Surgical treatment of synchronous multiple lung adenocarcinomas: experiment of 171 cases
Original Article

Surgical treatment of synchronous multiple lung adenocarcinomas: experiment of 171 cases

Koei Ikeda, Kosuke Fujino, Yoshiko Masuda, Makoto Suzuki

Departments of Thoracic Surgery, Graduate School of Medical Science, Kumamoto University, Kumamoto, Japan

Contributions: (I) Conception and design: K Ikeda; (II) Administrative support: M Suzuki; (III) Provision of study materials or patients: K Fujino, Y Masuda; (IV) Collection and assembly of data: K Ikeda; (V) Data analysis and interpretation: K Ikeda; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

Correspondence to: Koei Ikeda, MD, PhD. Department of Thoracic Surgery, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan. Email: koei@cg7.so-net.ne.jp.

Background: It is unclear how to treat synchronous multiple lung adenocarcinoma (SMLA) cases, which are increasing with the development of high-resolution computed tomography (HRCT).

Methods: Retrospective review of 171 cases of SMLA who underwent curative intent surgery between 2010 and 2018. Lung volume-preserving surgery, segmentectomy or wedge resection, is preferred for ground glass opacity nodules (GGN) within 2.0 cm. Clinical observation is allowed for pure GGN within 1.0 cm.

Results: The 5-year recurrence-free survival rate after surgery was 95.2%, and the overall survival rate was 93%. Prognosis was correlated with the degree of progression of the dominant tumor. Tumor number, surgical procedure and remnant tumor after surgery were not correlated with prognosis.

Conclusions: The prognosis of SMLA was relatively good, and was dependent on the stage and malignant potential of the dominant tumor. Limited resection and clinical observation for GGN are acceptable.

Keywords: Synchronous multiple lung adenocarcinoma (SMLA); limited surgery; clinical observation


Received: 10 November 2019; Accepted: 04 December 2019; Published: 05 April 2020.

doi: 10.21037/jovs.2019.12.07


Introduction

Synchronous multiple lung adenocarcinoma (SMLA) cases are increasing with the development of high-resolution computed tomography (HRCT). In these cases, multiple ground glass opacity nodules (GGN) are detected in the peripheral lung, and are often diagnosed as adenocarcinomas with lepidic growth or atypical adenomatous hyperplasia (AAH). The prognoses are reported to be relatively good (1,2). In these cases, surgeons tend to choose lung-preserving surgery because of the multiple lesions in the peripheral lung, which are often bilateral. Limited resection for single GGN is reported to be acceptable in some non-randomized trials (3,4), and clinical trials are ongoing in Japan (5,6). The National Comprehensive Cancer Network (NCCN) guideline recommends clinical follow-up for pure GGN less than 2 cm (7).

In this study, the prognosis of SMLA after surgery was retrospectively reviewed, and optimal treatment was examined.


Methods

We included 171 patients with SMLA who underwent surgical resection between January 2010 and Marth 2018 in Kumamoto University Hospital. SMLAs were diagnosed clinically, at least two nodules were noted on HRCT, and the nodules were pathologically diagnosed as lung adenocarcinomas; pulmonary metastases were deniable based on CT images or pathological findings. Mucinous adenocarcinomas, which show a pneumonia-like shadow in the peripheral lung, were excluded from this study. Our policies of treatment for SMLA were as follows: (I) treatments for the most progressive nodules were prioritized; (II) lung volume-preserving surgery, segmentectomy or wedge resection, was preferred for GGN (part solid nodules or pure GGN) within 2.0 cm; (III) pure GGN were resected by wedge resection, if possible. Lipiodol markings were performed for untouchable nodules; and (IV) clinical observation was allowed for pure GGN within 1.0 cm.

Seventy-one patients were male, and 100 were female. Their median [range] age was 70 [39–87] years. Smoking histories were negative in 99 patients, and positive in 72. The numbers of nodules first found on HRCT were 2 in 86 patients, 3 in 32 patients, 4 in 35 patients and more than 4 in 18 patients. Pathological stages of the most progressive nodule were 0/IA1 in 101 cases (59.1%), IA2/IA3 in 49 cases (28.7%) and IB or above (IB in 11, IIA in 2, IIB in 5, IIIA in 2 and and IIIB in 1) in 21 cases (12.3%). The most surgeries performed in each lung are shown in Table 1. Bilateral surgeries were performed in 19 patients. In 49 cases, limited resection (segmentectomy or wedge resection) was performed for the most progressive nodules. A representative case of surgery for SMLA is shown in Figure 1. Right S3 segmentectomy for a part-solid nodule and rt. S6 wedge resection for a pure GGN nodule were performed. A pure GGN nodule in the left upper lobe was left unresected and observed clinically.

Table 1
Table 1 Most surgeries performed on SMLA cases
Full table
Figure 1 A representative case of surgery for SMLA (8). Rt. S3 segmentectomy for a part-solid nodule and rt. S6 wedge resection for a pure GGN were performed on a 71-year-old male patient. SMLA, synchronous multiple lung adenocarcinoma; GGN, ground glass opacity nodules. Available online: http://www.asvide.com/watch/33074

Statistical methodology

All statistical analyses were performed with the SPSS program for Windows (version 18 statistical software; Texas Instruments, IL, USA). Numerical data were compared with an independent sample t-test, and categorical data were compared with a Pearson chi-square test. Recurrence-free survival (RFS) and overall survival (OS) were calculated from the date of surgery and estimated using Kaplan-Meier analysis. Differences between curves were evaluated using log-rank tests. To evaluate whether a biomarker was an independent prognostic factor for survival, a multivariate, stage-stratified Cox proportional hazard model was constructed to compute a hazard ratio (HR) that was based on the clinicopathological parameters. All p values were two-sided, and differences with P values of less than 0.05 were considered significant.


