Perioperative outcomes and survival of indocyanine green-guided minimally esophagectomy in patients with esophageal cancer: a retrospective comparison study

Introduction

Esophageal cancer (EC) is a highly prevalent malignant gastrointestinal tumor worldwide (1). Esophageal squamous cell carcinoma (ESCC) accounts for 90–95% of all EC cases (1). Its incidence is particularly high in East Asian regions, including China, which accounts for approximately half of all new EC cases and deaths worldwide (2,3). Unlike esophageal adenocarcinoma, which is the predominant pathological type of EC in Europe and America, ESCC has a unique pattern of lymphatic metastasis, characterized by early regional lymph node (LN) spread, complex metastatic pathways, and high rates of mediastinal and cervical LN involvement, all of which are key factors affecting patient prognosis (3,4). Despite continuous developments in comprehensive treatments such as surgery, radiotherapy, and chemotherapy, the 5-year survival rate of ESCC patients is only 15–20% (3,4). This is mainly due to limitations in the accurate diagnosis and complete dissection of regional LN metastases. Thus, surgical strategies based on the lymphatic metastasis characteristics of ESCC need to be optimized to achieve precise LN dissection and thus improve patient prognosis.

This study sought to examine ESCC in terms of certain pathological and clinical characteristics. The lymphatic metastasis pathways of ESCC vary significantly between patients. Further, metastatic regions differ significantly based on the tumor location in the upper, middle, or lower esophageal segments (5). Traditional empiric LN dissection often leads to either missed metastases or excessive resection, failing to achieve an optimal balance between oncologic efficacy and surgical safety (6-8). In ESCC patients, the incidence of small LN metastases (diameter <5 mm) ranges from 30–40% (6-8). These micrometastases are notoriously difficult to identify during conventional white-light surgery (9-11).

The optimal extent of LN dissection in radical esophagectomy has long been debated (1,12). Overly extensive systematic LN dissection can lead to higher postoperative complications, and may result in prolonged hospital stays, increased mortality rates, and reduced quality of life for patients (13). Thus, it is particularly important to identify individual patterns of lymphatic metastasis in EC and to achieve precise LN dissection whenever possible.

To ease the difficulty of LN dissection, many surgeons use LN tracers to distinguish the affected LNs. Indocyanine green (ICG) is a water-soluble dye with a relative molecular mass of 776 Da. Near-infrared (NIR) fluorescence imaging with ICG is a novel surgical navigation technique (14,15). However, current reports on the use of ICG-guided LN dissection in advanced EC remain limited, and this approach is still in the early stages of development (16-18). Additionally, the sample sizes of several relevant EC studies reported abroad have been small, and the conclusions inconsistent (18-21). To date, no studies on accurate LN dissection with NIR fluorescence detection for ESCC have been conducted. Further, there is no standardized optimal protocol for implementing ICG-guided LN tracing in EC. Thus, this study aimed to evaluate the safety and feasibility of using ICG-guided LN dissection in radical esophagectomy for patients with ESCC and to assess its long-term outcomes, providing a theoretical basis for further research. We present this article in accordance with the STROBE reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-918/rc).

Methods

Study design

The data of patients who underwent thoraco-laparoscopic radical esophagectomy for ESCC at the Nanjing First Hospital and the Fourth Affiliated Hospital of Anhui Medical University between November 2019 and November 2021 were collected. In the ICG group, ICG was injected via endoscopy 15 mins before surgery, while in the control group, surgery was performed without any such marking. The general clinical characteristics of the two groups were analyzed, including age, gender, body mass index (BMI), tumor location, pulmonary function, hypertension, diabetes mellitus, chronic bronchitis, history of smoking, history of drinking, American Society of Anesthesiologists (ASA) classification, clinicopathological stage, and mediastinal lymph node (mLN) dissection.

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of Nanjing First Hospital (No. KY20210603-KS-04) and the Fourth Affiliated Hospital of Anhui Medical University (No. AYDSY-EC-2019-086). All the patients included in the study provided written informed consent for the publication of the related research results.

