A retrospective evaluation of risk factors for an inadequate surgical margin in preoperative lipiodol marking for small-sized pulmonary lesions.

Introduction
Accurate localization and complete resection of pulmonary nodules are paramount in management of lung cancer (1). Despite advances in minimally invasive surgical techniques such as video-assisted thoracoscopic surgery (VATS), challenges persist in identifying and removing small or deeply situated nodules, often necessitating adjunctive approaches to enhance surgical outcomes (2).
Among these adjunctive techniques, computed tomography (CT)-guided lipiodol marking is used for preoperative localization of pulmonary nodules, especially those that are challenging to visualize intraoperatively or located in complex anatomical regions (3,4). This technique involves precise injection of lipiodol, an iodized oil contrast agent, adjacent to the target lesion under CT guidance. Marking the position of the nodule accurately can facilitate its localization and ensure complete removal during subsequent surgery (5).
The distance of the surgical margin in lung resections requiring marking has not been widely investigated (6). However, inadequate surgical margins can affect local recurrence and prognosis, especially in wedge resections (7,8), and the distance of the surgical margin is an important factor in successful resection (9). Therefore, the aim of this retrospective study was to identify predictors of surgical margin adequacy in wedge resection with lipiodol marking, using the distance of the surgical margin as the primary endpoint. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1450/rc).

Methods
This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study protocol was approved by the Institutional Review Board of Osaka Medical and Pharmaceutical University Hospital (approval No. 2024-139). Written informed consent for CT-guided lipiodol marking was obtained from all patients prior to the procedure.

Patients
From June 2015 to December 2022, 200 consecutive patients with 211 pulmonary nodules who underwent CT-guided lipiodol marking prior to lung resection in our department were enrolled in the study. The criteria for pulmonary localization and subsequent wedge resection were defined by the thoracic surgical team. Lesions selected for this approach included those considered challenging to identify thoracoscopically, such as ground-glass opacity nodules, deeply situated nodules away from the pleural surface, and lesions measuring less than 10 mm in diameter. The exclusion criterion were (I) a pathological non-malignant tumor; and (II) missing data for the surgical margin. In addition, 10 patients were excluded because lobectomy was performed after intraoperative frozen-section diagnosis of primary lung cancer, according to patient preference rather than insufficient margins. The analysis was restricted to patients who underwent wedge resection, and 134 patients with 140 pulmonary nodules met the inclusion criteria. A study consort diagram is shown in Figure 1.

Marking technique
All procedures were carried out in a hybrid operating room equipped with a sliding-gantry CT scanner (Somatom Definition AS + SLID, Siemens, Germany) (Figure 2A). Both the marking and the subsequent resection were undertaken by a surgical team led by a board-certified thoracic surgeon (S.F.) experienced in this technique. The detailed methodology has been reported previously (10). Following induction of general anesthesia, patients were positioned either supine or prone according to the location of the target lesion, to facilitate optimal needle access. A scale sheet with an embedded metal wire was attached to the patient’s body surface, after which a CT scan using the gantry system was performed (Figure 2B,2C). The shortest distance from the nodule to the chest wall was chosen as the injection site. A 23-gauge needle was inserted through the skin into the perilesional target lesion, avoiding structures such as blood vessels and bronchi, as well as direct injection into the tumor itself (Figure 2D). The syringe was gently withdrawn to confirm the absence of blood or air reflux, after which respiratory ventilation was temporarily suspended, and 0.2 mL of lipiodol (Lipiodol UltraFluid; Laboratory Guerbet, Aulnay-Sous-Bois, France) was injected in a single bolus close to the target lesion, as confirmed on CT images, while ensuring an injection pathway that allows adequate grasping of the marked area without compressing or displacing the tumor during stapling. Immediately after lipiodol injection, whole-chest CT images were obtained to evaluate the lipiodol nodule and complications related to marking (Figure 2E).

Surgical procedure
Immediately after localization, the patient was repositioned into the lateral decubitus position. Surgery was performed under general anesthesia using single lung ventilation via a double-lumen endobronchial tube. A C-arm-shaped fluoroscopy unit was placed horizontally in an appropriate position. Based on preoperative images, a thoracoscopic port was inserted into the pleural cavity through the appropriate intercostal space. Another one or two ports were placed to insert a grasping instrument and a linear stapling device. Finger palpation to identify the target lesion was not performed in any cases. The lipiodol spot was grasped with ring-shaped forceps during fluoroscopy and then resected with an endoscopic stapler (Figure 3).

