Ann Thorac Surg 2007;84:1675-1679. doi:10.1016/j.athoracsur.2007.03.015
© 2007 The Society of Thoracic Surgeons
Original Articles: General Thoracic
Sublobar Resection for Patients With Peripheral Small Adenocarcinomas of the Lung: Surgical Outcome is Associated With Features on Computed Tomographic Imaging
Haruhiko Nakayama, MDa,*,
Kouzo Yamada, MDb,
Haruhiro Saito, MDb,
Fumihiro Oshita, MDb,
Hiroyuki Ito, MDa,
Yoichi Kameda, MDc,
Kazumasa Noda, MDb
a Division of Thoracic Surgery, Kanagawa Cancer Center, Yokohama, Japan
b Division of Thoracic Oncology, Kanagawa Cancer Center, Yokohama, Japan
c Division of Pathology, Kanagawa Cancer Center, Yokohama, Japan
Accepted for publication March 5, 2007.
* Address correspondence to Dr Nakayama, Division of Thoracic Surgery, Kanagawa Cancer Center, 1-1-2, Nakao, Asahi-ku, Yokohama, 241-0815, Japan (Email: nakayama-h{at}kcch.jp).
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Abstract
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Background: Sublobar resection for peripheral small adenocarcinomas of the lung remains controversial. We studied the feasibility of deciding whether to perform limited pulmonary resection on the basis of preoperative images obtained by high-resolution computed tomography.
Methods: A total of 123 patients with adenocarcinoma of the lung underwent sublobar resection of clinical T1N0M0 tumors measuring 2 cm or less in diameter on high-resolution computed tomography. Patients with multiple lung cancers or a history of lung cancer or other malignancies were excluded. The remaining 63 patients were studied. All tumors were classified as "air-containing type" or "solid-density type" according to the tumor shadow disappearance rate on high-resolution computed tomography. We evaluated the surgical outcomes of sublobar resection with respect to findings on high-resolution computed tomography images.
Results: Forty-six patients had air-containing type tumors (tumor shadow disappearance rate 
50%), and 17 had solid-density type tumors (tumor shadow disappearance rate <50%). Forty-nine wedge resections and 14 segmentectomies were performed. Wedge resection was the most common procedure in patients with air-containing type tumors. Pathologically, air-containing type tumors comprised 38 bronchioloalveolar carcinomas and 8 nonbronchioloalveolar carcinomas. No patient with air-containing type tumors had recurrence after a median follow-up of 70 months (range, 21 to 133 months). Overall and relapse-free survival rates at 5 years were 95% and 100%, respectively, in patients with air-containing type tumors, as compared with 69% and 57%, respectively, in those with solid-density type tumors.
Conclusions: Sublobar resection might be an acceptable procedure for the treatment of small air-containing type adenocarcinomas of the lung on preoperative high-resolution computed tomography. However, our findings must be confirmed in larger, multicenter studies.
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Introduction
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Lobectomy has been established as the procedure of choice for most peripheral, clinical T1 N0 M0 lung cancers. This recommendation was based on the results of a randomized trial performed by the Lung Cancer Study Group, showing that sublobar resections, ie, segmental or wedge resections, had a significantly higher risk of locoregional recurrence [1]. However, increased use of computed tomography (CT) and improved scanning techniques after the 1980s, when the Lung Cancer Study Group trial was performed, have enhanced the detection rate of small cancers, leading thoracic surgeons to reassess the potential benefits of sublobar resection for small peripheral lung cancers [2–4]. Important advances have also been made in pathologic and CT evaluations of adenocarcinoma of the lung, especially bronchioloalveolar carcinoma (BAC) [5, 6].
We previously reported that the tumor shadow disappearance rate (TDR) on high-resolution CT (HRCT), defined as the ratio of the tumor area of the mediastinal window to that of the lung window, closely reflected the biologic characteristics of small peripheral adenocarcinomas of the lung. Tumors with a TDR of 50% or higher showed no lymph node involvement and rarely had microscopic invasion. Such tumors might therefore be appropriate candidates for limited pulmonary resection [7, 8]. In this study, we analyzed follow-up data in patients in whom sublobar resection was performed on the basis of HRCT findings. We focused on the outcomes of limited pulmonary resection in patients with early adenocarcinomas of the lung on radiologic evaluation.
