A Clinicopathological Study of Resected Subcentimeter Lung Cancers: A Favorable Prognosis for Ground Glass Opacity Lesions

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1 A Clinicopathological Study of Resected Subcentimeter Lung Cancers: A Favorable Prognosis for Ground Glass Opacity Lesions Hisao Asamura, MD, Kenji Suzuki, MD, Shun-ichi Watanabe, MD, Yoshihiro Matsuno, MD, Arafumi Maeshima, MD, and Ryosuke Tsuchiya, MD Division of Thoracic Surgery, National Cancer Center Hospital, and Pathology Division, National Cancer Center Research Institute, Tokyo, Japan Background. Owing to the advent of refined chest computed tomography (CT) images with higher resolution and CT screening programs, more faint and smaller lung cancers are being discovered. These include smallsized lung cancers such as those with a subcentimeter diameter, which had never been picked up on the routine chest roentgenogram films. However their clinicopathologcial characteristics with special reference to the proper surgical mode are not fully described so far. Methods. During a 10-year period from 1991 through 2000 a total of 1,769 lung tumors were resected at the National Cancer Center Hospital, Tokyo. According to the pathology files of these patients, 51 patients had a primary tumor with the diameter of 1 cm or less. Three tumors arising in the bronchial lumina of hilum with a squamous cell carcinoma histology were excluded and the remaining 48 tumors of peripheral origin were studied. The clinicopathological features were analyzed according to three types of appearance on high-resolution CT: non-solid ground glass opacity (GGO) type ; part-solid GGO type ; and solid type. GGO is made up of homogeneous moderate increased density on CT, which cannot obscure the bronchovascular structure, whereas partly solid GGO contains a mere solid part but did not exceed 50% of the whole area. All other lesions were considered solid type. Results. For the three types of lesions, the distribution of age and sex was similar with the average age of 61 years and an almost even distribution of male/female patients. Although 6 patients had symptoms, the symptoms were not associated with the nodule itself. Twentysix patients (54%) were screen-detected (16 chest roentgenogram films and 10 CT scans) and the others were detected by incidentally taken chest roentgenogram film or CT for other reasons than nodules detected. Two squamous carcinomas were positive for sputum cytology. Preoperative cytologic/histologic diagnosis was given in 14 patients (29%). The histologic type of GGO lesion was bronchioloalveolar carcinoma in all 28 cases. In solid lesions, besides 16 adenocarcinomas 2 cases of squamous cell carcinoma, 1 case each of small cell carcinoma and carcinoid tumor was seen. Lymph node involvement was seen only in 3 patients with solid lesions (N1 in 2 patients, N2 in 1 patient). As for operative mode, the limited resection was performed for 15 GGO lesions (54%) and 4 solid lesions (20%). Tumor recurrence was seen in 2 patients with solid lesions 1 in bone and the other in locoregional lymph node, and the former died of disease. Conclusions. Among subcentimeter lung cancers, GGO lesions (both non-solid and part-solid) constitute true early lung cancers. Since they have minimal or no invasive growth, limited resection for cure is justified. Conversely the solid lesion had significant invasive features such as lymph node metastasis. Lobectomy should remain as the standard mode of surgery despite such small size. (Ann Thorac Surg 2003;76: ) 2003 by The Society of Thoracic Surgeons The pathobiological behavior and management of small-sized peripheral lung cancer has not been fully defined. Recent studies demonstrated that screening with low-dose computed tomography (CT) could improve the detection of lung cancer, especially adenocarcinomas of the peripheral location, at an earlier and potentially more curable stage [1, 2]. In some patients minute lung cancers are being found by chance on chest Presented at the Poster Session of the Thirty-ninth Annual Meeting of The Society of Thoracic Surgeons, San Diego, CA, Jan 31 Feb 2, Address reprint requests to Dr Asamura, Division of Thoracic Surgery, National Cancer Center Hospital, 1-1, Tsukiji 5-chome, Chuo-ku, Tokyo , Japan; hasamura@ncc.go.jp. CT performed for the evaluation of other lung lesions. Many of