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Department of Oncology, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Shandong Province, China
Address for reprints: Zhongmin Peng, MD, Department of Thoracic Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 9677 Jing 10 Rd, Jinan 250000, China.
The intraoperative localization of nonpalpable pulmonary nodules for thoracoscopic wedge resection is technically challenging. Current preoperative image-guided localization techniques require additional time, costs, procedural risks, advanced facilities, and well-trained operators. In this study, we explored a cost-effective method of well-matched interaction between virtuality and reality for accurate intraoperative localization.
Methods
Through the integration of techniques involving preoperative 3-dimensional (3D) reconstruction, temporary clamping of target vessel and the modified inflation-deflation method, the segment on the 3D virtual model and the segment under the thoracoscopic monitor were well matched in the inflated state. Then the spatial relationships of target nodule to the virtual segment could be applied to the actual segment. The well-matched interaction between virtuality and reality would facilitate nodule localization.
Results
A total of 53 nodules were successfully localized. The median maximum diameter of the nodules was 9.0 mm (interquartile range [IQR], 7.0-12.5 mm). The median depthmin and depthmax were 10.0 mm and 18.2 mm, respectively. The median macroscopic resection margin was 16 mm (IQR, 7.0-12.5 mm). The median duration of chest tube drainage was 27 hours, with a median total drainage of 170 mL. The median postoperative length of hospital stay was 2 days.
Conclusions
The well-matched interaction between virtuality and reality is safe and feasible for intraoperative localization of nonpalpable pulmonary nodules. It may be proposed as a preferred alternative to traditional localization methods.
We explored a cost-effective method of well-matched interaction between virtuality and reality for accurate intraoperative localization of nonpalpable pulmonary nodules.
Our method for intraoperative localization is based on integration with innovative technologies involving preoperative 3-dimensional reconstruction, temporary clamping of target vessels, and the modified inflation-deflation method. Our cost-effective method, without radiation exposure and procedural risks, should be applied to all nonpalpable pulmonary nodules requiring localization and wedge resection.
See Commentary on page XXX.
With the increasing use of low-dose computed tomography (CT) scans for health examination and cancer screening, more small lung nodules suspicious of early-stage lung cancer are being detected.
Based on their radiologic appearance, these nodules can be divided into solid nodules, mixed ground-glass nodules (mGGNs), and pure ground-glass nodules (pGGNs). The management of these small nodules is particularly challenging and inconsistent.
Evaluation of individuals with pulmonary nodules: when is it lung cancer? Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines.
When a preoperative biopsy is unavailable or unnecessary for treatment decisions, surgery with intraoperative diagnosis is required for these suspicious nodules. Then the preferred diagnostic procedure for peripheral (ie, outer one-third) nodules is wedge resection. In addition, wedge resection with negative margins is an appropriate treatment for patients of advanced age, with multiple lung nodules, or with poor cardiopulmonary reserve. Furthermore, wedge resection with sufficient resection margins has been proposed as an alternative for treatment in ground-glass opacity (GGO)-dominant peripheral lung cancer.
A non-randomized confirmatory trial of segmentectomy for clinical T1N0 lung cancer with dominant ground glass opacity based on thin-section computed tomography (JCOG1211).
Wedge resection is based on accurate nodule localization. When the target nodule is small, GGO-dominant, distant from the pleural surface, or located far from the utility incision, nodule localization by visual inspection, finger palpation, and instrument palpation during thoracoscopic surgery will be particularly challenging.
Meanwhile, the geometric relationship of the target nodule to anatomic landmarks of the chest, as previously displayed on a preoperative CT image, are distorted by the collapse of the lung during surgery. There is a mismatch between the inflated lung on preoperative CT image and the deflated lung on the intraoperative monitor, which is unfavorable for accurate localization only by experience.
Failure of nodule localization may lead to the need for conversion to open thoracotomy or extensive resection. Extensive resection, either segmentectomy or lobectomy, inevitably results in more sophisticated surgical procedures, more unnecessary sacrifices of lung parenchyma, and more postoperative complications. Therefore, several preoperative and intraoperative adjunctive localization techniques have been developed for localization of nonvisible and nonpalpable nodules.
Preoperative image-guided localization techniques involve 2 main imaging tools: CT and electromagnetic navigation bronchoscopy (ENB). These techniques can be categorized into 4 groups according to the materials used: metallic materials (hook wire,
Each of these technique requires additional time, costs, advanced facilities, and well-trained operators. In most cases, the localization operator is not the surgeon for wedge resection. Dislodgement or displacement of metallic material and rapid diffusion of dye would cause failure in localization. CT-guided percutaneous puncture is associated with more complications, especially pneumothorax and hemorrhage. Radiation exposure, as well as the possibility of interference with pathologic diagnosis, remain unresolved.
