf-. Melanoma survival rates [Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://melanomafocus.org/melanoma-patient-treatment-guide/living-with-melanoma/melanoma-survival-rates/\u003c/span\u003e\u003cspan address=\"https://melanomafocus.org/melanoma-patient-treatment-guide/living-with-melanoma/melanoma-survival-rates/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHolmberg CJ, Mikiver R, Isaksson K, Ingvar C, Moncrieff M, Nielsen K, et al. Prognostic Significance of Sentinel Lymph Node Status in Thick Primary Melanomas (\u0026gt;\u0026thinsp;4 mm). Ann Surg Oncol. 2023;30(13):8026\u0026ndash;33.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eThompson JF, Soong SJ, Balch CM, Gershenwald JE, Ding S, Coit DG, et al. Prognostic significance of mitotic rate in localized primary cutaneous melanoma: an analysis of patients in the multi-institutional American Joint Committee on Cancer melanoma staging database. J Clin Oncol. 2011;29(16):2199\u0026ndash;205.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAzzola MF, Shaw HM, Thompson JF, Soong SJ, Scolyer RA, Watson GF, et al. Tumor mitotic rate is a more powerful prognostic indicator than ulceration in patients with primary cutaneous melanoma: an analysis of 3661 patients from a single center. Cancer. 2003;97(6):1488\u0026ndash;98.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGyorki DE, Sanelli A, Herschtal A, Lazarakis S, McArthur GA, Speakman D, et al. Sentinel Lymph Node Biopsy in T4 Melanoma: An Important Risk-Stratification Tool. Ann Surg Oncol. 2016;23(2):579\u0026ndash;84.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHan D, Han G, Duque MT, Morrison S, Leong SP, Kashani-Sabet M, et al. Sentinel Lymph Node Biopsy Is Prognostic in Thickest Melanoma Cases and Should Be Performed for Thick Melanomas. Ann Surg Oncol. 2021;28(2):1007\u0026ndash;16.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBlank CU, Lucas MW, Scolyer RA, Wiel BAvd, Menzies AM, Lopez-Yurda MI, et al. Neoadjuvant nivolumab plus ipilimumab versus adjuvant nivolumab in macroscopic, resectable stage III melanoma: The phase 3 NADINA trial. J Clin Oncol. 2024;42(17suppl):LBA2\u0026ndash;LBA.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStassen RC, Maas C, van der Veldt AAM, Lo SN, Saw RPM, Varey AHR, et al. Development and validation of a novel model to predict recurrence-free survival and melanoma-specific survival after sentinel lymph node biopsy in patients with melanoma: an international, retrospective, multicentre analysis. Lancet Oncol. 2024;25(4):509\u0026ndash;17.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGarbe C, Keim U, Suciu S, Amaral T, Eigentler TK, Gesierich A, et al. Prognosis of Patients With Stage III Melanoma According to American Joint Committee on Cancer Version 8: A Reassessment on the Basis of 3 Independent Stage III Melanoma Cohorts. J Clin Oncol. 2020;38(22):2543\u0026ndash;51.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIsaksson K, Katsarelias D, Mikiver R, Carneiro A, Ny L, Olofsson Bagge R. A Population-Based Comparison of the AJCC 7th and AJCC 8th Editions for Patients Diagnosed with Stage III Cutaneous Malignant Melanoma in Sweden. Ann Surg Oncol. 2019;26(9):2839\u0026ndash;45.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGhaferi AA, Wong SL, Johnson TM, Lowe L, Chang AE, Cimmino VM, et al. Prognostic significance of a positive nonsentinel lymph node in cutaneous melanoma. Ann Surg Oncol. 2009;16(11):2978\u0026ndash;84.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAriyan C, Brady MS, Gonen M, Busam K, Coit D. Positive nonsentinel node status predicts mortality in patients with cutaneous melanoma. Ann Surg Oncol. 2009;16(1):186\u0026ndash;90.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBrown RE, Ross MI, Edwards MJ, Noyes RD, Reintgen DS, Hagendoorn LJ, et al. The prognostic significance of nonsentinel lymph node metastasis in melanoma. Ann Surg Oncol. 2010;17(12):3330\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJakub JW, Huebner M, Shivers S, Nobo C, Puleo C, Harmsen WS, et al. The number of lymph nodes involved with metastatic disease does not affect outcome in melanoma patients as long as all disease is confined to the sentinel lymph node. Ann Surg Oncol. 2009;16(8):2245\u0026ndash;51.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDedeilia A, Lwin T, Li S, Tarantino G, Tunsiricharoengul S, Lawless A, et al. Factors Affecting Recurrence and Survival for Patients with High-Risk Stage II Melanoma. Ann Surg Oncol. 2024;31(4):2713\u0026ndash;26.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLuke JJ, Rutkowski P, Queirolo P, Del Vecchio M, Mackiewicz J, Chiarion-Sileni V, et al. Pembrolizumab versus placebo as adjuvant therapy in completely resected stage IIB or IIC melanoma (KEYNOTE-716): a randomised, double-blind, phase 3 trial. Lancet. 2022;399(10336):1718\u0026ndash;29.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1.\u003c/strong\u003e Baseline characteristics of low-risk melanoma (Group A: T1, T2 and T3a) and high-risk melanoma (Group B: T3b, T4a and T4b). ASA, American Society of Anesthesiologists; SD, standard deviation; SLNB, sentinel lymph node biopsy.