Pathological analysis
All clinical specimens and pathological reports were reviewed. The resection margin of all specimens was measured after surgery. This margin was defined as the distance from the tumor to the nearest resection line in a formalin-inflated lung with staples removed. In our institution, immediately after resection, the specimen is inflated with formalin through the bronchus to achieve near-complete inflation, after which the staples are carefully removed for margin measurement. The cut staple line removes 0.5 cm. The tumor size and resection margin distance was measured macroscopically by a pathologist and recorded on the final pathology report. When the distance between the tumor and the resection margin was very close, the margin width was measured using a microscope. Successful resection was defined as resection margin distance (mm)/tumor size (mm) (M/T) ratio ≥1.

Statistical analysis
Continuous variables are expressed as median and interquartile range (IQR) (25th and 75th percentiles) and categorical variables are expressed as number (%). Dichotomous variables were compared by Fisher exact test. The required resection depth proposed by Sato et al. was used as one of the lipiodol marking-related variables (6). This depth is calculated from preoperative CT images as: required resection depth (mm) = depth (distance from closest pleura) + {[diameter ×2 (for tumor <2 cm)] or [diameter + 20 (for tumor ≥2 cm)]}. Based on pathological analysis, tumors were divided into groups with resection success (M/T ratio ≥1) and resection failure (M/T ratio <1). Clinical characteristics and marking-related variables of the nodules were analyzed by Mann-Whitney U test and Fisher exact test to evaluate differences between these groups. Factors with P<0.1 in univariate analysis were used in logistic regression analysis to identify independent factors associated with resection failure. Statistical analyses were performed in EZR v.1.51 (Saitama Medical Center, Jichi Medical University, Saitama, Japan), a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria). P<0.05 was considered statistically significant.

Results

Patients
The clinical characteristics of the patients are shown in Table 1. Tumors were classified into pure ground-glass opacity (GGO) (n=65, 46.4%), GGO with solid component (n=21, 15.0%), and solid (n=54, 38.6%). The median tumor size was 7.16 (range, 4.38–10.1) mm and the median distance from the closest pleura was 11.8 (5.83–19.8) mm on CT images. The median required resection depth was 27.7 (20.1–36.3) mm.

Preoperative lipiodol marking and surgical procedure
Details of the marking and surgical procedures are shown in Table 2. The lipiodol spot was detected in all target tumors on CT and intraoperative fluoroscopy. There were 78 nodules (55.7%) marked in a supine position and 62 nodules (44.3%) marked in a prone position during the localization procedure. No major complications occurred during lipiodol marking. Common complications included pneumothorax (n=17, 12.1%) and bloody sputum (n=1, 0.7%). These conditions did not require additional intervention. The surgical technique was mostly VATS (n=129, 92.1%). All cases of conversion surgery (n=11, 7.9%) were due to intrapleural adhesions and were not caused by the marking technique. Pathological diagnosis included 34 invasive adenocarcinomas (24.2%), 50 non-invasive adenocarcinomas (35.7%), 52 metastases (37.1%), and 4 other tumors (2.9%). The median tumor diameter was 8 (range, 6.0–11.3) mm, the median resection margin distance was 12.0 (8.0–17.0) mm, and the median M/T ratio was 1.44 (0.87–2.50) mm.

Risk factors for failure resection
Of the 140 lesions in 134 patients, 100 (71.4%) were resected successfully (M/T ratio ≥1) and 40 (28.6%) had resection failure (M/T ratio <1). The median required resection depth and M/T ratio of each segment and the resection success rate are shown in Figure 4. For both lungs, there was a trend towards lower resection success rates in segment 6 compared to other segments. However, there were no factors that differed significantly between segment 6 and the other segments.
A comparison of the resection success and failure cases is shown in Table 3. These groups had significant differences in radiological findings (P=0.04), tumor diameter on CT (P<0.001), and required resection depth (P<0.001). There was no significant difference in age, gender, body mass index (BMI), smoking history, tumor location, distance from closest pleura, marking position, and surgical procedure.
A cut-off value for the required resection depth was determined using a receiver operating characteristic (ROC) curve (Figure 5). A depth of 32.4 mm was found to be the best cut-off, with an area under the curve (AUC) of 0.68 [95% confidence interval (CI): 0.577–0.778], sensitivity of 57.5%, and specificity of 73.0%. In univariate analysis, CT characteristics and required resection depth were significant (P<0.01). In multivariate models using these factors, the depth of the required resection line was identified as a significant independent factor for resection failure (P<0.001) (Table 4).