Inclusion criteria

Patients were included in the study if they: (I) underwent thoraco-laparoscopic radical esophagectomy for ESCC; (II) had pathologically confirmed ESCC post-surgery; (III) had their LN specimens classified following the 11th edition of the Japanese Classification of Esophageal Cancer by senior surgeons and pathologists during and post-surgery; and (IV) underwent standardized preoperative staging evaluations to assess LN involvement. The staging protocol included: contrast-enhanced chest and upper abdominal computed tomography (CT) to evaluate primary tumor invasion depth and regional LN status; esophageal endoscopic ultrasound (EUS) to assess tumor infiltration depth and peri-esophageal LN involvement; positron emission tomography-computed tomography (PET-CT) to rule out distant spread in patients with clinical stage ≥ T3 or suspected distant metastasis. All the imaging results were independently reviewed by two experienced radiologists, and any inconsistencies were resolved through consensus to ensure accuracy (5). The patients underwent the endoscopic examination and received the ICG injection 15 min before surgery.

Exclusion criteria

Patients were excluded from the study if they: (I) had distant metastases to the liver, lungs, and peritoneum discovered through preoperative examinations or intraoperative exploration; (II) required palliative surgery; (III) had other concurrent malignancies; (IV) had received neoadjuvant therapies (chemotherapy and targeted therapy) before surgery; and/or (V) required emergency surgery due to bleeding, perforation, or obstruction.

Experimental drugs and methods

In the ICG group, a 25-mg vial of ICG (DaLian Beier Pharmaceutical Co., Ltd., Dalian, China) was diluted in sterile water for injection. Specifically, 25 mg of ICG powder was dissolved in 10 mL of sterile water, resulting in a final volume of 10 mL. During the procedure, 0.5 mL of the 2.5 mg/mL ICG solution was injected submucosally at four points (i.e., the proximal, distal, left, and right sides, 0.5–1 cm from the tumor edge). Thus, the total injected dose per patient was 5 mg (2.5 mg/mL × 0.5 mL × 4 points). The procedures were performed using a domestically produced three-dimensional/4K fluorescence laparoscopic system (UX7, Mindray Bio-Medical Electronics Co., Ltd., Shenzhen, China). The system integrates NIR fluorescence imaging (wavelength: 780–820 nm) with 4K resolution (3,840×2,160 pixels) stereoscopic visualization. A designated medical practitioner performed both procedures.

All the patients underwent thoracic duct visualization using NIR fluorescence imaging. The NIR fluorescence of ICG provides approximately 1 cm of tissue penetration, enabling the identification of the thoracic duct course without incising the posterior mediastinal pleura. After further opening the pleura, the thoracic duct was visualized more clearly under direct vision, enabling the identification of even small branches. This prevented iatrogenic injury and ensured the complete ligation of variant branches during dissection.

For the blood supply assessment, ICG was administered via tissue injection. Following its administration, ICG binds to plasma proteins (primarily albumin) and remains within the capillary vasculature. Using fluorescence laparoscopy equipment, NIR fluorescence angiography was performed to visualize the vascular network. By observing the fluorescence intensity at the anastomotic site, the blood perfusion status of the tissue could be objectively evaluated, ensuring adequate vascular supply before finalizing the anastomosis.

Surgical quality control

All patients underwent curative EC surgery. Intraoperative LN dissection was performed following the 11th edition of the Japanese Esophageal Cancer Staging guidelines (22).

In the ICG group, the fluorescence mode was adjusted based on specific intraoperative conditions, and LN dissection was performed simultaneously. The LN classification was conducted under direct visualization by designated, experienced clinicians (Figure 1).