\u003c/p\u003e\n\u003ctable style=\"border-collapse: collapse; border: none; width: 100%;\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"border: 1pt solid windowtext;background: white;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:14px;font-family:\"Aptos\",sans-serif;text-align:left;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height: 150%;font-family:\"Calibri\",sans-serif;color:black;'\u003eCharacteristic\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border-top: 1pt solid windowtext;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-image: initial;border-left: none;background: white;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:14px;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Calibri\",sans-serif;color:black;'\u003eGroup A (n=211)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border-top: 1pt solid windowtext;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-image: initial;border-left: none;background: white;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:14px;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Calibri\",sans-serif;color:black;'\u003eGroup B (n=89)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border-top: 1pt solid windowtext;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-image: initial;border-left: none;background: white;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:14px;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Calibri\",sans-serif;color:black;'\u003ep-value\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;background: white;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:14px;font-family:\"Aptos\",sans-serif;text-align:left;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height: 150%;font-family:\"Calibri\",sans-serif;color:black;'\u003eAge\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:14px;font-family:\"Aptos\",sans-serif;text-align:left;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height: 150%;font-family:\"Calibri\",sans-serif;color:black;'\u003eYears (median \u0026plusmn; SD)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;background: rgb(204, 204, 204);padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:14px;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Calibri\",sans-serif;color:black;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:14px;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Calibri\",sans-serif;color:black;'\u003e61 \u0026plusmn; 14.7\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;background: rgb(204, 204, 204);padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:14px;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Calibri\",sans-serif;color:black;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:14px;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Calibri\",sans-serif;color:black;'\u003e67 \u0026plusmn; 16.0\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;background: rgb(204, 204, 204);padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:14px;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Calibri\",sans-serif;color:black;'\u003e0.003\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;background: white;padding: 0in 5.4pt;height: 55.95pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:14px;font-family:\"Aptos\",sans-serif;text-align:left;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height: 150%;font-family:\"Calibri\",sans-serif;color:black;'\u003eGender\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:14px;font-family:\"Aptos\",sans-serif;text-align:left;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height: 150%;font-family:\"Calibri\",sans-serif;color:black;'\u003e\u0026ndash; Female\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:14px;font-family:\"Aptos\",sans-serif;text-align:left;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height: 150%;font-family:\"Calibri\",sans-serif;color:black;'\u003e\u0026ndash; Male\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 55.95pt;vertical-align: top;\"\u003e\n \u003cp 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5.4pt;height: 55.95pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:14px;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Calibri\",sans-serif;color:black;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:14px;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Calibri\",sans-serif;color:black;'\u003e38 (42.7%)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:14px;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Calibri\",sans-serif;color:black;'\u003e51 (57.3%)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border-top: none;border-left: none;border-bottom: 1pt solid 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style='margin:0in;font-size:14px;font-family:\"Aptos\",sans-serif;text-align:left;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height: 150%;font-family:\"Calibri\",sans-serif;color:black;'\u003e\u0026ndash; One\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:14px;font-family:\"Aptos\",sans-serif;text-align:left;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height: 150%;font-family:\"Calibri\",sans-serif;color:black;'\u003e\u0026ndash; Two\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:14px;font-family:\"Aptos\",sans-serif;text-align:left;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height: 150%;font-family:\"Calibri\",sans-serif;color:black;'\u003e\u0026ndash; Three\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:14px;font-family:\"Aptos\",sans-serif;text-align:left;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height: 150%;font-family:\"Calibri\",sans-serif;color:black;'\u003e\u0026ndash; Unknown\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;background: rgb(204, 204, 204);padding: 0in 5.4pt;height: 93.55pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:14px;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Calibri\",sans-serif;color:black;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:14px;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan 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style='font-size:13px;line-height:150%;font-family:\"Calibri\",sans-serif;color:black;'\u003e49 (55.1%)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:14px;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Calibri\",sans-serif;color:black;'\u003e15 (16.9%)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:14px;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Calibri\",sans-serif;color:black;'\u003e1 (1.1%)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;background: rgb(204, 204, 204);padding: 0in 5.4pt;height: 93.55pt;vertical-align: top;\"\u003e\n \u003cp 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style='margin:0in;font-size:14px;font-family:\"Aptos\",sans-serif;text-align:left;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height: 150%;font-family:\"Calibri\",sans-serif;color:black;'\u003e\u0026ndash; Absent\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:14px;font-family:\"Aptos\",sans-serif;text-align:left;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height: 150%;font-family:\"Calibri\",sans-serif;color:black;'\u003e\u0026ndash; Present\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:14px;font-family:\"Aptos\",sans-serif;text-align:left;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height: 150%;font-family:\"Calibri\",sans-serif;color:black;'\u003e\u0026ndash; Unknown\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 74.75pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:14px;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Calibri\",sans-serif;color:black;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:14px;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Calibri\",sans-serif;color:black;'\u003e175 (82.9%)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:14px;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Calibri\",sans-serif;color:black;'\u003e23 (10.9%)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:14px;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Calibri\",sans-serif;color:black;'\u003e13 (6.2%)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 74.75pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:14px;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Calibri\",sans-serif;color:black;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:14px;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Calibri\",sans-serif;color:black;'\u003e20 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style='font-size:13px;line-height:150%;font-family:\"Calibri\",sans-serif;color:black;'\u003e\u0026lt;0.001\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;background: white;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:14px;font-family:\"Aptos\",sans-serif;text-align:left;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height: 150%;font-family:\"Calibri\",sans-serif;color:black;'\u003eMitoses\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:14px;font-family:\"Aptos\",sans-serif;text-align:left;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height: 150%;font-family:\"Calibri\",sans-serif;color:black;'\u003emedian 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windowtext;background: rgb(204, 204, 204);padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:14px;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Calibri\",sans-serif;color:black;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:14px;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Calibri\",sans-serif;color:black;'\u003e5 \u0026plusmn; 5.4\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;background: rgb(204, 204, 204);padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:14px;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Calibri\",sans-serif;color:black;'\u003e\u0026lt;0.001\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;background: white;padding: 0in 5.4pt;height: 74.75pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:14px;font-family:\"Aptos\",sans-serif;text-align:left;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height: 150%;font-family:\"Calibri\",sans-serif;color:black;'\u003eSLNB\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:14px;font-family:\"Aptos\",sans-serif;text-align:left;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height: 150%;font-family:\"Calibri\",sans-serif;color:black;'\u003e\u0026ndash; Negative\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:14px;font-family:\"Aptos\",sans-serif;text-align:left;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height: 150%;font-family:\"Calibri\",sans-serif;color:black;'\u003e\u0026ndash; Positive\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:14px;font-family:\"Aptos\",sans-serif;text-align:left;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height: 150%;font-family:\"Calibri\",sans-serif;color:black;'\u003e\u0026ndash; Unknown\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 