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Patients and Methods
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Our ethics committee was informed of this retrospective study and gave their approval for publication. Individual patient consent was waived by the chairman of the ethics committee. Between July 1992 and October 2004, 329 patients with adenocarcinoma of the lung underwent complete resection of clinical T1 N0 M0 tumors measuring 2 cm or less in diameter on HRCT at our hospital. Preoperative evaluation included a detailed history and physical examination, chest radiography, CT of the chest and upper abdomen, and bone scintigraphy for staging and assessment of resectability.
Chest images were acquired with a model TCT 900S Super HELIX or X-Vigor/Real CT scanner (Toshiba Medical Systems, Tokyo, Japan). High-resolution images targeted to the tumor were obtained continuously at 120 kVp and 200 mAs, with 2-mm section thickness, pitch 1, 1- to 2-mm section spacing, 512 x 512 pixel resolution, 1-second scanning time, and a high spatial reconstruction algorithm with a 20-cm field of view. Images were photographed onto each sheet of film using the mediastinal (level, 40 HU; width, 400 HU) and lung (level, –600 HU; width, 1,600 HU) window settings. As previously reported [7, 8], we classified tumors into two types according to the TDR. Tumor shadow disappearance rate was defined as follows:
A TDR of 50% or greater was defined as "air-containing type" (Fig 1), and a TDR of less than 50% was defined as "solid-density type" (Fig 2).
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Fig 1. High-resolution computed tomographic image of air-containing type adenocarcinoma (tumor shadow disappearance rate 50%).
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Fig 2. High-resolution computed tomographic image of solid-density type adenocarcinoma (tumor shadow disappearance rate <50%).
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Among the 329 patients who underwent complete resection of small adenocarcinomas, lobectomy was performed in 206 (92 with air-containing type, 114 with solid-density type), and sublobar resection was performed in 123 (78 with air-containing type, 45 with solid-density type). Fifty-one patients who underwent sublobar resection were considered unsuitable candidates for lobectomy because of limited pulmonary function or other comorbidities. These patients were considered to have undergone compromised resections. Based on the results of lobectomy with lymph node dissection for the air-containing type tumors, which showed no lymph node involvement and rarely had microscopic invasion [7, 8], we started to perform intentional sublobar resection in patients with air-containing type tumors in 1995 after obtaining complete, written informed consent from each patient. Intentional sublobar resection was defined as wedge resection or segmentectomy for patients who were considered suitable candidates for lobectomy. Intentional sublobar resections were performed for air-containing type tumor on CT images, provided they were located in the outer third of the lung parenchyma. Wedge or segmental resection was performed on the basis of only lesion location and size, and the procedure was selected to achieve adequate resection margins. Sixty-eight patients underwent intentional sublobar resection. The other 4 patients with solid-density type tumors on HRCT underwent sublobar resection because metastatic lung cancer or low-grade malignant tumors were diagnosed on frozen section analysis during operation. Among 123 patients who underwent sublobar resection, a total of 60 patients were excluded because they had a history of previously treated cancer or malignancy of other organs (21 patients), multiple lung cancers (27 patients), or second lung cancers detected during follow-up after resection of their primary lung cancers (12 patients). The remaining 63 patients were studied retrospectively.
Tumor types on HRCT were compared with respect to pathologic findings and surgical outcomes. Pathologic findings included pathologic TNM stage, histologic type of adenocarcinoma, pleural involvement, vessel invasion, and lymphatic invasion. The histologic type of adenocarcinoma and TNM stage were determined according to the World Health Organization classification [9] and UICC staging system [10]. Pleural involvement was defined according to the Japanese Lung Cancer Society classification [11]: p0, visceral pleura is not involved by tumor; p1, tumor has reached but not invaded the visceral pleura; and p2, tumor has invaded the visceral pleura but does not involve the parietal pleura. Briefly, p0 and p1 are classified as T1 disease, and p2 as T2 disease. Survival was calculated by the Kaplan–Meier method, and differences in survival were determined by the log-rank test. Unpaired two-tailed Student’s t tests were used to compare mean values. The 
2 test was used to compare observed percentages. Differences with probability values of less than 0.05 were considered statistically significant.
