Abstract

OBJECTIVES

Phase III trials regarding the feasibility of segmentectomy for lung cancer ≤2 cm in size are now underway in Japan and the USA. However, despite their small size, lung cancers that show a pure-solid appearance on thin-section computed tomograpy (CT) are considered to be invasive with a high frequency of nodal involvement.

METHODS

Between 2008 and 2011, 556 clinical Stage IA lung cancer patients underwent pulmonary resection. For all patients, the findings obtained by preoperative thin-section CT were reviewed and the maximum standardized uptake value (SUVmax) on positron emission tomography was recorded. Several clinicopathological features were investigated to identify predictors of nodal metastasis using multivariate analyses.

RESULTS

One hundred and eighty-four clinical Stage IA lung cancer patients showed a pure-solid appearance on thin-section CT. Among them, air bronchogram was found radiologically in 58 (32%) patients. Nodal involvement was observed in 10 (17%) patients with air bronchogram, compared with 43 (34%) without air bronchogram, in clinical Stage IA pure-solid lung cancer. A multivariate analysis revealed that air bronchogram, clinical T1a and SUVmax were significant predictors of postoperative nodal involvement (P < 0.01, <0.01, and 0.03, respectively). Furthermore, nodal metastasis was never seen in patients with clinical T1a pure-solid lung cancers who had both air bronchogram and low SUVmax.

CONCLUSIONS

The presence of air bronchogram was a novel predictor of negative nodal involvement in clinical Stage IA pure-solid lung cancer. Segmentectomy with thorough lymph node dissection is a feasible option for these patients despite a pure-solid appearance.

INTRODUCTION

Lung cancers that show a wide area of ground-grass opacity (GGO) are considered to have a good prognosis and in most cases their pathological features are minimally invasive [1, 2]. Recently, the indication for limited surgery has been extended to very early lung cancers that are located peripherally and show a GGO appearance on thin-section computed tomography (CT) scan [3–7]. While there has been considerable discussion on limited surgical resection for lung cancer with a GGO appearance, there have been few studies on limited surgery for lung cancer with a solid appearance on thin-section CT scan, i.e. invasive lung cancer. Intentional segmentectomy is now indicated for part-solid or pure-solid lung cancers 2 cm or less in size in both Japan [8] and the USA [9]. However, postoperative nodal involvement is found in ∼20% of cases, even in clinical Stage IA disease [10], and invasive lung cancer can be associated with occult lymph node metastasis, which would result in incomplete resection and loco-regional failure by the indication of limited surgical resection. Furthermore, postoperative nodal involvement is often found in patients with radiologically pure-solid lung cancer [11]. Thus, pure-solid lung cancer is considered to be highly invasive and is in a different category among lung cancers with a solid appearance on thin-section CT scan.

Thus, there is still some controversy regarding the use of limited surgical resection for pure-solid tumours because of the high frequency of lymph node involvement. On the other hand, limited surgery such as segmentectomy is becoming increasingly important as an option for resectable small lung cancer with N0 status [12, 13]. For the more precise application of limited surgical resection, preoperative diagnosis for predicting invasive lung cancer is warranted through the classification of these pure-solid tumours into several subgroups. In the current retrospective study, we focused on the radiological findings of pure-solid lung cancer, especially with regard to air bronchogram on thin-section CT scan, and tried to determine criteria for identifying candidates for limited surgical resection for small-sized tumours.

MATERIALS AND METHODS

This protocol was approved by the ethics committee at our institute. All patients provided their written informed consent before trial enrolment.

Between January 2008 and December 2011, 556 clinical Stage IA lung cancer patients underwent pulmonary resection at our institute. For all patients, the findings of preoperative computed tomography were reviewed by the authors (A.H., T.M. and K.S.). A contrast-enhanced CT scan was performed to evaluate the entire lung for preoperative staging. The size of the tumours was determined preoperatively based on the findings of thin-section CT scan. In addition, all tumours were subsequently evaluated to estimate the extent of GGO with thin-section CT scan with 2 mm collimation. The lung was photographed with a window level of −500 to −700 H and a window depth of 1000–2000 H as a lung window. The solid component was defined as an area of increased opacification that completely obscured the underlying vascular markings. GGO was defined as an area of a slight, homogeneous increase in density that did not obscure the underlying vascular markings. In the current study, a radiological pure-solid tumour was defined as a lung tumour that only showed consolidation without GGO on thin-section CT, i.e. the ratio of the maximum diameter of consolidation to the maximum tumour diameter (consolidation/tumour ratio, C/T ratio) was equal to 1.0. Air bronchogram was a radiological finding on thin-section CT scan that was defined as an air-filled bronchus surrounded by fluid-filled airspaces in the primary tumour. Typical images of pure-solid lung cancer with air bronchogram are shown in Fig. 1.

