Results of Wedge Resection for Focal Bronchioloalveolar Carcinoma Showing Pure Ground-Glass Attenuation on Computed Tomography

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1 Results of Wedge Resection for Focal Bronchioloalveolar Carcinoma Showing Pure Ground-Glass Attenuation on Computed Tomography Shun-ichi Watanabe, MD, Toshio Watanabe, MD, Kazunori Arai, MD, Takahiko Kasai, MD, Joji Haratake, MD, and Hiroshi Urayama, MD Departments of Thoracic and Vascular Surgery, Radiology, and Pathology, Kurobe City Hospital, Kurobe, Japan Background. Focal bronchioloalveolar carcinoma (BAC) showing pure ground-glass attenuation (GGA) on thinsection computed tomography (CT), which is considered to be an early-stage adenocarcinoma, has been diagnosed with increasing frequency due to the development and spread of the helical CT scanner. We discussed the appropriateness of limited resection for this type of lesion. Methods. Between July 1996 and June 2001, 17 patients with localized BAC showing pure GGA (GGA without central scar formation) on thin-section CT underwent limited pulmonary resections. The mean patient age was years old. Among these patients, four tumors were detected in a CT mass-screening program and the others were incidentally detected on CT during follow-up for other diseases. Fourteen patients underwent thoracoscopic wedge resection, and 3 underwent segmentectomy because of tumor location. Results. The mean tumor diameter was mm. On pathological examination, all tumors showed a pure bronchioloalveolar growth pattern and no evidence of stromal, vascular, or pleural invasion. The median follow-up time was 32.0 months, with no cancer death or relapse to date. Conclusions. Focal BAC showing pure GGA on thinsection CT is peripheral in situ adenocarcinoma. Wedge resection by VATS is considered to be an appropriate treatment for this type of lung cancer. It can be a minimally invasive complete resection for this type of early cancer, and offer the best chance for long-term survival and good quality of life. (Ann Thorac Surg 2002;73:1071 5) 2002 by The Society of Thoracic Surgeons Bronchioloalveolar carcinoma (BAC) is one of subtypes of adenocarcinoma, and has a broad spectrum of radiographic and pathological appearances [1 3]. Among the various types of BAC, the diagnosis of focal BAC, which is chest film negative and showing groundglass attenuation (GGA) on thin-section computed tomography (CT), has been increasing with the development and spread of the helical CT scanner. Shimosato and colleagues [4] demonstrated that the characteristics of the central fibrosis (scar) were probably more important than the size of tumor for estimating the prognosis of patients with peripheral adenocarcinoma of the lung. Suzuki and colleagues [5] reported that the size of central fibrosis was a significant prognostic factor in adenocarcinoma. Therefore a focal area of pure GGA (GGA without central scar formation) on thin-section CT seems to be an early sign of BAC [6, 7]. We considered that this type of focal lesion could be peripheral in situ adenocarcinoma and a candidate for pulmonary wedge resection. This report describes the results and discusses Accepted for publication Dec 11, Address reprint requests to Dr Shun-ichi Watanabe, Department of Thoracic and Vascular Surgery, Kurobe City Hospital, Kurobe , Japan; shunuk@aol.com. the appropriateness of wedge resection by videoassisted thoracoscopic surgery (VATS) as a minimally invasive and curative surgery for this type of peripheral adenocarcinoma. Patients and Methods Patients Between July 1996 and June 2001, 17 patients with focal peripheral BAC showing pure GGA on thin-section CT underwent pulmonary resection. GGA was defined as a hazy increased attenuation of the lung without obscuration of the underlying vascular marking [8]. Preoperative Investigations When a round-shaped GGA without central scar formation was detected on thin-section CT (Fig 1), repeat CT was performed 3 months later on suspicion of focal BAC. If the tumor size had increased or was unchanged, surgery was planned because of the high probability of BAC (Fig 2). According to this management schedule, 20 patients agreed to surgery and underwent pulmonary resection. Among them, 17 patients were histopathologically revealed to have noninvasive BAC and 3 to have 2002 by The Society of Thoracic Surgeons /02/$22.00 Published by Elsevier Science Inc PII S (01)