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Results
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The 63 patients ranged in age from 43 to 84 years (median, 67 years) and comprised 28 men and 35 women. The clinical and pathologic findings of the patients according to tumor type on HRCT are summarized in Table 1. Eleven air-containing type tumors showed pure ground-glass opacity (GGO), defined as a hazy increase in lung attenuation without obscuring the underlying vascular markings on HRCT. Among the patients with air-containing type tumors, intentional sublobar resection was performed in 39 (85%) and compromised resection in 7. On the other hand, 15 (88%) of the 17 patients with solid-density type tumors underwent compromised sublobar resection; in the other 2 patients low-grade malignant tumors were diagnosed on frozen section analysis during operation. As for the type of surgical resection, 49 wedge resections (78%) and 14 segmentectomies (22%) were performed. Most (83%) of the patients with air-containing type tumors underwent wedge resections. Because most of the sublobar resections in the patients with solid-density type tumors were compromised procedures, wedge resection was more common than segmental resection in these patients. Lymph-node sampling was done in 8 patients with air-containing type tumors. As for the patients with solid-density type tumors, lymph-node sampling was done in 6 patients and dissection in 2. The other 9 patients (53%) with solid-density type tumors had limited cardiopulmonary reserve; lymph node exploration was considered not to be beneficial mainly because of calcified nodes, dense pleural adhesion, and hypoxemia during operation.
Histopathologically, none of the patients with air-containing type tumors had vascular invasion or pleural involvement; however, 8 (17%) were given a diagnosis of not pure BAC (adenocarcinoma with mixed subtypes) because of minimal stromal invasion. In contrast, all solid-density type tumors were non-BACs associated with high rates (47% of all solid-density type tumors) of pleural involvement or vascular invasion.
There were no serious complications after operation and no surgical mortality. Two patients with air-containing type tumors and 1 with a solid-density type tumor died of other diseases, with no evidence of recurrence. Seven patients with solid-density type tumors died of recurrent lung cancer; the first site of recurrence was locoregional in 5 patients (3 wedge resections, 2 segmentectomies) and liver metastasis in 2 (1 wedge resection, 1 segmentectomy). The sites of locoregional recurrence were pleural dissemination in 2 patients (1 wedge resection, 1 segmentectomy), pulmonary metastasis in 2 (1 wedge resection, 1 segmentectomy), and mediastinal lymph node in 1 (wedge resection). No patient with air-containing type tumors had recurrence. Overall and relapse-free survival curves are shown in Figures 3 and 4.
Median follow-up of the survivors was 70 months (range, 21 to 133 months) in patients with air-containing type tumors and 49 months (range, 25 to 112 months) in those with solid-density type tumors. Overall and relapse-free survival rates at 5 years were 95% and 100%, respectively, in patients with air-containing type tumors, as compared with 69% and 57%, respectively, in those with solid-density type tumors. Both survival rates were significantly better in patients with air-containing type tumors than in those with solid-density type tumors (p < 0.0001).
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Fig 3. Overall survival curve for patients with air-containing type (solid line; n = 46) and solid-density type (dotted line; n = 17) tumors.
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Fig 4. Relapse-free survival curve for patients with air-containing type (solid line; n = 46) and solid-density type (dotted line; n = 17) tumors.
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Comment
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Lobectomy remains the standard operation for small non–small-cell lung cancers. The role of intentional sublobar resection for these tumors should be evaluated in well-designed clinical trials. At present, there are two possible indications for intentional sublobar resection. The first is for clinically diagnosed very early lung cancers, usually defined as clinical T1 N0 M0 tumors 2 cm or less in diameter that are located in the periphery of the lung. Because lymph node metastasis accompanies approximately 15% of adenocarcinomas of this size [12], N0 status must be confirmed at operation. In most series of patients undergoing sublobar resection for clinically very early lung cancers, segmental resection is the procedure of choice to gain access to the hilar lymph nodes [2–4]. In addition, segmentectomy for confirming N0 status should be selected in the patients with adenocarcinomas of solid-density type on HRCT because nodal involvement was found in 12% of these patients [7].
