Association of primary lesion surgery and surgical modality with overall survival in patients with stage IV cutaneous melanoma: a population-based study

Introduction

Melanoma poses a substantial global health burden, with an estimated 325,000 new cases diagnosed each year (1). Cutaneous melanoma (CM) is the most common subtype, accounting for more than 90% of all melanoma cases (2). In contrast to patients with early or intermediate-stage melanoma, those with stage IV CM have a poor prognosis, as the disease is largely unresponsive to conventional chemotherapy and radiotherapy (3). Prior to the advent of innovative therapeutic strategies including targeted therapy and immune checkpoint inhibitors, effective treatment options for stage IV melanoma patients were extremely limited, leading to a 5-year overall survival (OS) rate of less than 10% (4).

Surgical excision remains the first-line treatment for patients with early-stage melanoma (5-7), and evidence has shown that wide excision with a surgical margin of at least 1 cm and no more than 2 cm is sufficient for such patients (8). However, the role of surgery as a local treatment for stage IV melanoma is rather limited, as systemic therapy is the standard treatment for patients with unresectable disease (9). It is estimated that only a small proportion of stage IV melanoma patients are suitable for surgical intervention, and cases with completely resectable lesions are even rarer (10). According to international clinical guidelines, for patients with oligometastatic melanoma who are deemed eligible for surgical intervention, Class IA evidence supports surgical resection of both the primary tumor and metastatic lesions, followed by adjuvant systemic therapy (11,12).

In clinical practice, three main surgical modalities have been adopted for primary tumor resection, including local tumor excision, gross excision, and wide excision. Local tumor excision generally refers to the removal of the visible tumor with a minimal margin, often used in palliative or minimally invasive settings. Gross excision aims to resect the primary tumor mass macroscopically but without strict standardized margin control. Wide excision, the standard approach for early-stage melanoma, involves removing the primary tumor with a defined healthy tissue margin to reduce local recurrence risk. However, standardized surgical protocols and clinical guidelines for the management of metastatic melanoma are still lacking, and there are no comprehensive reports evaluating the impact of primary lesion surgery and different surgical modalities on patient survival outcomes. As a result, the current surgical strategies for stage IV melanoma remain controversial in clinical practice. Key unanswered questions include whether surgical resection of the primary lesion can improve OS in stage IV melanoma patients, which tumor sub-stages (M1a, M1b, or M1c) are appropriate for surgical intervention, and what the survival differences are among patients receiving different surgical techniques (e.g., local tumor excision, gross excision, or wide excision). In addition, it is still debatable whether wide excision of the primary lesion, as applied in early-stage melanoma, is necessary for stage IV patients. Therefore, large-scale retrospective studies are urgently needed to investigate the effect of primary lesion surgery on the survival of stage IV melanoma patients.

In this study, we conducted a comprehensive retrospective analysis using large-scale data from the Surveillance, Epidemiology, and End Results (SEER) database to evaluate the impact of primary lesion surgical intervention on the survival outcomes of patients with stage IV CM, and further attempted to identify the optimal surgical approach for this patient population. We present this article in accordance with the STROBE reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2026-1-0313/rc).

Methods

Study design and participants

This retrospective study extracted data from the SEER database covering 17 U.S. states from 2010 to 2015, and no new human or animal subjects were enrolled. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The inclusion criteria were: pathologically diagnosed stage IV (M1a–c) melanoma (ICD-O-3, SEER codes C440–C449, International Classification of Diseases for Oncology, 3rd Edition); no age restrictions; and complete relevant clinical data including age, sex, race, diagnostic stage, primary tumor site and pathology, lactate dehydrogenase (LDH) levels, treatment strategies (primary lesion surgery, radiotherapy, chemotherapy), as well as complete and assessable survival data. The exclusion criteria were: ambiguous pathological diagnosis or unclear primary tumor site; stage I–III tumors; indeterminate M-stage (unable to classify as M1a, M1b, or M1c); incomplete data on surgery, chemotherapy, or radiotherapy; and missing follow-up data or unknown survival status. The tumor staging standard was uniformly based on the seventh edition of the American Joint Committee on Cancer (AJCC) staging system. After data screening using SEER*Stat 8.4.3, a total of 3,155 patients (656 surgical patients and 2,499 non-surgical patients) met the above inclusion and exclusion criteria. After 1:2 propensity score matching (PSM) based on surgical status, 1,876 patients were finally included in the analysis, with 648 in the surgical group and 1,228 in the non-surgical group.