2 1072 WATANABE ET AL Ann Thorac Surg WEDGE RESECTION FOR BAC 2002;73: tumor markers (carcinoembryonic antigens [CEA] and sialyl-sse1 [SLX]) examination every 3 months, and helical CT scan of the chest and upper abdomen every 6 months. All values were expressed as means standard deviation (SD) throughout the article. Fig 1. Typical thin-section CT finding of focal BAC showing pure GGA appearance, in which vessels can be seen. GGA was defined as a hazy increased attenuation of the lung without obscuration of the underlying vascular marking. (BAC bronchioloalveolar carcinoma; CT computed tomography; GGA ground-glass attenuation.) atypical adenomatous hyperplasia (AAH). Percutaneous biopsy was not attempted in our series. Preoperative staging included CT of the chest and abdomen in all patients, and there was no cervical mediastinoscopy employed. All tumors were indeterminate before surgery. The diagnosis was confirmed by frozen-section examination intraoperatively. Surgical Procedure When the tumors were separate from the pleura, CTguided marking of the tumor was performed immediately before surgery using a marking kit. Under general anesthesia, 14 patients underwent wide-wedge resection by VATS with a surgical margin of at least 15 mm in the collapsed lung, and 3 underwent segmentectomy through open thoracotomy because of tumor location. When the tumor is located in the peripheral lung, we confirm the lesion by touching with a finger through the port-site wound to secure the surgical margin of wedge resection. No systematic nodal dissection or nodal sampling was performed intraoperatively. Surgical specimens were submitted for further examination, and the surgical procedure was finished regardless of the results of frozen-section examination. The maximal diameter of the tumor was measured by surgeons intraoperatively on the fresh resected specimen (Fig 3A). Follow-up All patients in this study were followed at the outpatient clinic by chest roentgenogram every 2 months, serum Results Patient Characteristics The patient characteristics are shown in Table 1. The patient population consisted of 4 men and 13 women with a mean age of years (range 39 to 72) at the time of surgery. All patients were asymptomatic and detected by chest CT scan. Among these patients, four lesions were detected in a CT mass-screening program, which we started on May 1997, and the remaining 13 patients were incidentally detected on CT during follow-up for other diseases. Fourteen (82.4%) patients had no smoking history. The lobe of origin was the right upper lobe in 4 patients, right middle lobe in 1, right lower lobe in 6, left upper lobe in 4, and left lower lobe in 2. Tumor diameter ranged from 5 to 12 mm with a mean value of mm. Sixteen out of 17 (94.1%) lesions measured 10 mm or less, and only one lesion was more than 10 mm. Pathological Examination On pathological examination, all tumors showed a pure bronchioloalveolar growth pattern with no evidence of Fig 2. Management schedule after detection of pure GGA lesion. When a round-shaped GGA without central scar formation was detected on thin-section CT as shown in Figure 1, repeat CT was performed 3 mo later on suspicion of focal BAC. If the tumor size had increased or was unchanged, surgery was planned because of the high probability of BAC. (BAC bronchioloalveolar carcinoma; CT computed tomography; GGA ground-glass attenuation.)

3 Ann Thorac Surg WATANABE ET AL 2002;73: WEDGE RESECTION FOR BAC 1073 periods have ranged from 4 to 62 months, the median follow-up period was 32.0 months. No postoperative death (including other causes of death) and cancer relapse has been detected to date. Comment Bronchioloalveolar carcinoma is considered to be one of the adenocarcinoma subtypes. The increasing incidence of BAC seems to be contributing to the dramatic rise in the number of cases of adenocarcinoma [9]. Although the original report of BAC described patients with advanced bilateral pulmonary tumors, more recent studies on BAC have focused on patients with early stage disease [10, 11]. The pathologic features of BAC are the presence of aerogenous spread and advance along the alveolar wall [12]. Eto and colleagues [13] classified BAC into two subtypes. In the early development of peripheral adenocarcinoma, there is preservation of the elastic network of the stroma due to contraction and thickening of the alveolar walls (type 1). As the tumor grows, the elastic framework is disrupted, indicating stromal invasion (type 2). Based on the clinicopathologic findings and outcome, type 1 tumor is considered in situ peripheral lung adenocarcinoma. In this article, we focused on the appropriateness of minimally invasive pulmonary resection for this type of lesion. As for the detection of this lesion, all patients participating in this study were asymptomatic and detected by CT. Early detection and treatment are essential for improving the survival of lung cancer patients. In our series, four lesions were detected by a CT mass-screening pro- Table 1. Patients Characteristics Fig 3. (A) Surgical specimen and focal bronchioloalveolar carcinoma lesion (arrow). (B,C) Microscopic examination showing pure bronchioloalveolar growth pattern and no evidence of stromal, vascular, lymphatic, or pleural invasion (hematoxylin and eosin stain; B: 20, C: 400 original magnifications). stromal, vascular, lymphatic, or pleural invasion (Fig 3B and 3C). Prognosis All patients were discharged from hospital within 3 days after surgery without any complications. The follow-up Number of patients 17 Sex (M/F) 4/13 Age (y) Range Mean Symptoms Yes 0 No 17 Detection of the tumor CT mass-screening 4 Incidental 13 Smoking history No 13 Current or ex-smoker 4 Location of primary tumor Right upper lobe 4 Right middle lobe 1 Right lower lobe 6 Left upper lobe 4 Left lower lobe 2 Tumor diameter (mm) Range 5 12 Mean CT computed tomography.