Figure 1:

Typical images of pure-solid lung cancer with air bronchogram. An air-filled bronchus is surrounded by a lung tumour that only shows consolidation without ground-grass opacity on thin-section CT scan.

Figure 1:

Typical images of pure-solid lung cancer with air bronchogram. An air-filled bronchus is surrounded by a lung tumour that only shows consolidation without ground-grass opacity on thin-section CT scan.

There were 184 patients with clinical Stage IA lung cancer with a pure-solid appearance on thin-section CT. All patients were evaluated by positron emission tomography (PET) and the maximum standardized uptake value (SUVmax) was recorded. Regarding the operation, a major lung dissection with systemic lymph node dissection was warranted for a pure-solid tumour in our institute, whereas intentional segmentectomy is now indicated for part-solid or pure-solid lung cancers 2 cm or smaller according to the Japan Clinical Oncology Group (JCOG 0802 [8]). Non-anatomical wedge resection was performed for a few elderly patients or for patients with a high cardiopulmonary risk.

The medical record of each patient was reviewed with regard to gender, sex, pack-year smoking, clinical T-status (c-T1a vs c-T1b), pleural involvement, presence of air bronchogram in the tumour, serum carcinoembryonic antigen level (ng/ml, CEA) and SUVmax on PET. The relationships between these factors and postoperative nodal status were investigated to identify significant predictors in clinical Stage IA pure-solid lung cancer. Fisher's exact test or χ2 test was used to compare two factors. Univariate and multivariate analyses were used to identify the clinical factors that predicted nodal involvement in clinical Stage IA pure-solid lung cancer. Multivariate analysis was performed by logistic regression analysis using SPSS Statistics 20 (SPSS, Inc.). Forward and backward stepwise procedures were used to determine the combination of factors that were essential for predicting the prognosis. Hosmer–Lemeshow test for a logistic regression analysis was used to assess overall model fit and precision. Reported continuous data were shown with mean and standard deviation (SD) for normality. Statistical analysis was considered to be significant when the probability value was <0.05.

RESULTS

Among 184 eligible pure-solid lung cancers, 102 patients were men and 72 were women. Patients ranged in age from 35 to 89 years, with an average of 67 years. Among them, air bronchogram was found radiologically in 58 (32%) patients. The relationships between several clinical factors and nodal involvement in patients with clinical Stage IA pure-solid lung cancer are summarized in Table 1. Postoperative nodal metastasis was found in 10 (17%) patients with air bronchogram and in 43 (34%) without air bronchogram in clinical Stage IA pure-solid lung cancer.

Table 1:

Results of a univariate analysis for predictors of nodal involvement in patients with clinical Stage IA pure-solid lung cancer

Clinical factors Number of patients Number of patients with nodal involvement (%) P-value* 
Total 184 53 (29)  
Gender 
 Male 112 36 (32) 0.21 
 Female 72 17 (24) 
Age (years) 
 >70 78 16 (21) 0.03 
 ≤70 106 37 (35) 
Pack-year smoking 
 >20 100 28 (28) 0.79 
 ≤20 84 25 (30) 
Clinical T-status 
 c-T1a 102 14 (14) <0.01 
 c-T1b 82 39 (48) 
Pleural involvement 
 Absent 107 31 (29) 0.95 
 Present 77 22 (29) 
Air bronchogram 
 Absent 126 43 (34) 0.02 
 Present 58 10 (17) 
CEA (ng/ml) 
 ≤3 92 26 (28) 0.87 
 >3 92 27 (29) 
SUVmax 
 ≤2.5 42 4 (10) <0.01 
 >2.5 142 49 (35) 
Clinical factors Number of patients Number of patients with nodal involvement (%) P-value* 
Total 184 53 (29)  
Gender 
 Male 112 36 (32) 0.21 
 Female 72 17 (24) 
Age (years) 
 >70 78 16 (21) 0.03 
 ≤70 106 37 (35) 
Pack-year smoking 
 >20 100 28 (28) 0.79 
 ≤20 84 25 (30) 
Clinical T-status 
 c-T1a 102 14 (14) <0.01 
 c-T1b 82 39 (48) 
Pleural involvement 
 Absent 107 31 (29) 0.95 
 Present 77 22 (29) 
Air bronchogram 
 Absent 126 43 (34) 0.02 
 Present 58 10 (17) 
CEA (ng/ml) 
 ≤3 92 26 (28) 0.87 
 >3 92 27 (29) 
SUVmax 
 ≤2.5 42 4 (10) <0.01 
 >2.5 142 49 (35) 

CEA: carcinoembryonic antigen; SUVmax: maximum standardized uptake value.