The hope is that through integration with innovative technologies and optimization of surgical procedures, nonpalpable pulmonary nodules suitable for wedge resection can be successfully localized by the surgeon himself.
Our previous study confirmed that the arterial ligation–alone method can effectively and accurately identify the intersegmental demarcation (ISD) for segmentectomy.
Furthermore, when target artery/vein is temporarily clamped by a bulldog clip, the inflated segment can be displayed using a modified inflation-deflation method. Given that the spatial relationship of the target nodule to the inflated segment can be revealed by 3-dimensional (3D) virtual models, the well-matched interaction between virtuality and reality should aid nodule localization and wedge resection. However, the utility of this approach has not yet been investigated, and thus the aim of the present study was to examine the feasibility and safety of the virtuality–reality interaction for nodule localization.
Methods
Patients
This study was approved by the Ethics Committee of Shandong Provincial Hospital in Jinan (registration no. 2020-034). The need for written informed consent from individual patients was waived in accordance with institutional guidelines.
Between March 2020 and October 2021, patients scheduled for thoracoscopic wedge resection and nodule localization were recruited for participation in this study. Their eligibility was determined by their referring surgeons and radiologists based on the following inclusion criteria: (1) target nodules were located in the outer one-third of the lung parenchyma and were <20 mm in greatest dimension; (2) depthmax, defined as the minimum distance between the nodule inner edge and the pleural surface, was <35 mm; (3) depthmin, defined as the minimum distance between the nodule's outer edge and the pleural surface, was >5 mm for solid nodules; and (4) depthmin was >3 mm for GGNs.
Exclusion criteria included (1) visible or palpable nodules under thoracoscopic exploration; (2) inaccessible or mistaken blocking of the target vessel; and (3) unclear ISD due to severe emphysema and interstitial pneumonia. Eventually, 53 patients met the selection criteria and were enrolled in our study; however, 2 of these patients were excluded because the nodules were localized by exploratory palpation.
3D Reconstruction and Preoperative Planning
Thin-section contrast-enhanced CT scans were performed using a 320-slice volume CT scanner (Aquilion ONE; Toshiba Medical Systems) within 2 weeks before surgery. Using 0.625-mm or 1.3-mm thick slices, CT data of all patients in the DICOM format were imported to a computer-assisted surgery system (Hisense Medical) for 3D reconstruction. On average, the manufacturing process of 3D virtual model took approximately 30 minutes, at a cost of approximately $300 (USD) per patient. The 3D virtual model could display the spatial relationships of target nodule to the corresponding segment or subsegment (Figure 1, B) and allow determination of which artery or vein should be clamped intraoperatively (Figure 1, C).
Figure 1A-F, Temporary clamping of A1 for localization of non-palpable pulmonary nodule located in RS1.
All surgeries were performed by the same group of surgeons. The operations were performed through a 3- to 4-cm muscle-sparing anterolateral incision. First, thoracoscopic exploration was performed to exclude visible or palpable nodules. Separation and exposure of the target artery/vein was followed by temporary clamping with a bulldog clip (Figure 1, D). Then the ISD was determined by the expansion–collapse boundary using the modified inflation-deflation method via pure oxygen. With reference to the spatial relationships of the target nodule to the corresponding segment as revealed by the 3D virtual model, the surgeon could accurately localize the target nodule on the inflated segment and determine the extent of wedge resection (Figure 1, E).
Wedge resection was performed with staplers. The macroscopic resection margin was measured on the fresh specimen after wedge resection. Resected lesions were subsequently sent for intraoperative frozen pathology to determine the need for segmentectomy, lobectomy, or lymphadenectomy. The resection margin was intraoperatively evaluated (Figure 1, F). If the resection margin was <20 mm or the maximum diameter of the nodule, the absence of cancer cells at the resection margin was histologically or cytologically confirmed before completing the operation.
Postoperative Management
Routinely, through the dorsal end of the incision, a single chest tube (22 Fr) was inserted in the top of chest for drainage of both effusion and air. Criteria for chest tube extubation were (1) absence of air leakage, (2) daily drainage <200 mL, and (3) no hemothorax, pneumothorax, or chylothorax.
