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Eur J Cardiothorac Surg 2008;34:1068-1074. doi:10.1016/j.ejcts.2008.07.044
Copyright © 2008, European Association for Cardio-thoracic Surgery. Published by Elsevier. All rights reserved.
Treatment strategy for patients with small peripheral lung lesion(s): intermediate-term results of prospective study
Ken Kodamaa,*,
Masahiko Higashiyamaa,
Koji Takamia,
Kazuyuki Odaa,
Jiro Okamia,
Jun Maedaa,
Mitsuhiro Koyamab,
Tomio Nakayamac
a Department of Thoracic Surgery, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan
b Diagnostic Radiology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan
c Cancer Control and Statistics, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan
Received 1 June 2008;
received in revised form 19 July 2008;
accepted 21 July 2008.
* Corresponding author. Address: Department of Thoracic Surgery, Osaka Medical Center for Cancer and Cardiovascular Diseases, 1-3-3 Nakamichi, Higashinari-ku, Osaka 537-8511, Japan. Tel.: +81 6 6972 1181; fax: +81 6 6981 8055. (Email: kodama-ke{at}mc.pref.osaka.jp).
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Abstract
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Background: This prospective study was undertaken to establish a novel management algorithm using new indicators to decide the type of lung resection for small peripheral lung lesions. Methods: Inclusion criteria were: (1) 
20 mm peripheral lung lesion(s) and (2) absence of significant lymph node swelling on preoperative CT. Along with the conventional criteria, the percentage of ground-glass opacity (GGO) (
50% as GGO type and <50% as solid type) on high-resolution CT scan was employed. In accordance with such indicators, a wide wedge resection (WWR), segmentectomy or lobectomy was planned for individual patients. The primary endpoint was to estimate the effectiveness of limited resection in patients with lung cancer by analyzing their locally disease-free survival rates at 5 and 10 years. Results: Of 179 patients enrolled between 1997 and 2002, 90 were male and 89 female. They were divided into 77 GGO types and 102 solid types. During surgery, conversions from limited resections to standard operations were performed on six patients to avoid the risk of local-regional recurrence. Finally, WWR was performed on 73 patients, segmentectomy on 26 and lobectomy on 80, respectively. There were 138 lung cancers and 41 non-cancers. Of 138 cancer patients, 114 patients are alive and 24 died. There were no local-regional recurrences among the 58 cancer patients who underwent limited resection. Conclusions: This intermediate-term outcome suggests that the selection of the type for lung resection using this management algorithm for small peripheral lung lesions was effective for preventing both local-regional recurrences and the excessive resection of normal lung tissue.
Key Words: Lung cancer • Ground-glass opacity • Peripheral lung lesion • Bronchioloalveolar carcinoma • Limited resection
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1. Introduction
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In the last decade, the development of mass screening using low-dose spiral (helical) computed tomographic (CT) scan (low-dose CT) or increased opportunities to take chest CT scans during disease follow-up have enabled the discovery of very small or very fine hazy lesions in the lung field. Most such lesions are invisible on plain chest X-ray film. After detecting lesion sites using low-dose or conventional CT, further examinations by high-resolution (thin section) CT (HRCT) are usually conducted in order to establish radiological diagnoses. As the next step, it depends on the result of informed consent to each patient whether a CT-guided-transbronchial [1] or percutaneous biopsy [2] is employed for diagnosis, a thoracotomy with or without video-assisted thoracic surgery (VATS) is employed for diagnosis and treatment, or diligent follow-up is continued.
Solitary ground-glass opacity (GGO) lesions that cannot be detected by plain chest X-ray film or early generation CT scan have been highlighted as a new entity in the last decade. If the lesion does not decrease in size or does not disappear during further follow-up for 3–6 months, it is strongly suspected to be lung cancer. Non-invasive bronchioloalveolar carcinoma (BAC) is represented as pure GGO lesions on HRCT [3]. However, it is difficult to establish a definitive histo(cyto)diagnosis for small lesions measuring 10 mm or less in diameter.
Previous reports on intentional limited resections never enrolled such small peripheral lung lesions as study candidates [4,5]. However, in the future, a dramatic increase of such lesions is likely in accordance with rapid progress in the development of diagnostic technologies.
Therefore, the establishment of a systematic management algorithm for small peripheral lung lesions, from detection of the lesions to treatment, is important. Thus, we have carried out this prospective study concerning diagnoses and treatment strategies for patients with such small peripheral lung lesions. The intermediate-term results of this study are presented here.