*P-value in χ2 test or Fisher's exact test.

The relationships between the status of air bronchogram, the mode of surgical resection and the pathological aspects are presented in Table 2. With regard to patients with air bronchogram, standard lobectomy was performed in 51 (88%) patients (6 in N1 station and 3 in N2 station), segmentectomy in 3 (5%) (nodal metastasis was not found) and non-anatomical wedge resection in 4 (7%) (1 in N2 station). One hundred and two (81%) patients without air bronchogram underwent standard lobectomy (15 in N1 station and 25 in N2 station), 12 (9.5%) underwent segmentectomy (2 in N1 station and 1 in N2 station) and 12 (9.5%) underwent non-anatomical wedge resection.

Table 2:

Relationships between the status of air bronchogram, the mode of resection and pathological aspects among clinical Stage IA pure-solid lung cancer patients

 No. of patients with air bronchogram No. of patients without air bronchogram 
Total number of patients 58 126 
Operative mode 
 Wedge resection 12 
 Segmentectomy 12 
 Lobectomy 51 102 
Lymph node dissection 
 None 13 
 Hilar only 10 14 
 Mediastinal/Hilar 45 99 
Nodal involvement 
 N0 48 83 
 N1 14 
 N2 29 
Pathology 
 Adenocarcinoma 47 83 
 Adeno-squamous cell carcinoma 
 Squamous cell carcinoma 29 
 Others 11 
 No. of patients with air bronchogram No. of patients without air bronchogram 
Total number of patients 58 126 
Operative mode 
 Wedge resection 12 
 Segmentectomy 12 
 Lobectomy 51 102 
Lymph node dissection 
 None 13 
 Hilar only 10 14 
 Mediastinal/Hilar 45 99 
Nodal involvement 
 N0 48 83 
 N1 14 
 N2 29 
Pathology 
 Adenocarcinoma 47 83 
 Adeno-squamous cell carcinoma 
 Squamous cell carcinoma 29 
 Others 11 

According to a multivariate analysis in patients with clinical Stage IA pure-solid lung cancer, the following factors significantly predicted lymph node metastasis: the presence of air bronchogram, maximum tumour dimension (mean and SD; 15.4 ± 3.4 mm) and SUVmax level (mean and SD; 4.7 ± 3.2) (P < 0.01, <0.01 and 0.03, respectively; Table 3). The result of the Hosmer–Lemeshow test was 0.290, which revealed the reliability of our model.

Table 3:

Results of a multivariate analysis for predictors of nodal involvement in patients with clinical Stage IA pure-solid lung cancer

Variable Odds ratio 95% Confidence interval P-value* 
Air bronchogram 0.28 0.11−0.71 <0.01 
Maximum tumour dimension 8.92 3.78−21.88 <0.01 
SUVmax 3.81 1.12−12.82 0.03 
Variable Odds ratio 95% Confidence interval P-value* 
Air bronchogram 0.28 0.11−0.71 <0.01 
Maximum tumour dimension 8.92 3.78−21.88 <0.01 
SUVmax 3.81 1.12−12.82 0.03 

SUVmax: maximum standardized uptake value.

*P-value in logistic regression analysis.

Based on these results, among patients with clinical T1a disease, there were 29 patients with a pure-solid lung cancer with air bronchogram, including 2 (7%) with postoperative nodal involvement. By combining these predictors, we identified subgroups that showed various frequencies of nodal involvement among clinical T1a pure-solid lung cancer (Table 4). Patients with clinical T1a pure-solid lung cancers who had both air bronchogram and SUVmax of ≥2.5 never showed nodal involvement. On the other hand, among patients with clinical T1a pure-solid lung cancer with neither of these predictors, >30% showed pathological nodal involvement. This new radiological sign as a potential predictor for negative nodal involvement indicated several accuracies as the following number; sensitivity = 16%, specificity = 100%, positive predictive value = 100% and negative predictive value = 16%.

Table 4:

Probability of the presence of nodal involvement in patients with clinical T1a pure-solid lung cancer

Subgroups Number of patients Number of patients with nodal involvement (%) P-value* 
Total clinical T1a disease 102 14 (14)  
Presence of air bronchogram and SUVmax ≦≤2.5 
 with both factors 14 0 (0) 0.03 
 with either factors 41 3 (7) 
 with neither factors 47 11 (23) 
Subgroups Number of patients Number of patients with nodal involvement (%) P-value* 
Total clinical T1a disease 102 14 (14)  
Presence of air bronchogram and SUVmax ≦≤2.5 
 with both factors 14 0 (0) 0.03 
 with either factors 41 3 (7) 
 with neither factors 47 11 (23) 

SUVmax: maximum standardized uptake value.

