Prognostic role of surgical margin status in pediatric neuroblastoma: a systematic review

Introduction

Neuroblastoma (NB) is a malignancy originating from neural crest cells that give rise to the sympathetic nervous system. It is the most common extracranial solid tumor of childhood and comprises roughly 8–10% of all childhood cancers, while accounting for about 12–15% of cancer-related deaths in the pediatric population (1). While 90% of cases are diagnosed before age 5 years, with 30% diagnosed within the first year of life. The median age of diagnosis is 22 months. This indicates the importance of early detection and the therapeutic challenges in very young patients (2-4). In some infants, the tumor may be identified incidentally via prenatal ultrasound, potentially allowing earlier intervention and improved outcomes in biologically favorable cases (5). The biological and clinical heterogeneity of NB, ranging from tumors that spontaneously regress to those that aggressively disseminate despite multimodal therapy, presents a critical challenge for both clinicians and researchers (6). Over the past few decades, advances in genetic profiling, risk stratification, and treatment protocols have improved outcomes, yet NB remains a major focus of pediatric oncologic research due to suboptimal survival in high-risk subgroups (7).

NB is characterized by marked biological heterogeneity driven by diverse genetic and molecular aberrations (8). MYCN amplification, present in 20–25% of NB cases, is a key genetic alteration linked to aggressive disease and poor prognosis (9). Other critical aberrations include 1p and 11q deletions, 17q gain and ALK mutations (10), all of which contribute to pathogenesis and inform risk stratification and targeted therapies (11).

For high-risk NB, the regimen starts with induction chemotherapy to shrink the tumor before safe surgical intervention, with consolidation treatment that incorporates high-dose chemotherapy and autologous stem cell transplant for residual disease. Surgery is an important treatment option, as gross-total or near-complete resection is associated with better local control and survival. Most patients undergo resection following induction chemotherapy to downstage large or invasive tumors and lessen perioperative risks. Experienced pediatric surgical oncologists are required to deal with challenging anatomy, especially when tumors encase vital vascular structures or visceral organs (12,13). Immunotherapy using dinutuximab and other agents also results in improved overall survival (OS) and event-free survival (EFS) and is used as part of the standard of care in developed countries (14,15). Nevertheless, surgical resection as the most important factor for long-term outcome continues to be the major concern.

The prognostic significance of positive surgical margins (PSMs), indicating residual microscopic or macroscopic disease at the resection boundary, remains debated in pediatric solid tumors, including NB (6). In many malignancies, complete resection with negative margins (R0) is the surgical goal, as residual tumor is associated with increased risk of local recurrence and potentially reduced long-term survival (4). Whether achieving negative surgical margins is universally essential or if positive margins can be tolerated without adversely affecting long-term outcomes particularly in the context of effective multimodal therapy, remains a subject of ongoing debate in pediatric oncology (16).

The aim of this systematic review is to investigate the influence of PSMs on oncological outcomes in children with NB and to primarily assess OS, EFS and local recurrence rates. Furthermore, this article will summarize the patient and tumor-related factors that might affect the impact of PSMs, with a special focus on the impact of surgical resection on long-term outcomes. We present this article in accordance with the PRISMA reporting checklist (available at https://pm.amegroups.com/article/view/10.21037/pm-25-75/rc).

Methods

Search strategy and selection criteria

A systematic literature search was performed in PubMed, Embase, Cochrane Library, Web of Science and Scopus for studies published between January 2014 and December 2024, examining the association between surgical margin status and oncologic outcomes in pediatric NB. Search terms included “neuroblastoma”, “surgical margins”, “positive margins”, “negative margins”, and “oncologic outcomes”, combined with pediatric-related synonyms using Boolean and wildcard operators. The search period from January 2014 to December 2024 was selected to include the most recent studies that reflect contemporary treatment protocols and outcomes, though this period could introduce potential selection bias. Details of search strategies and search results across the five databases are demonstrated in Table S1.

