Computer tomography guided thoracoscopic resection of small pulmonary nodules in the hybrid theatre.

PURPOSE: Thoracic surgeons are currently asked to resect smaller and deeper lesions which are difficult to detect thoracoscopically. The growing number of those lesions arises both from lung cancer screening programs and from follow-up of extrathoracic malignancies. This study analyzed the routine use of a CT-aided thoracoscopic approach to small pulmonary nodules in the hybrid theatre and the resulting changes in the treatment pathway.
METHODS: 50 patients were retrospectively included. The clinical indication for histological diagnosis was suspected metastasis in 46 patients. Technically, the radiological distance between the periphery of the lesion and the visceral pleura had to exceed the maximum diameter of the lesion for the patient to be included. A spiral wire was placed using intraoperative CT-based laser navigation to guide the thoracoscopic resection.
RESULTS: The mean diameter of the lesions was 8.4 mm (SD 4.27 mm). 29.4 minutes (SD 28.5) were required on average for the wire placement and 42.3 minutes (SD 20.1) for the resection of the lesion. Histopathology confirmed the expected diagnosis in 30 of 52 lesions. In the remaining 22 lesions, 9 cases of primary lung cancer were detected while 12 patients showed a benign disease.
CONCLUSION: Computer tomography assisted thoracoscopic surgery (CATS) enabled successful resection in all cases with minimal morbidity. The histological diagnosis led to a treatment change in 42% of the patients. The hybrid-CATS technique provides good access to deeply located small pulmonary nodules and could be particularly valuable in the emerging setting of lung cancer screening.

Introduction

The introduction of lung cancer screening and the implementation of structured follow-up programs for solid malignancies have led to a rapid increase in the number of small pulmonary nodules detected in CT scans [1, 2]. Parallel to that, the spread of the thoracoscopic surgery has given the medical community access to pulmonary lesions avoiding the morbidity associated with the thoracotomy [3].

Both the lung cancer screening programs and the guidelines of the Fleischner Society focus on incidentally detected pulmonary nodules and less on lesions diagnosed during follow-up CT scans in cancer patients [4]. In oncological patients, more than two lesions occurring newly in the lung are considered to represent metastases. This scenario requires a different treatment approach depending on the primary tumor and on whether a potentially curative or palliative status is assumed. Malignancies such as colorectal cancer are considered curable in an oligometastatic stage and resection of colorectal pulmonary metastases is routinely performed worldwide [5]. Interestingly enough, the most common type of surgery performed in thoracic centres is pulmonary metastasectomy representing almost 50% of the work load of a European thoracic center [6, 7]. However, a recent analysis of the “National Lung Cancer Screening Trial” showed an increased risk of interventions following false positive diagnosis [8]. This underlines the dilemma on how to treat a patient with a cured primary tumor who is referred with an unclear pulmonary lesion, especially if previous CT scans are not available for comparison [9].

Computed tomography assisted thoracoscopic surgery (CATS) was introduced to enable access and achieve histological diagnosis from small pulmonary nodules, located deep in the lung parenchyma. The aim of this study was to examine the histology of pulmonary nodules resected with CATS and the influence of the histology on the treatment algorithm.

Materials and methods

The study was approved by the local ethics committee (Ethikkommission II, Medical Faculty Mannheim, University of Heidelberg, #2016-865R-MA). Due to the retrospective nature of the study an informed consent was not required.

Patients who had undergone CATS from June 2014 to March 2019 were included in this retrospective analysis. The following inclusion criteria were applied in order to select patients for the CATS procedure:

Patients with a maximum of 2 pulmonary nodules

Either suspected pulmonary metastasis in patients with previous malignancy (46 cases) or a persistent ground glass opacity (GGO) without solid components (simple GGO)

Indication for surgical biopsy confirmed in the multidisciplinary team meeting

Distance between the periphery of the lesion and the visceral pleura exceeded the maximum diameter of the lesion (lesion depth/lesion diameter ratio > 1).

Patients with a depth/diameter ratio < 1 were treated by VATS which was performed in 131 patients during the same time period. Patients with ground glass opacities without solid components in the lung tissue were included in the study regardless of the depth of the lesion, due to the fact that these lesions can hardly be detected through thoracoscopic palpation [10]. All 50 patients were treated by the same surgical-radiological team. Patients with lesions fulfilling the above mentioned criteria but non suitable for wire marking (e.g. due to proximity to major vessels or surrounded by major vessels) were excluded from this analysis.