Discussion
The efficacy of CT-guided lipiodol marking for pulmonary nodules prior to lung resection and factors influencing resection success were examined in this study. The resection success rate, defined as a M/T ratio ≥1, was 71.4%. This indicates that lipiodol marking was effective in facilitating resection in most cases. However, this also means that in 28.6% of cases, resection failed to achieve oncologically adequate margins. We consider this failure rate to be clinically meaningful, as nearly one-third of patients may be left with insufficient margins if wedge resection is selected. This highlights the limitations of lipiodol marking alone and underscores the importance of careful preoperative assessment. In particular, for patients with deeper or more complex lesions, wedge resection may not always be appropriate, and segmentectomy should be considered as an alternative strategy. The study identified factors associated with resection failure, which will permit optimization of patient outcomes and refinement of the technique.
A key finding was the significant impact of the required resection depth on the success of resection. This variable, calculated from preoperative CT images, incorporates the depth from the closest pleura and the diameter of the tumor. A deeper required resection depth was strongly associated with resection failure. This shows the importance of accurate preoperative planning and assessment of tumor characteristics to ensure adequate surgical margins and minimize the risk of incomplete resection (6). Our findings suggest that tumors requiring deeper resection may pose greater challenges during wedge resection, potentially due to their proximity to critical structures or increased technical complexity.
Radiological characteristics of the pulmonary nodules, including the presence of solid components and a larger tumor diameter, were also identified as significant factors associated with resection failure (10-12). These findings are consistent with studies suggesting that larger and more complex nodules may be more challenging to resect completely (13). Solid components within the nodules may indicate a higher likelihood of invasive malignancy and require more extensive resection to achieve clear margins (14,15). In addition, analysis by segment revealed that not only segment 6 but also apical (right S1) and basal (left S8–S9) segments had relatively low success rates. These findings may reflect anatomical challenges such as difficult stapler access angles, deeper lesion locations, and the proximity of nodules to segmental bronchi or vessels. Such anatomical factors likely contributed to the higher risk of inadequate margins in these segments, underscoring the importance of anticipating technical difficulties during surgical planning.
Determination of optimal cut-off values for factors such as required resection depth through ROC curve analysis provided insights into predictive thresholds for resection success. A required resection depth of 32.4 mm was identified as the optimal cut-off point, with reasonable sensitivity and specificity. However, we acknowledge that the AUC value of 0.68 indicates only moderate predictive performance, with sensitivity of 57.5% and specificity of 73.0%. While this level may not be sufficient as a sole determinant in daily clinical practice, we consider the identified cut-off for required resection depth to be a supportive tool when used in combination with other clinical factors for preoperative risk assessment. This information can aid clinicians in preoperative decision-making and risk stratification, which can guide the selection of appropriate surgical approaches and adjunctive techniques. Specifically, required resection depth may serve as a practical guide for determining whether wedge resection is likely to achieve adequate margins or whether segmentectomy should be pursued instead. In addition, these findings could inform the development of new localization or margin-assurance strategies—such as combined dye or microcoil marking—for deep-seated lesions where wedge resection is technically limited.
While our study provides insights into the efficacy and factors influencing the success of CT-guided lipiodol marking, several limitations should be acknowledged. First, the retrospective nature of the study may introduce inherent biases and limitations in data collection and analysis. Additionally, the study was conducted at a single center, which may limit the generalizability of the findings to other settings. Further prospective studies in larger patient cohorts and multi-center collaborations are needed to validate our findings and identify additional factors influencing resection outcomes.

Conclusions
CT-guided lipiodol marking can facilitate successful resection of pulmonary nodules prior to lung resection. Nonetheless, the 28.6% failure rate emphasizes that wedge resection with lipiodol marking alone may not always be sufficient, and alternative strategies such as segmentectomy should be considered in high-risk cases. Factors such as required resection depth, radiological characteristics of the nodules, as well as segment-specific anatomical challenges, are predictors of resection outcomes. In future clinical practice, integrating depth-based risk assessment into preoperative planning may help tailor surgical strategies and improve case selection between wedge and segmentectomy. By identifying these factors, clinicians can better tailor surgical strategies and optimize patient outcomes in management of pulmonary nodules. These findings show the importance of ongoing research and refinement of techniques in the field of thoracic surgery.

Supplementary
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