these lung cancers are more likely to have adenocarcinoma histology, especially bronchioloalveolar carcinoma (BAC). In the recent revised histologic classification of lung and pleural tumors [3] nonmucinous BAC was clearly defined as a form of adenocarcinoma with a pure bronchioloalveolar growth pattern and no evidence of stromal, vascular, or pleural invasion. The CT appearance of small-sized peripheral adenocarcinomas has been described [4 8] and adenocarcinoma that appears as localized GGO without spiculation is likely to be BAC [9]. The correlation between CT appearance and pathology has been also studied [10, 11] by The Society of Thoracic Surgeons /03/$30.00 Published by Elsevier Inc PII S (03)00835-X

2 Ann Thorac Surg ASAMURA ET AL 2003;76: SUBCENTIMETER LUNG CANCER The prognosis of very small lung cancers in relation to the CT appearance and histology has not been fully clarified however. Therefore in this retrospective study we focused on the resected lung cancers with tumor diameter of 1 cm or less and studied their pathologic features and prognoses. The clinicopathological characteristics of these lung cancers were also described in detail. The surgical management of such small-sized lung cancer seems to have more clinical importance because of the increasing discovery in our practice. Material and Methods Patients For the 10-year period from January 1991 through December 2000 there were 1,769 pulmonary resections for primary lung cancer including low-grade malignancy at the National Cancer Center Hospital, Tokyo. Among these the diameter of resected primary tumor was 1.0 cm or less in 51 patients (subcentimeter lung cancers). The location of tumor was central in the bronchial lumen in 3 patients and peripheral in the lung parenchyma in 48 patients. The clinicopathological characteristics of these 48 tumors of peripheral origin were the focus of this retrospective study. Forty-eight patients with peripheral subcentimeter lung cancer comprised 2.5% of the total. Their histologic type and TNM stage were determined according to the World Health Organization (WHO) classification [3] and UICC staging system [12], respectively. As for adenocarcinoma histology, WHO classification describes BAC as a form of adenocarcinoma with a pure bronchioloalveolar growth pattern and no evidence of stromal, vascular, or pleural invasion. If there is histologic evidence of invasive growth it is termed as adenocarcinoma with mixed subtypes. The patients medical, operative, and pathologic records were reviewed to characterize the pathobiological features of such subcentimeter lung tumors. The patients ranged in age from 43 to 77 years (median, 63). Twenty-five patients were female and 23 were male. Most of the patients underwent a physical examination, chest roentgenography, chest CT scan, bone scintigraphy, and abdominal ultrasonography for staging and the evaluation of resectability before the operation. Especially for chest CT scan, the thin-sliced, high-resolution images (2-mm thickness) of the primary lesion were taken to characterize the CT appearance besides the routine 1-cm thickness images of the entire lung and mediastinum. The clinical characteristics, diagnostic workup, surgical intervention, postsurgical pathologic evaluation, and prognosis were analyzed in detail. As for the cause of discovery, incidental chest roentgenogram and incidental CT were used to describe those taken for any other reasons than the nodule itself for the evaluation. Type of Lesions According to the CT appearance, type of lesion was categorized as GGO lesion (Figs 1 and 2) or solid lesion (Fig 3). The GGO refers to the CT appearance, in which the internal density of nodule is low and the bronchovascular structures in the GGO area still can be visualized. Conversely in the solid lesions the internal density of solid nodule is so high as to obscure the bronchovascular structures. The GGO lesion may or may not be accompanied by solid part mainly in the center of the nodule: GGO without a solid part is defined as nonsolid GGO (Fig 1) and GGO with a solid part that occupies less than 50% of the whole area, as part-solid GGO (Fig 2). In these series, if the solid component exceeds 50% of the whole area the nodule was defined as a solid lesion. Results 1017 The clinicopathological aspects of 48 subcentimeter cancers were analyzed according