Figure 1 ICG imaging for complete mLN dissection. (A) A tumor under ICG fluorescence mode in the ICG group. The injection concentration dose was 5 mg/mL. (B) A tumor under ICG fluorescence mode in the ICG group. The injection concentration dose was 2.5 mg/mL. By reducing the ICG dose, we maintained a low background level, decreased the perilesional background, and improved the signal-to-noise ratio. (C) Corresponding white-light imaging. Intraoperative station 106 tbLs (left tracheobronchial LNs) were missed under white-light mode in the ICG group. (D) Intraoperative station 106 tbLs were easily visualized in the fluorescence mode in the ICG group, particularly the microscopic LNs with the potential for micrometastasis (as indicated by the white arrow). (E,F) LN dissection followed the course of the recurrent laryngeal nerves (station 106recL/Rs) in fluorescence mode. Chyle leak was avoided by fluorescent imaging of the thoracic duct (as indicated by the white arrow). (G) During mLN dissection, the thoracic duct was visualized (as indicated by the white arrow). (H) Station 106 tbLs (left tracheobronchial LNs) were removed completely in the fluorescence mode in the ICG group. ICG, indocyanine green; LNs, lymph nodes; mLN, mediastinal lymph node; recL/R, left/right recurrent laryngeal nerve lymph node; tbLs, left tracheobronchial lymph nodes.

Postoperative therapy and follow-up

All the resected specimens were carefully marked for margins and resected structures, and subsequently sent for comprehensive histological examination. The patients were admitted to the intensive care unit on the first postoperative day, and transferred to the general ward on the second postoperative day. The decision to use postoperative chemotherapy and radiotherapy was individualized for each patient, ensuring that they received the appropriate standard-of-care adjuvant therapy.

Disease-free survival (DFS) was defined as the time from surgery to tumor progression (as diagnosed by endoscopic or imaging examinations during the follow-up period) or the last follow-up. Deaths without documented progression were treated as censored observations in the DFS analysis. Overall survival (OS) was defined as the time from surgery to death or the last scheduled follow-up.

Statistical analysis

The statistical analysis was performed using the Statistical Package for Social Sciences software (version 20.0; IBM, Armonk, NY, USA). The measurement data are expressed as the mean and standard deviation (x¯±s). Before performing the t-test, the data were tested for normality and homogeneity of distribution to ensure they met the underlying test assumptions. Comparisons between groups were conducted using the F-test, t-test, and analysis of variance. The categorical data from each group were tested using the Chi-squared test or Fisher’s exact probability test as appropriate. For pairwise comparisons, the least significant difference t-test was used. A P value <0.05 was considered statistically significant. Univariable and multivariable Cox proportional hazard model analyses were performed to identify the prognostic factors for DFS and OS. A two-tailed P value <0.05 was considered statistically significant.

Results

From November 2019 to November 2021, 176 consecutive patients diagnosed with locally advanced ESCC underwent radical esophagectomy. The ICG group comprised 60 patients who underwent ICG-guided LN dissection, while the non-ICG group comprised 116 patients. There were no statistically significant differences between the two groups in terms of age, gender, BMI, tumor location, pulmonary function, the proportion of patients undergoing CT, EUS, or PET-CT, and the prevalence of underlying conditions, including hypertension, diabetes mellitus, chronic bronchitis, smoking, and a history of drinking. However, a significant difference was observed between the two groups in terms of ASA classification (P=0.023). Notably, no statistically significant differences were observed between the two groups in terms of clinicopathological staging [tumor-node-metastasis (TNM) stage, P>0.05] and other key variables. These findings indicate that the baseline characteristics of the patients were well-balanced between the two groups, facilitating the comparative analysis (Table 1).

LN dissection

The mean number of LN stations dissected in the non-ICG group did not differ significantly from that in the ICG group (P=0.995). The mean number of dissected LNs by pathologists in the ICG group was 15.1±1.6, which was significantly higher than that in the non-ICG group (12.5±3.0; P<0.01). The number of small LNs (diameter <5 mm) detected was significantly higher in the ICG group than the non-ICG group (6.2±1.8 vs. 3.1±1.2; P<0.001) (Table S1). The number of positive LN stations (metastatic mLNs) in the ICG group did not differ significantly from that in the non-ICG group (P>0.05). However, in terms of the metastatic mLNs in the small lymph nodes (smLNs), significant differences were observed between the ICG group and the non-ICG group. The ICG group had a higher number of metastatic smLNs than the non-ICG group (2.3±1.1 vs. 1.2±0.8, P<0.05) (Table 1).

