Computed tomography-guided lipiodol marking enables margin-secure wedge resection for colorectal pulmonary metastases

Introduction

Pulmonary metastasectomy (PM) for colorectal cancer is widely recognized as a treatment that can improve survival (1,2). Complete resection (R0) is crucial, and achieving adequate surgical margins is essential for preventing local recurrence (3). Wedge resection is the most common technique for PM (4,5). However, for deep lesions, visualization or palpation of the lesion may be challenging during thoracoscopic surgery, making it technically difficult to perform wedge resection with an adequate margin. In such cases, preoperative marking techniques can play a valuable role in assisting with precise tumor localization and determining appropriate resection lines, thereby ensuring the quality of resection.

Computed tomography (CT)-guided lipiodol marking using the iodized contrast agent lipiodol has recently been reported for the localization of pulmonary lesions (6-15). Because lipiodol deposits can be clearly visualized under fluoroscopy, this method has become increasingly utilized in clinical practice for accurate resection of lesions that are difficult to identify visually or by palpation. Although the technique has been widely applied, there are few reports on its use for pulmonary metastases from colorectal cancer, and little evidence regarding its utility and limitations.

In this retrospective study, we evaluated patients with colorectal cancer who underwent wedge resection following CT-guided lipiodol marking at Osaka Medical and Pharmaceutical University Hospital. The primary objective was to assess the effectiveness of this technique for achieving adequate surgical margins and ensuring the overall quality of resection. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1823/rc).

Methods

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Institutional Review Board of Osaka Medical and Pharmaceutical University Hospital (approval No. 2024-068). Written informed consent was obtained from all patients.

Patients

This single-center retrospective cohort study was based on a clinical database and review of medical records at Osaka Medical and Pharmaceutical University Hospital. We included 324 patients who underwent PM for colorectal cancer in our department between January 2016 and December 2023. Of these patients, 98 who received preoperative CT-guided lipiodol marking were selected based on difficulty with intraoperative palpation. The criteria for selecting cases eligible for lipiodol marking were lesions with a maximum diameter <10 mm or at a depth of ≥5 mm from the pleural surface. Medical records, imaging findings, and pathological reports were reviewed. The exclusion criteria were (I) incomplete clinical or pathological data; (II) patients who did not undergo wedge resection; and (III) multiple lesions resected during the same surgical procedure on the ipsilateral lung. In patients with multiple metastatic lung lesions, each lesion that underwent individual marking and wedge resection was treated as a separate data entry (one lesion = one data point) for analysis. The patient selection flowchart is shown in Figure 1. Finally, 47 patients with a total of 61 pulmonary nodules were deemed eligible for analysis.

Figure 1 CONSORT diagram of patient selection. CT, computed tomography.

Marking technique and surgical procedure

CT-guided lipiodol marking was performed by thoracic surgeons in a hybrid operating room equipped with a sliding-gantry multi-detector CT (MDCT) system. The procedures were conducted in accordance with the protocol described by Fumimoto et al. (16). After induction of general anesthesia, the patient was positioned optimally based on the location of the lesion. A 23-gauge Chiba needle was used to puncture the lung parenchyma near the target lesion. The syringe was withdrawn to ensure that no blood or air had refluxed, respiratory ventilation was stopped, and 0.3 mL of lipiodol was injected. Immediately after the injection, a chest CT scan was performed to evaluate the adequacy of marking and to check for complications. Surgery performed under one-lung ventilation using a double-lumen endotracheal tube was then promptly initiated in the same operating room. Intraoperative palpation was not conducted; instead, the lipiodol spot was identified using X-ray fluoroscopy. The radio-opaque nodule was grasped with a ring forceps, and wedge resection was performed. Complete resection was confirmed by gross inspection or intraoperative frozen section analysis. This study was designed on the premise that, if the intraoperative margin was considered inadequate by the surgeon, additional resection would be planned.

