Synchronous computed tomography-guided percutaneous biopsy and microwave ablation for highly suspicious malignant lung ground-glass opacities adjacent to mediastinum

Abstract Background This retrospective study aimed to assess the safety and efficacy of synchronous biopsy and microwave ablation (MWA) for highly suspected malignant lung ground-glass opacities (GGOs) adjacent to the mediastinum (distance ≤10 mm). Materials and methods Ninety patients with 98 GGOs (diameter range, 6–30 mm), located within 10 mm of the mediastinum, underwent synchronous biopsy and MWA at a single institution from 1 May 2020, to 31 October 2021 and were enrolled in this study. Synchronous biopsy and MWA involving the completion of the biopsy and MWA in a single procedure was performed. Safety, technical success rate, and local progression-free survival (LPFS) were evaluated. The risk factors for local progression were calculated using the Mann–Whitney U test. Results The technical success rate was 97.96% (96/98 patients). The LPFS rates at 3, 6, and 12 months were 95.0%, 90.0%, and 82.0%, respectively. The diagnostic rate of biopsy-proven malignancy was 72.45% (n = 71/98). Invasion of lesions into the mediastinum was a risk factor for local progression (p = 0.0077). The 30-day mortality rate was 0. The major complications were pneumothorax (13.27%), ventricular arrhythmias (3.06%), pleural effusion (1.02%), hemoptysis (1.02%), and infection (1.02%). Minor complications included pneumothorax (30.61%), pleural effusion (24.49%), hemoptysis (18.37%), ventricular arrhythmias (11.22%), structural changes in adjacent organs (3.06%), and infection (3.06%). Conclusions Synchronous biopsy and MWA was effective for treating GGOs adjacent to the mediastinum without severe complications (Society of Interventional Radiology classification E or F). Invasion of lesions into the mediastinum was identified as a risk factor for local progression.


Introduction
Globally, lung cancer is the second most common cancer and is associated with the highest mortality rate, accounting for an estimated 1.8 million deaths [1].The use of low-dose computed tomography (CT) to detect highly suspicious malignant lesions has greatly improved the efficiency of early lung cancer screening.However, there are still many problems in pathological diagnosis and treatment [2].In general, for persistent ground-glass opacities (GGOs) with a solid component > 6 mm or for cases with an increase in the solid component during a sufficient 6-9 months follow-up, malignancy should be suspected, and biopsy or surgical resection should be considered [3].Surgical resection is widely recognized as the first-line treatment for early-stage resectable primary lung cancer (PLC).However, approximately 60% of PLCs cannot be surgically resected for various reasons including a poor cardiopulmonary function or advanced age [4].Stereotactic ablative body radiotherapy is a good option for most patients with lung cancer who cannot undergo surgical resection, but it has certain limitations such as local recurrence and radioactive lung injury [5,6].Recently, image-guided thermal ablation (IGTA) therapies, including radiofrequency ablation (RFA), microwave ablation (MWA), cryoablation, and laser ablation, have been developed for the treatment of early-stage PLC.Moreover, it has been applied in highly suspicious malignant lung GGOs [7][8][9][10].Both RFA and MWA are based on precise puncture and thermal field distribution, and their technical success rates may be limited in areas where the precise puncture is difficult or in areas with rich blood flow [11][12][13].Previous studies have reported that tumors adjacent to critical sites, such as the mediastinum, are difficult to puncture accurately [14,15].Thus, a single biopsy at these critical sites may induce severe bleeding, gas embolism, or off-target, thereby affecting the success and positivity rates of the biopsy.Furthermore, abundant blood flow causes uneven local heat distribution.MWA has several advantages for lung tumor ablation over other methods including faster ablations, higher temperatures, larger ablation zones, less sensitivity to tissue type, and less 'heat sink' impact to treat perivascular tissues better [8,16,17].Theoretically, these advantages make MWA more suitable for the treatment of these lesions.The combined use of biopsy and ablation techniques in the same procedure and moderate local ablation before a biopsy has the potential to reduce the risk of severe bleeding and air embolism.In the literature, only a few studies have addressed the issues related to MWA treatment for lung GGOs adjacent to mediastinum [18][19][20][21].Therefore, we aimed to assess the safety and efficacy of synchronous CT-guided percutaneous biopsy and MWA for GGOs adjacent to the mediastinum.