Systematic and extensive LN dissection is crucial in EC surgery. Under white-light thoracoscopic visualization, some tissues—particularly lymphatic tissues and adipose tissues in certain patients with advanced EC—are indistinguishable to the naked eye, making them difficult to identify. The differing abilities of various tissues to uptake ICG can be leveraged that by using the NIR fluorescence of ICG technology intraoperatively, different tissue types can be distinguished, preventing the omission of small LNs. Due to the clustered distribution of LNs in tissues, this imaging approach provides precise directional guidance for dissection.

In the ICG group, all the visibly enlarged LNs were systematically dissected regardless of their fluorescence status. Fluorescence status was cross-tabulated against the pathological results for all the dissected nodes in the ICG group (n=381 nodes). The results were as follows: true positives, 41 metastatic nodes with positive fluorescence (12.5% of fluorescent nodes); false negatives, 23 metastatic nodes with negative fluorescence (44.2% of non-fluorescent nodes); true negatives, 29 non-metastatic nodes with negative fluorescence; and false positives, 288 non-metastatic nodes with positive fluorescence. In the ICG group, the LNs with a macroscopically enlarged short-axis diameter (>1 cm) but no fluorescent visualization during surgery were dissected according to standard protocols and included in the pathological analysis. Among all the LNs dissected in the ICG group, there were 52 fluorescence-negative nodes, of which 23 were pathologically confirmed to be metastatic (false-negative rate: 44.2%). A total of 329 fluorescence-positive nodes were identified, of which, 41 were pathologically confirmed to be metastatic (true-positive rate: 12.5%) (Table S1).

Surgical outcomes

This study also compared postoperative arrhythmia, pleural effusion, pneumothorax, postoperative pneumonia, anastomotic fistula, chylothorax, postoperative delirium, and the length of hospital stay between the two groups. There was no significant difference in the postoperative complications between the two groups (P>0.05).

The key procedural metrics were compared between the two groups, and the results revealed no statistically significant differences. The total operative time was 245.3±32.6 min in the ICG group, and 238.5±29.4 min in the non-ICG group (P=0.215). Lymphadenectomy duration was 72.5±11.8 min in the ICG group and 69.8±10.5 min in the non-ICG group (P=0.187). Intraoperative blood loss was 125.6±35.2 mL in the ICG group and 132.3±38.7 mL in the non-ICG group (P=0.324) (Table 2).

A significant difference was found in the locoregional recurrence rates between the two groups. Specifically, in the ICG group, 12 of 25 recurrent patients (48.0%) had locoregional recurrence, while 10 (40.0%) had distant metastasis, and 3 (12.0%) had local recurrence. Conversely, in the non-ICG group, 49 of 75 recurrent patients (65.3%) had locoregional recurrence, 21 (28.0%) had distant metastasis, and 5 (6.7%) had local recurrence. The statistical analysis confirmed that the locoregional recurrence rate was significantly lower in the ICG group than the non-ICG (P=0.042), but no such significant differences were observed between the two groups in terms of the distant or local recurrence rates (P>0.05) (Table S2).

Univariate and multivariate analyses of OS and DFS were conducted. The univariate analysis revealed a significant association between the ICG group and DFS. The unadjusted hazard ratio (HR) of the non-ICG group was 2.78 [95% confidence interval (CI): 1.72–4.48; P<0.001]. After multivariate adjustment, the HR of the non-ICG group further increased to 3.38 (95% CI: 1.99–5.74; P<0.001). Therefore, DFS was found to be significantly improved in the ICG group (Table 3). The unadjusted HR of the non-ICG group was 2.21 (95% CI: 1.25–3.9; P<0.001). After multivariate adjustment, the HR of the non-ICG group further increased to 2.86 (95% CI: 1.51–5.43; P<0.001). Therefore, the univariate and multivariate analyses revealed that OS was significantly improved in the ICG group (Table 4).

In relation to the DFS of the 60 participants in the ICG group, 25 (41.7%) experienced events over a median follow-up period of 30.1 months. Conversely, in the non-ICG group of 116 participants, 75 (64.7%) experienced events over a median follow-up period of 28.7 months. The non-ICG group had a HR of 2.78 (95% CI: 1.72–4.48) with a P value <0.001, indicating a significantly poorer DFS outcome compared to the ICG group (Figure 2).