Outcome measurements

The primary outcome was a ratio of the surgical margin to maximum tumor diameter [margin-to-tumor (M/T) ratio] ≥1. Both tumor diameter and surgical margin were evaluated using the pathological report. The surgical margin was defined as the shortest distance from the tumor edge to the closest resection line on the pathological specimen after formalin fixation and removal of staples. A correction value of 5 mm was added to compensate for tissue loss due to staple removal. Secondary endpoints included postoperative complications within 30 days (Clavien-Dindo classification) and local recurrence rate. Tumor size was defined as the maximum diameter of the lesion. Tumor depth was measured on axial or coronal chest CT images as the longest vertical distance from the deepest point of the lesion to the visceral pleura. For the lipiodol spot formed after injection, the maximum diameter was measured similarly to the tumor. The relative position of the lesion and lipiodol spot was assessed based on their respective depths and spatial relationship on three-dimensional (3D) reconstructed images (Figure 2). Lipiodol spots located more centrally than the lesion were classified as “deep”, while all others were classified as “shallow”. Local recurrence was defined as the appearance of a new pulmonary shadow adjacent to the resection staple line in the lung, corresponding to the site of previously resected pulmonary metastasis. Recurrence was diagnosed based on imaging findings and, when available, pathological confirmation.

Figure 2 Preoperative CT-guided lipiodol marking for localization of pulmonary metastases. (A) A 52-year-old man with a 7.5-mm tumor in RS2, located at a depth of 27.9 mm from the pleural surface. (B) Lipiodol marking was performed in the supine position. The three-dimensional deviation between the lipiodol spot and the lesion was 13.6 mm. Based on this positional relationship, the lesion was classified as deep. The surgical margin was 22 mm, and an M/T ratio ≥1 was achieved. (C) A 78-year-old man with a 10.8-mm tumor in RS10, located 31.7 mm from the pleural surface. (D) Lipiodol marking was performed in the prone position. The three-dimensional deviation between the lipiodol spot and the lesion was 13.5 mm. Based on this positional relationship, the lesion was classified as shallow. The surgical margin was 6 mm, and the M/T ratio was <1. Red spots/arrows: lesion; yellow spots: lipiodol spot. CT, computed tomography; M/T, margin-to-tumor.

Statistical analysis

Continuous variables are expressed as medians with interquartile ranges, and categorical variables as counts and percentages. Patients were divided into two groups based on an M/T ratio ≥1 or <1, and intergroup comparisons were conducted. Continuous variables were tested for normality using a Shapiro-Wilk test and compared by Student t-test or Mann-Whitney U test, as appropriate. Categorical variables were compared by Chi-squared test or Fisher exact test. Local recurrence-free survival (LRFS) was defined as the time from surgery to local recurrence and analyzed using Kaplan-Meier methods. To identify factors associated with an M/T ratio ≥1, variable selection was performed using the Kick-One-Out method based on the Bayesian Information Criterion (BIC). Subsequently, multivariable logistic regression analysis was conducted with 1,000 bootstrap replications to obtain robust estimates and confidence intervals (CIs). A two-sided P value <0.05 was considered significant for all analyses. Statistical analyses were performed using EZR (Easy R, v.1.61), a free software developed by Jichi Medical University (17). However, as EZR does not support BIC-based variable selection or bootstrapped logistic regression, these analyses were conducted in RStudio (v. 2023.12.1+402).

Results

Patient characteristics

The median age was 64 years (range, 56–70 years), and 28 patients (45.9%) were male. The median tumor diameter on preoperative CT was 6.2 mm (range, 5.0–7.3 mm). The tumor location was in the upper lobe in 24 patients (39.3%), middle lobe in 5 (8.1%), and lower lobe in 32 (52.5%). The median tumor depth was 21.1 mm (range, 14.2–27.9 mm). Of the 61 lesions, 50 (82.0%) had an M/T ratio ≥1 and 11 (18.0%) had an M/T ratio <1. A comparison of patient characteristics in these two groups is shown in Table 1. The characteristics of the 11 lesions with an M/T ratio <1 are shown in Table 2.