CT guided wire placement

The procedure was conducted under general anaesthesia. After intubation and ventilation the patient was turned to a lateral decubitus position and the surgical field was prepared for the thoracoscopic access. The C-arm cone beam CT (CBCT) was then performed according to the protocol published earlier [10]. Using the inherent laser navigation system of the multiaxis C-arm system (Syngo X-Workplace; Siemens Healthcare GmbH, Germany) an 18-gauge marking wire with a spiral end (Somatex Lung Marker; Somatex Medical Technologies GmbH, Germany) was positioned. After lesion-marking a repeat CBCT scan was performed to verify the correct position of the wire and detect potential complications.

Thoracoscopic resection

The lesion was resected through a standard 3-port thoracoscopic approach (Copenhagen approach). The previously placed wire was shortened in order to allow thoracoscopic manipulation. Intraoperatively, the marked part of the lung was lifted up by holding the wire. After palpation of the wire tip, the wedge was resected using a commercially available stapling device. A 20 Ch. thoracic drain was routinely inserted in all but 2 cases. The complete workflow has been published before [10].

Results

50 patients (22 males, 28 females; mean age 63.1 years, SD 10.6) with a total of 52 lesions were included to this study. The histopathological findings of the resected specimens are summarized on Table 1. For detailed characteristics of the patients, the histopathology and the procedure see the online supplementary material (Tables 2 and 3 in S1 File). The mean diameter of the lesions resected (for the calculation the longest diameter of the lesion was measured in the pre-interventional CT scan) was 8.41 mm (SD 4.27 mm). The mean lesion depth measured in the pre-interventional CT scan was 18.3 mm (SD 10.3). The mean depth to diameter ratio was 2.45 (SD 1.38). Lesions with a depth to diameter ratio under 1 were only GGOs without solid components.

Table 1

Histopathological findings (n = 50 patients).

n	Suspected diagnosis	Final diagnosis	Treatment change
29	Metastatic cancer	Metastatic cancer	Further oncological treatment
6	Metastatic cancer	Primary lung cancer	Lobectomy n = 4
			Follow-up n = 2
11	Metastatic cancer	Benign disease	No treatment change n = 9
			Antitubercular treatment N = 2
3	GGO	Primary lung cancer	Lobectomy n = 2
			Follow-up n = 1
1	GGO	Benign disease	Antitubercular treatment

n: patient number, GGO: ground glass opacity.

In two patients resection of two lesions was performed during one procedure (#14 and 28). One patient (#29) was operated two separate times for one lesion in each lung. The average hospital stay was 4.7 days (SD 2.8 range 2–20). Three patients stayed significantly longer in the hospital than the average. In one patient a prolonged air leak was treated conservatively (#5), while another patient required surgical reintervention (VATS) for a postoperative haemothorax (#11). In another patient, a complex anticoagulation algorithm had to be followed (#43). Two cases had to be converted to thoracotomy due to a system failure (collision of the CT-arm with the operating table after the installation of a new update).

The mean time required for wire placement and confirmation of the correct position of the wire was 29.4 minutes (SD 28.48, Fig 1) and for the thoracoscopic resection was 42.3 minutes (SD 20.1). There were two cases exceeding 2 hours of intervention time. In the first case collision between the C-arm and the operating table was experienced after installation of a system update as described above. In the second case, the patient developed a tension pneumothorax after the placement of the wire and a thoracic drainage had to be placed before continuing the procedure. Overall, the rate of grade ≥ 3 complication according to the Clavien-Dindo classification after the CATS procedure was 2% [11].

Fig 1

Time (min) for guide wire placement and thoracoscopic resection per patient.

Analysis of the histological reports

A comparison of the histological reports of the lung tissue with the histology of the primary tumor revealed that 75% (n = 39) of the 52 resected lesions were malignant. However, in 37% (n = 19) of patients with previous malignant tumours, the histological report of the lung nodule did not match that of the primary. In 25% (n = 13) of the patients the malignancy could not be confirmed and a benign nodule was diagnosed (Fig 2).

Fig 2

Distribution of histological results.

When analysing the nine patients with a previous history of primary lung cancer or current ground glass opacity, the histological report revealed an adenocarcinoma of the lung in 7 patients, one case each of tuberculosis and benign lesion. Out of 11 patients with gastrointestinal primary tumors, five patients had corresponding lung metastases, one patient had an adenocarcinoma of the lung, 1 patient showed a tuberculotic affection (Fig 3) and the other patients had 4 benign lesions like intrapulmonary lymph nodes.