The other possible indication for intentional sublobar resection is pathologically confirmed noninvasive adenocarcinoma of the lung. The histologic classification of the World Health Organization defines BAC as noninvasive adenocarcinoma showing pure lepidic growth without vascular, stromal, or pleural invasion [9]. Lymph node metastasis has not been found in patients with BAC, and cure is likely after complete resection [5]. An improved understanding of the pathologic characteristics of peripheral lung adenocarcinoma and increased use of CT scanning has led interest to focus on the correlation of CT images with the histologic features of BAC. Attempts have been made to identify CT findings that could serve as landmarks for sublobar resection [6–8, 13–18]. Bronchioloalveolar carcinoma components showing lepidic growth along alveoli, without areas of invasion, present as areas of GGO on HRCT [14]. The proportion of GGO is directly related to tumor histology and behavior. Patients with adenocarcinomas measuring 2 cm or less in which the proportion of GGO to the whole tumor area on HRCT was 50% or greater have no lymph node involvement and survive without any recurrence after resection [13, 15]. The TDR on HRCT images is also a simple and useful index for identifying early adenocarcinoma of the lung [7, 8, 16]. Visual evaluation of the GGO ratio is subject to considerable variability among examiners [18]. In contrast, evaluation of the TDR on HRCT has the advantage of simplicity and does not require the use of complex instrumentation: tumor opacity on lung window images is simply compared with that on mediastinal images [7]. Okada and colleagues [16] reported that the extent of both TDR and GGO correlate well with that of the BAC growth of adenocarcinomas; however, the TDR more strongly correlates with the BAC proportion than does the GGO ratio. Previously, we also reported that adenocarcinomas measuring 2 cm or less in diameter in which the TDR on HRCT was 50% or greater have no lymph node involvement and rarely show microscopic invasion. These findings suggested that sublobar resection might be an appropriate approach for the management of such tumors [7, 8]. Few studies have evaluated the outcomes of sublobar resections performed on the basis of HRCT characteristics other than pure GGO. We therefore retrospectively investigated surgical outcomes in patients who underwent sublobar resections according to findings on preoperative HRCT images.
The outcomes of sublobar resection for these possibly indolent tumors should be assessed on the basis of long-term disease-free survival and recurrence patterns. We therefore excluded patients who had a history of previous primary lung cancers or other malignancies, as well as those with multiple lung cancers. About half of the initially screened patients with these small-sized adenocarcinomas of the lung who underwent sublobar resection were excluded. In our series, all patients with air-containing type tumors, excluding 2 who died of other diseases, survived with no evidence of recurrence, despite incomplete lymph node exploration. Sublobar resections for these air-containing type tumors did not require lymph node sampling or dissection, and the extent of resection depended on only lesion size or location. In addition, not all of the air-containing type lesions were diagnosed as BAC, whereas 8 (17%) were diagnosed as mixed adenocarcinomas with minimal stromal invasion. Those patients who had BAC with focal or minimal invasion survived with no relapse for 41 to 82 months (median, 51 months) after operation. This result suggested that some patients with radiologic evidence of early lung adenocarcinoma on the basis of TDR show minimal invasion on pathologic examination and might be cured by sublobar resection. However, this point remains controversial, and further studies are needed.
In conclusion, our results suggest that the TDR on HRCT images is a simple and useful variable for identifying small adenocarcinomas indicated for limited pulmonary resection. The outcome of sublobar resection for air-containing type lesions may be favorable in patients with curable disease. Larger, multicenter trials are needed to identify HRCT images that more precisely reflect the biologic behavior of these tumors and to assess the surgical outcomes of sublobar resection indicated on the basis of these HRCT images.
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Acknowledgments
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This work was supported in part by a grant-in-aid for cancer research (grant 15-1) from the Ministry of Health, Labor and Welfare, Japan.
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Abstract
Introduction