Study outcomes and statistical analysis

The primary endpoint of the study was OS, defined as the time from the date of cancer diagnosis to the date of death, as recorded in the SEER database. All statistical analyses were performed using R software (version 4.4.0). To balance baseline variables including age (<65 or ≥65 years), gender (male or female), race (White, Black, or other), year of diagnosis (2010–2012 or 2013–2015), chemotherapy (yes or no), radiotherapy (yes or no), and LDH levels [below normal (≤250 U/L), above normal (>250 U/L), or unknown], 1:2 PSM was performed between the surgical and non-surgical groups. For patients with stage IV melanoma, the PSM model was pre-defined to prioritize M stage (M1a, M1b, M1c) as the key prognostic factor for advanced disease. T stage and N stage were not included in the model, and their prognostic impacts were evaluated through subsequent subgroup analyses. The Chi-squared test or Fisher’s exact test was used to compare clinical variables between the two treatment groups. Multivariate Cox regression analysis was applied to assess the association between each risk factor and overall survival. The Kaplan-Meier method was used to compare OS between the surgical and non-surgical groups and among different surgical modalities, with the log-rank test used to evaluate survival differences. To further validate the robustness of the primary findings, additional subgroup survival analyses stratified by T stage and N stage were performed in the PSM-matched cohort. A two-sided P value <0.05 was considered statistically significant.

Results

Patient characteristics

A total of 3,155 eligible patients with stage IV (M1a–c) CM were identified from the SEER database, among whom 656 (20.8%) underwent primary lesion surgery and 2,499 (79.2%) did not receive primary lesion surgical intervention. The baseline characteristics and treatment information of the two groups before and after PSM are presented in Table 1. Before matching, significant imbalances were observed in several baseline variables between the surgical and non-surgical groups, including age, race, disease stage, radiotherapy administration, and LDH levels. After 1:2 PSM, all baseline characteristics were well balanced between the two groups.

Survival before PSM

Before PSM, patients who underwent primary lesion surgery had significantly longer OS than those who did not. The median OS was 16 months in the surgical cohort and 6 months in the non-surgical cohort [hazard ratio (HR) 0.65; 95% confidence interval (CI): 0.59–0.71; P<0.001; Figure 1A]. Furthermore, surgical patients had significantly longer OS than non-surgical patients in the M1a subgroup (P<0.001; Figure 1B). In the M1b subgroup, surgical patients exhibited a trend toward improved OS, though this difference did not reach statistical significance (P=0.054; Figure 1C). A similar survival benefit was also observed in the M1c subgroup (P<0.001; Figure 1D). The survival benefit of surgery was consistently observed across various subgroups stratified by age, gender, year of treatment, disease stage, radiotherapy and chemotherapy administration (Figure 2).

Figure 1 Kaplan-Meier analysis. Overall survival in participants with stage IV cutaneous melanoma before propensity score matching. (A) Overall population; (B) M1a population; (C) M1b population; (D) M1c population.

Figure 2 Subgroup analyses of overall survival according to baseline characteristics before propensity score matching. CI, confidence interval; HR, hazard ratio; LDH, lactate dehydrogenase.

Multivariate Cox regression analysis showed that in addition to surgery, age, tumor stage, chemotherapy, and LDH levels were independent prognostic factors for OS in patients with stage IV CM (Table 2).

Survival after PSM

After PSM, the median OS was 16 months in the surgical cohort and 8 months in the non-surgical cohort (HR 0.71; 95% CI: 0.64–0.79; P<0.001; Figure 3A). Surgical patients still had significantly longer OS than non-surgical patients in the M1a subgroup (P<0.001; Figure 3B). In the M1b subgroup, there was still a trend toward improved OS in surgical patients, but the difference was not statistically significant (P=0.11; Figure 3C). A consistent survival benefit was observed in the M1c subgroup (P<0.001; Figure 3D). The results of subgroup analyses after matching were consistent with those before matching (Figure 4).

