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Ann Thorac Surg 2003;76:350-355
© 2003 The Society of Thoracic Surgeons
a Department of General Thoracic Surgery, Shizuoka Saiseikai General Hospital,Shizuoka Japan
b Department of Pathology, Shizuoka Saiseikai General Hospital,Shizuoka, Japan
Accepted for publication February 12, 2003.
* Address reprint requests to Dr Kondo, Department of General Thoracic Surgery, Shizuoka Saiseikai General Hospital, Oshika 1-1-1, Shizuoka 422-8021, Japan
e-mail: d130893{at}siz.saiseikai.or.jp
| Abstract |
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METHODS: Clinicopathologic studies were performed in 57 patients with peripheral lung adenocarcinomas of 10 mm or less in diameter. Outcomes were compared with two other groups that consisted of 32 patients with adenocarcinomas between 11 and 15 mm in diameter and 35 patients with adenocarcinomas between 16 and 20 mm in diameter. Tumors were curatively resected between 1992 and 2002.
RESULTS: The mean age was 61.7 years. The following three features were more frequent: female sex (78.9%), nonsmokers (77.2%), and cases with carcinoma detected by computed tomography despite negative chest radiography (96.5%). Negative lymphatic invasion (94.7%) was significantly higher. Three cases showed lymphatic invasion that was classified as types E or F, according to Noguchis classification. There were no cases of lymph node metastasis, pleural involvement, or intrapulmonary metastasis. Well-differentiated type was in 93.0%. Types A and B, which are noninvasive alveolar replacement-type adenocarcinomas, were significantly dominant (86.0%). The 5-year postoperative survival rate was 97.3%, which was significantly better than in the other two groups (75.5%, 78.1%).
CONCLUSIONS: Histopathologic features of most peripheral lung adenocarcinomas of 10 mm or less in diameter were types A and B. Types A and B were considered fundamentally indicated for thoracoscopic wedge resections. However, the other types required the standard operation.
| Introduction |
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Since the introduction of spiral computed tomography (CT) in the early 1990s, smaller diameter lung cancers are being diagnosed [6]. We performed surgical resections in 57 patients with small peripheral lung adenocarcinomas that were 10 mm or less in diameter and were mainly diagnosed by CT. The aim of the present study was to compare clinicopathologic features of small peripheral lung adenocarcinomas of 10 mm or less in diameter with tumor groups of 11 to 20 mm in size. Thus, we herein discuss the significance of limited operations.
| Material and methods |
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Patients who visited to the outpatient clinic routinely underwent chest radiography (CxR) and thoracic CT scanning for lung cancer screenings. Noncalcified pulmonary nodules were examined by thin-slice CT (TSCT). Thin-slice CTs were reexamined after 1 month and again after 3 months if no changes were found. After 6 months up to June l998, TSCT was repeated if there were again no changes. When nodule enlargement was observed, CT-guided transcutaneous needle lung biopsy, thoracoscopic biopsy, or open lung biopsy was indicated. Between July l998 and February 2001, patients with nodules that had a ground-glass opacity (GGO) appearance on TSCT underwent a TSCT examination again after 3 months. Furthermore, when a reduction in tumor size did not occur, a lung biopsy was performed. Since March 2001, CT-guided transcutaneous needle biopsies were not performed for a nodule with GGO appearance, because of questionable diagnostic characteristics. Also, this policy was followed to eliminate the risk of postoperative cancer tissue remnants related to the unresectability of the pulmonary biopsy site by wedge resection.
The surgical principle for lung adenocarcinomas less than 10 mm in size was altered according to our experience in previous cases. Between April l992 and June l998, all patients with lung cancers underwent a lobectomy with systematic lymphadenectomy. Because six of eight cases were type A or B, intraoperative histopathologic examination by frozen section was performed. Therefore, segmentectomy with systematic lymphadenectomy was indicated for types A or B. Of the 28 patients with type A or B lung cancer, 4 were misdiagnosed as type C by intraoperative frozen-section histopathologic examination. All 31 patients with pure GGO on TSCT, which were experienced before February 2001, were classified as type A or B. Therefore, intraoperative histopathologic examination by frozen section was discontinued after March 2001. Cases with pure GGO since underwent wedge resection without lymphadenectomy. As a result, 23 of the 57 patients in group 1 underwent lobectomy with systematic lymphadenectomy, previously described by Naruke and colleagues [7]. Thirteen of the 57 patients underwent segmentectomy with systematic lymphadenectomy, and the remaining 21 underwent a wedge resection without nodal sampling. Of the 13 patients who underwent segmentectomy, 11 were performed as intentionally limited operations. The remaining two cases were because of low pulmonary function. Of the 21 patients who underwent a wedge resection, 17 were intentionally limited operations, 2 owing to low pulmonary function, and 2 because of other impaired conditions. Resected specimens were all fixed with formalin, cut into 5-mm to 10-mm slices, and evaluated by conventional hematoxylin and eosin staining.