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2. Patients and methods
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2.1 Study design
This study, a prospective trial done in one center (Osaka Medical Center for Cancer and Cardiovascular Diseases), was designed to deliver a high-quality service to patients with small peripheral lung lesions. This is an essential requirement to inform patients of the different approaches available and select the most appropriate surgical treatment. Since the study began in 1997, written informed consent was obtained from each patient. Data for this study were retrieved from our hospital database whose use for research was approved by the ethical review board of the Osaka Medical Center for Cancer and Cardiovascular Diseases on March 7, 2008 (Approval No.: 0803095086).
2.2 Patients
One hundred and seventy-nine patients with proven or suspected lung cancers were enrolled in this study.
All patients eligible for the trial who presented over the 5-year recruitment period (between October 1997 and September 2002) were offered entry into the study. Inclusion criteria for the trial were: (1) peripheral lung lesion(s) 20 mm or less in diameter on preoperative HRCT and (2) absence of hilar or mediastinal lymph node swellings greater than 10 mm in diameter on preoperative contrast-enhanced CT (clinically N0). Exclusion criteria were: (1) poor cardio-pulmonary or other organ dysfunction that would make the patient intolerable to standard surgical procedures such as lobectomy with systematic lymph node dissection (compromised cases); and (2) coexistence of active malignant lesions in any other organs.
2.3 Preoperative selection criteria for the type of lung resection
Lesions were classified into three groups: 10 mm or less, 11–15 mm, and 16–20 mm, according to the maximal diameter on HRCT. Three expert radiologists measured the percentage of GGO area at the maximal slice of the lesions on HRCT, and participants were divided into those with 50% GGO area as GGO type or <50% GGO area as solid type [6]. Pure GGO was defined as a complete hazy shadow, with preservation of the bronchial and vascular margins in the lesion on HRCT. Lesion location and lesion number were also taken into consideration in deciding the type of lung resection. At the time informed consent was obtained from patients with very small lesions measuring less than 10 mm in diameter or pure GGO, diligent observation was also available as one of the selection arms. When the lesion increased in size and/or density on HRCT during observation, it would be recruited as a candidate for resection (Fig. 1
).
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Fig. 1. Algorithms for deciding the type of resection. The main procedure also depends on the number and/or the location of lesion(s) beside the size and ground-glass opacity (GGO) pattern. If cytology of the resection margin and/or lymph node (LN) frozen section histology are positive, the procedure is converted to lobectomy with LN dissection as a final procedure. VATS: video-assisted thoracic surgery; WWR: wide angle resection.
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In accordance with these selection criteria, wide wedge resection (WWR), segmentectomy, or lobectomy with or without systematic lymph node dissection, were planned for individual patients. We designated the method of wedge resection with safe margin macroscopically greater than the lesion diameter as WWR.
2.4 Intraoperative process for the final decision on the type of resection
Fig. 1 shows the algorithms for deciding the type of surgery. First, we consider lesion size and GGO area when deciding the type of lung resection. However, lesion location, number and intraoperative factors are also important. For the GGO type less than 20 mm in diameter, we basically planned limited resection. For the solid type, less than 15 mm in diameter, we basically planned limited resection.
If a definitive histo(cyto)diagnosis of lung cancer was obtained, we started the planned resection. For limited resection cases, if positive findings were obtained from the intraoperative histodiagnosis of lymph nodes using frozen sections, or the lavage cytology of the resection margin [7], we converted the procedure immediately from a limited resection to a lobectomy with systematic lymph node dissection. Of course, if we judged that the resection margin was macroscopically insufficient, we also converted the procedure from a limited resection to a lobectomy. Basically, we do not try to perform additional resection, even for WWR.
If preoperative histological or cytological diagnoses could not be made, we usually performed needle aspiration cytology on lesions through the thoracotomy wound. However, some specimens were too small to confirm the cytology. If cytological diagnosis was difficult, we performed WWR with a curative intent. Then, lavage cytology of the resection margin was employed as previously described [7]. In brief, when limited resection was performed with a stapler alone, all fired cartridges were washed in 200 ml of saline solution. When the lesion was excised with the aid of a neodymium:yttrium-aluminum-garnet (Nd:YAG) laser or electric scissors alone, the resected specimen was similarly washed without flooding of the pleural surface. When lesions were resected by a combination of methods, both the fired cartridges and the resected specimen were washed. After centrifugation, the sediment was immediately fixed with Saccomano solution and then smeared on a glass slide by the cytospin method. After final refixation with ethanol and diethyl ether, the sediment was stained by means of the Papanicolaou method.
