Chyle leak (CL) after esophagectomy accounts for 4.6% of postoperative complications, leading to higher rates of respiratory insufficiency and 90-day mortality (1). The intraoperative injury of the thoracic duct (TD) is the most common cause of CL, which occurs during intrathoracic esophageal dissection and lymphadenectomy and appears as a milky discharge from chest drainage upon the initiation of enteric feeding. Postoperative diagnosis can be accurately made through pleural fluid analysis demonstrating triglyceride level >110 mg/dL and/or chylomicrons in pleural fluid (2). Patients with CL are more likely to experience pulmonary complications entailing extended length of hospital stay (LOS) or an increase in the level of care, due to higher rates of atelectasis, pneumonia, or need for re-intubation (3). Recently, stepwise complication management has been established as the most appropriate treatment for CL depending on the severity of clinical presentation. Complication management involves a stepwise approach that includes multiple therapeutic options of consecutive invasiveness, such as dietary interventions (e.g., intake of a low-fat diet, medium-chain triglycerides enteral nutrition, total parenteral nutrition), administration of medications (Somatostatin analogs like Octreotide or alpha-agonists like Etilefrine), interventional radiology procedures (e.g., intranodal lymphography and Lipiodol^® embolization), and reoperation for leak repair (4). Given the uncertain outcomes following CL treatments, several high-volume esophageal centers developed and relied on different types of surgical prevention, although their efficacy remains controversial. Traditionally, control strategies were restricted to pre-emptive TD preservation or ligation during the intrathoracic dissection of the esophagus, although poor visualization and possible anatomical variations may limit the accuracy of surgical maneuvers. Conversely, both issues have been overcome by using intraoperative near-infrared (NIR) lymphography with indocyanine green (ICG), a fluorescent dye with amphiphilic properties that facilitates solubility in biological fluids and bioavailability. Excitation and emission wavelengths of ICG are located in the NIR range (780 to 830nm), making it suitable for detection by dedicated NIR-camera systems (5). However, the literature has not previously reported on procedural standardization for ICG-mediated lymphography (ICG-Lg) for TD visualization, including significant heterogeneity has been described in terms of dosages, administration routes, and injection timing (6).

The rationale of this systematic review is that intraoperative ICG-Lg can provide an effective and safe TD visualization, potentially leading to CL prevention and adequate oncological resections for esophageal cancer. Therefore, this study aims to assess the ICG-Lg effectiveness over the literature, in esophageal cancer surgery, and highlight operative characteristics and outcomes regarding TD visualization, CL prevention, and procedural complications.

This systematic review of the literature was conducted and reported in compliance with the PRISMA guidelines (PRISMA checklist in the Supplementary Material 1) and was recorded in PROSPERO database (registration number: CRD42025638309) (7, 8).

The present systematic review provided a measurable opportunity to evaluate the current literature reporting on fluorescence-guided surgery to identify underlying similarities and divergent determinants of effectiveness for CL prevention during esophageal cancer resections. Indocyanine green is a tricarbocyanine iodide compound that was approved by the U.S. Food and Drug Administration in 1959 for medical purposes and has become extensively used over several clinical applications as a fluorescent diagnostic agent. Ultimately, the literature demonstrated large evidence of successful implementations in upper gastrointestinal surgery, particularly in the field of esophageal cancer care (26–28).

However, the increasing clinical experience in the ICG-assisted esophagectomy has been recently reported by other authors, who did not include the newest comparative analyses from high-volume series (6). Types of fluorescence-based guidance primarily integrated with esophagectomy include ICG-mediated angiography and lymphography, which provide a measure for visceral perfusion and clear visualization of the TD, respectively. Intraoperative ICG angiography has recently been established as a routine procedure that provides enhanced assessment of the integrity of the right gastroepiploic artery and tissue perfusion of the gastric conduit, to document adequate visceral state before fashioning the esophagogastric anastomosis (27). On the other hand, ICG-Lg has been developed to spread the fluorescent tracer over the lymphatic system, allowing the prompt identification of TD throughout the thoracoscopic stage of minimally invasive esophagectomy, especially showing its transdiaphragmatic course and the confluence of tributary or aberrant ducts. The expedited blood outflow and the pharmacokinetics of ICG allow angiographic and lymphographic techniques to be performed simultaneously, with no interference reported in any of the studies included in this systematic review. The administration of diluted concentrations of ICG has been reported via different routes, including the injection into the interdigital folds of the feet, the subcutaneous space, the inguinal lymph nodes, or the mesentery root of the small intestine. The findings from this systematic review demonstrated high proportions of accurate visualizations after every type of administration, assuming the rare failures of the technique to be due to independent anatomical features. Therefore, none of the reported ICG-Lg procedures demonstrated technical superiority or significant patient risk, allowing esophageal centers to adopt an individualized approach based on their routine surgical practice. No specific findings supported the definition of an optimal IGC concentration, as no evidence of defective TD visualization or dose-induced toxicity (median lethal dose, 50–80 mg/kg) was reported (29). It has to be stated that ICG-Lg procedures were cautiously performed in selected patients, while medical conditions were clinical reasons for exclusion from ICG administration (i.e., iodine allergy, pregnancy, preoperative liver dysfunction, any evidence of uncontrolled systemic diseases, or other inappropriate conditions to physicians). Eventually, the present systematic review provides the benefit of the concentration range of current administration (0.2-0.5 mg/kg or 2–25 mg), which represents an evidence-based recommendation of safety and clinical efficacy.