Data Analysis and Statistics
Imaging parameters of all nodules (ie, location, maximum diameter, depthmin, depthmax, and consolidation-to-tumor ratio [CTR]) were measured on thin-section CT images by the same thoracic surgeon. Demographic data (ie, age, sex, smoking status, and preoperative imaging follow-up), intraoperative data (ie, target artery/vein, macroscopic resection margin, frozen pathology, duration of operation, and blood loss), and postoperative data (ie, duration of chest tube drainage, total drainage, paraffin pathology, postoperative hospital stay, and complications) were extracted from clinical records. For this study, continuous variables were represented as a median value with interquartile range (IQR), whereas categorical variables were expressed as count with percentage. Data analysis was conducting using SPSS version 24 (IBM).
Results
Table 1 summarizes the baseline information and perioperative data. Twenty-two male and 29 female patients were enrolled, with a median age of 51 years. Of the 51 patients, 20 had other suspicious nodules and underwent simultaneous (n = 16) or staged (n = 4) sublobar resection. However, we focused on the localization of nonpalpable nodules for wedge resection. All 53 of these nodules were successfully localized. For these nodules, the median maximum diameter was 9.0 mm (measured on the lung window), and the median depthmin and depthmax were 10.0 mm and 18.2 mm, respectively. Radiologic examination revealed 14 pGGNs, 33 mGGNs, and 6 solid nodules. Among the 33 mGGNs, 2 had a CTR of >0.75 and 20 had a CTR of <0.25. No suspected lymph node metastasis was observed before surgery.
Table 1Patient and lesion characteristics
Characteristic
Value
Total patients
51
Age, y, median (IQR)
51 (46-58)
Sex, n (%)
Male
22 (43.14)
Female
29 (56.86)
Smoking status, n (%)
Former smoker
7 (13.73)
Nonsmoker
44 (86.27)
FEV1, L, median (IQR)
2.79 (2.35-3.27)
Total nodules
53
Maximum nodule diameter, mm, median (IQR)
9.0 (7.0-12.5)
Nodule depthmin, mm, median (IQR)
10.0 (5.6-16.0)
Nodule depthmax, mm, median (IQR)
18.2 (14.0-26.1)
Nodule location, n (%)
Right upper lobe
17 (32.08)
Right middle lobe
1 (1.89)
Right lower lobe
10 (18.87)
Left upper lobe
20 (37.73)
Left lower lobe
5 (9.43)
CTR, n (%)
0
14 (26.42)
0-0.25
20 (37.73)
0.25-0.50
11 (20.76)
0.50-0.75
0
0.75-1
2 (3.77)
1
6 (11.32)
Target vessel, n (%)
Artery
49 (92.45)
Vein
4 (7.55)
Macroscopic resection margin, mm, median (IQR)
16 (14-20)
Intraoperative frozen pathology, n (%)
Benign
8 (15.09)
AAH
3 (5.66)
AIS
17 (32.08)
MIA
13 (24.53)
IAC
11 (20.75)
SCC
1 (1.89)
Operation duration, min, median (IQR)
90 (90-120)
Blood loss, mL, median (IQR)
20 (10-20)
Postoperative paraffin pathology, n (%)
Benign
8 (15.09)
AAH
4 (7.55)
AIS
14 (26.41)
MIA
16 (30.19)
IAC (lepidic predominant)
4 (7.55)
IAC (acinar predominant)
6 (11.32)
SCC
1 (1.89)
Duration of chest tube drainage, h, median (IQR)
27 (24-42)
Total drainage, mL, median (IQR)
170 (140-230)
Postoperative hospital stay, d, median (IQR)
2 (2-3)
Pneumothorax, n (%)
1 (1.96)
IQR, Interquartile range; FEV1, forced expiratory volume in 1 second; depthmin, minimum distance between the nodule outer edge and the pleural surface; depthmax, minimum distance between the nodule inner edge and the pleural surface; CTR, consolidation-to-tumor ratio; AAH, atypical adenomatous hyperplasia; AIS, adenocarcinoma in situ; MIA, minimally invasive adenocarcinoma; IAC, invasive adenocarcinoma; SCC, squamous cell carcinoma.
