Highlights
• Near-infrared fluorescence imaging with indocyanine green injection successfully identified 80% of histopathology-positive lymph nodes during esophagectomy for esophageal squamous cell carcinoma.
• The technique demonstrated a high negative predictive value of 99.4%, suggesting ICG-negative nodes can reliably exclude malignancy with minimal false-negative rates.
• Despite moderate positive predictive value (28.3%), the technology serves as a complementary mapping tool rather than a replacement for standard anatomic lymphadenectomy.
• All 30 patients had received neoadjuvant chemoradiotherapy prior to surgery, reflecting current multimodal treatment protocols for locally advanced esophageal cancer.
Background
Esophageal squamous cell carcinoma remains one of the most lethal gastrointestinal malignancies worldwide, with lymph node metastasis serving as the single most critical prognostic factor influencing survival outcomes and treatment planning. The presence of lymph node involvement in esophageal cancer dramatically worsens staging and dictates the extent of therapeutic intervention required. Complete lymphadenectomy during esophagectomy is therefore paramount, not only for accurate pathological staging but also for ensuring optimal oncological clearance and improved long-term survival.
Traditional surgical approaches to lymph node dissection rely heavily on anatomical landmarks and surgeon expertise, which can result in variable nodal yield and potential missed metastases. The quest for enhanced visualization techniques has led to the exploration of fluorescence-guided surgery, particularly using indocyanine green (ICG) dye and near-infrared (NIR) imaging technology. ICG, when administered peritumorally, accumulates in lymphatic channels and regional lymph nodes, potentially enabling real-time intraoperative identification of draining nodal basins that may not be apparent through visual inspection or palpation alone.
Recent years have witnessed growing interest in applying NIR fluorescence imaging across various surgical specialties, including sentinel lymph node mapping in breast cancer and melanoma. However, its utility in esophageal cancer surgery, particularly during minimally invasive esophagectomy, remains inadequately explored. The study by Singh and colleagues addresses this critical gap by prospectively evaluating the role of ICG fluorescence-guided lymphadenectomy in patients with esophageal squamous cell carcinoma undergoing curative resection.
Study Design and Methods
This prospective cohort investigation enrolled 30 patients with histologically confirmed esophageal squamous cell carcinoma who underwent minimally invasive esophagectomy with 2-field lymphadenectomy at a single tertiary care center between January 2023 and December 2024. All participants received neoadjuvant chemoradiotherapy according to standard protocols before surgical intervention, reflecting contemporary multidisciplinary management of locally advanced esophageal malignancy.
The technical protocol involved preoperative peritumoral injection of ICG dye (0.5 mL containing 2.5 mg) distributed across four quadrants around the tumor location. This injection strategy was designed to optimize lymphatic uptake and migration of the fluorescent dye toward regional draining lymph nodes. During the surgical procedure, the near-infrared fluorescence imaging system was employed to visualize ICG-positive lymph nodes in real-time.
Crucially, the surgical team systematically retrieved and documented all lymph nodes—regardless of fluorescence status—station-wise according to established anatomical classifications. This approach enabled comprehensive comparison between ICG-positive and ICG-negative nodal groups. The primary endpoint focused on correlating ICG fluorescence positivity with histopathologic examination results, while secondary analyses examined nodal yield, distribution patterns, and diagnostic performance characteristics including sensitivity, specificity, positive predictive value, and negative predictive value.
Key Findings
The study cohort presented with a median age of 51 years (interquartile range: 45-61 years), with the lower thoracic esophagus representing the predominant tumor location in 47% of patients (14 of 30). All participants successfully completed the neoadjuvant chemoradiotherapy protocol followed by planned minimally invasive esophagectomy with 2-field lymphadenectomy.
Surgical outcomes demonstrated robust lymph node retrieval, with a total of 678 lymph nodes harvested across all procedures. The median nodal yield per patient reached 23.5 nodes (interquartile range: 9-40), providing adequate tissue for comprehensive pathological assessment and staging.
Regarding fluorescence imaging performance, 56 of 678 retrieved lymph nodes (8.3%) demonstrated ICG positivity on NIR imaging. Among these fluorescent nodes, 16 (28.6%) were confirmed positive for malignancy on histopathological examination. Overall, 20 of 678 total harvested nodes (2.9%) contained metastatic carcinoma.