Inclusion criteria

We utilized the PICOS framework to select relevant studies: (I) Patient population (P): patients aged 1–18 years with an NB diagnosis. (II) Intervention/exposure (I): studies reporting on surgical margin status and its association with oncologic outcomes. (III) Comparison (C): patients with gross total resection (GTR) and negative margins (R0) compared to those with incomplete resection (R1/R2) or positive margins. (IV) Outcomes of interest (O): OS, EFS, and local recurrence rate. (V) Study design (S): cohort studies, case-control studies, cross-sectional studies or interventional clinical trials (prospective or retrospective). We included cohort studies due to their relevance to the research question, and we have clarified the inclusion criteria to ensure consistency.

Exclusion criteria

Studies were excluded if they were: (I) non-NB tumors: studies on adult neoplasms or other pediatric malignancies unrelated to NB; (II) non-English language: studies not in English due to logistical limitations; (III) case reports, editorial letters, and review articles that did not include primary data; (IV) inadequate reporting of outcomes: studies lacking numeric or descriptive data on OS, EFS, or local recurrence stratified by margin status.

Screening process

Records were exported into reference management software and duplicates were removed. The studies included in this review span all stages of NB (International Neuroblastoma Risk Group staging system), with a mix of L1, L2, and metastatic (M) cases, including surgeries performed at various stages.

Title and abstract screening

Two independent reviewers screened records based on predefined eligibility criteria. Studies that obviously did not meet the criteria were excluded.

Full-text screening

Relevant studies were reviewed in detail. Discrepancies were resolved through discussion, with a third reviewer acting as a tiebreaker if needed. This process minimized selection bias (Figure 1).

Figure 1 PRISMA flowchart for the systematic review process.

Data extraction

A standardized data extraction form was used to capture essential study characteristics, participant data, surgical margin status, adjuvant therapies, and outcomes. Key details extracted included: (I) study characteristics: author(s), year of publication, study design, multicenter vs. single-center, country, and setting; (II) participant characteristics: number of cases, age range, gender distribution, staging, MYCN status and histopathological classification; (III) surgical margin data: method of evaluation, definition (positive/negative), extent of resection such as: GTR, incomplete macroscopic resection (IME), and PSMs; (IV) adjuvant therapies: chemotherapy, radiotherapy, immunotherapy, and stem cell transplantation; (V) primary and secondary endpoints: OS, EFS and local recurrence rates. Data extraction was conducted by the same two reviewers. Disagreements were resolved by consensus or by involving a third reviewer.

Quality assessment and risk of bias

The Newcastle-Ottawa Scale (NOS) was used to assess the methodological quality of observational studies. It evaluates three general areas: selection, comparability, and outcome. Each study could receive a maximum of nine stars. Studies with ≥7 stars were considered high quality, 4–6 stars as moderate, and <4 stars as low quality.

The Cochrane risk of bias tool was employed for clinical trials, focusing on random sequence generation, allocation concealment, blinding, incomplete outcome data and selective outcome reporting (Table S2).

Synthesis of results

The review primarily follows a qualitative systematic review approach due to significant heterogeneity across the included studies. As the studies varied in terms of surgical techniques, margin definitions (positive versus negative) and outcome reporting, formal statistical synthesis, including meta-analysis and pooled effect estimates, was not feasible. Instead, we used a narrative synthesis to summarize and interpret the findings. The inclusion of heterogeneous studies and the absence of standardized data reporting led us to refrain from conducting statistical tests such as meta-analysis. This decision was made to ensure that the synthesis remained accurate and meaningful without overgeneralizing the results. This is discussed further in the Limitations section.

Results

This particular systematic review was conducted to pool data from 19 NB studies in order to assess the effects of surgical margin status and other treatment factors on OS, EFS and local recurrence. The reviewed studies were mainly retrospective cohort studies (n=15), and there were three prospective cohort studies and one observational study included, with a total of 3,251 cases from multiple countries (USA, Germany, Japan, China, and others) (4,12,17-33) (Table 1).

Surgical margin status and its impact

Surgical margin status was one of the main reasons for reported differences in results from studies. GTR rates ranged from 59.2% to 95%. IME or PSMs were also associated with inferior OS and EFS. In high-risk stage NB, complete resection (R0) is often not feasible, and R1 resection is the best achievable outcome, which still leaves microscopic residual disease. For instance, the study by Holmes et al. (19) found OS was 45%, and for IME it was 37%. On the other hand, reports such as Shirota et al. (18) found that in patients who completed resection, the results were promising, with no recurrences in the laparoscopic group with complete resection (Tables 2,3).