*P-value in χ2 test.

DISCUSSION

Important prospective studies are now underway in Japan and the USA, which consist of Phase III trials regarding the feasibility of limited resection for clinical T1a non-small-cell lung cancer (NSCLC) with a radiologically part-solid or pure-solid appearance. If the prognosis of patients who undergo limited surgery such as segmentectomy is equivalent to those who undergo lobectomy, the standard treatment procedure for resectable lung cancer may change based on the results of Lung Cancer Study Group [14]. Owing to the improvements in and widespread use of CT scan for detecting small lung cancer [15], segmentectomy is of greater importance as an option for resectable small lung cancer with N0 status [12, 13]. In contrast, the greatest concern regarding the indication for limited surgery in patients with solid lung cancer is a potential risk for postoperative nodal metastasis, despite their small size. Historically, lymph node metastasis is found in ∼15% of small lung cancers 2.0 cm or less in size. However, pathological nodal metastasis is frequently observed, especially in patients with pure-solid compared with those with part-solid tumours on thin-section CT scan [5, 11]. Furthermore, invasive lung cancer could be associated with occult lymph node metastasis, which would result in incomplete resection following limited surgical resection [16, 17]. Therefore, limited surgical resection should be applied with great caution for pure-solid tumours.

Air bronchogram is a radiological finding in which an air-filled bronchus is surrounded by fluid-filled airspaces. Several authors have confirmed the significance of the presence of air bronchogram in the primary nodules, as a predictor of pathological N0 status [7, 11, 18]. However, an intratumoural air bronchogram is mostly identified in areas with a slight, homogeneous increase in density on thin-section CT scan, such as a GGO lesion. This indicates that the main tumour structure is preserved by the alveolar and bronchiole space, which is due to a lepidic growth pattern [1]. This pattern is a radiological feature of minimally invasive lung cancer. On the other hand, the prognostic significance of the presence of air bronchogram in pure-solid lung cancer has not yet been evaluated. However, the radiological presence of air bronchogram might be useful for predicting a negative lymph node in pure-solid lung cancer, which may help to identify patients who are candidates for limited surgical resection. Thus, in the current retrospective study, we focused on the invasiveness of pure-solid lung cancer with air bronchogram from the perspective of lymph node metastasis.

In this study, a multivariate analysis revealed that the presence of air bronchogram, maximum tumour dimension and SUVmax level were significant predictors of postoperative lymph node metastasis. Furthermore, when we combined the radiological findings and the SUVmax level in 102 clinical T1a pure-solid lung cancers, 30.6% of patients with both the absence of air bronchogram and a high SUVmax showed postoperative nodal involvement, whereas none of the patients with both the presence of air bronchogram and low SUVmax showed nodal metastasis. Our studies indicate that lobectomy with a radical mediastinal lymphadenectomy should not be denied for patients with clinical Stage IA pure-solid lung cancer with a good lung function even in the presence of air bronchogram, because of their high probability of lymph node metastasis (17%) in our study. According to these results, however, the combination of the presence of air bronchogram and a low SUVmax level may be an alternative new radiological finding that is associated with a good prognosis in clinical T1a pure-solid lung cancer.

Thus, we would like to suggest that major lung resection with mediastinal lymph node dissection should be, in principle, the standard treatment for tumours that show a pure-solid appearance on thin-section CT scan. With regard to the appropriate surgical strategy for clinical T1a NSCLC with a radiologically part-solid or pure-solid appearance, the final results of the JCOG [8] and CALGB [9] trials should help thoracic surgeons decide whether or not to apply limited surgery for patients who are at low risk. However, our results indicate that the further classification of small-sized lung cancers with a pure-solid appearance is warranted to determine the optimal indications for limited surgical resection. The combination of the presence of air bronchogram and a low SUVmax level was shown to be significantly effective for predicting node-negative clinical T1a pure-solid lung cancers. Segmentectomy with a thorough lymph node dissection may be a feasible option for these patients, even for those with a pure-solid appearance.

This study was limited by a short median follow-up period, and thus, further investigations are warranted.

In conclusion, the combination of the presence of air bronchogram and a low SUVmax level was shown to be useful for predicting negative nodal involvement in clinical T1a pure-solid lung cancer. With regard to the efficacy of limited surgical resection for small lung cancers, any definitive conclusions should be based on the results of the Phase III trials JCOG.0802 and CALGB-140503.

Funding

This work was supported in part by a grant-in-aid for Cancer Research from the Ministry of Health, Labour and Welfare, Japan.

Conflict of interest: none declared.

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Author notes

Presented at the 21st European Conference on General Thoracic Surgery, Birmingham, UK, 26–29 May 2013.