ANTICANCER RESEARCH 28 : 3153-3156 (2008)

Diagnostic Procedures for Small Pulmonary Nodules Detected by Mass-screening KOUJI KANEMOTO 1, HIROAKI SATOH 2, HIROICHI ISHIKAWA 1, KATSUNORI KAGOHASHI 2, KOICHI KURISHIMA 2 and KIYOHISA SEKIZAWA 2

1Division of Respiratory Medicine, Tsukuba Medical Center Hospital; 2Division of Respiratory Medicine, Institute of Clinical Medicine, University of Tsukuba, Tsukuba-city, Ibaraki, Japan

Abstract. Background: A retrospective study was performed peripheral pulmonary nodules. But open is now to evaluate the diagnostic procedures performed in small largely being replaced by video-assisted thoracoscopic peripheral pulmonary nodules that were detected at mass surgery (VATS) biops y (5), which ha s the advantage of screening. Patients and Methods: The medical records were being less invasive than open lung biopsy. Positron emission reviewed of patients who had peripheral pulmonary nodules tomography (PET) using fluorodeoxyglucose is useful in ≤20 mm detected by mass screening between 1995 and 2007. assessing the likelihood of malignancy in a pulmonary Results: A total of 41.7% of patients were diagnosed based nodule, particularly if the nodule is solid and 10 mm or on pathological findings of specimens obtained by larger in diameter (6). However, the sensitivity of PET in bronchoscopic procedures ( group), while the adenocarcinoma with alveolar cell features is questioned (7). remainder were diagnosed using specimens obtained by Therefore, obtaining pathological specimens from peripheral surgical biopsy (surgery group). The median diameter of lung pulmonary nodules is still essential for establishing the tumors in the bronchoscopy group was 20 mm, while that in correct diagnosis. the surgery group was 15 mm. Of patients with in In this study, we evaluated the diagnostic procedures the bronchoscopy group 22.9% had tumors ≤15 mm, however, performed in peripheral pulmonary nodules 20 mm or 63.8% of patients in the surgery group had tumors ≤15 mm. smaller that were detected at population-based mass Conclusion: Pulmonary nodules ≤15 mm in diameter found screening for lung cancer. in specimens obtained by bronchoscopic procedures should be diagnosed by surgical biopsy. Patients and Methods

Screening for lung cancer with conventional chest The medical records of all patients who underwent diagnostic radiography or computed tomography (CT) can detect cancer procedures at the University of Tsukuba Hospital and Tsukuba Medical Center Hospital between January 1995 and August 2007 at an earlier stage (1-3) but may also result in overdiagnosis. were retrospectively reviewed. The diagnostic procedures used to The size of a pulmonary nodule seems to be one of the most obtain pathological specimens were evaluated in patients with the important indicators of the likelihood of malignancy. The following criteria: (ⅰ) peripheral pulmonary nodule 20 mm or vast majority of nodules more than 20 mm in size are smaller in size detected by population-based mass screening; (ⅱ) malignant, compared to a 50% rate of malignancy in all presence of a single circumscribed pulmonary nodule completely nodules 20 mm or smaller (4). surrounded by aerated lung without associated abnormalities Pathological findings of transbronchial biopsy specimens (including atelectasis, pneumonia, satellite lesions, or cavity); (ⅲ) lesions that were not visible endoscopically (no endobronchial of the lung have contributed to definitive diagnosis of lesions or extrinsic compression); (ⅳ) availability of standard chest pulmonary lesions. In some undiagnosed patients, open lung radiographs and CT scans; (ⅴ) availability of fluoroscopically- biopsy has been conventionally conducted to diagnose small guided brushing, washing and transbronchial ; and (ⅵ) a final diagnosis based on findings of the pathological features of biopsy specimens obtained by bronchoscopic procedures, VATS biopsy, or open lung biopsy. Correspondence to: Hiroaki Satoh, MD, Division of Respiratory All bronchoscopy procedures were performed by pulmonary Medicine, Institute of Clinical Medicine, University of Tsukuba, fellows at our hospitals under pulmonary faculty supervision. Tsukuba-city, Ibaraki, 305-8575, Japan. Tel: +81 298533210, Fax: Fiberoptic bronchoscopes ( e.g. model BF P20D, BF 1T10, +81 298533320, e-mail: [email protected] Olympus, Tokyo, Japan) along with brushes and biopsy forceps supplied with them were used. All procedures were performed under Key Words: Diagnosis, lung cancer, pulmonary nodule, mass- local anesthesia. After complete inspection of the bronchial tree, the screening, bronchoscopy, video-assisted thoracoscopic surgery. peripheral nodules were visualized using fluoroscopy, and