Patients
This retrospective study complied with the standards of the Declaration of Helsinki and obtained approval from the Institutional Ethics Committee of The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong, China.The approved protocol number is YXLL-KY-2020 (S071).The Institutional Review Board waived the requirement for informed consent since this was a retrospective study.Written informed consent to perform percutaneous biopsy and MWA was obtained before procedure.According to our institutional database, 348 patients with 377 lesions underwent synchronous CT-guided percutaneous biopsy and MWA between 1 May 2020 and 31 October 2021.All nodules were diagnosed as highly suspicious malignant lung GGOs after a sufficient follow-up of 6-9 months and multidisciplinary consultation.A multidisciplinary team of thoracic surgeons, radiation therapists, medical oncologists, and interventional radiologists determined that these patients were not candidates for surgery or radiotherapy.According to previous studies [22,23], large vessels were defined as those with a diameter of !3 mm, such as the pulmonary and mediastinal vessels.GGOs adjacent to mediastinum were defined as index tumors occurring within 10 mm distance from the organs based on CT scans.The inclusion criteria were as follows: (1) patients with GGOs adjacent to mediastinum; (2) those with GGOs measuring 6-30 mm and highly suspected of being malignant; and (3) those with Eastern Cooperative Oncology Group performance status score of 2. The exclusion criteria were as follows: (1) patients with poorly controlled infections; (2) those with a history of severe uncontrolled cardiovascular and cerebrovascular diseases and malignant pleural effusion; (3) those with lymph node and distant metastases; (4) those who were lost to follow-up; (5) those with moderate or serious interstitial pulmonary disease; (6) platelet count <50 Â 10 9 /L; (7) antiplatelet treatment discontinuation for <5 days; and (8) acute myocardial or acute cerebral infarction during the past 30 days.Overall, 90 patients (45 men and 45 women; mean age, 60.5 [range, 25-81] years) with 98 tumors were included in the present study.A flowchart of the patient selection process is shown in Figure 1.The baseline characteristics of the study participants are shown in Table 1.
All treatments were considered after a multidisciplinary team discussion, including individuals from thoracic surgery, oncology, respiratory diseases, radiotherapy, interventional radiology, imaging, and pathology departments, based on expert consensus [24].Lesions were classified based on the distance from the lesion to the mediastinum as follows: 0, 1-5, and 5-10 mm (Figure 2).

Procedure
The main steps of synchronous biopsy and MWA used in this study are as follows.
1. To relieve the pain of the patient during the procedure, local anesthesia (1% lidocaine) and intravenous anesthesia (sufentanil 0.25 lg/kg) were achieved, respectively.The patients were under moderate sedation with oxygen via a nasal tube [25].After local anesthesia with 5-10 mL of 2% lidocaine, an antenna (19G) was inserted using a three-step approach along the designated path approximately 5 mm distal to the lesion.The angle and depth of the needle were observed using CT scans obtained between each step.Ablation was performed for 1-2 min at 30-50 W power. CT was performed again to observe changes at the ablation site.2. A coaxial guiding needle (17G, GMT Medical) was inserted along the designated path or along the ablation antenna to the proximal end of the lesion.The position of the needle tip was confirmed before the 18G biopsy needle was inserted along the coaxial catheter.After confirming the observations on CT, samples were collected and preserved in 10% formalin for subsequent pathological examination.If severe pulmonary hemorrhage was observed, MWA with a power of 30-50 W was applied for 1-2 min to promote hemostasis.3. MWA was performed to achieve a complete ablation zone, with an optimal circumferential margin of !10 mm for solid lesions and !5 mm for solid lesions and GGO margins, respectively [26,27].The ablation power was 30-50 W, and the ablation duration was 3-13 min.During ablation, CT scans were obtained every 2-5 min to monitor the ablation zone and identify any complications.4.After the ablation, the biopsy trocar needle was removed.Subsequently, the needle tract was ablated to promote hemostasis and reduce metastasis. 5. Chest CT was performed 24 h after the procedure.If there were no complications that required further treatment, the patients were usually discharged 3-4 days after the procedure.