OS and EFS

OS and EFS were significantly associated with gross total resection and no residual tumor on magnetic resonance imaging (MRI). The average OS varied between 35% and 92.3% in the studies. For instance, Fischer et al. (20) extracted an OS at 5 years of 92.3% for patients with complete resection. In comparison, works such as Liu et al. (34) demonstrated that the 5-year OS of high-risk disease patients with incomplete resection was 68.4%. The EFS was also between 32.5% and 87.8% in studies. The best EFS was described by Shirota et al. (18) at 100% for laparoscopic patients who had a complete resection (Tables 3,4).

Local recurrence and metastasis

Local recurrence was a major problem, especially in patients undergoing incomplete resections. Local recurrence was reported anywhere from 3% to 40%. For example, Holmes et al. (19) reported a 17% recurrence in the GTR group. Metastatic dissemination also appeared common, with reported rates of distant metastases of 8%–30%. Increased risk of local or combined failure was observed in relation to the residual tumor, as reported in Schäfer et al. (22), where 50% of patients with residual disease relapsed or progressed locally (Tables 3,5).

Positive margins or suboptimal resections were highly associated with increased recurrence rate and reduced survival (19,21,22,34), where GTR provided a positive impact on OS and EFS (18,20). Survival at 5 years varied between 35% and 92%, with those having complete resections or no residual tumour faring better (20,24). EFS was significantly better in patients without residual tumor, where the median EFS was 81 months, compared to 43 months for those with residual disease. Local recurrence was most common in those whose resections were incomplete, with rates of up to 40%, and least common in patients with complete resections, for which some series have reported rates around 3% (18,19,22,34-36).

Discussion

The purpose of this systematic review is to evaluate the influence of margin status, resection completeness, and the existence of remaining disease on the surgical management of patients with NB. The results emphasize the importance of margin status and no residual disease for survival and recurrence. PSMs and non-R0 resections were significantly correlated with higher local recurrence rates, worse OS and EFS. In contrast, GTR and negative imaging for residual disease were associated with a favorable outcome in all patients. In high-risk NB, R0 resection is rarely achievable, and most cases involve R1 resection with some degree of residual disease.

Surgical margin status and its clinical implications

Prognosis was undoubtedly one of the major focuses of discussion for the included studies, which highlighted the role of surgical margin status on patient survival. PSMs and IME were significantly associated with worse survival and recurrence rates. For instance, Holmes et al. (19) revealed that complete resection in patients was associated with 45% and 37% OS for complete and incomplete resections, respectively, highlighting the necessity of performing a complete resection in order to increase survival. These results are consistent with other studies including Fischer et al. (20), who reported a statistically significant better OS and EFS in GTR patients in comparison to those with incomplete resections. In contrast, Shirota et al. (18) found no recurrence in their total resection laparoscopy patients, which also suggests a direct relationship between complete resection and good prognosis. These findings are consistent with previous reports demonstrating that incomplete resections and positive margins are associated with significantly worse survival, especially for high-risk NB patients. Recent studies have indicated that a radical surgery, when possible, is the goal of surgical treatment and it is crucial for local control and long-term survival (21,34). Residual tumor after surgery has also been identified as a prognostic risk factor of recurrence, requiring more frequent follow-up and, in some cases, adjuvant treatment (20).

OS and EFS

Complete resection and the absence of residual disease were both favorable to OS and EFS. It is consistently reported in studies that patients with no residual tumor, as evidenced by imaging as determined by MRI, also have remarkably better OS. Fischer et al. (20) described an OS of 92.3% at 5 years for patients treated with complete resection, also highlighting the importance of complete tumor removal. However, high-risk patients with incomplete resection had significantly worse prognosis, with 5-year OS of 68.4% as reported by Liu et al. (34). The results of Shirota et al. (18) are especially remarkable since they demonstrated 100% OS and disease-free survival (DFS) in cases with an R0 resection performed by laparoscopy. This strongly supports the survival advantages of radical surgery. These findings are consistent with those of other investigators in the field, which emphasize the significance of decreasing tumor bulk by total resection to enhance OS (18). Complete resection not only improves OS, it is also a significant predictor of increased EFS, indicating that achieving an R0 resection is important for both short- and long-term disease control (34). In addition, a number of reports have emphasized the role of postoperative imaging, preferably MRI, in the evaluation of surgical completeness in guiding subsequent treatment (22,37).