The amphiphilic and dimensional characteristics (mass = 751.4 Da) of ICG tracer allow an extensive trans-diaphragmatic spread over the lymphatic system, entailing the clear visualization of TD and the associated variants of secondary tributaries (30, 31). The crucial point that emerges from the studies of this systematic review is the preventing strategy for CL (i.e., pre-emptive TD preservation or ligation), and the subsequent degree of surgical manipulation throughout the thoracoscopic phase of esophagectomy. Pre-emptive TD preservation appears to be the predominant technique of choice (68.1%) to minimize the occurrence of lymphatic injuries from surgical maneuvers. However, it has been reported that specific oncological, anatomical, or accidental/iatrogenic circumstances can occasionally force surgeons to TD handling or dissection (32). For this reason, an ultimate NIR inspection is commonly recommended to verify the integrity of lymphatic ducts after the mediastinal dissection of the lower esophagus, although no procedural guidelines have been shared to definitely exclude residual leaks. Conversely, other esophageal centers endorse the empirical belief that the pre-emptive TD ligation should be routinely performed, as the most accurate form of surgical control over the risk of iatrogenesis (33, 34). From the oncological standpoint, previous large-series studies demonstrated that TD dissection should not be legitimately considered among the targets of surgical resection for esophageal cancer, due to its rare tumor invasion and the low impact on survival (35, 36). However, some groups argue that the anatomical proximity between lymphatic ducts and the locoregional lymph nodes of the lower thoracic esophagus does not safely allow sparing TD during an extended mediastinal dissection. In accordance with the literature, the present systematic review reports significantly wider LNH after TD ligation and resection (OR 0.40, 95% CI -0.20 to 1.00, P<0.001), entailing higher chances for surgical removal of those lymph node stations which are more likely to be the site of locoregional metastases (Figure 2) (37). Eventually, the current ICG-assisted visualization of TD has allowed a highly heterogeneous management process (Figure 3), and no conclusive evidence has been supporting a specific surgical strategy.

CL is a severe postoperative complication that may entail acute respiratory failure or progressive physical deterioration, potentially leading to death (up to 17% of cases) (38). Although conservative treatment could avoid the need for further surgery, a successful resolution is uncertain and requires prolonged hospital stay and delayed chest drainage discontinuation. Despite improvements from applying IGC guidance for intraoperative CL identification, reoperation also demonstrated suboptimal success rates (80%) and a significant impact on patient functions and postoperative recovery (i.e., associated morbidity of 6–33%, and mortality of 0–33%) (39). Consequently, the occurrence of CL after esophagectomy potentially means the loss of eligibility for adjuvant therapy and the interruption of the multimodal sequence, preventing patients from undergoing optimal care. For this reason, the effective prevention strategy, early diagnosis, and standardized multidisciplinary management are fundamental requirements for such a deceptive surgical aspect, demanding high-level infrastructural resources and the selection of tertiary centers for esophageal cancer care.

Despite the methodological assumptions, this systematic review includes biases related to the structure and level of evidence of the selected articles. Further to the FDA approval and the experimental validation, intraoperative ICG-Lg for TD identification has been rapidly integrated into clinical practice and preliminary experience was reported in non-randomized observational studies. The quality assessment of this review (Supplementary Material 3) highlighted the moderate quality of the selected studies, which was exacerbated by the variety in ICG administration and surgical practice of each center. In addition to the ICG-Lg heterogeneity, the results of the present review were also impaired by the population size of individual studies, determining higher weighted relevance for larger series reports and their respective findings. Next-generation analysis should be designed to evaluate the efficacy of specific prevention strategies for CL, performed through ICG assistance and within uniform and controlled study settings.

This review restrictively focused on a specific subject in esophageal cancer surgery, which demonstrated great effectiveness and procedural safety, with high potential for the development of ICG-Lg as a routine procedure to be performed throughout esophagectomy. However, the high accuracy and safety of intraoperative ICG-Lg did not associate with a standardized mitigation strategy for postoperative CL, generating inconclusive evidence on the effect of pre-emptive maneuvers and the subsequent extent of lymph node dissection. Although ICG-Lg significantly demonstrated to enhance anatomical landmarks for esophageal surgeons, the next randomized trials should be specifically designed to identify proper indications and mediastinal dissection in esophageal cancer surgery.

Italy: Lavinia A. Barbieri, Riccardo Calef, Agnese Carresi, Andrea Cossu, Carolina Nardi, Floriana Iannace, Filippo Ostinelli, Lorenzo Rosi, Davide Socci, Elio Treppiedi, Stefano Turi (Department of Gastrointestinal Surgery, IRCCS San Raffaele Scientific Institute).