Figure 2 DFS analysis between the ICG and non-ICG groups. DFS, disease-free survival; ICG, indocyanine green.

The OS analysis revealed that of the 60 participants in the ICG group, which served as the reference group, 17 (28.3%) experienced events during a median follow-up period of 32.7 months. Conversely, of the 116 participants in the non-ICG group, 45 (38.8%) experienced events over a median follow-up period of 29.9 months, indicating a HR of 2.21 (95% CI: 1.25–3.9) with a significant P value of 0.006, suggesting a poorer OS outcome in the non-ICG group (Figure 3).

Figure 3 OS analysis between the ICG and non-ICG groups. ICG, indocyanine green; OS, overall survival.

In summary, the non-ICG group exhibited higher event rates and poorer survival outcomes in terms of both DFS and OS compared to the ICG group, with statistically significant differences observed.

Discussion

This study investigated the use of ICG fluorescence imaging during minimally invasive EC surgery, and found that ICG-guided lymphatic dissection is a feasible, safe, and beneficial technique. The ICG-guided LN dissection did not result in excessive LN clearance compared to that in the control group; rather, it improved surgical precision in LN identification and retrieval, thereby significantly improving patient prognosis.

The optimal depth and extent of LN dissection in EC surgery have long been debated (23). Most ESCCs are detected at an advanced stage, by which time LN metastasis has often occurred (24), which is a crucial factor influencing the prognosis of patients with ESCC (25). As the prognostic importance of the characteristics and number of LN metastases in EC has become increasingly recognized, the standards for curative LN dissection have also continued to increase. The minimum requirement for LN dissection increased from at least six LNs in the 6th edition of the TNM staging system to at least 15 LNs in the latest guidelines (26).

Previous research reported that overly extensive mLN dissection during early development in EC radical surgery causes extremely high postoperative complication rates and in-hospital mortality (12,27). However, with advancements in perioperative care, anesthesiology, and surgical techniques, there has been a significant improvement in postoperative complications and a reduction in surgical risks for EC patients (28-30).

Recently, the widespread adoption of minimally invasive thoracoscopic-assisted esophagectomy has further improved postoperative complications and perioperative mortality rates (31-35). However, excessively broad systematic LN dissection may lead to higher postoperative complications, including recurrent laryngeal nerve injury, chylothorax, and airway necrosis (36,37). These complications can lead to prolonged hospital stays, increased mortality, and decreases in quality of life (38,39). NIR fluorescence imaging has been widely applied in the treatment of various malignant tumors, delivering substantial patient benefits (40,41). An increasing number of esophageal surgeons have begun to apply this technique in esophageal surgery to enable more precise and personalized mLN dissection. Multiple clinical studies on intraoperative fluorescence imaging for EC have shown the advantages of this technology in the accurate identification and dissection of LNs (20,42-44).

Our comparative analysis of the non-ICG and ICG-guided approaches revealed some interesting differences. With ICG, dye migration and leakage through the mucosa during anatomical dissection may interfere with the intraoperative identification of local NIR LNs, potentially leading to excessive mediastinal disruption. This study used low-dose ICG injections to reduce overdissection. The ICG dosage was optimized as follows: 25 mg of ICG was diluted in 2.5 mg/mL of sterile water, and a total of 5 mg (0.5 mL × 4 points) was injected submucosally to maintain a low background level while ensuring effective LN visualization. We hypothesized that reducing the ICG dose while maintaining a low background level would significantly decrease the perilesional background and improve the signal-to-noise ratio, thereby enhancing the detection rate of local tumor-draining LNs and avoiding the extensive mediastinal damage that can occur with indiscriminate nodal dissection guided by diffuse ICG staining (Figure 1).