Figure 3 Kaplan-Meier analysis. Overall survival in participants with stage IV cutaneous melanoma after propensity score matching. (A) Overall population; (B) M1a population; (C) M1b population; (D) M1c population.

Figure 4 Subgroup analyses of overall survival according to baseline characteristics after propensity score matching. CI, confidence interval; HR, hazard ratio; LDH, lactate dehydrogenase.

Multivariate Cox regression analysis identified surgery, age, tumor stage, and LDH levels as independent prognostic factors for OS, while chemotherapy was not found to be a predictor of improved OS (Table 2).

Given the potential imbalance of T and N stages between the surgical and non-surgical groups, subgroup analyses stratified by T and N classification were conducted in the PSM cohort to verify the consistency of the primary findings. Detailed results are shown in Figure S1. Consistent with the main survival outcomes, primary tumor resection was associated with a significant OS benefit across nearly all evaluated T stage subgroups (T0, T1, T2, T3, T4, and Tx) and N stage subgroups (N0, N1, N2, N3, and Nx). No significant interaction was observed between surgery status and either T stage or N stage (all P for interaction >0.05).

Survival with surgical modalities

There were no significant differences in the baseline characteristics of surgical patients before and after PSM based on surgical modalities (Table 1). Therefore, we focused on analyzing the differences in OS among surgical patients receiving different surgical modalities after matching.

As shown in Table 1, among the 648 surgical patients, the surgical modalities included local tumor destruction [3 patients (0.5%); surgical codes 10–14], local tumor excision [282 patients (43.5%); surgical codes 20–27], gross excision [173 patients (26.7%); surgical codes 30–36], wide excision [150 patients (23.1%); surgical codes 45–47], major amputation [7 patients (1.1%); surgical code 60], and not otherwise specified (NOS) [33 patients (5.1%); surgical code 90]. Detailed descriptions of the SEER surgical codes are provided in the supplementary materials. Among these modalities, three main surgical approaches (local tumor excision, gross excision, and wide excision) accounted for 93.3% of all cases, with the remaining modalities accounting for a small proportion. Thus, we focused on comparing the prognostic effects of these three surgical modalities. The median OS was 16 months for local tumor excision, 25 months for gross excision, and 11 months for wide excision (P<0.001; Figure 5A). Both gross excision and wide excision were associated with significantly better OS than local tumor excision (P<0.001 and P=0.002, respectively; Figure 5B,5C). Gross excision showed a trend toward improved OS compared with wide excision, but this difference did not reach statistical significance (P=0.08; Figure 5D).

Figure 5 Kaplan-Meier analysis. Overall survival among surgical patients receiving different surgical modalities after propensity score matching. (A) Gross excision versus wide excision versus local tumor excision. (B) Gross excision versus local tumor excision. (C) Wide excision versus local tumor excision. (D) Gross excision versus wide excision.

Discussion

To the best of our knowledge, this retrospective analysis is the first comprehensive study to evaluate the impact of primary lesion surgical intervention and different surgical modalities on the prognosis of patients with stage IV CM. Our findings suggest that surgery is an independent prognostic factor for OS in this patient population. Notably, surgical resection of the primary tumor can significantly improve OS, especially in the M1a and M1c subgroups. In addition, our results indicate that different main surgical modalities have a notable impact on patient survival outcomes: patients who underwent gross excision or wide excision had better survival outcomes than those who only received local tumor excision, and gross excision showed a trend toward better survival than wide excision. Although the difference in OS between the gross excision and wide excision groups was not statistically significant, a clinical benefit-risk assessment suggests that gross excision may be a more favorable option, as it can avoid the potential greater surgical trauma associated with wide excision.