to the three types of lesion. Clinical Profiles of Subcentimeter Lung Cancers In terms of age and sex distributions there was no difference between non-solid GGO, part-solid GGO, and solid lesions (Table 1). One characteristic feature was that almost half of patients were female for every type of lesion. Although there were some symptoms such as cough and chest pain in 6 patients, all of these symptoms were nonspecific in nature and in no case the lung nodules were speculated to be the cause of symptoms even though the symptoms became a trigger for chest examinations. Preoperative Diagnostic Work-Up Twenty-four diagnostic workup procedures were attempted in 21 patients (44%; Table 2). For the remaining 27 patients (56%) no diagnostic intervention was performed and instead, the intraoperative examination on frozen section was done. For GGO lesions positive results as neoplasia were obtained only in 5 of 13 procedures (38%), even though CT-guided procedures were preferably used in 9 of 13 procedures. Conversely for solid lesions, positive results as malignancy were given in 9 of 11 procedures (82%). Pathological Findings The distribution of histologic type is presented in Table 3. Other histologic types than adenocarcinoma (squamous cell carcinoma, small cell carcinoma, and carcinoid tumor) were found only in solid lesions. All the GGO type of lesions were exclusively bronchioloalveolar carcinoma or adenocarcinoma with predominantly bronchioloalveolar spread. The vascular/lymphatic permeation in the nodule was seen in 2 part-solid GGO and 10 solid lesions but not in non-solid GGO. Lymph node involvement was seen only for 3 cases of solid type of lung cancer, 2 in N1 stations and 1 in N2 stations. Conversely there was no lymph node metastasis for GGO type of lesions. Among 48 patients, multiple lesions were identified in 6 (13%). Especially for GGO type of lesions, 5 of 28 patients (18%) had multiple lesions, which indicated the multicentric nature of GGO type of BAC. GENERAL THORACIC

3 1018 ASAMURA ET AL Ann Thorac Surg SUBCENTIMETER LUNG CANCER 2003;76: Fig 1. ground glass opacity lesion. Computed tomography appearance (a) and pathologic findings of lower (b) and higher (c) magnitude. Note there is no consolidation or solid part within the nodule (arrow). The pathologic diagnosis is bronchioloalveolar carcinoma. Fig 2. ground glass opacity lesion. Computed tomography appearance (a) and pathologic findings of lower (b) and higher (c) magnitude. Note there is solid component (arrow) in ground glass opacity lesions. A solid part does not exceed 50% of the whole area. The pathologic diagnosis is bronchioloalveolar carcinoma.

4 Ann Thorac Surg ASAMURA ET AL 2003;76: SUBCENTIMETER LUNG CANCER Table 1. Patient Characteristics Character Type of Lesion 1019 GENERAL THORACIC Age Average (years) Minimum (years) Maximum (years) Sex Male Female Smoking habit Nonsmoker Exsmoker Smoker Symptom Asymptomatic Symptomatic Cause of discovery Screening CXR Screening CT Incidental CXR Incidental CT Screening sputum CT computed tomography; CXR chest radiograph; GGO ground glass opacity. Surgical Intervention and Prognosis As for the mode of surgical resection, the limited resections such as wedge resection and segmentectomy were selected for GGO type of lesions so far as they were located in the outer one third of the lung parenchyma and are palpable during the surgery (Table 4). Otherwise lobectomy was preferred. As a result 15 patients (45%) Table 2. Preoperative Work-Up Diagnostic work-up Type of Lesion Fig 3. lesion. Computed tomography appearance (a) and pathologic findings of lower (b) and higher (c) magnitude. Note the vascular and bronchial convergence toward the solid nodule (arrow). The pathologic diagnosis is adenocarcinoma with mixed subtype in which the lymphatic, vascular, and stromal invasion are shown. Not performed Transbronchial 3 (2) a 1 3 (3) 7 (5) biopsy (TBB) CT-guided TBB 2 (1) 2 (1) 3 (1) 7 (3) Percutaneous (3) 3 (3) fine needle aspiration (FNA) CT-guided FNA 3 (1) (1) Sputum cytology (2) 2 (2) procedures performed 8 (4) b 5 (1) b 11 (9) b 24 (14) b a Numbers in the parentheses indicate those with positive results as malignancy. b Different procedures were performed in the same patients. Therefore, a total of 24 procedures were performed for 21 patients. CT computed tomography; GGO ground glass opacity.