The diagnostic accuracy analysis revealed compelling performance characteristics for ICG fluorescence in detecting malignant lymph nodes. The technique achieved 80% sensitivity, meaning four out of five histopathology-positive nodes were correctly identified preoperatively by their fluorescence signal. Specificity reached 93%, indicating excellent ability to correctly identify truly negative nodes. The positive predictive value of 28.3% reflected the low prevalence of nodal metastasis in this cohort, where most ICG-positive nodes contained reactive or inflammatory changes rather than tumor deposits. Perhaps most clinically relevant, the negative predictive value reached 99.4%, demonstrating that ICG-negative nodes were highly reliable indicators of absence of malignancy.
Of particular note, 80% of all histopathology-positive lymph nodes (16 of 20) exhibited ICG fluorescence positivity, validating the imaging approach’s ability to target the most clinically significant nodes. This high detection rate for metastatic nodes suggests potential for improving surgical completeness in lymphadenectomy when used as an adjunct to traditional anatomic dissection.
Expert Commentary
The findings from this investigation contribute valuable evidence to the emerging field of fluorescence-guided surgical oncology. Several aspects merit careful consideration when interpreting these results within the broader context of esophageal cancer management.
The 80% sensitivity achieved for detecting malignant nodes represents a meaningful improvement over purely anatomical dissection, where subtle or deeply situated lymph nodes may escape detection. The near-perfect negative predictive value of 99.4% carries particular clinical significance: when a lymph node fails to fluoresce following ICG injection, surgeons can be highly confident that the node is uninvolved by tumor. This characteristic makes the technology particularly valuable as a confirmatory tool rather than a primary diagnostic modality.
However, several limitations warrant acknowledgment. The moderate positive predictive value of 28.3% reflects the biological reality that ICG accumulates in functional lymphatic drainage regardless of nodal pathology. Reactive lymphadenopathy, chronic inflammation, and prior chemoradiotherapy effects can all produce ICG positivity without corresponding malignancy. Surgeons must therefore interpret fluorescent signals within the broader clinical context rather than using them as definitive diagnostic indicators.
The study’s single-center design and relatively modest sample size of 30 patients limit immediate generalizability. Multicenter validation with larger patient populations would strengthen confidence in these preliminary findings. Additionally, the exclusive focus on squamous cell carcinoma histology means applicability to esophageal adenocarcinoma remains uncertain, as these entities differ in their lymphatic drainage patterns and biological behavior.
The 2-field lymphadenectomy approach employed in this study represents standard practice for many centers, though some surgeons perform more extensive 3-field dissections for proximal tumors. Future investigations should evaluate ICG fluorescence guidance across different nodal dissection extents to determine optimal integration strategies.
Furthermore, the timing and technique of ICG administration continue to evolve. While peritumoral injection as performed in this study offers practical advantages, alternative approaches such as endoscopic submucosal injection or intravenous administration may yield different biodistribution patterns warranting comparative evaluation.
Conclusion
Near-infrared fluorescence-guided lymphadenectomy using indocyanine green represents a promising technological advancement in the surgical management of esophageal squamous cell carcinoma. This prospective investigation demonstrates that the technique can successfully identify the majority of malignant lymph nodes during minimally invasive esophagectomy, achieving diagnostic sensitivity of 80% and negative predictive value approaching 99%.
The high negative predictive value positions ICG fluorescence imaging as a particularly valuable complementary tool—providing surgeons with enhanced confidence when lymph nodes appear negative while highlighting potential metastatic nodes that merit particular attention during dissection. However, the moderate positive predictive value underscores that fluorescence positivity should not substitute for systematic anatomic lymphadenectomy based on established surgical principles.
Moving forward, larger prospective multicenter trials are needed to validate these findings, establish optimal ICG dosing and injection protocols, and determine whether fluorescence guidance can meaningfully improve long-term oncological outcomes through more complete nodal clearance. Until such evidence accumulates, ICG fluorescence imaging should be viewed as an adjunctive technology that enhances rather than replaces conventional surgical techniques for esophageal cancer resection.
The integration of real-time intraoperative imaging with traditional surgical skill represents the frontier of precision surgical oncology, and continued refinement of these approaches promises to improve outcomes for patients facing this challenging malignancy.
Funding and Registration
No specific funding information was disclosed for this study. The clinical investigation was registered and conducted prospectively with institutional review board approval.
References
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