LN dissection can be performed using direct visualization when dose-reduced ICG is used as a LN tracer. This greatly reduces the destruction of the mediastinal tissue and risk of bleeding. Additionally, compared to non-ICG approaches, ICG approaches may help lower the risk of anastomotic leaks by allowing intraoperative assessment of the blood supply to the anastomosis (45). Unfortunately, no statistical difference was found between the risk of anastomotic leaks of two groups in our study [6 (10%) vs. 8 (6.9%), P=0.559].

Surgeons can also clearly visualize the thoracic duct in fluorescence mode, providing real-time intraoperatively imaging guidance to locate the duct, which can prevent intraoperative thoracic duct injury, reduce the occurrence of chylothorax, and minimize the risk of iatrogenic chylothorax related to blind dissection. In the non-ICG group, 17 patients (14.7%) developed chylorrheax, while, in the ICG group, four patients (6.7%) developed chylothorax. While the incidence of chylothorax was higher in the non-ICG group than the ICG group, it may be that the difference was not statistically significant due to the small sample size of the study.

In terms of other postoperative outcomes, such as postoperative arrhythmia, pleural effusion, pneumothorax, postoperative pneumonia, anastomotic fistula, postoperative delirium, and length of hospital stay, there were no significant differences in the postoperative complication rates between the two groups. This suggests that even with the ICG imaging system, there was no evidence of overdissection, leading to serious postoperative complications.

The comparable operative parameters indicate that ICG-guided lymphadenectomy did not compromise the procedural efficiency. Despite the additional steps (e.g., preoperative endoscopic ICG injection and intraoperative fluorescence mode adjustment), the precise localization of LNs via fluorescence reduced the need for blind dissection and repetitive exploration of anatomical planes, offsetting the time required for technical setup. Further, the ICG visualization of critical structures (e.g., the thoracic duct and anastomotic blood supply) may have minimized accidental injuries, contributing to the similar blood loss between groups. This balance of precision and efficiency supports the practical applicability of ICG technology in routine clinical practice.

The use of ICG fluorescence imaging technology to predict metastatic LNs during the radical resection of ESCC may affect the mode of LN dissection (46). A previous study comparing preoperative, intraoperative, and postoperative features found that the ICG group had more metastatic LNs than the non-ICG group and that all the metastatic mLNs were NIR-positive (18). In our study, the mean number of LNs retrieved in the non-ICG group did not differ significantly from that retrieved in the ICG group (P=0.995). However, the mean number of dissected LNs by pathologists in the ICG group was 15.1±1.6, which was significantly higher than that in the non-ICG group (12.5±3.0; P<0.01). Additionally, there was no significant difference between the proportion of identified positive LNs between the ICG group and the non-ICG group (P=0.656). The increased total number of LNs (without a corresponding increase in the positivity rate) in the ICG group was due to the enhanced detection efficiency of small/occult LNs in the same anatomical station rather than an expansion of the dissection scope (there was no significant difference in the number of LN stations between groups, P=0.995). By labeling tumor-draining lymphatic pathways via fluorescence imaging, ICG enables surgeons to precisely locate and retrieve these small LNs, providing pathologists with additional specimens for microscopic examination, thereby more comprehensively reflecting the true status of LNs.

The number of small LNs (diameter <5 mm) detected was significantly higher in the ICG group than the non-ICG group (6.2±1.8 vs. 3.1±1.2; P<0.001). The number of positive LN stations (mLNs) in the ICG group did not differ significantly from that in the non-ICG group (P>0.05); however, significant differences were observed between the ICG group and the non-ICG group in terms of the smLNs. The ICG group had a higher number of micrometastatic LNs than the non-ICG group (2.3±1.1 vs. 1.2±0.8, P<0.05). Overall, LN dissection was superior in the ICG group than the non-ICG group. These findings suggest that ICG-guided LN dissection enhances the detection of micrometastases, which are often overlooked in conventional surgery. ICG fluorescence imaging does not lead to excessive mLN dissection, and it also improves the precision of mLN dissection and ensuring the detection of metastatic LNs.

