The prognostic significance of central fibrosis of adenocarcinoma

Prognostic Significance of the Size of Central Fibrosis in Peripheral Adenocarcinoma of the Lung Kenji Suzuki, MD, Tomoyuki Yokose, MD, Junji Yoshida, MD, Mitsuyo Nishimura, MD, Kenro Takahashi, MD, Kanji Nagai, MD, and Yutaka Nishiwaki, MD Division of Thoracic Oncology, National Cancer Center Hospital East, and Pathology Division, National Cancer Center Research Institute East, Chiba, Japan Background. The prognostic significance of the characteristics of central fibrosis in peripheral adenocarcinoma of the lung has been reported. However, the prognostic significance of the size of central fibrosis has never been evaluated. Methods. A total of 100 consecutive surgically resected peripheral adenocarcinomas of the lung measuring 3.0 cm or less in maximum dimension were reviewed histologically, and the maximum dimension of central fibrosis was measured on conventional hematoxylin and eosin stain. Results. Median follow-up for patients alive was 54 months. The overall 5-year survival rate was 75%. Twenty-one patients with adenocarcinoma having central fibrosis 5 mm or smaller in maximum dimension had a 5-year survival rate of 100%, whereas the other 79 patients had a 5-year survival less than 70%. Multivariate analysis showed the size of central fibrosis to be an independent prognostic factor as significant as vascular invasion and locoregional lymph node metastasis (p 0.010, 0.024, and 0.024, respectively). Conclusions. The size of central fibrosis is an independent prognostic factor in peripheral lung adenocarcinoma, as significant as the well-established prognostic factors vascular invasion and lymph node metastasis. (Ann Thorac Surg 2000;69:893 7) 2000 by The Society of Thoracic Surgeons The prognostic significance of central fibrosis of adenocarcinoma of the lung has been confirmed by several investigators [1 5]. However, most of the reports dealt with the relationship between the characteristics of central fibrosis and the prognosis, and the prognostic significance of the size of central fibrosis has never been evaluated. In Japan, small adenocarcinomas, which had been undetectable with conventional radiography, have been found as a result of the introduction of spiral computed tomographic (CT) screening for lung cancer [6]. Although a phase III trial by Lung Cancer Study Group failed to show the feasibility of limited resection of lung cancer compared with conventional major lung resection [7], there might be some possibility that certain specific lung cancers could be cured with limited surgical resection [8]. A potentially surgically curable lung carcinoma could be an in situ peripheral adenocarcinoma of the lung for which limited surgical resection could be enough, and small bronchioloalveolar carcinoma is one of such example. Thus, we attempt to clarify the indications for limited operation. The aim of this study is to define peripheral adenocarcinoma of the lung, which is curable by limited resection based on the size of central fibrosis. We consider that the size of central fibrosis could be evaluated preoperatively, because it could be measured by the findings of preoperative high-resolution CT Accepted for publication Aug 2, 1999. Address reprint requests to Dr Suzuki, Division of Thoracic Surgery, National Cancer Center, Tsukiji 5 chome, 1-1, Chuo-ku, Tokyo, 104-0045 Japan; e-mail: kjsuzuki@ncc.go.jp. scan (HRCT). Ground glass opacity or hazy attenuation at HRCT have been reported to reflect the lepidic growth pattern of lung adenocarcinoma [9, 10]. To determine prognostic significance of the size of central fibrosis region, we retrospectively examined 100 consecutive patients with peripheral lung adenocarcinomas 3.0 cm or less in maximum dimension, which had been resected in our institute before at least 5 years ago. Patients and Methods A consecutive series of 100 preoperatively untreated, surgically resected peripheral primary adenocarcinoma of the lung 3.0 cm or less in maximum tumor dimension was investigated retrospectively. These tumors had been resected at our institute between May 1987 and February 1992. The age of these patients ranged from 23 to 85 years old, with an average of 64 years. Forty-six were men and 54 were women. Among them, 67 patients were classified pathologically as stage IA, 12 as stage IIA, 14 as stage IIIA, 6 as stage IIIB, and 1 as stage IV. The following were excluded from the study: (1) patients who underwent incomplete resection or conservative resection (ie, partial resection or segmentectomy); (2) patients with multiple lung carcinoma; and (3) patients who did not undergo mediastinal sampling or dissection. Histologic typing was determined according to the World Health Organization classification [11] and the stage of the disease was based on the TNM classification of the International Union Against Cancer [12]. All resected specimens were formalin fixed and sliced at 5-mm to 10-mm intervals. 2000 by The Society of Thoracic Surgeons 0003-4975/00/$20.00 Published by Elsevier Science Inc PII S0003-4975(99)01331-4