Surgery has long been the main treatment for patients with resectable metastatic melanoma, particularly for stage III or IV disease, where complete surgical resection has been traditionally regarded as the gold standard (13). R0 resection has been shown to have a beneficial effect on the prognosis of stage IV melanoma patients (14). However, achieving complete resection of both primary and metastatic lesions remains a major clinical challenge. Since the development of modern surgical oncology, complete lymph node dissection has been routinely performed after a positive sentinel lymph node biopsy (15). Nevertheless, two randomized controlled trials have shown that complete lymph node dissection does not bring a survival benefit to patients with positive sentinel lymph node biopsy, leading to its no longer being recommended as a mandatory procedure (16,17). Therapeutic lymph node dissection is still used for patients with clinically evident lymph node metastasis, and surgical intervention may be considered in selected cases of distant melanoma metastasis (18). In addition, the emergence of adjuvant therapy and the potential of novel immunotherapeutic strategies in the future have prompted a re-evaluation of the role of systemic therapy in metastatic melanoma, with a tendency to adopt less extensive surgical approaches (19). This perspective is consistent with the findings of our study.

In our study, only approximately 20% of patients underwent primary lesion surgery, which is consistent with the results of other studies reporting a surgical rate of 13% to 30% (20). This suggests that most patients lose the opportunity for complete resection at the time of diagnosis of stage IV disease. Therefore, for the limited number of patients eligible for surgical treatment, the selection of the optimal surgical approach is crucial for improving their prognosis. Several studies have shown that resection of metastatic lesions can bring significant survival benefits to stage IV melanoma patients who undergo surgical resection, with the 5-year OS rate generally ranging from 15% to 30% depending on the disease severity and tumor biological characteristics (21,22). A major challenge in clinical practice is the difficulty of fully evaluating and establishing a unified standard for the complete excision of primary and metastatic tumors before surgery, as this evaluation largely depends on the surgeon’s clinical experience and expertise. As a result, there is still a lack of consistent clinical standards to guide surgical strategies for CM with distant metastatic lesions.

Most clinical studies have mainly focused on the impact of metastatic lesion resection on the prognosis of stage IV melanoma patients, with limited research on the effect of primary lesion surgery on patient outcomes. O’Neill’s study indicated that negative microscopic resection margins are sufficient for metastatic lesion resection in M1a disease, while wide excision of the primary lesion may require a margin of 1–2 cm (23). In addition, patients with favorable prognostic factors such as normal LDH levels are more likely to benefit from surgical intervention (24), which is consistent with the results of our subgroup analysis. Furthermore, Sukniam et al. found that molecular mutations such as NRAS, BRAF and NF1 are risk factors for the invasion and progression of metastatic melanoma; thus, the detection of these genetic alterations may provide important references for individualizing surgical strategies for patients (25). Although there is evidence that surgery can play a role in the management of stage IV melanoma, there is currently a lack of standardized criteria for the surgical approach to the primary lesion and the selection of surgical modalities. In this study, we used a large comparative dataset to analyze the impact of different surgical modalities on the OS of stage IV melanoma patients, and our findings suggest that gross excision may be the preferred surgical approach compared with local tumor excision and wide excision. This implies that expanding the surgical margin may not be necessary and could potentially result in overtreatment for stage IV melanoma patients. These insights may provide valuable references for clinicians engaged in the surgical management of stage IV melanoma and guide future research directions.