When it was predicted that the lesion would be too small to detect at the time of VATS or thoracotomy, CT-guided marking with indocyanine green (ICG) dye was performed immediately before surgery. VATS was employed for superficial lesions; while an Nd:YAG laser was employed for WWR or segmentectomy for deep-seated lesions to secure the safe margin [8].
2.5 Statistical analysis
The primary endpoint was the analysis of the locally disease-free survival rate at 5 and 10 years in lung cancer patients with limited resections. The secondary endpoint was the comparison of 5- and 10-year survival rates between patients with limited resections and lobectomies. We performed survival analysis with StatView J 5.0 (SAS Institute, Cary, North Carolina), and survival curves were calculated by the Kaplan–Meier method [9].
We estimated the sample size for this trial from the result of our previous retrospective study on intentional limited resection in highly selected T1N0 NSCLC patients. In our previous study, the recurrence at the resection margin occurred in only one of 46 patients (2.2%) and mediastinal recurrence was reported in 3 patients (6.5%) [5]. Based on these experiences, we estimated that 50 patients enrolled in the limited resection arm would be needed in this study.
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3. Results
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Between October 1997 and September 2002, 179 patients were enrolled. Of those, 90 were male and 89 were female. The median age was 60 years old. Of those, 159 had solitary lesions and 20 had multiple lesions. The average maximal diameter on HRCT was 13.7 mm, with a range from 5 mm to 20 mm (Table 1
). The lesions were divided into 77 GGO types and 102 solid types. Of the 77 GGO types, 30 were pure GGO. There were no surgery-related deaths in this series. Sixty-one of 179 patients were preoperatively proven to have lung cancer. However, 118 patients did not have any preoperative histological or cytological diagnosis. Preoperative CT-guided marking was employed for 35 patients with GGO lesions and intact pleura on HRCT. VATS procedure was employed for 40 patients. The median follow-up time of surviving patients was 92 months (Table 1).
The conversion from limited surgery to a standard procedure was performed in six patients. These consisted of three patients with lymph node metastases on frozen section histology; two with macroscopically insufficient margins, and one with a lavage cytology positive margin (Table 2
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Finally, adenocarcinoma was proven in 128 patients, non-adenocarcinoma in 10, AAH in 2, lymphoproliferative disorders (LPD) in 4, and benign lesion in 35. Of the 128 lung adenocarcinomas, 68 were GGO types including 22 pure GGO, and 60 solid types. All of the 10 non-adenocarcinomas, which consisted of 4 squamous cell carcinomas, 4 small cell carcinomas, one carcinosarcoma and one pleomorphic carcinoma were solid types. Two atypical adenomatous hyperplasia (AAH) cases were GGO types, one of which was a pure GGO type. These two AAH cases had been diagnosed as BAC at frozen section histology and corrected to AAH in the final report. All of the four LPDs were pure GGO types. All but three of the 35 benign lesions (benign tumors or inflammations) belonged to the solid type (Table 3
). All patients with benign lesions are alive and uneventful. Of 24 inflammations, 11 were tubercular nodules, 10 nonspecific inflammatory nodules and one of each cryptococcosis, mycobacterium avium complex (MAC) infection and sarcoidosis.
Table 4
shows the final surgical procedures employed for lesions with different histologies. WWRs were performed on 33 patients with adenocarcinomas and all but one non-cancer patient, including one AAH, 4 LPDs, 11 benign tumors and 24 inflammations. Segmentectomies were employed for 25 patients with adenocarcinomas and one with AAH. Lobectomies were employed for 70 patients with adenocarcinomas. Lobectomies were also employed for all 10 patients with non-adenocarcinomas. VATS was employed in 29 of 73 WWRs, 5 of 26 segmentectomies and 6 of 80 lobectomies.
Fig. 2
shows the distributions of 138 cancer patients treated at each of the major steps according to our study protocol. As a result of following our comprehensive judgment of the HRCT, tumor size, number and location, the surgical procedure employed was shifted from a WWR to lobectomy. However, lobectomy was also employed for deep-seated smaller lesions, the multiple smaller lesions found in one lobe or lesion(s) originated from the middle lobe. As a result, lobectomy was deemed to be necessary in three cases where GGO type was 10 mm or less in diameter. For one patient this decision was based on the existence of multiple BACs in the right upper lobe, for another it was based on histological diagnosis showing endometriosis in an adjacent segment of the same right lower lobe, and finally it was deemed necessary in another patient because the tumor was located in the deep parenchyma of the middle lobe.