74.75pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:14px;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Calibri\",sans-serif;color:black;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:14px;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Calibri\",sans-serif;color:black;'\u003e170 (80.6%)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:14px;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Calibri\",sans-serif;color:black;'\u003e38 (18.0%)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:14px;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Calibri\",sans-serif;color:black;'\u003e3 (1.4%)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 74.75pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:14px;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Calibri\",sans-serif;color:black;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:14px;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Calibri\",sans-serif;color:black;'\u003e59 (66.3%)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:14px;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Calibri\",sans-serif;color:black;'\u003e28 (31.5%)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:14px;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Calibri\",sans-serif;color:black;'\u003e2 (2.2%)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 74.75pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:14px;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Calibri\",sans-serif;color:black;'\u003e0.029\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;background: white;padding: 0in 5.4pt;height: 55.95pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:14px;font-family:\"Aptos\",sans-serif;text-align:left;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height: 150%;font-family:\"Calibri\",sans-serif;color:black;'\u003eAdjuvant treatment\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:14px;font-family:\"Aptos\",sans-serif;text-align:left;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height: 150%;font-family:\"Calibri\",sans-serif;color:black;'\u003e\u0026ndash; Administered\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:14px;font-family:\"Aptos\",sans-serif;text-align:left;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height: 150%;font-family:\"Calibri\",sans-serif;color:black;'\u003e\u0026ndash; Not administered\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;background: rgb(204, 204, 204);padding: 0in 5.4pt;height: 55.95pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:14px;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Calibri\",sans-serif;color:black;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:14px;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Calibri\",sans-serif;color:black;'\u003e34 (16.1%)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:14px;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Calibri\",sans-serif;color:black;'\u003e177 (83.9%)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;background: rgb(204, 204, 204);padding: 0in 5.4pt;height: 55.95pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:14px;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Calibri\",sans-serif;color:black;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:14px;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Calibri\",sans-serif;color:black;'\u003e44 (49.4%)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:14px;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Calibri\",sans-serif;color:black;'\u003e45 (50.6%)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;background: rgb(204, 204, 204);padding: 0in 5.4pt;height: 55.95pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:14px;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Calibri\",sans-serif;color:black;'\u003e\u0026lt;0.001\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;background: white;padding: 0in 5.4pt;height: 74.75pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:14px;font-family:\"Aptos\",sans-serif;text-align:left;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height: 150%;font-family:\"Calibri\",sans-serif;color:black;'\u003eLocation of melanoma\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:14px;font-family:\"Aptos\",sans-serif;text-align:left;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height: 150%;font-family:\"Calibri\",sans-serif;color:black;'\u003e\u0026ndash; Head \u0026amp; neck\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:14px;font-family:\"Aptos\",sans-serif;text-align:left;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height: 150%;font-family:\"Calibri\",sans-serif;color:black;'\u003e\u0026ndash; Trunk\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:14px;font-family:\"Aptos\",sans-serif;text-align:left;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height: 150%;font-family:\"Calibri\",sans-serif;color:black;'\u003e\u0026ndash; Extremities\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 74.75pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:14px;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Calibri\",sans-serif;color:black;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:14px;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Calibri\",sans-serif;color:black;'\u003e26 (12.3%)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:14px;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Calibri\",sans-serif;color:black;'\u003e72 (34.1%)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:14px;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Calibri\",sans-serif;color:black;'\u003e113 (53.5%)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 74.75pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:14px;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Calibri\",sans-serif;color:black;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:14px;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Calibri\",sans-serif;color:black;'\u003e18 (20.2%)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:14px;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Calibri\",sans-serif;color:black;'\u003e34 (38.2%)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:14px;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Calibri\",sans-serif;color:black;'\u003e37 (41.6%)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;height: 74.75pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:14px;font-family:\"Aptos\",sans-serif;line-height:150%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Calibri\",sans-serif;color:black;'\u003e0.093\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2.\u003c/strong\u003e Clinical stage prognostic information. Clinical stage refers to staging depending on clinical information without SLNB according to AJCC. Post SLNB stage refers to staging depending on clinical information with SLNB result according to AJCC. SLNB, sen\u003c/p\u003e\n\u003ctable style=\"margin-left: -0.25pt;border-collapse: collapse;border: none;width: 540px;\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\" style=\"width: 148.6pt;border: 1pt solid windowtext;padding: 0in 5.4pt;height: 16.1pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;vertical-align:baseline;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Calibri\",sans-serif;'\u003eT stage\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 127.6pt;border-top: 1pt solid windowtext;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-image: initial;border-left: none;padding: 0in 5.4pt;height: 16.1pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;vertical-align:baseline;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Calibri\",sans-serif;'\u003eClinical stage\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 127.55pt;border-top: 1pt solid windowtext;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-image: initial;border-left: none;padding: 0in 5.4pt;height: 16.1pt;vertical-align: bottom;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;vertical-align:baseline;'\u003e\u003cstrong\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Calibri\",sans-serif;'\u003ePost SLNB stage\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:49.4pt;border:solid windowtext 1.0pt;border-top: none;background:#E0DDB7;padding:0in 5.4pt 0in 5.4pt;height:23.05pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;vertical-align:baseline;'\u003e\u003cstrong\u003e\u003cem\u003e\u003cspan style='font-size:13px;line-height: 150%;font-family:\"Calibri\",sans-serif;color:black;'\u003eStage\u003c/span\u003e\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:49.6pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:#E0DDB7;padding:0in 5.4pt 0in 5.4pt;height:23.05pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;vertical-align:baseline;'\u003e\u003cstrong\u003e\u003cem\u003e\u003cspan style='font-size:13px;line-height: 150%;font-family:\"Calibri\",sans-serif;color:black;'\u003en\u003c/span\u003e\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:49.6pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:#E0DDB7;padding:0in 5.4pt 0in 5.4pt;height:23.05pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;vertical-align:baseline;'\u003e\u003cstrong\u003e\u003cem\u003e\u003cspan style='font-size:13px;line-height: 150%;font-family:\"Calibri\",sans-serif;color:black;'\u003e%\u003c/span\u003e\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:42.55pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:#FF8C3E;padding:0in 5.4pt 0in 5.4pt;height:23.05pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;vertical-align:baseline;'\u003e\u003cstrong\u003e\u003cem\u003e\u003cspan style='font-size:13px;line-height: 150%;font-family:\"Calibri\",sans-serif;color:black;'\u003eStage\u003c/span\u003e\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:42.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:#FF8C3E;padding:0in 5.4pt 0in 5.4pt;height:23.05pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;vertical-align:baseline;'\u003e\u003cstrong\u003e\u003cem\u003e\u003cspan style='font-size:13px;line-height: 150%;font-family:\"Calibri\",sans-serif;color:black;'\u003en\u003c/span\u003e\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:42.55pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:#FF8C3E;padding:0in 5.4pt 0in 5.4pt;height:23.05pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;vertical-align:baseline;'\u003e\u003cstrong\u003e\u003cem\u003e\u003cspan style='font-size:13px;line-height: 150%;font-family:\"Calibri\",sans-serif;color:black;'\u003e%\u003c/span\u003e\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:42.