Procedure outcomes

Details of the marking procedure and surgical technique are summarized in Table 1. Lipiodol spots were successfully identified in all target lesions under CT and intraoperative fluoroscopy, and R0 resection was achieved for all lesions. The patient position during marking was supine in 32 patients (52.5%) and prone in 29 (47.5%). In 37 cases (60.7%), the marking was placed deeper than the lesion. Pneumothorax occurred in 11 cases (18.0%) as the only lipiodol marking-related complication, but none required chest tube drainage. Video-assisted thoracoscopic surgery (VATS) was performed in 55 cases (90.2%). Conversion to thoracotomy occurred in 6 cases (9.8%), all due to intrathoracic adhesions, which were not related to the marking procedure. No additional resection was performed. There were postoperative complications in 5 patients (8.2%): prolonged air leak (n=3), neurological complication (n=1), and pneumonia (n=1). All were classified as Clavien-Dindo grade II or III. There were no deaths within 30 days postoperatively. The median pathological tumor diameter was 7 mm (range, 5–8 mm) and the median surgical margin was 13 mm (range, 8–16 mm).

Factors associated with M/T ratio ≥1

There was no significant difference in age, sex, body mass index (BMI), smoking history, tumor location, or marking procedure between the groups with an M/T ratio ≥1 and <1 (Table 1), but there were significant differences in tumor diameter (P=0.046) and tumor depth (P=0.02). Based on the receiver operating characteristic (ROC) curve (Figure S1), the optimal cutoff value for tumor depth was determined to be 25.6 mm [area under the curve (AUC) =0.734; 95% CI: 0.588–0.879; sensitivity: 72.0%; specificity: 72.7%]. Using nine variables related to lipiodol marking and the M/T ratio, variable selection was performed using the Kick-One-Out method based on the BIC. Exclusion of tumor diameter and tumor depth resulted in an increase in BIC, indicating that both variables significantly contributed to the model (Table 3). A multivariable logistic regression model including these two variables was subsequently constructed. Bootstrap-based 95% CIs (1,000 replications) demonstrated that both tumor diameter [odds ratio (OR) =0.635; 95% CI: 0.234–0.896; P=0.01] and tumor depth (OR =0.102; 95% CI: 0.000–0.444; P=0.006) were significantly associated with the outcome (Table S1).

Recurrence

The median follow-up period was 39 months (range, 2–55 months). Local recurrence occurred in 4 cases (6.6%), with 2 confirmed pathologically and 2 diagnosed by imaging. LRFS was evaluated based on the M/T ratio status (Figure 3). All cases of local recurrence occurred in the M/T ratio <1 group.

Figure 3 ROC curve for tumor depth predicting resection success (M/T ratio ≥1). The optimal cutoff was 25.6 mm (AUC =0.734; sensitivity: 72.0%; specificity: 72.7%). AUC, area under the curve; M/T, margin-to-tumor; ROC, receiver operating characteristic.

Discussion

In this study, CT-guided lipiodol marking achieved an M/T ratio ≥1 in 82% of pulmonary metastases (50/61 lesions) from colorectal cancer undergoing wedge resection. Notably, local recurrence only occurred in cases with M/T ratio <1, with a local recurrence rate of 36.4% (4/11 lesions) in that group. These findings support M/T ratio <1 as a significant risk factor in this cohort and reaffirm the clinical importance of securing an adequate surgical margin.