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Fig. 2. The number of cancer patients treated at each of the major steps of the study. GGO: ground-glass opacity. WWR: wide angle resection
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Of 138 cancer patients, 24 patients died. Of those, 16 died from disease-related causes and 8 from unrelated causes. Recurrences have been observed in 22 of 138 cancer patients. There were no local-regional recurrences among 58 patients with limited resection (Table 5
). One of the 33 patients with WWRs demonstrated distant metastasis in a different lobe of the lung. This recurrence might not have been avoidable, even if lobectomy had been performed as the standard operation. Of 80 patients undergoing lobectomy, 21 had recurrences (Table 5). Of those, 7 demonstrated local-regional recurrences: 5 ipsilateral carcinomatous pleuritis, 1 at the resection margin of the chest wall and 1 at the regional lymph node. The median follow-up times of surviving patients in the limited resection and lobectomy groups were 91 and 98 months, respectively.
Fig. 3
shows the comparison of relapse-free survival curves (a) and overall survival curves (b) between lung cancer patients with limited resection and with lobectomy. There were no operative deaths. Both 5- and 10-year relapse-free survival rates were 98.3% in the limited resection group, and 73.8% in the lobectomy group (Fig. 3a). The difference was significant (p
= 0.0001). Overall survival rates at 5 and 10 years were 96.6% and 94.7% in the limited resection group, and 80.0% and 71.4% in the lobectomy group, respectively (Fig. 3b). This difference was also significant (p
= 0.0014). All 18 patients with pathologically advanced lesions more than stage IA were included in the lobectomy group. There were no local recurrences but one distant metastasis in a different lobe was detected among the 58 patients undergoing limited resection. Of 21 patients with recurrences after lobectomy, 5 died more than 5 years postoperatively and 3 are alive with disease more than 5 years after surgery.
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Fig. 3. Intermediate-term results of lung cancer patients. Limited resection (segmentectomy or wide wedge resection) vs lobectomy. (a) Relapse-free survival (p
= 0.0001); (b) overall survival (p
= 0.0014).
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4. Discussion
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In a large collaborative study, the International Early Lung Cancer Action Program (IELCAP) Investigators [10] screened 31,567 asymptomatic persons at risk for lung cancer using low-dose CT (1993–2005). Of those participants, 484 received a diagnosis of lung cancer and 412 (85%) had clinical stage I lung cancer. The 10-year lung-cancer-specific survival rate among the 302 participants, who underwent resection regardless of the type of surgery, was 92%. They also reported that all 8 untreated stage I patients died within 5 years after diagnosis. However, the surgical procedure employed for 78% of the participants was lobectomy, although the median tumor diameter was 13 mm at baseline and 9 mm on annual CT. It may depend on the minority of the patients with bronchioloalveolar subtype (5%).
We reported previously that a novel classification based on the semiquantitative analysis of BAC component areas in small peripheral lung adenocarcinomas 20 mm or less in diameter reflects both clinicopathological and prognostic characteristics [11]. In order to better apply this data preoperatively, we conducted a study to clarify the prognostic value of GGOs found in small lung adenocarcinomas measuring 20 mm or less in diameter on HRCT scanning. There was good correlation between histological BAC and GGO area on HRCT scanning in patients with small adenocarcinomas measuring 20 mm or less in diameter, and there were no relapses among patients with GGO greater than 50% on the CT slice showing the maximal cross section of the lesion. This novel classification based on the semiquantitative analysis of GGO area on HRCT should become a useful independent preoperative indicator when deciding the surgical procedures [6].
Thus, as an indicator at the time of deciding surgical procedures in this prospective study, we employed the GGO area (<50% or >50%) on HRCT taken immediately before surgery. Pure GGO is a good candidate for WWR without lymph node dissection because of the extremely low risk of lymphatic invasion. Besides BACs or AAHs, LPDs, such as lymphoid interstitial pneumonitis (LIP) or early stage pulmonary marginal zone lymphoma of mucosa associated lymphoid tissue (MALT), are also detected as pure GGO on HRCT.