Response criteria
Chest-enhanced CT was performed in all patients to assess the local efficacy 1 month after the procedure as a baseline for follow-up.Technical success was defined as complete coverage of the ablation zone and the collection of biopsy specimens.GGO findings were classified as follows: (1) complete ablation, defined as postprocedural GGO completely covering the original lesion and exceeding the border by 5 mm; (2) residual lesion, defined as postprocedural GGO not completely covering the original lesion; and (3) off-target, defined as postprocedural GGO without overlap with the original lesion.Moreover, a 1-month follow-up contrastenhanced CT was used to determine procedural technical success and evaluate recurrence as follows: (1) complete absence of enhancement was defined as technical success; (2) irregular enhancement was defined as a residual or recurrent tumor; and (3) the absence of contact between the ablation area and target lesion was defined as off-target [24,28].Subsequently, the patients were instructed to undergo enhanced chest CT at 3, 6, and 12 months after the procedure.Local tumor progression (LTP) was determined during follow-up by enlargement of the ablation zone compared with baseline CT (1 month after MWA), provided that the initial technique was effective.The absence of LTP and tumor seeding during follow-up suggested that the treatment was effective.Treatment-related complications were defined as symptoms that occurred within 30 days of the procedure.
The incidence and mortality rates were evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE v. 5.0).Patients were followed up for !12 months.

Efficacy
Overall, 94 lesions were completely ablated using a single procedure.Further, two residual lesions (partially ablated) were re-ablated 1 week after the procedure, resulting in complete ablation.The technical success rate was 97.96% (96/98).Moreover, 16.33% (16/98) of tumors demonstrated local progression in a median follow-up duration of 9.2 (range, 3.5-16.5)months, which manifested as tumor enlargement (n ¼ 11) and abnormal enhancement at tumor margin (n ¼ 5).Thirteen patients underwent subsequent ablative treatment with a complete ablation rate of 100%.A typical case of subsequent ablative treatment is shown in Figure 3. Univariate analysis of whether the tumor invaded the mediastinum revealed a significant difference (p ¼ 0.0077).This finding suggested that tumor invasion of the mediastinum is an important factor affecting ablation efficiency.At 3, 6, and 12 months, overall LPFS rates were 95%, 90%, and 82%, respectively.Details of the short-term follow-up of LPFS are presented in Table 1.
The overall incidences of pneumothorax and pleural effusion were 43.88% and 25.51%, respectively.Only 14.29% (14/98) of the patients required chest tube drainage.The outer diameter of the chest tube was 10 Fr and the effective length of the chest tube was 300 mm.The mean length of chest tube insertion was 100 mm (range, 80-150 mm).None of the patients underwent any other invasive treatment for pneumothorax.Adhesion to neighboring extracardiac structures was defined as an ablation scar extending from the ablated tumor tissue to the virtual pericardial space.Three patients presented with local structural changes as a result of the procedure, such as adhesions to neighboring extracardiac tissue (Figure 4) and thickening of the pericardial layers (Figure 5), which had no effect on heart or blood vessel function and did not require any treatment.