Results

Kaplan-Meier curves for all patients are shown in Figure 2. The median follow-up period was 51.8 months. The 5-year RFS rate after surgery was 95.2%, and the OS rate was 93%.

Figure 2 General survival curves of patients with SMLAs. SMLA, synchronous multiple lung adenocarcinoma.

Survival comparisons among pathological stages of the dominant tumor are shown in Figure 3. The 5-year RFS rate was 100% for stage 0/IA1 and 94.3% for stage IA2/IA3; these rates were significantly higher than for stage IB and above (83.0%: P<0.01). The 5-year OS rate was 94.7% for stage 0/IA1 and 96.8% for stage IA2/IA3; these rates were significantly higher than for stage IB and above (88.2%: P=0.05). With regard to RFS, the survival analysis for clinicopathological factors is shown in Table 2. A CT finding of solid, high carcinoembryonic antigen (CEA) level (>5.0 µg/L), pleural invasion, vascular invasion, and lymph node metastasis were significantly associated with poor prognosis on univariate analysis. However, only a CT finding of solid remained significant on multivariate analysis. As for OS (Table 3), high age (>75 years) and high CEA (>5.0 µg/L) were significantly associated with poor prognosis. Both remained significant on multivariate analysis. Tumor number (>3), surgical procedure (limited surgery) or remnant tumors were not associated with prognosis.

Figure 3 Survival curves of patients by pathological stage.
Table 2
Table 2 Recurrence-free survival and patient characteristics
Full table
Table 3
Table 3 Overall survival and patient characteristics
Full table

Differences between the groups with and without remnant tumors are shown in Table 4. There was no significant difference between the groups except in tumor number (P=0.03). Existence of remnant tumors was not associated with prognosis for either RFS or OS (Figure 4).

Table 4
Table 4 Characteristics of patients with and without remnant tumors
Full table
Figure 4 Survival curves of patients with and without remnant nodules.

Discussion

Lepidic-type adenocarcinoma is known to occur frequently in Asians and non-smokers. The prognosis is good, and the propensity of lymph node and distant metastasis is low in comparison to solid adenocarcinomas (9). Multifocal parenchymal nodules are frequently found in patients with lepidic-type adenocarcinoma (10). In this study, we retrospectively reviewed the results of surgery for SMLAs. The most progressive nodules of our cases were GGN (part solid nodules or pure GGN) in 122 cases (71.3%), and their pathological stages were stage 0/IA in 101 cases (59.1%). That is why the prognosis of our series was extremely good (5-year RFS was 95.2%, and OS was 93%).

In the treatment of SMLAs, surgeons are forced to select limited resection to preserve lung function. The standard surgical procedure for lung cancer, even for small-sized lung cancer, is lobectomy with hilar and mediastinal nodal dissection, based on the results of a randomized controlled trial (11). Based on the results of a prospective multi-institutional study on the relationship between radiologic and pathologic findings in peripheral lung cancer (12), the Japan Clinical Oncology Group (JCOG) and the West Japan Oncology Group (WJOG) conducted a randomized, phase III trial investigating lobectomy versus limited resection for small invasive peripheral lung cancers (6). In our series, limited resection for dominant tumors was performed in 28.6% of patients, and surgical procedure was not associated with prognosis. In addition, the non-dominant tumors, mostly GGN, were frequently treated with limited resection. However, the survival of our patients was extremely good.

According to several studies (13,14), solitary pure GGN should be followed up until they increase in size or develop a new solid component. Nevertheless, whether this strategy is also appropriate for SMLAs is controversial. In this study, although GGN were left in 27.5% of cases, this was not associated with prognosis. In some cases, we could not treat all of the nodules because there were multifocal nodules in the lungs bilaterally. Our strategy for SMLA cases was to focus on invasive nodules, with CT findings that were solid or sub-solid, and to leave pure GGN unresected and observe them clinically. When a GGN became enlarged or a solid component appeared, additional local treatment, including radiofrequency ablation or stereotactic radiation therapy, could be incorporated.

This study had some limitations. Due to its retrospective nature, a prospective study is necessary to verify the results. The observation period was relatively short, and the safety of clinical observation of remnant tumors is unclear.

In conclusion, the prognosis of SMLA in these patients was relatively good. The prognosis was dependent on the pathological stage of the dominant tumor. Non-solid tumors less than 1 cm can be clinically observed, and GGN can be treated with limited surgery.


Acknowledgments

None.


Footnote

Conflicts of Interest: 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 approved by ethical committee of Kumamoto University (No. 202, 402) and written informed consent was obtained from all patients.


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doi: 10.21037/jovs.2019.12.07
Cite this article as: Ikeda K, Fujino K, Masuda Y, Suzuki M. Surgical treatment of synchronous multiple lung adenocarcinomas: experiment of 171 cases. J Vis Surg 2020;6:15.