Fig 3

Suspicious right lower lobe lesion which turned out to be tuberculosis.

Of the 13 lesions with a benign histology, 4 lesions were of inflammatory origin such as tuberculosis (n = 3), 4 lesions showed a benign lymphnode, 1 lesion an atelectasis, 1 lesion a granuloma and 2 lesions a hamartoma, respectively.

Discussion

Due to the high imaging quality and the low radiation exposure, the indication for low-dose CT scans has expanded both to the screening of primary lung cancer and to the follow-up of other malignancies. This will certainly lead to a further increase in the detection rate of small, nonspecific pulmonary lesions. The main problem resulting is the potential overtreatment caused by the invasive procedures performed due to falsely positive findings on chest CT scans as the NLST trial confirmed [8]. On the other hand, resecting lesions that prove to be metastases is probably beneficial for the patient, since improved survival has been shown following resection of pulmonary metastases. Furthermore, the current trend in the treatment of oligometastatic tumors is towards more aggressive surgical approaches. As a consequence, it is essential to find the optimal balance between oncological benefit and overtreatment of patients with small pulmonary nodules.

Several methods have been developed to support the intraoperative localization of small lesions prior to thoracoscopic resection [12-14]. The most profound approaches are preoperative guide wire placement by the interventional radiologists and electromagnetically guided bronchoscopy [15]. The preoperative CT-guided wire placement has the main advantage of being more easily accessible in various institutions. However, the dislocation rate of the wire goes up to 33%, particularly on the way from the radiology department to the operating theatre [16]. Development of an undetected pneumothorax is reported in another 12% which might make it dangerous for the patients if the time interval from wire placement to resection by VATS is long [17]. Furthermore, the patient discomfort and stress as well as the burden associated with the organisation of both procedures is not negligible.

Electromagnetic bronchoscopy is another modern method providing access to small peripheral lesions. The NAVIGATE study, a prospective multicentre study about electromagnetic bronchoscopy (ENB) lesion marking for thoracoscopy reported success rates up to 94% in experienced hands and a median procedural time of 25 minutes [18]. However, the risk of adverse event following ENB was not negligible (4.3% risk of pneumothorax and 1.5% risk of relevant haemorrhage, [18]). Furthermore, the procedure complexity and the learning curve for achieving proficiency in accessing the peripheral lesions with an acceptable diagnostic rate is significant, even in highly specialised centres [19]. Several methods for preoperative staining of the lesion with dyes like indocyanine green with either using a percutaneous needle, electromagnetic bronchoscope or even after intravenous injection have also been described [20, 21].

The intraoperative guide wire marking with subsequent thoracoscopic resection (described as iVATS by Ng CSH [22] or CATS by our group [10]) was developed in order to combine the advantages of the CT-guided wire placement with the benefits of the immediate resection via thoracoscopy. This approach combines the advantages of the CT-guided wire placement avoiding the problems of dislocation, clinically relevant pneumothorax, patient discomfort or the organisational burden. Furthermore, the spiral guide wire used, allows the intraoperative palpation of the peripheral margin of the lesion which is extremely helpful in defining the resection margins and preventing incomplete resections. The method is easy to learn as it is very similar to the traditional thoracoscopy and the learning curve is therefore rather flat. In our patient cohort we noticed an increase in the time required for thoracoscopic resection in the last 10 cases, which can probably be explained by the integration of new members to the team and the associated learning phase.

The success rate of direct CT-guided lesion marking was 80% (in 20% of the cases the lesion was not directly penetrated by the wire but the positioning of the wire enabled the localisation of the lesion) with an intraoperative pneumothorax rate of 82%. These results confirm the findings of Ng CSH, who successfully managed to localize tiny indeterminate pulmonary nodules in a group of 32 patients [22]. The authors described a pneumothorax rate of 47% in the post-interventional CT scan, which is significantly lower than the rate observed in our study. This increased post-interventional pneumothorax rate could be potentially explained by the depth of the resected lesions, which, in our study, was almost 1 cm deeper. The pneumothorax was clinically irrelevant in 49/50 patients since single lung ventilation with consequent thoracoscopy could be established immediately after the wire marking.