In most cases, the localization of nonpalpable nodules was navigated by the target artery, but 4 nodules were navigated by the target vein (V6c, V6, V8, and V9 and 10). Reasons for a change to venous navigation included the presence of arterial variation or a poorly developed interlobar fissure, which led to failure of separation of the target artery, and cases where the location of the nodule made venous navigation more advantageous than arterial navigation. The median macroscopic resection margin was 16 mm. The free resection margin was confirmed by frozen pathology. In 3 cases, lobectomy was performed after wedge resection because the frozen pathology was invasive adenocarcinoma (IAC) with a CTR ≥0.5 or squamous cell carcinoma (SCC). For 9 cases of IAC with CTR <0.5, we did not perform extensive resection, because sublobar resection offered a good long-term prognosis for GGO-dominant peripheral small lung cancer reported by the JCOG0804 study.
The median duration of the operation was 90 minutes, and the median intraoperative blood loss was 20 mL.
All patients received enhanced recovery after surgery, and the chest tube was safely removed when the extubation criteria were met. The median duration of chest tube drainage was 27 hours, and the median total drainage was 170 mL. The median postoperative hospital length of stay was 2 days. In 1 patient, pneumothorax and pneumoderma occurred after extubation on the second postoperative day. After reinsertion of chest tube, another 3 days of drainage was followed by discharge.
The postoperative paraffin pathology of the 6 solid nodules included 1 SCC, 1 hamartoma, 1 case of tuberculosis, and 3 benign fibroproliferative lesions. In total, there were 8 benign lesions, 4 atypical adenomatous hyperplasias (AAHs), and 41 carcinomas. The 8 benign lesions included 1 bronchiolar adenoma, 1 hamartoma, 1 tuberculosis, and 5 fibroproliferative lesions. The 41 carcinomas included 14 adenocarcinomas in situ (AIS), 16 minimally invasive adenocarcinomas (MIAs), 4 lepidic-predominant IACs, 6 acinar-predominant IACs, and 1 SCC. Paraffin pathology of the resected lymph nodes showed negative results in all.
Discussion
In this study, we implemented a safe and feasible method of virtuality–reality interaction for intraoperative localization of nonpalpable pulmonary nodules. The virtual segment and the actual segment were well matched in the inflated state through the integration of techniques involving preoperative 3D reconstruction, temporary clamping of target vessels,
and a modified inflation-deflation method with pure oxygen. The spatial relationships of the target nodule to the virtual segment, which had been revealed by the 3D virtual model during preoperative planning, could be applied and fed back to the actual segment. The well-matched interaction between virtuality and reality, just like augmented reality, makes the localization of target nodules easy and accurate. In our study, the rate of successful nodule localization and wedge resection was 100%.
Our method of virtuality–reality interaction seems to be readily accomplished by wedge resection, but the whole procedure is similar to a simplified version of segmentectomy based on 3D reconstruction. The identification of segmental bronchus is unnecessary, and the target artery or vein need not be severed or ligated. Identification and temporary clamping of the target vessel are required, which is a much easier and safer procedure than standard segmentectomy (Table 2).
Table 2Advantages and disadvantages of CT-guided localization, ENB-guided localization, segmentectomy, watershed analysis, and virtuality–reality interaction
Localization methods
Advantages
Disadvantages
Preoperative
CT-guided localization with hook wire or dye
1. Most commonly used 2. Simple technique 3. Lower requirements for additional time, costs, advanced facilities, and experienced operators
1. Exclusion zone of percutaneous localization 2. Procedural risks, including pneumothorax, hemorrhage, dislodgment, and dye diffusion 3. Radiation exposure 4. Occupying resources of CT room
ENB-guided localization with dye
1. High success rate 2. Rare complications 3. Not limited by exclusion zone of percutaneous localization;
1. More sophisticated technique 2. Greater requirements for additional time, costs, advanced facilities, and experienced operators
Intraoperative
Segmentectomy
1. Can be used to resect deep nodules unsuitable for wedge resection
Especially when located in the inner two-thirds of the lung parenchyma.
2. An alternative to failure of any other method
1. More sophisticated surgical procedure and longer operation duration 2. More sacrifices of lung parenchyma with more complications
Watershed analysis
1. Not limited by exclusion zone of percutaneous localization 2. An alternative to failure of preoperative localization 3. Time-saving
1. Target artery needs to be temporarily blocked 2. Requirement for fluorescent accessories and 3D reconstruction software with function of watershed analysis 3. Drug allergy
Virtuality–reality interaction
1. No requirement for any auxiliary equipment 2. An alternative to failure of preoperative localization 3. Either a target artery or vein is feasible
1. 3D reconstruction before surgery 2. Target vessel needs to be temporarily blocked 3. Waiting time for pulmonary inflation-deflation
is similar to our method. However, although both methods are navigated by the target segmental vessel, they are quite different in some respects (Table 2). First, blocking the target artery is indispensable for watershed analysis, whereas either the target artery or the target vein can be blocked in our method (Video 1). When the target artery is inaccessible owing to a poorly developed interlobar fissure, use of the target vein alternative increases the applicability of our method. Second, identification of the ISD with ICG occurs almost in real time, but with a waiting period for pulmonary inflation-deflation.