5 1020 ASAMURA ET AL Ann Thorac Surg SUBCENTIMETER LUNG CANCER 2003;76: Table 3. Pathological Aspects Type of Lesion Pathology Adenocarcinoma (including BAC) Squamous cell carcinoma Small cell carcinoma Carcinoid tumor Multicentricity Solitary Multiple Vascular/lymphatic permeation Absent Present Nodal involvement N N N BAC bronchioloalveolar carcinoma; GGO ground glass opacity. with the GGO type of lesions were resected by lesser resection than lobectomy whereas only 4 patients (20%) with solid lesions were resected by limited resection for functional reasons. As for the extent of lymph node dissection, the hilum and mediastinum were explored only in 7 patients (25%) for GGO lesions whereas 15 (75%) had lymph node dissection of at least the hilum. In 10 patients (21%) a video-assisted technique (VATS) was used. However VATS had problems in localizing the tumor, its use for limited resection had limitations, and the special technique of localization (coil injection or Table 4. Surgical Interventions Type of lesion Operative mode Wedge resection Segmentectomy Lobectomy Lymph node dissection None Hilar only Mediastinal/hilar VATS Non-VATS VATS VATS video-assisted thoracic sur- GGO ground glass opacity; gery. Fig 4. Survival curves of patients with non-solid, partsolid, and solid lesions. Five-year disease-free survival rates are 100%, 100%, and 94%, respectively. barium marking) was required. There has been no surgical mortality for these series. Also there has been no serious complication. Only two prolonged air leakages were seen. There were two cases of tumor recurrence after resection exclusively for solid lesions: one bone metastasis and one locoregional lymph node metastasis. No recurrence was observed in GGO type of lesions. Of 2 patients with recurrence, 1 died of disease at 34 months and the other was still alive with disease at 38 months. Survival curves are shown in Figure 4. The median follow-up period was 1,436 days, ranging from 102 days to 3,132 days. The 5-year survival rates were 100%, 100%, and 94% for non-solid GGOs, part-solid GGOs, and solid lesions, respectively. No difference in survival was observed. Comment Owing to the advent of new technology in CT scanning such small-sized lung cancers as those of subcentimeter size are being found in a daily practice. Subcentimeter lung cancers still belong to a rare category of tumor size as lung cancer and most of them are expected to be in an early stage of the disease. In the present series however the lymph node metastasis was seen in 3 (15%) of 48 patients with subcentimeter lung cancer and furthermore 2 of them had recurrence of the tumor. These observations clearly indicated that tumor size less than 1 cm does not simply mean the absence of the tumor spread through lymphatic or hematogenous pathways and actually some of these tumors are already in the advanced stage. However the present results also demonstrated the importance of distinction between GGO-BAC type and solid type of lesions as lung cancer. Lymph node metastasis and recurrence was seen exclusively for solid lesions; that is, the character of pathology and CT for lesion (solid versus GGO) is more accurately telling of the nature of tumors as lung cancer than the size. The correlation between CT appearance as GGO and pathologic findings has been studied. The replacing growth of adenocarcinoma cells along the alveolar wall is reflected as GGO appearance with patent alveolar

6 Ann Thorac Surg ASAMURA ET AL 2003;76: SUBCENTIMETER LUNG CANCER spaces and small airways on CT. The solid part on CT represents the collapse of the alveoli, subsequent formation of fibrotic focus, and proliferation of tumor cells. Therefore the absence or small, if any, amount of solid part within the nodule on CT generally indicates the absence of invasive growth. The prognostic significance of solid part in the small-sized GGO-type of adenocarcinoma has been already realized in the previous literature [13, 14]. In the present series the GGO appearance with or without minimal solid part on CT also correlated well with the degree of invasive growth of the tumor, where only 2 cases had a tiny amount of vascular/lymphatic permeation. Since the WHO classification of lung tumors denotes BAC only for tumors without invasive growth, they were not classified as BAC because of a tiny amount of lymphatic permeation. However they can be BAC with minimal invasion or minimally invasive BAC. Actually there has been neither tumor recurrence nor tumor-related death seen for 28 patients with GGO type of lung cancer in the previous series. The prognostic significance of the GGO appearance of subcentimeter lung cancer as a completely curable disease should be stressed. Several characteristic features in GGO type of lung cancer were noted in the present study. One of the distinct features of GGO type of lung cancer is the female dominancy: 16 of 28 patients (57.1%) with the GGO type of subcentimeter lung cancer were female. The second feature was that the half of the patients were nonsmokers and only 2 patients were present smokers. The GGO type of lung cancer seemed to be less related to the tobacco smoking. The third feature was the multicentric