There are several notable limitations in this study. First, as a retrospective study using SEER database data, the inherent heterogeneity of the study population and the non-prospective study design may have an impact on the research results. Second, the selection of primary tumor surgery in stage IV melanoma was based on multidisciplinary evaluation, including patient performance status, tumor burden, metastatic distribution, treating physician’s judgment, and patient preference, and such non-randomized treatment allocation leads to unavoidable selection bias, which may introduce additional heterogeneity and confound the survival analysis to a certain extent. Third, the observed survival benefit of primary tumor surgery may be confounded by inherent selection bias. Specifically, patients who underwent surgical resection likely had more favorable tumor biology, resectable primary lesions, and achievable locoregional control—factors that may independently contribute to improved survival outcomes, rather than the surgical intervention itself. This limits the ability to definitively attribute the survival advantage solely to the therapeutic effect of primary tumor resection. Fourth, although we classified surgical modalities according to standardized codes, the diversity of surgical approaches used in clinical practice may still introduce potential biases, so the results of this study should be interpreted with caution. Fifth, the differential effects of different surgical combination strategies (e.g., combined with adjuvant therapy) on patient prognosis have not been fully evaluated. Numerous studies have shown that surgery combined with adjuvant immune checkpoint inhibitors or targeted drugs can further improve the survival of stage IV melanoma patients (26-28). Sixth, the anatomical site of the primary melanoma, which may affect the decision for surgical resection, was not included in the present analysis. Given the focus of this study on survival outcomes in stage IV metastatic melanoma, detailed stratification by primary tumor site was not performed in the pre-established dataset, which represents another potential source of unmeasured confounding. Finally, due to resource constraints, we were unable to conduct more detailed subgroup analyses stratified by surgical modalities to clarify the prognostic impact of different surgical approaches across distinct tumor sub-stages (M1a, M1b, and M1c), which requires further investigation in future studies.

Conclusions

This retrospective cohort study using SEER database data demonstrates that surgical intervention for the primary lesion can significantly improve OS in patients with stage IV CM, and primary lesion surgery is an independent prognostic factor for this population. In addition, surgical modality has a significant impact on survival outcomes: among the three main surgical modalities analyzed, gross excision was associated with the most favorable survival outcomes, while wide excision did not appear to confer additional survival benefits. Considering the retrospective design of this study, prospective cohort studies are needed to validate and further explore these findings.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2026-1-0313/rc