Ensuring sufficient surgical margins is fundamental for local control in pulmonary metastasectomy for colorectal cancer (18-20). Although consensus has yet to be established regarding the optimal surgical margin, an M/T ratio ≥1 has been reported as a suppressor of local recurrence (3,21). Our findings suggest that lipiodol marking is a useful adjunctive technique for achieving this objective. Widespread adoption of thoracoscopic surgery has contributed significantly to less invasive approaches, but it has simultaneously reduced the ability to localize lesions through intraoperative palpation due to smaller incisions (22-24). In particular, small, deep nodules that are difficult to palpate present a challenge to securing an adequate surgical margin. In such situations, preoperative marking is crucial for visualization of the three-dimensional tumor location and determination of appropriate resection lines (6-13). Among various marking techniques, lipiodol marking offers several advantages. First, the depth of injection can be precisely monitored in real time under CT fluoroscopy. Second, the procedure is safe, with randomized trials showing a significantly lower incidence of adverse events compared to the hook wire method (12). In our study, pneumothorax occurred in 11 cases (18.0%) as the only complication attributable to lipiodol marking, and no pulmonary embolism related to lipiodol injection was observed. This is consistent with prior reports (10,11). Additionally, with the hybrid operating room system used in our institution, surgery is performed immediately after marking, which may reduce the need for chest drainage even in cases of pneumothorax (16). Third, lipiodol remains stable within the lung parenchyma and does not interfere with histopathological evaluation (7).

Pulmonary metastases from colorectal cancer have clinical features distinct from primary lung cancer. Notably, patients frequently have recurrence and often require multiple pulmonary resections over a lifetime (25-27). Anatomical resections involving hilar dissection during the initial surgery can lead to severe adhesions, which complicate reoperations and increase the risks of bleeding and conversion to thoracotomy (28-30). Therefore, considering the potential need for repeat metastasectomy, wedge resection that avoids hilar manipulation as much as possible is a good treatment option in many cases. As shown in this study, lipiodol marking facilitates precise wedge resection, even for deep lesions, and contributes to achieving the dual goals of local control and lung preservation, which are particularly important in the management of pulmonary metastases.

The technique also has certain restrictions. Although a previous study (13) suggested that the distance between the radiopaque lipiodol spot and the tumor may influence surgical margins, our study found no significant association between achieving an M/T ratio ≥1 and lipiodol-marking-related factors, including three-dimensional deviation, lipiodol spot size, or lipiodol spot-to-lesion depth. This suggests that preoperative 3D imaging enabled accurate spatial understanding and operative planning, regardless of the marking position. Some deep lesions near the hilum presented difficulties in securing adequate margins, even with appropriate marking, due to interference between the stapler and hilar structures such as pulmonary vessels or bronchi. Additionally, three of four cases with an M/T ratio <1 and local recurrence had rectal cancer as the primary tumor. Since rectal cancer may exhibit more aggressive biological behavior than colon cancer, special attention to surgical margins may be warranted when resecting pulmonary metastases from rectal cancer (31). For deep metastases of rectal origin, anatomical resection such as lobectomy or segmentectomy may be considered, prioritizing curability despite increased reoperation difficulty (32).

This study has several limitations. First, as a retrospective single-center study, selection bias is unavoidable. Second, there was no control group without marking, precluding objective evaluation of the efficacy of marking. To establish the true clinical value of lipiodol marking, prospective randomized controlled trials are needed. Moreover, recent reports have identified biologic factors such as spread through air spaces (STAS) and KRAS mutations as prognostic indicators that may influence surgical decision-making (20,33). These factors were not evaluated in the present study and should be addressed in future research.

Conclusions

Pulmonary metastases from colorectal cancer often require multiple surgical interventions over the course of a lifetime. Therefore, preserving lung function to maintain future surgical options is a critical component of the treatment strategy. This study showed that CT-guided lipiodol marking enables safe and precise wedge resection, even for deep lesions that are difficult to palpate during thoracoscopic surgery, and contributes to the achievement of an adequate surgical margin. This technique is a promising treatment option for metastatic lung tumors based on its favorable balance between minimal invasiveness and oncological curability.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1823/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1823/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1823/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1823/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. This study was approved by the Institutional Review Board of Osaka Medical and Pharmaceutical University Hospital (approval No. 2024-068). Written informed consent was obtained from all patients.

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/.