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Table Ⅰ. Characteristics of patients. Table Ⅱ. Differences between patients diagnosed based on pathological findings of specimens obtained by bronchoscopic procedures No. of patients 108 (bronchoscopy group) and those diagnosed based on pathological findings of specimens obtained by surgical procedures (surgery group). Age (years) median: 62, range: 18-83 Bronchoscopy Surgery p-Value Gender group group Male 63 Female 45 No. of patients 45 63 Bronchoscopy group 45 Tumor diameter (mm) Surgery group 63 Median 20 15 0.0002 Thoracoscopic lung biopsy 57 Range 5-20 5-20 Open lung biopsy 6 Pathological diagnosis Lung cancer patients with Primary lung cancer 79 tumor ≤15 mm 22.9% 63.8% 0.0002 Adenocarcinoma of the lung 61 Other 18 Inflammatory nodule 21 Metastatic lung cancer 3 For primary lung cancer lesions, the diagnostic efficiency Intrapulmonary lymph node 3 of bronchoscopic procedures from lesions located in the Benign lung tumor 1 upper lobes tended to be lower (24 out of 57 patients, Sarcoidosis 1 42.1%) than that from lesions in the other parts of the lung (11 out of 22 patients, 50.0%), but this difference was not statistically significant ( p= 0.5266). brushings, washings and transbronchial biopsies were performed. The indication for VATS or open lung biopsy was the presence of Discussion bronchoscopically non-diagnosable peripheral nodules. All the biopsy specimens were reviewed by staff in our hospitals. Statistical significance was determined by using Mann-Whitney Conventional chest radiography and CT scan have been used U- test and Chi-square test with statistically significant results for screening in lung cancer, but in some cases with small reported for p less than 0.05. peripheral nodules, there have been difficulties in reaching a final diagnosis. PET is useful in assessing the likelihood of Results malignancy in a pulmonary nodule, particularly if the nodule is solid and 10 mm or larger in diameter (6). However, the Among the patients who underwent diagnostic procedures in sensitivity of PET in adenocarcinoma with alveolar cell our hospitals during the study period, 108 patients met the features is questionable (7). Therefore, obtaining pathological inclusion criteria (Table Ι). The median age of the 108 specimens from the small peripheral nodules is still essential patients was 62 years (range: 18-83 years) and 63 were men. for establishing the correct diagnosis. Pathological findings Of the 108 patients, 45 (41.7%) were diagnosed based on of transbronchial biopsy specimens have contributed to pathological findings of biopsy specimens obtained by definitive diagnosis of pulmonary lesions. In undiagnosed bronchoscopic procedures (bronchoscopy group), and 63 cases, open lung biopsy and VATS have been used to obtain patients were diagnosed based on pathological features of tissues containing the lesions, which were used for biopsy specimens obtained by VATS or open lung biopsy intraoperative pathological diagnosis. However, these surgical (surgery group). Among the 108 patients, conditions included procedures require general anesthesia. On the other hand, primary lung cancer in 79 (73.1%) patients, of whom 61 bronchoscopy is a safe procedure with a low complication (77.2%) had adenocarcinoma. rate and allows the examination of the central as well as The median diameter of primary lung cancer in the peripheral lesions. Therefore, bronchoscopy is considered as bronchoscopy group was 20 mm (range: 5-20 mm), while the first diagnostic step in many hospitals. However, some that in the surgery group was 15 mm (range: 5-20 mm). previous studies on peripheral lung nodules have consistently There was a significant difference in tumor diameter between shown that lesion size influences the diagnostic accuracy of the two groups ( p= 0.0002, Mann-Whitney U- test) (Table Ⅱ). bronchoscopy (8, 9). In particular, the yield of bronchoscopy Eight (22.9%) out of 35 patients with lung cancer in the is low in lesions measuring 20 mm or smaller located in the bronchoscopy group had tumors ≤15 mm in diameter. On the outer third of the lung (10). In the diagnosis of small other hand, 30 (63.8%) out of 47 patients with lung cancer in peripheral pulmonary nodules not diagnosable by the surgery group (44 primary and 3 metastatic lung cancer) had bronchoscopic procedures, VATS is being increasingly used. tumors ≤15 mm. There was a statistical ly significant difference The accuracy and the low morbidity of the technique are the in these proportions ( p= 0.0002, Chi-square test) (Table Ⅱ). reason for its increasing use (11). In the present study, we