All patients in this study were followed at an outpatient clinic by thoracic surgeons. They were scheduled for the following testing: CT of the chest, upper abdomen, and brain; bone scintigraphy; and serum tumor markers (carcinoembryonic antigen). Examinations were scheduled every 3 months for 6 months after the operation. Thereafter, tests were scheduled every 6 months for 5 years after the operation. After 5 years, thoracic CT was taken every 6 months. None of the patients were lost to follow-up.
Clinical records of each patient were reviewed for age, sex, smoking history, symptoms, diagnostic technique for detection of tumor, and maximum tumor diameter on TSCT. The grade of tumor differentiation and the presence of lymph node metastasis were determined according to the TNM classification system of the International Union Against Cancer [8]. Furthermore, lymphatic invasion, pleural involvement, intrapulmonary metastasis, and the subtype of the small lung adenocarcinoma according to Noguchis histologic classification [5] were evaluated. Lymphatic invasion was defined as tumor cells that were identified in the lymphatic vessel lumen. Pleural involvement was determined when the tumor had invaded into the elastic layer of the visceral pleura. Intrapulmonary metastasis was defined as an independent mass that was isolated from the primary malignancy with histopathologic features identical to the primary tumor.
Statistical analysis was performed using StatView software (Abacus Concepts, Berkeley, CA). Intergroup comparisons of each factor were performed by the F test,
2 test, and Fishers exact test. Survival rate was determined by the Kaplan-Meier method, and the determination of significance was made by the log-rank test. A p value less than 0.05 was considered as the level of significance.
| Results |
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Prognosis
Regarding the observation period, there was a statistically significant difference (p = 0.0057) between groups 1 (880 days) and 3 (1,377 days). To date, there have not been any recurrences in group 1, but one patient died of an accidental cause. The recurrence of cancer was observed in two cases in group 2 and in eight cases in group 3. Postoperative 5-year survival was obtained in 97.3% of patients in group 1, 75.4% in group 2, and 78.1% in group 3. This indicated that group 1 had a significantly better prognosis than the latter two groups (p = 0.013 and p = 0.006, respectively), as shown in Figure 1.
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| Comment |
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Several reports have recently been published to emphasize the usefulness of detecting early stages of lung cancer with CT. The accuracy of CT for detecting lung cancer has been reported to be 4 to 10 times higher than CxR, and lung cancers were diagnosed by CT in stage IA in 60% to 80% [1315]. The present study demonstrated that 55 of 57 cases with peripheral lung adenocarcinomas of 10 mm or less in diameter were diagnosed by CT, but not CxR. All of these cases were stage IA cancers. Thus, CT examination is indispensable in detecting early stages of peripheral lung adenocarcinoma.
As to histopathologic findings, the percentage of alveolar epithelium replacement-type adenocarcinoma (equivalent to types A, B, and C of Noguchis classification) was high in peripheral lung adenocarcinomas of 20 mm or less. Noguchi and associates [5] reported a value of 74.2%. We found it to be 84.3% in the present study. However, the frequency of types A and B, equivalent to bronchioloalveolar carcinoma in the World Health Organization classification [16] and carcinoma in situ by Noguchi and coworkers [5], was different between the report by Noguchi and associates [5] and the present study. The former was 14.4% for tumor sizes less than 20 mm, and the latter was 86.0% (49 of 57 cases) in group 1. It appears significant that cancers detected at the size of 10 mm or less in diameter will almost always be carcinoma in situ. Nevertheless, alveolar epithelium nonreplacement-type adenocarcinoma (types D, E, and F) was found in 7 of 57 cases in group 1, and three of the seven cases demonstrated positive lymphatic invasion. Therefore, even if the cancer size is less than 10 mm, we could not consider it to be an early stage cancer.