Discussion
Early detection of lung cancer is receiving increasing attention.Early detection of malignant lung lesions and some highly suspicious malignant lung GGOs can provide tremendous benefits for subsequent treatments.Thermal ablation therapy is an alternative treatment modality for patients who are not candidates for surgical procedures or SBRT.Moreover, compared to other thermal ablation techniques, MWA is considered more suitable for the treatment of lung GGOs and has been increasingly used owing to its unique technical advantages and high efficiency [29,30].Previous studies have reported the effectiveness of simultaneous  MWA and biopsy and the accuracy of biopsy results [31,32].Furthermore, MWA involves inserting an antenna into a lesion and emitting microwaves, which thermally denature the lesion at a certain temperature.Lesions along the pleura, interlobar areas, and mediastinum are more difficult to treat because of the greater risk of needle puncture at these critical sites as well as the risk of thermal injury [33][34][35].For GGOs adjacent to the mediastinum, the patient's position and cardiac motion may affect puncture and treatment to some extent [36][37][38].Owing to recent advancements in IGTA and MWA techniques, experimental data and studies on MWA therapy for tumors adjacent to the mediastinum have been reported in the relevant literature [15,39].Based on subgroup analysis, a previous study concluded that closer proximity to the mediastinum and larger tumor volume were major risk factors for poor prognosis [19].
In the present study, we evaluated MWA treatment for lung tumors adjacent to the mediastinum and found a technical success rate of 97.96%.At 3, 6, and 12 months, overall LPFS rates were 95%, 90%, and 82%, respectively.We believe that compared with previous studies, this retrospective study presented better efficacy data.This may be attributed to the fact that only GGOs and tumors of 30 mm were included in our study.Furthermore, the total positive pathological diagnosis rate was 72.45%, which was comparable to that of GGOs at normal sites.This can be attributed to two reasons.First, because MWA can effectively reduce bleeding, we used a coaxial needle for multiple samples.Second, since GGOs are lesions composed of cells with edema, most have unclear boundaries on CT.After MWA, the edema is reduced and the lesion shrinks.Furthermore, after MWA, the GGOs may exhibit clearer boundaries, making biopsies more accurate.The statistical analysis also revealed a significant difference between GGOs that invaded the mediastinum and those that did not.Therefore, the invasion of lesions into the mediastinum was a factor affecting the efficacy of MWA.In the present study, we observed that the overall incidence of pneumothorax was 43.88%, with 13.26% of the patients requiring chest tube drainage.The slightly higher incidence of pneumothorax might be associated with longer puncture paths and more antenna adjustments, as reported in previous studies [40][41][42][43].Of the 98 patients, 14 had ventricular arrhythmia.Notably, two patients experienced asystole simultaneously at the start of ablation and recovered within 10 s after the ablation was paused.The lesions in these two patients were located adjacent to the aortic arch, where the vagus nerve runs.To the best of our knowledge, such complications have not been previously reported in studies on MWA.Based on our findings, we believe that when MWA is used to treat lesions adjacent to the aortic arch, the conditions of these at-risk locations should be carefully considered.
This study had several limitations.First, it was a retrospective study.Second, we excluded cancers measuring >30 mm, which may explain the high complete ablation and low complication rates.Third, the number of cases included was small and the follow-up time was short.
In conclusion, MWA should be considered an alternative treatment for highly suspicious malignant lung GGOs adjacent to the mediastinum.For tumors measuring <30 mm, the distance between the selected tumors and the mediastinum may affect the efficacy of MWA.More attention should be paid to changes in heart rate, and adequate rescue preparations should be made in patients with tumors adjacent to the aortic arch of the MWA.

Author contributions
Wang Nan and Jingwen Xu contributed equally to this article.Nan Wang was responsible for acquiring the data and drafting the manuscript.Nan Wang and Jingwen Xu were responsible for the analysis of the data.Guoliang Xue, Cuiping Han, Haitao Zhang, Wenhua Zhao, Zhichao Li, Pikun Cao and Yanting Hu provided and collected the clinical data.Zhigang Wei and Xin Ye were responsible for designing the experiments and supervising the study.All the listed authors have made a substantial, direct, and intellectual contribution to the work and have approved it for publication.

Figure 1 .
Figure 1.Flowchart of the patient selection criteria.