In essence, this is the difference between i.v. ICG injection and the modified inflation-deflation method with pure oxygen for identifying ISD. Third, a thoracoscope with fluorescent accessories and 3D reconstruction software with watershed analysis functionality are required for watershed analysis, whereas our method does not require any auxiliary equipment. Fourth, there is a difference in how the target vessel is blocked, with a bulldog clip used in watershed analysis and the colored ribbon with a slipknot used in out method. Finally, the most important difference is that in our method, both the virtual segment from the 3D model and the actual segment displayed during the operation are inflated and well-matched, whereas the whole lung is kept deflated for watershed analysis. These differences indicate that our localization method may be more feasible, accurate, and cost-effective. In a previous study, localization by watershed analysis failed in 1 case owing to an extremely unclear ISD, and segmentectomy using a modified inflation-deflation method was then performed.
If the authors had used our localization method before segmentectomy, the nodule could have been successfully localized and resected without segmentectomy.
As a simple preoperative technique without the need for 3D reconstruction, CT-guided localization can greatly shorten the duration of the operation and improve operating room efficiency. Currently, it is the most widely used method for localizing pulmonary nodules. However, percutaneous puncture is related to more complications, especially pneumothorax and hemorrhage. Dislodgement or displacement of metallic material and rapid diffusion of dye can cause failure of localization, and radiation exposure for patients and operators remains unresolved. As a preoperative localization technique, it may be abused for nodules with a probability of localization by palpation. In addition, there are always some pulmonary nodules located in the exclusion zone of percutaneous localization.
Our method of virtuality–reality interaction can be applied to resolve these problems and should be proposed as a preferred alternative to CT-guided localization.
At present, ENB-guided localization with dye also could be used to partly resolve the problems of CT-guided percutaneous localization. Although the success rate of this sophisticated technique is reported to be higher with rare complications, the increased time requirement and costs and the need for advanced facilities and experienced operators may preclude its wide use.
In China, as far as we know, the cost of CT-guided hook wire implantation is at least $300, and the cost of ENB-guided localization with dye averages approximately $3650.
There are several limitations to our method and the present study. First, this method requires highly accurate 3D reconstruction models, especially for vascular branches <1 mm in diameter.
If the feed vessels cannot be identified and blocked, an inaccurate ISD will render the virtuality–reality interaction mismatched. Second, the separation and clamping of the target vessel may be associated with an increased risk of bleeding or air leakage. Although the total drainage and rate of air leakage in our study were acceptable, further study is needed to discount such speculation. Third, it is difficult to shorten the waiting time for pulmonary inflation-deflation. Premixed 75% nitrous oxide and oxygen was reported to shorten the waiting time from 968.3 seconds to 320.2 seconds.
Combination of nitrous oxide and the modified inflation-deflation method for identifying the intersegmental plane in segmentectomy: a randomized controlled trial.
The results from this single-center study need corroboration from further detailed studies. At present, a no-waiting strategy can be applied to our method, and the waiting time can be used to sample lymph nodes.
Fourth, in elderly patients with severe emphysema, the appearance of ISD would be inefficient and unsatisfactory. Fifth, the virtuality–reality interaction was not entirely parametric and objective. Finally, this was a small-size, single-center study, and further large-scale multicenter studies are greatly needed.
In conclusion, through the integration of preoperative 3D reconstruction, temporary clamping of the target vessel, and a modified inflation-deflation method, the well-matched interaction between virtuality and reality is safe and feasible for intraoperative localization of nonpalpable pulmonary nodules. Owing to its ready accessibility and cost-effectiveness, our method should be proposed as a preferred alternative to traditional localization methods.
Conflict of Interest Statement
The authors reported no conflicts of interest.
The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest.
Evaluation of individuals with pulmonary nodules: when is it lung cancer? Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines.
A non-randomized confirmatory trial of segmentectomy for clinical T1N0 lung cancer with dominant ground glass opacity based on thin-section computed tomography (JCOG1211).
Combination of nitrous oxide and the modified inflation-deflation method for identifying the intersegmental plane in segmentectomy: a randomized controlled trial.
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