In the 1980s, Japanese scholars were the first to initiate research and implement three-field LN dissection for EC (47). LN dissection in EC has generated extensive discussion, and major medical centers worldwide have conducted retrospective and prospective clinical studies comparing three- and two-field LN dissection (12,48,49). Most of these studies have found that three-field LN dissection does not significantly improve patient survival, and has relatively high associated complication rates (50). Inconsistencies in the results may be due to the small sample sizes or suboptimal trial designs of the studies, causing inadequate efficacy assessments. Another important reason is the technical difficulty of LN dissection. Inappropriate LN dissection may actually increase postoperative complications, thus increasing patient mortality (51).

Despite the surgeons adhering to the standard for the number of dissected LNs during the operation, small metastatic LNs may be overlooked. The standardization and comprehensiveness of mLN dissection remains suboptimal. However, LN dissection, whether three- or two-field, needs to be more rigorous and standardized in EC. Thorough and standardized LN dissection provides definite survival benefits for patients with EC (52,53). Intraoperative NIR fluorescence lymphatic imaging is a safe and promising technique for EC surgery. It can visualize the lymphatic drainage areas of tumors, guide the removal of LNs at risk of metastasis, and identify sentinel LNs along the tumor-related lymphatic pathways. This technology aligns well with the increasingly high requirements for thorough LN dissection (54,55).

In our study, the ICG group had a higher number of pathologically examined LNs and a higher positive rate, suggesting that ICG-guided LN dissection achieves survival benefits by increasing the number of pathologically examined LNs and reducing residual LN metastases in patients with ESCC. However, ICG fluorescence imaging may also yield false-negative results in non-fluorescent LNs with metastatic involvement, with a reported incidence of 46.4–60.0% (56,57). These false-negative results may be due to extensive cancer cell invasion or lymphatic vessel blockage. However, for experienced esophageal surgeons, it may not be necessary to visualize every LN, as the guidance provided by ICG fluorescence may still help surgeons to identify LNs requiring dissection, which may ultimately benefit patient survival.

The overall sensitivity of ICG fluorescence for detecting metastatic nodes was 63.5% (41/64), indicating moderate performance. However, when ICG guidance was combined with clinical judgment (e.g., to dissect enlarged non-fluorescent nodes), the total metastatic node detection rate reached 87.5% (56/64). Thus, ICG serves as a valuable adjunct rather than a replacement for standard surgical principles. The false negatives were predominantly observed in nodes from fibrotic mediastinal regions or cases with tumor necrosis, suggesting that tissue microenvironment factors may impair ICG uptake (58). In the ICG group, all the visibly enlarged LNs (i.e., those with a short-axis diameter >1 cm by intraoperative palpation/visual inspection) were systematically dissected regardless of fluorescence status. This approach ensured that oncologic completeness was not compromised by ICG false negatives, adhering to the principle of comprehensive lymphadenectomy for EC.

To date, few studies have examined the effect of intraoperative fluorescence imaging techniques on the survival outcomes of patients with EC. This clinical study found that over a median follow-up period of 30.1 months for the ICG group and 28.7 months for the non-ICG group, the non-ICG group had a significantly worse DFS outcome (HR: 2.78, 95% CI: 1.72–4.48, P<0.001) compared to the ICG group. The improvement in DFS observed in this study is closely associated with differences in recurrence patterns. Notably, the ICG group had a significantly reduced regional recurrence rate (48.0% vs. 65.3%, P=0.042), which can be directly attributed to more precise regional LN dissection under ICG guidance. The lower locoregional recurrence rate in the ICG group directly supports the improvement in DFS. This finding aligns with the mechanism of ICG-guided LN dissection. By enhancing the detection of micrometastatic LNs in regional drainage areas [e.g., mediastinal station 106 left tracheobronchial lymph nodes (tbLs) as shown in Figure 1], ICG reduces residual locoregional disease, which is a major driver of early recurrence in EC. Conversely, the comparable distant metastasis rates suggest that ICG primarily affects local disease control rather than systemic metastasis, which is consistent with its role in optimizing locoregional lymphadenectomy rather than systemic therapy. This distinction strengthens our conclusion that the survival benefit of ICG guidance stems from more effective local tumor clearance.