Lung cancers classified in group 1 were CT-visible and CxR-invisible lung cancers in most cases. The group was different from the other groups in patient characteristics and pathologic features. Therefore, it is likely that this cancer group has a distinctly different tumor entity from the traditional CxR-visible lung cancer. Many cancers in group 1 are type A or B, which are slow-growing and remain within a 10-mm diameter for a long time. These would often fall into the category of overdiagnosis. The fact that type C is minimal in group 1 suggests that the type A or B becomes type C, which is rapidly growing and more aggressive so that it grows rapidly to more than 10 mm. This may also suggest that the size would change tumors to type C. Furthermore, of the seven cases with types E and F in group 1, two cases coexisted with types A and B. Noguchi and colleagues [5] reported that types D, E, and F are thought to be de novo adenocarcinomas because stepwise progression has not been observed in these types. They are few in frequency, rapidly growing, and more aggressive so that even CT cannot frequently detect these tumors that are within the size category of less than 10 mm.
There have been many reports [1, 4, 9, 1721] regarding limited operations of nonsmall-cell lung cancer. Most of these authors have discussed the indications for a limited operation from the size of the cancer or the results in detecting lymph node metastasis before and during the operation. Some authors have reported occult micrometastasis in the lymph nodes using immunohistochemical staining. Micrometastasis was observed in 35.7% [22] in pN0 adenocarcinoma and in 20.4% [9] in pN0 small-sized adenocarcinoma, and their postoperative prognosis was poor. Even if a limited operation is performed because of the absence of metastatic lymph nodes before and during the operation, considerable risks will remain because of residual metastatic lesions that cannot be completely removed. A prospective study of the operative results of limited resections of lung cancer has been recently reported in Japan. The authors concluded that extended segmentectomy with lymph node dissection is an alternative method as a standard operation for nonsmall-cell lung cancer less than 2 cm in diameter confirmed as N0 by intraoperative lymph node examination of frozen sections [17]. It is known that if systematic lymphadenectomy was performed for those cases, segmentectomy had the same radical cure rate as lobectomy. However, 86% of group 1 were occupied with types A and B, which did not require lymphadenectomy.
Postoperative stage of group 1 was stage IA in all cases; however, positive lymphatic invasion was observed in 5.3% of cases. The most important factor for discrimination of small advanced adenocarcinoma, which is known to be the poorest of all prognoses, will be more dependent on Noguchis classification rather than tumor size and stage. Types A and B lung adenocarcinoma are theoretically expected to be completely removed by limited operations without lymphadenectomy as previously reported [9]. It is important to diagnose types A and B before the operation. In our experience, the diagnostic ability of intraoperative histopathologic examination by frozen section was poor when using Noguchis classification.
An early stage of localized bronchioloalveolar carcinoma is recognized as a hazy, increased-density area, or GGO, on CT scans [23, 24]. Peripheral lung adenocarcinomas demonstrating pure GGO with 10 mm or less in diameter are highly suspected of types A and B as mentioned above. Such cases may be fundamentally suitable to undergo thoracoscopic wedge resections with minimal invasion. If histopathologic results of the resected specimen show type C, D, E, or F, a standard operation must then be added. However, this circumstance will not be common. On the other hand, because tumors without the appearance of pure GGO have the possibility of being types C, D, E, and F, the standard operation may currently be adequate. Lymph node sampling is not necessary in wedge resections for types A and B because these types never have metastasis caused by in situ carcinoma. Consequently, lymph node sampling makes thoracoscopic surgery hazardous for future cancers because of the resultant adhesions. Also, systematic lymph node dissection may be adequate for types C, D, E, and F, because lymph node sampling has a low curative potential.
As to the surgical treatment of nonsmall-cell lung cancers that are 10 mm or less in diameter, Miller and associates [25] recently reported that a standard operation is suitable because of lymph node metastases and recurrence of cancers. However, cases with tumors that were not detected on CxR, yet detected on CT, were uncommon (13%). Accordingly, types A and B were thought to be uncommon. The present study revealed different findings from the results reported by Miller and colleagues [25].
In conclusion, peripheral lung adenocarcinomas with a diameter of 10 mm or less are common in women and nonsmokers. Most cases were detected by CT. Histopathologic findings showed types A and B of Noguchis classification in 86%, which was different from the adenocarcinomas of 11 mm or more in diameter. Types A and B adenocarcinomas that demonstrate pure GGO on TSCT would be fundamentally indicated for thoracoscopic partial lung resections. However, type C and nonalveolar replacement-type adenocarcinoma (types D, E, and F) must be resected by the standard operation, even if the tumor is less than 10 mm in diameter.
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