nature. Nine of 28 GGO type lesions (32%) presented similar GGO lesions elsewhere in the lung. On the contrary, in solid lesions, multiple lesions were seen in only 1 patient. This contrast suggests that the process of tumor growth as well as tumorigenesis might be different between the two types of subcentimeter lung cancers. As for the mode of operation for T1 peripheral lung cancers, lobectomy has been the standard operation of choice since the randomized trial by the Lung Cancer Study Group in 1995 [15]. This study demonstrated that the lesser resection such as wedge/segmentectomy had three times more local recurrence than the lobectomy. However it is unfair to simply apply these results to the treatment of small-sized lung cancer as the LCSG study exclusively focused on the solid T1 tumors, in which the invasive growth within the nodule are most likely to happen. Especially for GGO type of lesions, another rationale is necessary as for the extent of surgical resection. Basically the radical resection by lobectomy and hilar/mediastinal lymph node dissection should be indicated only for tumors with present or possible risk of invasion. For tumors with no or very minimal if any invasion, the local excision might be curative enough. Considering the extremely low chance of invasive features in GGO type of small lung cancers, in which the solid part occupies less than 50% of the entire area of the nodule, the limited resection might well justified. Another rationale for choosing the limited resection for GGO type of lung cancer is the multicentric nature of the lesion. In 5 of 28 GGO types of subcentimeter lung cancers (18%), the lesions were multiple. We should expect that the surgical candidate with GGO type of lung cancer may develop another one after some years. In resecting the GGO type of lesions, the preservation of lung parenchyma has greater significance. The one important issue in the management of GGO type of lesions, especially the non-solid type of GGO, is the indolent nature of the tumor. The adenomaadenocarcinoma sequence is proposed also in the tumorigenesis in adenocarcinoma of the lung. However there has been no persuasive data as to what percentage of non-solid type of GGO lesions are indolent over a long clinical course and what percentage of GGO lesions progress to be solid lesions. Furthermore how long does it take for GGO lesions to progress to solid tumors? Indeed we anecdotally experience cases of nonsolid GGO lesions that remain the same size and appearance over some years. To date the nonsolid type of GGO with tumor diameter less than 1 cm might be managed without surgical intervention by periodic CT follow-up at proper intervals such as 4 months. Further study on CT-detected GGO type of lesions should include careful and watchful follow-up to establish the management of such minute lung cancers. Supported in part by a Grant-in-Aid for Cancer Research (Grant 11-19) from the Ministry of Health and Welfare, Japan References Henschke CI, McCauley DI, Yankelvitz DF, et al. Early lung cancer action project: overall design and findings from baseline screening. 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AJR Am J Roentgenol 2000;174: Aoki T, Nakata H, Watanabe H, et al. Evolution of peripheral lung adenocarcinomas: CT findings correlated with histology and tumor doubling time. AJR Am J Roentgenol 2000; 174: Aoki T, Tomoda Y, Watanabe H, et al. Peripheral lung adenocarcinoma: correlation of thin-section CT findings with histologic prognostic factors and survival. Radiology 2001;220: Yang Z, Sone S, Takashima S, et al. High-resolution CT analysis of small peripheral lung adenocarcinomas revealed GENERAL THORACIC

7 1022 ASAMURA ET AL Ann Thorac Surg SUBCENTIMETER LUNG CANCER 2003;76: on screening helical CT. AJR Am J Roentgenol 2001;176: International Union Against Cancer (UICC). TNM classification of malignant tumours, 6th ed. Sobin LH, Wittekind Ch, eds. New York: Wiley-Liss, Suzuki K, Yokose T, Yoshida J, et al. Prognostic significance of the size of central fibrosis in peripheral adenocarcinoma of the lung. Ann Thorac Surg 2000;69: Breathnach PS, Kwiatkowski DJ, Finkelstein DM, et al. Bronchioloalveolar carcinoma of the lung: recurrence and survival in patients with stage I disease. J Thorac Cardiovasc Surg 2001;121: Ginsberg RJ, Rubinstein LV, and the Lung Cancer Study Group. Randomized trial of lobectomy versus limited resection for T1N0 non-small cell lung cancer. Ann Thorac Surg 1995;60: Southern Thoracic Surgical Association: Fiftieth Annual Meeting The Fiftieth Annual Meeting of the Southern Thoracic Surgical Association will be held November 13 15, 2003, Bonita Springs, Florida. The Postgraduate Course will be held the morning of Thursday, November 13, 2003, and will provide in-depth coverage of thoracic surgical topics selected primarily as a means to enhance and broaden the knowledge of practicing thoracic and cardiac surgeons. John H. Calhoon, MD Secretary/Treasurer Southern Thoracic Surgical Association 633 N Saint Clair St, Suite 2320 Chicago, IL (800) 685-STSA or (312) fax: (312) stsa@stsa.org; website: by The Society of Thoracic Surgeons Ann Thorac Surg 2003;76: /03/$30.00 Published by Elsevier Inc