Local recurrence and metastasis

Local relapse continues to be a major problem in the treatment of NB, even in the presence of incomplete resections or positive margins. Local recurrence rates were 3% to 40% in the present review, similar to Holmes et al. (19), who reported GTR group recurrence prevalence of 17%. Moreover, Schäfer et al. (22) reported that half of the patients harboring residual disease relapsed or progressed locally, suggesting that even small volumes of residual tumor should be treated to accomplish effective local control (22). The association between residual tumor and local recurrence is well documented in the literature. A study by Holmes et al. (19) has repeatedly demonstrated that residual cancer, mostly in the form of PSMs, is an important factor for local recurrence. This is also supported by the results of Liu et al. (34), who showed that high risk patients with non-radical resections accrued a higher local progression rate, emphasizing the importance of careful surgery and postoperative follow-up (22,35). Furthermore, such patients frequently developed metastasis with a rate of distant metastasis between 8% and 30%. The association between residual tumor and risk of distant metastases is similar in studies like Schäfer et al. (22), which proposed that distant dissemination might be prevented with early detection and treatment with aggressive management of the residual disease.

If PSMs truly correlate with residual microscopic disease, they might increase the likelihood of local recurrence, though subsequent chemotherapy and radiation might still control or eradicate these residual cells. Some studies observing patients with positive margins have noted no significant difference in OS compared to those with negative margins, suggesting that adjuvant therapy compensates effectively in certain high-risk or high-intensity treatment protocols (36). However, in less aggressive disease, it remains unclear whether the presence of PSMs might prove more consequential, particularly if adjuvant treatments are less intensive (38).

This systematic review is the first to summarize the clinical effect of PSMs in childhood NB, pooling results from 19 international studies. Unlike most other studies that are related to the overall results of NB treatment, this study emphasizes the significance of the surgical margin status for determining long-term survival and recurrence rates. One of the most striking findings is that total macroscopic resection, when combined with negative surgical margins, strongly correlates with success and significantly increased OS and EFS. Notably, the 5-year OS showed wide variation, ranging from 35% to 92%, largely depending on the extent of resection and patient risk stratification—particularly favorable outcomes in low-risk and favorable-intermediate-risk patients with complete tumor removal. This in turn underscores the crucial role of total resection in the maximal management of patients and consequently the clear evidence base to guide clinical practice, as well as highlighting the necessity for surgical finesse in NB treatment.

Limitations

This review is constrained by the retrospective design of most of the included studies, which may lead to some selection bias. The heterogeneity of included studies, lack of standardized definitions, small sample sizes, short follow-up duration and publication bias are also considered as limitations for conducting this review. The inconsistency of results between the studies may be influenced by the diversity of surgical manipulations, the way to assess margins and the duration of follow-up. Due to the significant heterogeneity among the included studies, we did not perform a meta-analysis. Therefore, statistical analysis, forest plots and funnel plots were not generated. Furthermore, a lack of standardization in the reporting of outcomes such as local recurrence and metastasis confounds comparability.

Recommendations

The quality of investigation could be improved by future, large, prospective cohorts with standardized surgical techniques and margin assessment. Future long-term studies with homogeneous outcome definitions are needed to clarify the value of the surgical margins in survival and recurrence. In addition, the potential value of adjuvant therapies in those with positive margins can be tested.

Conclusions

In summary, the results of this systematic review further support that complete resection is pivotal in the enhancement of survival rates and reduction of relapse in NB patients. Positive or close resection margins and incomplete resections were the most significant predictors of increased rates of recurrence and poor OS. Adverse residual disease was significantly correlated with both local recurrence and metastasis, reiterating the importance of early detection and aggressive resection of residual tumor.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://pm.amegroups.com/article/view/10.21037/pm-25-75/rc

Peer Review File: Available at https://pm.amegroups.com/article/view/10.21037/pm-25-75/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://pm.amegroups.com/article/view/10.21037/pm-25-75/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.

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/.

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