Figure 3 .
Figure 3.A typical case of secondary ablation treatment.The following images were of a 75-year-old patient with a 28-mm lesion of primary lung squamous cell carcinoma.The patient developed local progression 6 months after the first-line ablation without any other drug therapy and achieved a long-term PFS (24 months after the deadline for submission) after secondary ablation combined with chemotherapy and immunotherapy.(A) Chest computed tomography (CT) scan obtained before microwave ablation (MWA) shows a 28-mm well-defined round tumor (white arrow) in the left lobe (lesion adjacent to the aorta).(B) In the supine position, MWA was performed for the lung tumor.(C) CT after 24 h of the procedure; exudation and pleural effusion reduced.(D) CT performed 1 month after the procedure; the ablation area completely covered the tumor.(E) CT after 6 months of the procedure; ablation area increased.(F) CT 6 months after the procedure; Enhancement was seen in part of the tumor (triangular arrows).(G) In the supine position, MWA was performed for the enhanced part.(H) CT performed 1 month after the procedure; The ablation area completely covered the tumor.(I) CT after 3 months of the procedure; ablation area reduced.(J) CT after 6 months of procedure; cavity occurred in ablation areas.(K) CT after 24 months of the procedure; cavity shrunk.(L) CT after 24 months of the procedure; ablation area reduced.
Wang et al.   developed an MWA experimental platform and a 3D simulation model to discuss the effects of blood flow parameters on temperature distribution during liver tumor MWA.The study concluded that:(1) the distance between the antenna and the vessel was the most important factor affecting the temperature distribution; (2) the smaller the distance, the lower the temperature; and (3) the blood vessels remove and block a portion of the conduction heat[22].Moreover, Izaaryene et al. evaluated MWA treatment for perivascular liver metastases from colorectal cancer and found that MWA was safe and effective, provided that satisfactory margins were achieved[34].Hu et al. compared the long-term outcomes of MWA and wedge resection in patients with stage I NSCLC adjacent to the pericardium, by propensity score analysis.The MWA group had 68 patients with poor baseline performance status, with PFS rates of 80.0%, 54.0%, and 36.0%at 1, 3, and 5 years, respectively, and OS rates of 90.0%, 60.0%, and 55.0% at 1, 3, and 5 years, respectively.

Figure 4 .
Figure 4. Structural changes: adhesions to extracardiac structures.(A) The tumor (white arrow) is adjacent to the pericardium (minimum distance was 4 mm).(B) In the supine position, the antenna punctured the proximal end of the tumor, parallel to the pericardium.(C) CT 24 h after the procedure; the exudation and ablation area completely covered the tumor.(D) CT 1 month after the procedure; Adhesions to the extracardiac tissue (triangular arrow).(E) CT after 6 months of the procedure; adhesions to the extracardiac tissue.(F) CT 14 months after the procedure; Abnormally thick adhesions reduced (triangular arrow).

Figure 5 .
Figure 5. Structural changes: thickening of the mediastinal layers.(A) An 18-mm mixed ground-glass nodule (white arrow) was closer to the mediastinum without an end-inspiratory hold (lesion near the mediastinum within 10 mm).(B) In the supine position, the antenna punctured the center of the tumor parallel to the mediastinum.The minimum distance between the ablation antenna and mediastinum was less than 10 mm [triangular arrow].(C) CT performed 24 h after the procedure revealed pleural effusion and further thickening of the mediastinal layers (triangular arrow).(D) CT 1 month after the procedure: The ablation area completely covered the tumor, and there was indistinct separation from the mediastinum layers.(E) CT 6 months after the procedure: Local thickening of the mediastinal layers.(F) CT performed 16 months after the procedure: The mediastinal layers returned to almost normal.
The statistical p-values are in italicized bold and mark with ' Ã '.LPFS: local progression-free survival.
Minor complications include Society of Interventional Radiology (SIR) classifications.A: no therapy, no consequence; B: nominal therapy, no consequence; Major complications include SIR classifications.C: requires therapy; D: requires major therapy; E: permanent adverse sequelae; and F: death.