As CT use becomes widespread in daily clinical practice and lung cancer screening settings, we have increasingly encountered small or faint, albeit clinically significant pulmonary lesions on CT (1, 2). According to the ELCAP trial, 55.5% of detected lung cancers were small nodules of 10 mm or smaller (3), and 51.7% of detected lung cancers found during baseline screening were ground-glass nodules (GGNs), most of which are typically faint or invisible on plain radiographs (4). The need for accurate early diagnosis of these small or faint nodules with high suspicion of malignancy is evident. Unfortunately diagnosis of these small or faint lung nodules has remained a challenge with dedicated CT, FDG-PET/CT or even image-guided percutaneous biopsy.

In order to diagnose and treat such small or faint lung nodules with high clinical suspicions of malignancy, video-assisted thoracoscopic surgery (VATS), a less invasive type of thoracic surgery, has recently been adopted (5). However, a problem often encountered during VATS of these lesions was localization of the target nodule, which depended on its position, size, and characteristics such as nodule consistency. Further, when small nodules were located 1 or 2 cm below the pleura or further, it was difficult for the surgeon to determine their exact locations (6).

In this context, preoperative nodule localization is of critical importance in the accurate resection of these lesions. Today, metallic hook wire localization under CT guidance is the most widely used method for this purpose (7). However, this presents disadvantages. One disadvantage of metallic hook wire localization is the possibility of wire dislodgement. Therefore it is best performed immediately prior to the operation (7). Also, pneumothorax due to pleural injury caused by the wire and patients' complaints of discomfort from the hook wire in the chest wall have been documented (8, 9).

In contrast, a localization technique using barium suspension can be much simpler to perform with no risk of dislodgement, allowing the patient to move freely prior to the operation. Furthermore, the barium ball shows as white visually, is radiopaque on fluoroscopy and can be palpable during the operation, making detection more accurate and easier (10-13). With this technique the target lesions can be much more accurately localized and resected.

There have been several published reports dealing with barium marking in the literature (10-13), although the localization procedures were performed using bronchoscopy. To our knowledge, there have been no reports on CT-guided percutaneous barium localization including procedure details and the pathologic findings associated with this method. Thus, the purpose of our study was to describe our initial experience with CT-guided barium marking for localization of small pulmonary nodules prior to VATS.

Our Institutional Review Board approved this retrospective study with waiver of informed consent for inclusion into this study. Written informed consent for the use of CT-guided percutaneous localization using barium sulfate was obtained from all patients after discussion of all related risks and benefits.

All target nodules were marked within 3 mm distance (mean distance, 1.1 mm; range, 0-3 mm) from the injected barium sulfate suspension, which formed round or oval shaped balls, using the barium localization method (Figs. 2, 3). On CT scans, the barium balls were placed 2-3 mm from the nodule in 5 patients and were superimposed on the nodules in the remaining 5 patients. Table 2 shows the procedure details of barium localization. Pneumothorax occurred in 2 patients, for which one needed aspiration. Other than these 2 patients, no complications occurred during or after this localization procedure.

All VATS procedures were performed 2 to 24 hours (mean, 13.2 hours) after barium localization. The surgeons were able to palpate the barium balls during VATS (n = 10) and the radiopaque barium balls were able to be indentified in all patients under intraoperative fluoroscopy (n = 10) (Figs. 1C, 2C, 3C). Under fluoroscopy, all radiopaque barium balls and target nodules near the barium balls were successfully resected with sufficient surgical margins. In all patients, the barium balls were identified as whitish nodules in the surgical specimens with both the barium balls and target nodules able to be identified in the frozen specimens. Pathologically, all nodules were definitively diagnosed (Table 3). The 10 target nodules were confirmed as invasive adenocarcinoma (n = 1), adenocarcinoma-in-situ (n = 5), atypical adenomatous hyperplasias (n = 2), and benign lesions (n = 2). On histopathologic examination, a nodule was encroached with barium in one patient, closely located within 0.1 mm in 3, and separated from barium materials within 3 mm in the remaining 6 patients. In all patients, there were acute inflammations infiltrated by neutrophils and histocytes and a considerable amount of eosinophils in the barium-containing sites (Figs. 1D, 2D, 3D). However, these inflammations did not hinder the pathologic diagnosis of the nodules.