4 1074 WATANABE ET AL Ann Thorac Surg WEDGE RESECTION FOR BAC 2002;73: gram which we started in Sone and colleagues [14] reported that CT screening was an important investigation for the detection of early peripheral lung cancer. Patients with BAC in our series tended to be younger at diagnosis, were more likely to be female, and less likely to be cigarette smokers when compared with other patients with non-small cell lung cancer as previously described [10, 12, 15]. A CT screening program widely performed regardless of smoking history, age, or gender may be effective to detect early BAC and consequently reduce the death rate of lung cancer. Lobectomy and regional lymph node dissection, termed radical lobectomy, has been a standard surgery for lung cancer since Cahan [16] reported the first 48 cases successfully undergoing this procedure in However, this procedure can be an excessive resection for early lesions. Although sleeve bronchial resection has been accepted as a standard procedure for hilar early cancer, there is no standard limited resection for peripheral early cancer established to date. As the number of early-stage peripheral lung cancers is increasing, we consider that the surgical procedure for lung cancer should be tailored to each case. Trials of limited resection for lung cancer have already been undertaken [11, 17]. In lung parenchyma-preserving surgery, however, increased rates of recurrence and cancer death in the clinical stage I patients undergoing segmentectomy or wedge resection compared with those in patients undergoing lobectomy have been reported [18]. Therefore, sufficient criteria for limited resection have been explored in clinical stage I disease [19]. In this study, every BAC showing focal GGA on thin-section CT was revealed to be in situ adenocarcinoma by histopathological examination. We consider that wide-wedge resection by VATS would be a minimally invasive and curative surgery for this type of lung cancer as well as lung biopsy for indeterminate lesion. Noguchi and colleagues [20] classified small adenocarcinoma into six subgroups (type A to F) according to the clinicopathological characteristics. Two of these six types, named type A (localized bronchioloalveolar carcinoma [LBAC]) and type B (LBAC with foci of alveolar structural collapse) showed a 100% 5-year survival after lobectomy with systematic nodal dissection and no lymph node metastasis. These types correspond to BAC without central scar formation as shown here and can be candidates for limited resection. This classification, however, was made postoperatively by microscopic pathological examination of tumors fixed in 10% formalin and embedded in paraffin after lobectomy. Therefore this technique is not very helpful in the surgical setting. This is the reason why we employed thin-section CT findings to preoperatively select candidates for limited resection in this study. Among 20 patients operated upon for pure GGA lesion in our series, three patients were histopathologically revealed to be AAH as described. It appears to be difficult to discriminate AAH from noninvasive BAC preoperatively, because both lesions show the similar thin-section CT finding, focal round-shaped GGA without solid component. AAH was classified as a preinvasive lesion of adenocarcinoma by the World Health Organization in 1998 [21], for many investigators had provided evidence of a sequence from AAH to adenocarcinoma [22, 23]. Although AAH is not classified as a malignant lesion, wedge resection of this potential precursor lesion from which adenocarcinoma arises also seems to be an acceptable option. The prognosis for BAC was originally thought to be poor. The lungs are the predominant sites of BAC recurrences, especially when BAC is of the pneumonic type [24]. However, more recent reports demonstrate a good prognosis for localized tumors [4, 25]. Breathnach and colleagues [10] described that stage I BAC are fourfold less prone to the development of extrathoracic disease. Our good results of wedge resection for BAC as described here support their opinion. In conclusion, this study illustrates that focal BACs showing pure GGA on thin-section CT were histopathologically proven to be in situ adenocarcinomas. Wedge resection by VATS will achieve complete surgical resection of this type of early cancer, and offer the best chance for long-term survival and good quality of life. Detection and treatment of pure GGA lesions may improve a dismal prognosis of lung cancer. References 1. Dumont P, Gasser B, Rouge C, Massard G, Wihlm J-M. Bronchial carcinoma. Histopathologic study of evolution in a series of 105 surgically treated patients. 