References

1. Pastorino U, Buyse M, Friedel G, et al. Long-term results of lung metastasectomy: prognostic analyses based on 5206 cases. J Thorac Cardiovasc Surg 1997;113:37-49. [Crossref] [PubMed]
2. Antonoff MB, Kui N, Sun R, et al. Factors associated with receipt of pulmonary metastasectomy in patients with lung-limited metastatic colorectal cancer: Disparities in care and impact on overall survival. J Thorac Cardiovasc Surg 2024;168:263-71. [Crossref] [PubMed]
3. Shiono S, Matsutani N, Hashimoto H, et al. Prospective study of recurrence at the surgical margin after wedge resection of pulmonary metastases. Gen Thorac Cardiovasc Surg 2021;69:950-9. [Crossref] [PubMed]
4. Higashiyama M, Tokunaga T, Nakagiri T, et al. Pulmonary metastasectomy: outcomes and issues according to the type of surgical resection. Gen Thorac Cardiovasc Surg 2015;63:320-30. [Crossref] [PubMed]
5. Gonzalez M, Brunelli A, Szanto Z, et al. Report from the European Society of Thoracic Surgeons database 2019: current surgical practice and perioperative outcomes of pulmonary metastasectomy. Eur J Cardiothorac Surg 2021;59:996-1003. [Crossref] [PubMed]
6. Moon SW, Wang YP, Jo KH, et al. Fluoroscopy-aided thoracoscopic resection of pulmonary nodule localized with contrast media. Ann Thorac Surg 1999;68:1815-20. [Crossref] [PubMed]
7. Watanabe K, Nomori H, Ohtsuka T, et al. Usefulness and complications of computed tomography-guided lipiodol marking for fluoroscopy-assisted thoracoscopic resection of small pulmonary nodules: experience with 174 nodules. J Thorac Cardiovasc Surg 2006;132:320-4. [Crossref] [PubMed]
8. Mogi A, Yajima T, Tomizawa K, et al. Video-Assisted Thoracoscopic Surgery after Preoperative CT-Guided Lipiodol Marking of Small or Impalpable Pulmonary Nodules. Ann Thorac Cardiovasc Surg 2015;21:435-9. [Crossref] [PubMed]
9. Tsunezuka H, Kato D, Okada S, et al. Surgical outcome of wide wedge resection in poor-risk patients with clinical-N0 non-small cell lung cancer. Gen Thorac Cardiovasc Surg 2017;65:581-6. [Crossref] [PubMed]
10. Ito K, Shimada J, Shimomura M, et al. Safety and reliability of computed tomography-guided lipiodol marking for undetectable pulmonary lesions. Interact Cardiovasc Thorac Surg 2020;30:546-51. [Crossref] [PubMed]
11. Park CH, Han K, Hur J, et al. Comparative Effectiveness and Safety of Preoperative Lung Localization for Pulmonary Nodules: A Systematic Review and Meta-analysis. Chest 2017;151:316-28. [Crossref] [PubMed]
12. Park CH, Lee SM, Lee JW, et al. Hook-wire localization versus lipiodol localization for patients with pulmonary lesions having ground-glass opacity. J Thorac Cardiovasc Surg 2020;159:1571-1579.e2. [Crossref] [PubMed]
13. Fumimoto S, Sato K, Hanaoka N, et al. Identification of factors affecting the surgical margin in wedge resection using preoperative lipiodol marking. J Thorac Dis 2021;13:3383-91. [Crossref] [PubMed]
14. Wang Y, Chen E. Advances in the localization of pulmonary nodules: a comprehensive review. J Cardiothorac Surg 2024;19:396. [Crossref] [PubMed]
15. Wang A, Rosenberg GM, Woodard GA, et al. Image-guided and bronchoscopic localization techniques used to facilitate minimally invasive pulmonary metastasectomies. Video-assist Thorac Surg 2024;9:19.
16. Fumimoto S, Sato K, Koyama M, et al. Combined lipiodol marking and video-assisted thoracoscopic surgery in a hybrid operating room. J Thorac Dis 2018;10:2940-7. [Crossref] [PubMed]