894 SUZUKI ET AL Ann Thorac Surg CENTRAL FIBROSIS IN LUNG ADENOCARCINOMA 2000;69:893 7 in peripheral adenocarcinoma of the lung. Statistical analysis was considered to be significant when the probability value was less than 0.05. Fig 1. Histologic findings of a lung adenocarcinoma 2.3 cm in size having central collapse/fibrosis (hematoxylin and eosin stain). The size of central collapse/fibrosis region was determined at its maximum dimension (black line) on low power view. Thus the size of central collapse/fibrosis of this lesion was determined as 6 mm (original magnification 5). Primary lung neoplasms were evaluated microscopically by conventional hematoxylin and eosin, and also by elastica van Gieson stain. The following histologic features were studied: the size of the central fibrosis region (in millimeters), the maximum tumor dimension (in centimeters), the pleural involvement, the lymphatic invasion, and the vascular invasion by tumor. The size of central fibrosis region was diagnosed histologically as previously reported [2, 3, 5] and determined at its maximum dimension on low power view (Fig 1). Pleural involvement was classified as P0, P1, P2, and P3; P0 included tumor with no pleural involvement or reaching the visceral pleura but not extending beyond its elastic pleural layer; P1 included tumor reaching visceral pleural elastic layer but not exposed on the pleural surface; P2 included tumor exposed on the pleural surface; and P3 included tumor invading parietal pleura or chest wall. In lymphatic and vascular invasion, tumor cells were identifiable in the lymphatic lumen or blood vessel lumen, respectively [2, 5]. The median follow-up period for the 78 patients alive was 54 months. The length of survival was defined as the interval in months between the day of surgical resection of lung carcinoma and the date of death due to any cause or the last follow-up. The survival rates were calculated by the Kaplan-Meier method [13] and univariate analyses were performed by means of the log rank test. Because the median potential follow-up time was less than 5 years, we calculated 3- and 5-year survival rates separately. Multivariate analyses were also performed by means of Cox s proportional hazards model on Stat View software (version 411J; Abacus Concepts, Inc, Berkeley, CA) with a Power Macintosh 8100/100AV (Apple Computer Inc, Cupertino, CA) [14]. Forward and backward stepwise procedures were used to determine the combination of factors that were essential in predicting prognosis. The 2 test or Fisher s exact test were used to compare several prognostic factors between subgroups Results The 3-year and 5-year survival rates of the overall patients were 85.4% and 74.7% (Fig 2). Overall characteristics of adenocarcinoma of the lung based on the several clinicopathologic features are shown in Table 1. The size of central fibrosis ranged from 0 to 29 mm in maximum dimension. The outcome of adenocarcinoma with central fibrosis 5 mm or less in size (n 21) was excellent (5-year survival rate 100%; Fig 3). The 5-year survival rate of adenocarcinoma with central fibrosis more than 5 mm and 15 mm or less in size was 72.3%, and this was significantly better than that of adenocarcinoma with larger central fibrosis (p 0.006). Thus, these results demonstrated that the size of central fibrosis could be a significant prognostic factor. Other conventional pathologic factors, such as pathologic staging, lymph node metastasis, or vascular invasion, showed prognostic significance as previously reported [5]. The relationship between conventional clinicopathologic features and the size of central fibrosis is shown in Table 2. Adenocarcinoma with central fibrosis 5 mm or less in size tended to have no lymph node metastasis, and negative vessels invasion. In multivariate analysis (Table 3), the size of the central fibrosis region (in centimeters) was shown to be a significant prognostic factor (p 0.010; hazard ratio 2.263; 95% confidence interval 1.213 to 4.220), as significant as vascular invasion and locoregional lymph node metastasis (p 0.024; hazard ratio 3.041; 95% confidence interval 1.159 to 7.974, and p 0.024; hazard ratio 2.698; 95% confidence interval 1.143 to 6.366, respectively). Adenocarcinoma with central fibrosis 5 mm or smaller in size, no vascular invasion, and no lymph node involvement showed a 5-year survival rate of 100%, Fig 2. Survival curves for patients with peripheral adenocarcinoma of the lung 3.0 cm or less in maximum tumor dimension. Bars indicate 95% confidence intervals (CI).