3154 Kanemoto et al : Diagnosis of Small Pulmonary Nodules confirmed that the size of a lesion is the most important 3 Maeno T, Satoh H, Ishikawa H, Yamashita YT, Kamma H, determinant of diagnostic yield in bronchoscopic procedures Ohtsuka M and Hasegawa S: Does earlier detection of lung when evaluating small peripheral nodules. We also showed cancer on mass screening improve outcome in younger and middle-age patients? Oncol Rep 5: 1217-1219, 1998. that lung tumors in the bronchoscopy group were larger than 4 Shure D and Fedullo PF: Transbronchial needle aspiration of those in the surgery group. The efficiency of bronchoscopic peripheral masses. Am Rev Respir Dis 128 : 1090-1092, 1983. procedures was particularly low in 15 mm or smaller 5 Mitruka S, Landreneau RJ, Mack MJ, Fetterman LS, Gammie J, pulmonary nodules. Bartley S, Sutherland SR, Bowers CM, Keenan RJ, Ferson PF Clinically, percutaneous fine-needle aspiration biopsy is and Weyant RJ: Diagnosing indeterminate pulmonary nodules: also a well-established technique for diagnosis (12). CT- percutaneous biopsy versus thoracoscopy. Surgery 118 : 676-684, guided percutaneous needle aspiration could be considered 1995. 6 Gould MK, Maclean CC, Kuschner WG, Rydzak CE and Owens as a diagnostic step, especially in very small, peripheral and DK: Accuracy of positron emission tomography for diagnosis of easily accessible lesions. However, this technique carries a pulmonary nodules and mass lesions: a meta-analysis. JAMA high risk of complications such as and may 285 : 914-924, 2001. also be difficult to conduct depending on the exact location 7 Cheran SK, Nielsen ND and Patz EF Jr: False-negative findings of the lesion. In addition, the diagnostic yield for ground- for primary lung tumors on FDG positron emission tomography: glass opacity-dominant lesions is not significantly better than staging and prognostic implications. Am J Roentgenol 182 : for solid-dominant lesions (13). Moreover, tumor cell 1129-1132, 2004. 8 Wallace JM and Deutsch AL: Flexible fiberoptic bronchoscopy implantation along the needle tract is an extremely rare but and percutaneous needle lung aspiration for evaluating the potential complication of this technique (14, 15). During the solitary pulmonary nodule. Chest 81 : 665-670, 1982. study period, therefore, percutaneous fine-needle aspiration 9 Chechani V: Bronchoscopic diagnosis of solitary pulmonary biopsy was not performed in any of our patients whose nodules and lung masses in the absence of endobronchial pulmonary nodule was 20 mm or smaller in size. abnormality. Chest 109 : 620-625, 1996. Several previous studies described the characteristics of 10 Baaklini WA, Reinoso MA, Gorin AB, Sharafkaneh A and Manian malignant solitary nodules (16-18). The presence of an P: Diagnostic yield of fiberoptic bronchoscopy in evaluating solitary pulmonary nodules. Chest 117 : 1049-1054, 2000. irregular margin, specula, convergence of the surrounding 11 Hau T, Forster E, Gandawidjaja L and Heemken R: structure and the involvement of vessels was observed more Thoracoscopic pulmonary surgery: indications and results. Eur frequently in malignant nodules than in benign nodules more J Surg 162 : 23-28, 1996. than 20 mm in diameter (16), although these characteristics 12 Collins CD, Breatnach E and Nath PH: Percutaneous needle may not always be observed in very small malignant tumors. biopsy of lung nodules following failed bronchoscopic biopsy. In conclusion, we confirmed that lesion size is one of the Eur J Radiol 15 : 49-53, 1992. most important determinants of the yield of bronchoscopic 13 Shimizu K, Ikeda N, Tsuboi M, Hirano T and Kato H: Percutaneous CT-guided fine-needle aspiration for lung cancer procedures. The yield of bronchoscopic procedures is smaller than 2 cm and revealed by ground-glass opacity at CT. particularly low in 15 mm or smaller nodules in the Lung Cancer 51 : 173-179, 2006. peripheral lung. Mass screening resulted in overdiagnosis 14 Lalli AF, McCormack LJ, Zelch M, Reich NE and Belovich D: in some patients, however, peripheral pulmonary nodules Aspiration biopsies of chest lesions. 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