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:#1DDAA4;padding:0in 5.4pt 0in 5.4pt;height:23.05pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;vertical-align:baseline;'\u003e\u003cstrong\u003e\u003cem\u003e\u003cspan style='font-size:13px;line-height: 150%;font-family:\"Calibri\",sans-serif;color:black;'\u003eStage\u003c/span\u003e\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:42.55pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:#1DDAA4;padding:0in 5.4pt 0in 5.4pt;height:23.05pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;vertical-align:baseline;'\u003e\u003cstrong\u003e\u003cem\u003e\u003cspan style='font-size:13px;line-height: 150%;font-family:\"Calibri\",sans-serif;color:black;'\u003en\u003c/span\u003e\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:42.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:#1DDAA4;padding:0in 5.4pt 0in 5.4pt;height:23.05pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;vertical-align:baseline;'\u003e\u003cstrong\u003e\u003cem\u003e\u003cspan style='font-size:13px;line-height: 150%;font-family:\"Calibri\",sans-serif;color:black;'\u003e%\u003c/span\u003e\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:49.4pt;border:solid windowtext 1.0pt;border-top: none;background:#E0DDB7;padding:0in 5.4pt 0in 5.4pt;height:15.75pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;vertical-align:baseline;'\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Calibri\",sans-serif;color:black;'\u003eT3b\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:49.6pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:#E0DDB7;padding:0in 5.4pt 0in 5.4pt;height:15.75pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;vertical-align:baseline;'\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Calibri\",sans-serif;color:black;'\u003e36\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:49.6pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:#E0DDB7;padding:0in 5.4pt 0in 5.4pt;height:15.75pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;vertical-align:baseline;'\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Calibri\",sans-serif;color:black;'\u003e40.45%\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width:42.55pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:#FF8C3E;padding:0in 5.4pt 0in 5.4pt;height:15.75pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;vertical-align:baseline;'\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Calibri\",sans-serif;color:black;'\u003eIIB\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width:42.5pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:#FF8C3E;padding:0in 5.4pt 0in 5.4pt;height:15.75pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;vertical-align:baseline;'\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Calibri\",sans-serif;color:black;'\u003e58\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width:42.55pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:#FF8C3E;padding:0in 5.4pt 0in 5.4pt;height:15.75pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;vertical-align:baseline;'\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Calibri\",sans-serif;color:black;'\u003e65.17%\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:42.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:#1DDAA4;padding:0in 5.4pt 0in 5.4pt;height:15.75pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;vertical-align:baseline;'\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Calibri\",sans-serif;color:black;'\u003eIIB\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:42.55pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:#1DDAA4;padding:0in 5.4pt 0in 5.4pt;height:15.75pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;vertical-align:baseline;'\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Calibri\",sans-serif;color:black;'\u003e37\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:42.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:#1DDAA4;padding:0in 5.4pt 0in 5.4pt;height:15.75pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;vertical-align:baseline;'\u003e\u003cspan style='font-size:13px;line-height: 150%;font-family:\"Calibri\",sans-serif;color:black;'\u003e41.57%\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:49.4pt;border:solid windowtext 1.0pt;border-top: none;background:#E0DDB7;padding:0in 5.4pt 0in 5.4pt;height:26.45pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;vertical-align:baseline;'\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Calibri\",sans-serif;color:black;'\u003eT4a\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:49.6pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:#E0DDB7;padding:0in 5.4pt 0in 5.4pt;height:26.45pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;vertical-align:baseline;'\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Calibri\",sans-serif;color:black;'\u003e22\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:49.6pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:#E0DDB7;padding:0in 5.4pt 0in 5.4pt;height:26.45pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;vertical-align:baseline;'\u003e\u003cspan style='font-size:13px;line-height: 150%;font-family:\"Calibri\",sans-serif;color:black;'\u003e24.72%\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:42.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:#1DDAA4;padding:0in 5.4pt 0in 5.4pt;height:26.45pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;vertical-align:baseline;'\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Calibri\",sans-serif;color:black;'\u003eIIC\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:42.55pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:#1DDAA4;padding:0in 5.4pt 0in 5.4pt;height:26.45pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;vertical-align:baseline;'\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Calibri\",sans-serif;color:black;'\u003e24\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:42.