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2026-1-0313/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2026-1-0313/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Siegel RL, Kratzer TB, Wagle NS, et al. Cancer statistics, 2026. CA Cancer J Clin 2026;76:e70043. [Crossref] [PubMed]
2. Joshi UM, Kashani-Sabet M, Kirkwood JM. Cutaneous Melanoma: A Review. JAMA 2025;334:2113-25. [Crossref] [PubMed]
3. Wang X, Ma S, Zhu S, et al. Advances in Immunotherapy and Targeted Therapy of Malignant Melanoma. Biomedicines 2025;13:225. [Crossref] [PubMed]
4. Tasdogan A, Sullivan RJ, Katalinic A, et al. Cutaneous melanoma. Nat Rev Dis Primers 2025;11:23. [Crossref] [PubMed]
5. Utjés D, Malmstedt J, Teras J, et al. 2-cm versus 4-cm surgical excision margins for primary cutaneous melanoma thicker than 2 mm: long-term follow-up of a multicentre, randomised trial. Lancet 2019;394:471-7. [Crossref] [PubMed]
6. Orme SE, Moncrieff MD. A Review of Contemporary Guidelines and Evidence for Wide Local Excision in Primary Cutaneous Melanoma Management. Cancers (Basel) 2024;16:895. [Crossref] [PubMed]
7. Hayes AJ, Maynard L, Coombes G, et al. Wide versus narrow excision margins for high-risk, primary cutaneous melanomas: long-term follow-up of survival in a randomised trial. Lancet Oncol 2016;17:184-92. [Crossref] [PubMed]
8. Haigh PI, DiFronzo LA, McCready DR. Optimal excision margins for primary cutaneous melanoma: a systematic review and meta-analysis. Can J Surg 2003;46:419-26. [PubMed]
9. Lauters R, Brown AD, Harrington KA. Melanoma: Diagnosis and Treatment. Am Fam Physician 2024;110:367-77. [PubMed]
10. Wevers KP, Hoekstra HJ. Stage IV melanoma: completely resectable patients are scarce. Ann Surg Oncol 2013;20:2352-6. [Crossref] [PubMed]
11. Swetter SM, Johnson D, Albertini MR, et al. NCCN Guidelines® Insights: Melanoma: Cutaneous, Version 2.2024. J Natl Compr Canc Netw 2024;22:290-8. [Crossref] [PubMed]
12. Farma JM, Olszanski AJ, Messina JL, et al. Annals of Surgical Oncology Practice Guidelines Series: Adjuvant and Neoadjuvant Therapy for Melanoma. Ann Surg Oncol 2025;32:3-11. [Crossref] [PubMed]
13. Testori AAE, Blankenstein SA, van Akkooi ACJ. Surgery for Metastatic Melanoma: an Evolving Concept. Curr Oncol Rep 2019;21:98. [Crossref] [PubMed]
14. Leung AM, Hari DM, Morton DL. Surgery for distant melanoma metastasis. Cancer J 2012;18:176-84. [Crossref] [PubMed]
15. Allard-Coutu A, Dobson V, Schmitz E, et al. The Evolution of the Sentinel Node Biopsy in Melanoma. Life (Basel) 2023;13:489. [Crossref] [PubMed]
16. Faries MB, Thompson JF, Cochran AJ, et al. Completion Dissection or Observation for Sentinel-Node Metastasis in Melanoma. N Engl J Med 2017;376:2211-22. [Crossref] [PubMed]
17. Leiter U, Stadler R, Mauch C, et al. Complete lymph node dissection versus no dissection in patients with sentinel lymph node biopsy positive melanoma (DeCOG-SLT): a multicentre, randomised, phase 3 trial. Lancet Oncol 2016;17:757-67. [Crossref] [PubMed]
18. Walker RJB, Look Hong NJ, Moncrieff M, et al. Predictors of Sentinel Lymph Node Metastasis in Patients with Thin Melanoma: An International Multi-institutional Collaboration. Ann Surg Oncol 2022;29:7010-7. [Crossref] [PubMed]
19. Tarhini AA. Adjuvant Therapy of Melanoma. Hematol Oncol Clin North Am 2021;35:73-84. [Crossref] [PubMed]
20. Huo J, Du XL, Lairson DR, et al. Utilization of surgery, chemotherapy, radiation therapy, and hospice at the end of life for patients diagnosed with metastatic melanoma. Am J Clin Oncol 2015;38:235-41. [Crossref] [PubMed]
21. Martinez SR, Young SE. A rational surgical approach to the treatment of distant melanoma metastases. Cancer Treat Rev 2008;34:614-20. [Crossref] [PubMed]
22. Howard JH, Thompson JF, Mozzillo N, et al. Metastasectomy for distant metastatic melanoma: analysis of data from the first Multicenter Selective Lymphadenectomy Trial (MSLT-I). Ann Surg Oncol 2012;19:2547-55. [Crossref] [PubMed]
23. O'Neill CH, McMasters KM, Egger ME. Role of Surgery in Stage IV Melanoma. Surg Oncol Clin N Am 2020;29:485-95. [Crossref] [PubMed]
24. Agrawal S, Yao TJ, Coit DG. Surgery for melanoma metastatic to the gastrointestinal tract. Ann Surg Oncol 1999;6:336-44. [Crossref] [PubMed]
25. Sukniam K, Manaise HK, Popp K, et al. Role of Surgery in Metastatic Melanoma and Review of Melanoma Molecular Characteristics. Cells 2024;13:465. [Crossref] [PubMed]
26. Livingstone E, Zimmer L, Hassel JC, et al. Adjuvant nivolumab plus ipilimumab or nivolumab alone versus placebo in patients with resected stage IV melanoma with no evidence of disease (IMMUNED): final results of a randomised, double-blind, phase 2 trial. Lancet 2022;400:1117-29. [Crossref] [PubMed]
27. Eggermont AMM, Blank CU, Mandalà M, et al. Adjuvant pembrolizumab versus placebo in resected stage III melanoma (EORTC 1325-MG/KEYNOTE-054): distant metastasis-free survival results from a double-blind, randomised, controlled, phase 3 trial. Lancet Oncol 2021;22:643-54. [Crossref] [PubMed]
28. Weber J, Haque W, Markovic SN, et al. Relapse-free survival with adjuvant dabrafenib/trametinib therapy after relapse on a prior adjuvant CPI in BRAF V600-mutated stage III/IV melanoma. Oncologist 2025;30:oyae289. [Crossref] [PubMed]