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5 Ann Thorac Surg WATANABE ET AL 2002;73: WEDGE RESECTION FOR BAC 1075 its unique clinicopathologic features. Cancer 1994;73: Eto T, Suzuki H, Honda A, Nagashima Y. The changes of the stromal elastic framework in the growth of peripheral lung adenocarcinomas. Cancer 1996;77: Sone S, Takashima S, Li F, et al. Mass screening for lung cancer with mobile spiral computed tomography scanner. Lancet 1998;351: Grover FL, Piantadosi S, The Lung Cancer Study Group. Recurrence and survival following resection of bronchioloalveolar carcinoma of the lung the Lung Cancer Study Group experience. Ann Surg 1989;209: Cahan WG. Radical lobectomy. J Thorac Cardiovasc Surg 1960;39: Okada M, Yoshikawa K, Hatta T, Tsubota N. Is segmentectomy with lymph node assessment an alternative to lobectomy for non-small cell lung cancer of 2 cm or smaller? Ann Thorac Surg 2001;71: Ginsberg RJ, Rubenstein LV, Lung Cancer Study Group. 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Bronchioloalveolar carcinoma. Results of surgical treatment and prognostic factors. Chest 1998;114: Higashiyama M, Kodama K, Yokouchi H, et al. Prognostic value of bronchiolo-alveolar carcinoma component of small lung adenocarcinoma. Ann Thorac Surg 1999;68: INVITED COMMENTARY The paper by Watanabe and colleagues reflects an interesting and important trend in the surgical management of patients with non-small cell lung cancer (NSCLC). The evolution of the surgical management of patients with NSCLC is well known. Pneumonectomy, introduced in 1933, was displaced by lobectomy approximately a decade later. Lobectomy, it was shown, yielded cancer survival results equal to pneumonectomy with considerably less morbidity and mortality. Since that time, lobectomy has withstood challenges from open and videoassisted thoracic surgery (VATS) segmental and wedge resections, and remains the standard lung resection for patients with NSCLC, as it continues to yield the best combination of survival and local control rates of any resection technique. The treatment algorithm in the study by Watanabe and colleagues, which advocates VATS wedge resection for patients with focal bronchioalveolar lung cancer, would at first seem to defy thoracic surgical historical experience. Rather than ignoring the lessons of the past, however, this treatment protocol is a result of two important developments in the present. The first of these is a developing understanding of the pathogenesis of peripheral glandular lung cancers. Rather than developing de novo, it is now believed that adenocarcinoma, like central bronchogenic tumors, develop through a well-defined sequence: metaplasia-dysplasiacarcinoma in situ-invasive carcinoma. Acceptance of this new pathogenesis model has important therapeutic implications. If lung adenocarcinoma arises through a well-defined sequence, and if this progression can be identified and interrupted, then invasive adenocarcinoma could be prevented or resected at its earliest stage. This is exactly what the current study is advocating. Early surgical resection for preinvasive lung adenocarcinoma would, therefore, be analogous to prophylactic esophagectomy for high grade dysplasia in patients with Barrett mucosa. The second new development is in computed tomographic (CT) imaging. Spiral CT scanning has now achieved such high resolution that not only can small lung cancers be detected, but also early, pre-invasive peripheral glandular lung pathology. The accurate correlation between CT and pathologic findings, for in situ bronchioalveolar adenocarcinoma, is clearly cited in this study by Watanabe and colleagues. For the last 70 years, thoracic surgeons have worked to determine the optimal therapy to treat lung cancers which are already well-established by the time of initial presentation. We have compared and refined resection techniques, and developed combination therapy protocols to treat patients with locally advanced-stage disease. However, this study suggests that the next major development in NSCLC treatment will come from advances in our understanding of lung tumor pathogenesis, and our increasing ability to identify patients at an early or preinvasive stage of disease. Richard F. Heitmiller, MD Chief of Surgery Union Memorial Hospital 3333 North Calvert St, Suite 610 Baltimore, MD richardhe@helix.org by The Society of Thoracic Surgeons /02/$22.00 Published by Elsevier Science Inc PII S (02)