17. Kanda Y. Investigation of the freely available easy-to-use software 'EZR' for medical statistics. Bone Marrow Transplant 2013;48:452-8. [Crossref] [PubMed]
18. Rusch VW. Pulmonary metastasectomy. Current indications. Chest 1995;107:322S-31S. [Crossref] [PubMed]
19. Nelson DB, Tayob N, Mitchell KG, et al. Surgical margins and risk of local recurrence after wedge resection of colorectal pulmonary metastases. J Thorac Cardiovasc Surg 2019;157:1648-55. [Crossref] [PubMed]
20. Davini F, Ricciardi S, Zirafa CC, et al. Lung metastasectomy after colorectal cancer: prognostic impact of resection margin on long term survival, a retrospective cohort study. Int J Colorectal Dis 2020;35:9-18. [Crossref] [PubMed]
21. Mishima S, Hamanaka K, Shimura M, et al. Role of segmentectomy for lung metastases from colorectal cancer: latest insights and technical developments—a review. Shanghai Chest 2022;6:34.
22. Prenafeta Claramunt N, Hwang D, de Perrot M, et al. Incidence of Ipsilateral Side Recurrence After Open or Video-Assisted Thoracic Surgery Resection of Colorectal Lung Metastases. Ann Thorac Surg 2020;109:1591-7. [Crossref] [PubMed]
23. Mangiameli G, Cioffi U, Alloisio M, et al. Lung Metastases: Current Surgical Indications and New Perspectives. Front Surg 2022;9:884915. [Crossref] [PubMed]
24. Mangiameli G, Cioffi U, Alloisio M, et al. Pulmonary Metastases: Surgical Principles, Surgical Indications, and Innovations. In: Sergi CM. editor. Metastasis. Brisbane: Exon Publications; 2022:49-62.
25. Salah S, Watanabe K, Park JS, et al. Repeated resection of colorectal cancer pulmonary oligometastases: pooled analysis and prognostic assessment. Ann Surg Oncol 2013;20:1955-61. [Crossref] [PubMed]
26. Sponholz S, Schirren M, Baldes N, et al. Repeat resection for recurrent pulmonary metastasis of colorectal cancer. Langenbecks Arch Surg 2017;402:77-85. [Crossref] [PubMed]
27. Hishida T, Tsuboi M, Okumura T, et al. Does Repeated Lung Resection Provide Long-Term Survival for Recurrent Pulmonary Metastases of Colorectal Cancer? Results of a Retrospective Japanese Multicenter Study. Ann Thorac Surg 2017;103:399-405. [Crossref] [PubMed]
28. Hattori A, Matsunaga T, Watanabe Y, et al. Repeated anatomical pulmonary resection for metachronous ipsilateral second non-small cell lung cancer. J Thorac Cardiovasc Surg 2021;162:1389-1398.e2. [Crossref] [PubMed]
29. Liu YW, Kao CN, Chiang HH, et al. Pulmonary completion lobectomy after segmentectomy: An integrated analysis of perioperative outcomes. Thorac Cancer 2022;13:2331-9. [Crossref] [PubMed]
30. Takamori S, Oizumi H, Suzuki J, et al. Completion lobectomy after anatomical segmentectomy. Interact Cardiovasc Thorac Surg 2022;34:1038-44. [Crossref] [PubMed]
31. Cho JH, Hamaji M, Allen MS, et al. The prognosis of pulmonary metastasectomy depends on the location of the primary colorectal cancer. Ann Thorac Surg 2014;98:1231-7. [Crossref] [PubMed]
32. Chung JH, Lee SH, Yi E, et al. Impact of resection margin length and tumor depth on the local recurrence after thoracoscopic pulmonary wedge resection of a single colorectal metastasis. J Thorac Dis 2019;11:1879-87. [Crossref] [PubMed]
33. Renaud S, Seitlinger J, Lawati YA, et al. Anatomical Resections Improve Survival Following Lung Metastasectomy of Colorectal Cancer Harboring KRAS Mutations. Ann Surg 2019;270:1170-7. [Crossref] [PubMed]