The histological results of 52 lesions resected with CATS were analyzed in order to detect if the histopathology from the resected pulmonary lesions corresponded with the histology of the primary tumors. In 37% of the cases the histology of the lung lesion differed from the one of the primary changing the therapeutic algorithm. Furthermore, 9 cases of primary lung cancer were discovered in an early stage allowing for further oncological treatment with curative intent. Furthermore, 13 lesions could be classified as benign despite initially suspected malignancy, and the patients could be relieved from the stage of suffering from metastatic disease. Three patients were diagnosed with tuberculosis and were treated accordingly.

The results of this study confirm the high detection rate of lung cancer and other malignancies by CT scans performed for oncologic follow-up or screening purposes. The CATS procedure is associated with very low morbidity, early recovery and the advantage of simultaneous diagnosis and treatment without the burden of coordinating surgery with radiological guide wire placement, wire dislocation and without the morbidity of iatrogenic pneumothorax.

Limitations

The collection of the data in this study was performed prospectively but the interpretation and process of the information was performed retrospectively, encompassing a certain possibility of selection bias. Furthermore, although this is a large cohort of patients with very small pulmonary nodules, the patients’ characteristics regarding the primary tumors are heterogeneous, which limits the generalizability of the conclusions.

Conclusion

In this study 40% of the patients underwent surgery for a lesion that was proven to be histologically different from what the MDT was expecting, including 9 new cases of primary lung cancer, 3 patients with tuberculosis requiring treatment and 9 other benign lesions. It is therefore reasonable to suggest that the CATS method can be considered for the resection of small pulmonary lesions, which require histological confirmation and cannot be accessed in a less invasive way.

The raw data table sheet is available as a supplement.

(XLSX)

Click here for additional data file.

Additional table have been uploaded as a supplement.

(DOCX)

Click here for additional data file.

3 Aug 2021

PONE-D-21-12920

Computer tomography guided thoracoscopic resection of small pulmonary nodules in the hybrid theatre.

PLOS ONE

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Reviewers have raised some constructive comments. Your study provides a descriptive information about intraoperative CT-assisted thoracoscopic surgery for small pulmonary nodules. To strengthen your manuscript, it would be better to provide comparative analysis including others' reports.

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Reviewer #1: The authors reported the C-arm cone beam CT guided localization of pulmonary nodule with hookwire.

This paper doesn't seem new and very informative.

How is the depth of pulmonary nodules and how deep lesion is able to be localized.

Authors should clarify the number of patients (12 or 13) showed a benign disease.

And, the percentage of the benign disease seems to be a bit high, which means that unnecessary surgery had been done.

Table 1 and Figure 1 need to be summarized according to disease categories.

Reviewer #2: This is a single-institution, retrospective cohort study that examines 50 patients with a history of intraoperative computed tomography assisted thoracoscopic surgery (CATS) in 2014 and 2019 to analyze the routine use of a CT-aided thoracoscopic approach to small pulmonary nodules in the hybrid theatre and examine the influence of the histology on the treatment algorithm. You have demonstrated that CATS enabled successful resection in all cases with minimal morbidity and the histological diagnosis led to a treatment change in 42% of the patients. You have concluded that the hybrid-CATS technique provides good access to deeply located small pulmonary nodules and could be particularly valuable in the emerging setting of lung cancer screening.

Your study provides the descriptive information about CATS as the one of nodule localization methods for VATS wedge resection of small pulmonary nodules. Your study is interesting, but you need to provide more data to emphasize the feasibility of CATS and the alteration of further treatment plan after this procedure.

1. Please generate the CONSORT diagram about patient selection for this study.

2. It would be better to generate a table of patient characteristics of 50 patients including tumor location. Normally distributed continuous variables are reported as mean/standard deviation; non-normally distributed continuous variables are reported as median and interquartile range.

3. Please summarize table 1. It would be better to move all the detailed patient information to the supplementary table. Please describe the detailed histology of non-small cell lung cancer.

4. Are there any cases of intraoperative surgical extension from wedge resection to lobectomy and mediastinal lymph node dissection after intraoperative histology confirmation by frozen samples?

5. It would be better to illustrate the treatment change after CATS. Further treatment has not been demonstrated in detail.

6. To emphasize the feasibility of CATS, please generate a table of CATS-related complications in detail.

7. You can emphasize the merit of CATS by reviewing other localization tools of pulmonary nodules.

8. Several typo errors such as ration were found.

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Reviewer #1: No

Reviewer #2: No

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10 Sep 2021

Dear Dr. Lee,

thank you for the opportunity to revise our manuscript and resubmit it. Here you can find a point- to- point response to both yours and to the reviewers’ comments.