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:#1DDAA4;padding:0in 5.4pt 0in 5.4pt;height:26.45pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;vertical-align:baseline;'\u003e\u003cspan style='font-size:13px;line-height: 150%;font-family:\"Calibri\",sans-serif;color:black;'\u003e26.97%\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:49.4pt;border:solid windowtext 1.0pt;border-top: none;background:#E0DDB7;padding:0in 5.4pt 0in 5.4pt;height:31.45pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;vertical-align:baseline;'\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Calibri\",sans-serif;color:black;'\u003eT4b\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:49.6pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:#E0DDB7;padding:0in 5.4pt 0in 5.4pt;height:31.45pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;vertical-align:baseline;'\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Calibri\",sans-serif;color:black;'\u003e31\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:49.6pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:#E0DDB7;padding:0in 5.4pt 0in 5.4pt;height:31.45pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;vertical-align:baseline;'\u003e\u003cspan style='font-size:13px;line-height: 150%;font-family:\"Calibri\",sans-serif;color:black;'\u003e34.83%\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:42.55pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:#FF8C3E;padding:0in 5.4pt 0in 5.4pt;height:31.45pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;vertical-align:baseline;'\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Calibri\",sans-serif;color:black;'\u003eIIC\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:42.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:#FF8C3E;padding:0in 5.4pt 0in 5.4pt;height:31.45pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;vertical-align:baseline;'\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Calibri\",sans-serif;color:black;'\u003e31\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:42.55pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:#FF8C3E;padding:0in 5.4pt 0in 5.4pt;height:31.45pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;vertical-align:baseline;'\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Calibri\",sans-serif;color:black;'\u003e34.83%\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:42.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:#1DDAA4;padding:0in 5.4pt 0in 5.4pt;height:31.45pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;vertical-align:baseline;'\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Calibri\",sans-serif;color:black;'\u003eIIIC\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:42.55pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:#1DDAA4;padding:0in 5.4pt 0in 5.4pt;height:31.45pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;vertical-align:baseline;'\u003e\u003cspan style='font-size:13px;line-height:150%;font-family:\"Calibri\",sans-serif;color:black;'\u003e28\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:42.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;background:#1DDAA4;padding:0in 5.4pt 0in 5.4pt;height:31.45pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;line-height:150%;vertical-align:baseline;'\u003e\u003cspan style='font-size:13px;line-height: 150%;font-family:\"Calibri\",sans-serif;color:black;'\u003e31.46%\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3.\u003c/strong\u003e The sentinel lymph node positivity, mean MIA score, adjuvant treatment, recurrence and disease-free survival percentage of patients in the high-risk melanoma group (T3b, T4a and T4b). MIA, Melanoma Institute Australia; SLNB, sentinel lymph node\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"643\" class=\"fr-table-selection-hover\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eT3b (n=36)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eT4a (n=22)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eT4b (n=31)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMean MIA prediction\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e24.0% (6%-58%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e27.1% (1%-51%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e35.4% (18%-71%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eActual SLNB positivity\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e13 (36.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e8 (36.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e7 (22.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAdjuvant treatment\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e14 (38.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e17 (77.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e13 (41.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRecurrence recorded\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e10 (27.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e6 (27.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e12 (38.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAlive without disease recurrence\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e24 (66.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e10 (45.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e19 (61.