Video-assisted thoracoscopic surgery has been widely accepted as a useful and minimally invasive procedure for the resection of peripheral small or faint, albeit clinically significant lesions. However, as such lesions may not be palpable or visible during the operation (7), a conversion from VATS to thoracotomy is sometimes prescribed after failure to localize these lesions (14). Therefore, it is crucial to accurately localize such lesions prior to VATS, especially in the case of small nodules not near the pleural surface or in faint nodules such as GGNs.

In this endeavor, several localization techniques have been introduced using either a percutaneous approach or a transbronchial approach. However, the transbronchial approach has remained technically challenging, particularly with peripherally located small nodules. Thus percutaneous localization procedures are often the main method for localization of lung nodules, particularly under the guidance of CT scans.

Various materials have been used for the percutaneous localization of nodules under CT guidance, including the injection of a methylene blue solution (15), colored collagen (16), or lipiodol (17-19), as well as the introduction of a metallic hook-wire (7, 20, 21) or metallic microcoils (22, 23). They all present some problems. In the case of methylene blue, a tendency to diffuse rapidly into the surrounding lung parenchyma after dye injection was observed, and therefore, lesion localizations using methylene blue should be performed within 3 hours prior to VATS resection. This requires the simultaneous use of both CT and the operating room (15). Furthermore, it has been reported that up to 7% of attempts to localize nodules failed during VATS (15) due to the diffusion of dye or severe anthracosis of the visceral pleura. Lipiodol has been shown to sometimes cause aspiration into the lung, leading to damage and acute inflammations in the marking site (24). The introduction of a metallic hook wire is currently the most commonly used method for percutaneous localization of lung nodules. However, wire dislodgement occurs in up to 20% of cases (13). In addition, having a metallic wire in the chest wall can cause discomfort to the patients, and once again the simultaneous use of both CT and the operating room is necessary. Moreover, recently, massive air embolisms have been reported during the hook-wire the localization procedure (8, 9), although every percutaneous localization technique has a potential risk of air embolism. In another lesion localization method, Lizza et al. (22) adapted a micro-coil 15-mm long and 5-mm in diameter. However, this is even larger than the hook-wire and lung tissue damage can be even greater than the hook wire localization, possibly increasing the risk of massive air embolism. A study by Iwasaki et al. (13) reported that bronchoscopic barium localization under the guidance of X-ray fluoroscopy is possible with lesions that are visible on fluoroscopy. In addition, as barium has been observed to remain in the body for a relatively long period of time, the loss of the lesions due to dye diffusion can be avoided (25). This, in turn, can lead to flexible scheduling of the operation room and CT as there is no need for simultaneous use. As for complications, we observed symptomatic pneumothorax requiring air aspiration in only 1 of 10 (10%) patients, with no significant consequences.

Several studies have reported that barium provoked a mild acute inflammatory and edematous reaction within hours followed by bronchopneumonia, and eventually granulomatous inflammation and fibrosis over succeeding days and months (26, 27). Yet according to an animal experiment (28) and previous clinical studies (10-13), a small volume of barium instillation did not show significant pulmonary parenchymal damage and is considered to be safe (10-13, 28). We believe that the very small amount of barium sulfate used in our study is does not pose that risk. The injected barium material may have caused focal inflammation but it did not hinder the histopathologic diagnosis of the target nodule in our study. Indeed, several previous studies dealing with barium localization also showed that injected barium did not cause any difficulty in the pathologic diagnosis of the target nodules (10-13). However, we would like to stress is that in the case of GGNs or potential inflammatory lesions, care should be taken to avoid directly injecting the barium into the target nodule as this may make the pathologic diagnosis of the target nodule difficult due to acute inflammation associated with barium materials.

Our study had several limitations. First, we included only a small number of patients. Second, we did not directly compare barium localization to other localization methods. We expect that further comparative studies with a prospective randomized design can give a more definitive answer on which localization method is the best for the purpose of lung nodule localization prior to VATS.

In conclusion, CT-guided percutaneous transthoracic barium localization can be an effective, safe, and convenient pre-operative localization procedure with minimal invasiveness for non-palpable small or ground-glass nodules prior to VATS.