The OS analysis revealed that 17 (28.3%) patients experienced events over a median follow-up period of 32.7 months in the ICG group, and 45 (38.8%) experienced events over a median follow-up period of 29.9 months in the non-ICG group (HR: 2.21, 95% CI: 1.25–3.9, P=0.006), suggesting a poorer OS outcome in the non-ICG group. The non-ICG group exhibited higher event rates and poorer survival outcomes in both DFS and OS compared to the ICG group, with statistically significant differences observed. This is likely due to the more extensive and complete LN dissection achieved in the ICG group. Under the guidance of ICG imaging, surgeons can assess the completeness of LN dissection by visualizing any remaining LNs in the dissection area, effectively reducing the risk of incomplete LN clearance.

The present study also had a number of limitations. First, despite including patients from two centers, the sample size was relatively small, and the retrospective nature of data collection introduced inherent biases, such as selection bias and incomplete data capture. High-quality prospective studies with larger cohorts need to be conducted to validate the findings and provide more robust evidence. Second, neoadjuvant therapies may disrupt the lymphatic drainage around the tumor, potentially affecting the distribution of ICG in the lymphatic system (59). In our study, none of the enrolled participants received any neoadjuvant treatments, which allowed for a more accurate assessment of the value of ICG fluorescence technology in exploring lymphatic drainage and mLNs in ESCC. However, in clinical practice, many patients receive preoperative neoadjuvant therapies, and current research indicates that ICG may have a lower specificity in these patients. Future research on NIR lymphatic imaging in EC should seek to enhance the specificity of these methods. Third, as this study was performed in patients with ESCC, it is unclear whether the findings can be extrapolated to patients with adenocarcinoma.

Despite the significant improvements in DFS and OS observed in the ICG group in this study, the causal relationship should be interpreted with caution. First, subtle differences in baseline characteristics, such as ASA classification (P=0.023), and unmeasured confounding factors might have interfered with the survival outcomes. Second, ICG fluorescence imaging has a false-negative rate ranging from 46.4% to 60%, and some high-risk LNs may not be fluorescently labeled. Thus, ICG technology is not a perfect tool for LN detection and still requires integration with surgeons’ clinical judgment of anatomical regions. Further, heterogeneity in tumor location and staging might have also affected the results. Although there was no significant difference in the clinicopathological staging between the two groups in this study, lymphatic drainage patterns vary across different tumor sites, which might have led to differences in ICG labeling efficiency. This was not further explored in the subgroup analyses. Future studies should validate the practical value of ICG in diverse clinical scenarios through larger-sample prospective designs, combined with multicenter data and stratified analyses, to avoid overattributing survival benefits to a single technology. Notably, the current study relied on a retrospective post-hoc analysis to explain survival advantages in the ICG group, and conclusions derived from such analyses should be interpreted with caution. Moreover, the procedures were performed by three senior surgeons with extensive experience in EC surgery (over 1,000 cases each surgeon). However, future research needs to be conducted to determine whether ICG-guided laparoscopic and thoracoscopic esophagectomy can similarly benefit less experienced surgeons, thereby improving patient outcomes.

Conclusions

ICG-guided LN dissection during minimally invasive EC surgery may contribute to improved DFS and OS in patients with ESCC, likely by enhancing the detection of small LNs and reducing locoregional recurrence. This technique does not increase the rate of relevant postoperative complications, supporting its feasibility in clinical practice.

Acknowledgments

We sincerely thank all patients and their families for their participation and trust in this study, as their involvement was fundamental to the completion of this research. Special thanks are owed to our colleague Ms. Liu for her selfless assistance and valuable contributions during the revision of this manuscript. Her insights and efforts significantly improved the quality of the work.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-2025-918/rc

Data Sharing Statement: Available at https://qims.amegroups.com/article/view/10.21037/qims-2025-918/dss

Funding: This study was supported by China Postdoctoral Science Foundation (No. 2018M642199).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-918/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. The study was approved by the Ethics Committee of Nanjing First Hospital (No. KY20210603-KS-04) and the Fourth Affiliated Hospital of Anhui Medical University (No. AYDSY-EC-2019-086). All patients included in the study provided paper-based written consent to publish the related research results.

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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