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"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":"[email protected]","identity":"world-journal-of-surgical-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"wjso","sideBox":"Learn more about [World Journal of Surgical Oncology](http://wjso.biomedcentral.com)","snPcode":"12957","submissionUrl":"https://submission.nature.com/new-submission/12957/3","title":"World Journal of Surgical Oncology","twitterHandle":"@OncoBioMed","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Melanoma, lymph node, SLNB, immunotherapy, Surgery, oncology","lastPublishedDoi":"10.21203/rs.3.rs-8321644/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8321644/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eIntroduction:\u003c/h2\u003e \u003cp\u003eSentinel lymph node (SLN) status remains a key prognostic factor in melanoma. However, recent advances in immunotherapy have prompted debate over the necessity of Sentinel lymph node biopsy (SLNB). This study evaluates the impact of SLN on disease-free survival (DFS), recurrence, and staging in melanoma patients.\u003c/p\u003e\u003ch2\u003eMethods:\u003c/h2\u003e \u003cp\u003eA retrospective analysis was conducted on 300 patients with histologically confirmed cutaneous melanoma who underwent SLN biopsy between April 2018 and April 2023. Patients were classified as low-risk (T1\u0026ndash;T3a) or high-risk (T3b\u0026ndash;T4b). Clinical, pathological, and outcome data were analysed. Variables were compared using Mann-Whitney U test and Fisher\u0026rsquo;s exact test where appropriate. DFS and recurrence were evaluated relative to SLN status using Kaplan-Meier and log-rank test.\u003c/p\u003e\u003ch2\u003eResults:\u003c/h2\u003e \u003cp\u003eMedian age was 60.7 years; 51.3% were female. SLN positivity was observed in 22% overall, significantly higher in high-risk patients (31.5% vs. 18.0%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.009). Recurrence occurred in 16%, more frequently in high-risk patients (31.5% vs. 9.5%). Median DFS was 1389 days; lower in high-risk patients (1141 vs. 1481 days, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). SLN positivity correlated with reduced DFS (1168 vs. 1481 days, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.056). Breslow thickness and mitotic index predicted recurrence. SLNB led to major reclassification of clinical stage, identifying Stage IIIC disease in 31.46%. of cases presumed Stage IIB/C.\u003c/p\u003e\u003ch2\u003eConclusion:\u003c/h2\u003e \u003cp\u003eSLNB provides essential prognostic and staging information. Its omission risks misclassification and mismanagement, impacting survival predictions and treatment decisions. SLNB should remain a cornerstone of staging especially in high-risk melanoma, even in the evolving context of immunotherapy.\u003c/p\u003e","manuscriptTitle":"Sentinel lymph node status and oncological outcomes of high-risk and low-risk cutaneous primary melanoma","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-22 09:27:27","doi":"10.21203/rs.3.rs-8321644/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-12-30T09:40:52+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"170946467690591448645874820721616320185","date":"2025-12-29T14:52:47+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-27T23:49:22+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"162070050105741265310621392594553814850","date":"2025-12-25T18:43:44+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-22T20:12:18+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"4589455367180373591019280912909841535","date":"2025-12-22T19:56:07+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-21T16:57:50+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"249684743846585081233769991198148967415","date":"2025-12-20T06:44:26+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-12-20T05:43:58+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-12-13T13:33:27+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-12-11T09:05:28+00:00","index":"","fulltext":""},{"type":"submitted","content":"World Journal of Surgical Oncology","date":"2025-12-09T23:44:39+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"world-journal-of-surgical-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"wjso","sideBox":"Learn more about [World Journal of Surgical Oncology](http://wjso.biomedcentral.com)","snPcode":"12957","submissionUrl":"https://submission.nature.com/new-submission/12957/3","title":"World Journal of Surgical Oncology","twitterHandle":"@OncoBioMed","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"9455f930-4e72-4e89-bb50-189bb187157b","owner":[],"postedDate":"December 22nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-03-16T16:10:28+00:00","versionOfRecord":{"articleIdentity":"rs-8321644","link":"https://doi.org/10.1186/s12957-026-04278-7","journal":{"identity":"world-journal-of-surgical-oncology","isVorOnly":false,"title":"World Journal of Surgical Oncology"},"publishedOn":"2026-03-13 15:58:54","publishedOnDateReadable":"March 13th, 2026"},"versionCreatedAt":"2025-12-22 09:27:27","video":"","vorDoi":"10.1186/s12957-026-04278-7","vorDoiUrl":"https://doi.org/10.1186/s12957-026-04278-7","workflowStages":[]},"version":"v1","identity":"rs-8321644","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8321644","identity":"rs-8321644","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}