Kind regards,

Ioannis Karampinis, Nils Rathmann and Eric Roessner

Response to comments from the editorial office:

Point 2: Grant information has been updated to be identical in both the sections you pointed.

Point 3: The data availability statement has been updated accordingly. In order to meet the reviewers’ requests, we have added 2 additional tables, which has been uploaded as suppl. material. This way our complete datasets are publicly available either in the body of the manuscript, or as a supplement.

Response to reviewers’ comments:

Dear colleagues, thank you for reviewing our work and for the points you raised. We hope the changes made will meet your expectations.

Response to reviewer 1:

Point 1: Concerning the depth and the location of the nodules, we have added a table as a supplement, where you can find the information that you requested.

Point 2: The maximum depth that you can reach with this technique is probably not a question that we can directly answer. The deepest nodule in this study was a 7 mm lesion lying 53 mm deep in the lung tissue. The path length for the marking wire was 64 mm. However, it is probably the vascular and bronchial anatomy that limits the resection of these nodules and less the absolute depth of the lesion itself, as you can usually manage to place a stapler around the lesion and resect it, if you manage to locate it securely (in rare cases you can run an additional CT scan to make sure that the tip of the wire is enclosed in your stapler).

Point 3: There were 12 patients with benign disease but 13 benign lesions (one patient had two suspicious lesions and both of them turned to be anthracotic lymphnodes, patient #14).

Point 4: Regarding the benign histology of the resected lesions, you are absolutely right. In this study we found a benign pathology in 25% of the cases, which is clearly high. However, the patient population of this study is different from the populations presented in all the well-known trials of patients with incidentally diagnosed solitary nodules or patients undergoing screening for lung cancer. The patients discussed here are not healthy individuals but patients with another known solid tumor and suspected pulmonary metastasis (46 the 50 cases). It is certainly a difficult decision to offer surgery to such a patient. From our point of view and taking the very low complication rate into account, it is rather positive to be able to relieve 25% of these patients from the diagnosis of metastatic cancer.

Point 5: You requested to summarize table 1 and figure 1 according to disease categories. Table 1 has been summarized. The bigger table from the first submission was kept as suppl. material. Figure 1 presents the time that was required for the procedure in each patient. We are not sure, what exactly you mean by summarizing this table based on the histology, as the histology does not really affect the time required to perform the procedure according to our opinion. If you wish to see another figure please explain in detail exactly what type of figure you expect.

Response to reviewer 2:

Point 1: Thank you for the issue you raised. As you pointed out, this is a single institution, retrospective study and not an interim analysis of data that were collected parallel to a formal prospective trial. It is therefore not possible for us to include a CONSORT diagram because the necessary data on enrollment, eligibility etc. are not available.

Point 2: Another table has been created and submitted as suppl. material including the information that you requested. We have changed the medians with means.

Point 3: The changes you requested have been made accordingly and are included in the table in the suppl. material.

Pont 4: This is an excellent comment. It is our policy not to extend surgery in this specific subgroup of patients (patient with a malignant background undergoing operation for suspected metastasis) directly to an oncological resection for two different reasons: first, the result of the frozen section that we receive does not always allow us to securely differentiate metastatic disease from a new primary tumour and we often have to wait for the immunohistochemistry. Second, these patients have not received formal staging for lung cancer according to the national guidelines so we might end up performing a lobectomy in a patient with extensive disease, which is not justified. We prefer to complete the staging and then discuss with the patient the possibility of a completion lobectomy with SND, follow up or other types of treatment, depending on the histology and stage of the disease. Our policy is different for patient without previous malignant disease.

Point 5: The treatment changes have been added in table 1

Point 6 + 7: The purpose of this article was not to describe CATS as a method but to discuss the histopathological findings of this specific patient cohort, that was operated using this method. This is the reason why we did not go into further detail in the CATS complications or discussed this method compared with other localization techniques. However, due to the fact that the latter was pointed out from both the reviewers and the editor we have added a paragraph in the discussion focused on this point.

Point 8: Thank you for pointing this out, we have cross-read the article again for typing errors and hope we have not missed further errors.

Submitted filename: Response to Reviewers (copy).docx

Click here for additional data file.

8 Oct 2021

Computer tomography guided thoracoscopic resection of small pulmonary nodules in the hybrid theatre.

PONE-D-21-12920R1

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PLOS ONE

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25 Oct 2021

PONE-D-21-12920R1

Computer tomography guided thoracoscopic resection of small pulmonary nodules in the hybrid theatre.

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