The final decision on conversion to lobectomy in each patient scheduled for limited resection was done according to the results of not only conventional intraoperative histologies or cytologies of the lesions or lymph nodes, but also intraoperative lavage cytologies of the resection margins [8]. This technique was developed in our department, and is routinely employed in patients undergoing limited resection, if lavage cytology of the chest cavity immediately after thoracotomy was negative. Previously, we reported that 21 of 199 patients (10.5%) showed cytologically positive results on the surgical margin during the attempted procedure [7]. Needless to say, the percentage was higher in compromised limited resection for patients with poor cardio-pulmonary or other organ function. Of note in this prospective study, only one of 58 cancer patients (1.7%) undergoing planned limited resection had a positive cytological result at the resection margin. The patient then underwent conversion from a limited to a standard operation, i.e. lobectomy. Thus, the patient was finally included in the lobectomy group in this study. Limited resection should be performed while maintaining a macroscopically safe surgical margin. In our institute, lesions were resected in keeping with this principle: more than 20 mm if possible, or at least with a safe margin greater than the lesion diameter under deflated condition of the lung [7]. Sawabata et al. [12] demonstrated that there were no microscopically malignant positive margins when the margin distance was greater than the maximum tumor diameter. Recently, Schuchert et al. [13] reported that a margin/tumor ratio of less than 1 is associated with a higher rate of recurrence. Lobectomy should be considered as primary therapy when such margins are not obtainable with segmentectomy in good-risk patients.
As shown in Table 4, there was no excessive resection of normal lung tissue in patients with suspected lung cancer eventually that was confirmed as benign in this study. Therefore, present management algorithm seems to be acceptable. These outcomes may indicate that invasive diagnostic approaches such as percutaneous or transbronchial lung biopsies are unnecessary for very tiny lesions or GGO lesions invisible on plain X-ray film, and surgery is indicated in tubercular or inflammatory nodules for both diagnostic and curative purposes, especially when the suspicion of cancer arises. According to the results of the Mayo Clinic low-dose spiral CT screening program for lung cancer, 1112 of 1520 participants (73%) had one or more indeterminate pulmonary nodules. Of those, 55 patients (3.6%) underwent surgery. Of those highly selected patients, 10 (18.1%) were diagnosed with benign lesions, while 45 (89.1%) were diagnosed with lung cancer [14]. In our study, 35 (19.6%) of 179 patients were determined to have benign tumors or inflammatory diseases. However, imaging techniques, including reviews of previous CT films, might allow us to determine conclusively that the lesion in question is benign [15]. It is highly likely, considering tumor doubling time, that most lesions can be identified as potentially malignant within as short a period of observation as 3–6 months. Thus, we have provided one selection arm of ‘observation’, especially for noncalcified lesions less than 10 mm, or pure GGO regardless of size. However, AAH and LPD produce images that are indistinguishable from BAC on HRCT. At the time of patient entry in the present study, positron emission tomography (PET) was not available in our institute. Integrated PET/CT may demonstrate an excellent performance in classifying the lesions with solid density as benign or malignant with higher sensitivity and accuracy than helical dynamic CT [16,17].
A recent revision in the World Health Organization (WHO) criteria has restricted the definition of BAC to include only those tumors with a pure alveolar growth pattern without any evidence of invasion [18]. Whether these changes will translate into actual improvements in lung cancer death rates or overdiagnosis is not yet known. We reported on noninvasive BAC showing pure GGO removed after long-term follow-up for more than 2 years. Some of these lesions were unchanged both in size and density, during the follow-up. The natural history of pure GGO is now under investigation in our department [3]. Recently, Henschke et al. [15] reported that, in modern CT screening for lung cancer at the baseline, detection of noncalcified nodules smaller than 5.0 mm in diameter does not justify immediate work-up but only annual repeat screenings to determine whether interim growth has occurred.
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5. Conclusion
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In conclusion, our novel treatment algorithm for small peripheral lung lesions measuring 20 mm or less in diameter, employing semiquantitative assessments of GGO area on HRCT and intraoperative lavage cytologies of resection margin of the lung as new indicators, may not only completely prevent local-regional recurrences after limited resection in cancer patients, but also avoid excessive resection of normal lung tissue in patients with non-cancerous lesions. Of 21 patients with recurrences after lobectomy, 5 died more than 5 years postoperatively and 3 are alive with disease more than 5 years after surgery. In light of this evidence, we feel that long-term follow-up is necessary to collect reliable data for survival analysis, especially for tumors that exhibit slow growth characteristics such as BAC.
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Acknowledgments
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We thank Jun-ichi Ashimura, CT, Akemi Takenaka, CT, and Yasuyoshi Naruse, CT, for their technical assistance in performing cytologic analysis.
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Footnotes
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This work was supported in part by a Grant-in Aid for Cancer Research (17-6) from the Ministry of Health, Labor and Welfare, Japan.
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Abstract
1. Introduction