Ann Thorac Surg SUZUKI ET AL 2000;69:893 7 CENTRAL FIBROSIS IN LUNG ADENOCARCINOMA 895 Table 1. Overall Characteristics of Adenocarcinoma of the Lung 3.0 cm or Less in Longest Dimension No. of Patients Survival Rates (%) 3-Year 5-Year 2 p Value a Total 100 85.4 74.7...... Gender Male 46 76.6 65.2 2.215 0.137 Female 54 92.5 83.4 Size of central collapse/fibrosis 5 mm 21 100 100...... b 5to 15 mm 55 90.0 72.3 7.491 0.006 15 mm 24 62.5 57.3 Pathological stage Stage I 67 93.5 81.9 11.925 0.003 Stage II 12 74.1 61.7 Stage III IV 21 65.9 59.3 Tumor size 2.0 cm 36 91.0 83.4 1.092 0.296 2.0 cm 64 82.1 69.8 Lymph node metastasis Negative 68 93.6 82.0 11.604 0.001 Positive 32 67.9 59.4 Lymphatic invasion Negative 78 87.9 79.2 1.494 0.222 Positive 22 76.6 60.9 Negative 64 96.8 87.1 16.972 0.001 Positive 36 65.8 52.8 Pleural involvement c Negative 65 88.8 76.9 1.560 0.212 Positive 35 79.3 71.5 a p Value in the log rank test. b p Value could not be evaluated because of no events in subgroup of central collapse/fibrosis 5 mm or less in size. c Negative was defined as P0, and positive was defined as P1, P2, and P3. whereas other patients with none of the three factors had a 5-year survival of 43% (p 0.001; Table 4). Relationship between conventional prognostic factors and the size of the central fibrosis region among lung adenocarcinoma 2.0 cm or less in size was also investigated (Table 5). Lung adenocarcinoma with central fibrosis 5 mm or less in maximum dimension tended to have favorable pathologic features and to be related to negative mediastinal or hilar lymph node metastasis, and negative vascular invasion. The outcome of adenocarcinoma 2.0 cm or less in size and with central fibrosis 5 mm or less in size was excellent (5-year survival rate, 100%). Comment Our results showed that the size of central fibrosis was an independent prognostic factor among peripheral lung adenocarcinomas 3.0 cm or less in size, and that it was as significant as the well-established prognostic factors of vascular invasion and lymph node metastasis. This newly Fig 3. Survival for patients with peripheral adenocarcinoma of the lung 3.0 cm or less in maximum tumor dimension was compared based on the size of central collapse/fibrosis (CF). The prognosis of patients with collapse/fibrosis 15 mm or less was significantly better than those with larger collapse/fibrosis (log-rank test, p 0.05). defined prognostic factor is different in an important way from the other conventional pathologic prognostic factors: it can be evaluated preoperatively. Several investigators have reported that ground glass opacity or hazy attenuation demonstrated by HRCT is due to lepidic tumor growth [9, 10]. Therefore, if a lung tumor shows focal ground glass opacity on HRCT, we would know the Table 2. Relationship Between Conventional Prognostic Factors and the Size of Central Collapse/Fibrosis Region Size of Central Collapse/Fibrosis Region (mm) 5 5 2 p Value a Gender Male 10 36 0.028 0.867 Female 11 43 Pathological stage Stage I or II 19 60 2.110 0.146 Stage III IV 2 19 Tumor size 2.0 cm 10 26 1.558 0.212 2.0 cm 11 53 Positive 3 29 3.833 0.050 Negative 18 50 Lymphatic invasion Positive 2 20 2.411 0.121 Negative 19 59 Positive 3 33 5.440 0.020 Negative 42 22 Pleural involvement b Positive 6 29 0.203 0.652 Negative 15 50 a p Value in 2 test. b Negative was defined as P0, and positive was defined as P1, P2, and P3.

896 SUZUKI ET AL Ann Thorac Surg CENTRAL FIBROSIS IN LUNG ADENOCARCINOMA 2000;69:893 7 Table 3. Multivariate Analyses of s in Adenocarcinoma of the Lung Variable area of pathologic lepidic tumor growth, and then the size of central fibrosis could be predicted. As shown in this study, lung adenocarcinoma with small areas of central fibrosis had mostly favorable pathologic features, and some of them would have been surgically curable in situ lung adenocarcinoma. Although limited surgical resection for T1 lung cancer failed to show the same effectiveness as lobectomy [7], limited surgical resection for properly selected lung cancer patients could offer the same therapeutic impact. Therefore, patients with small peripheral lung adenocarcinomas with focal area of consolidation and wider area of ground glass opacity on HRCT could be selected as candidates for limited surgical resection. This would be appropriate, especially for adenocarcinomas 2.0 cm or less in size. If lung adenocarcinoma 2.0 cm or less in size has central fibrosis 5 mm or less in size, the probability of pathologic lymph node involvement would be low (Table 5) and the outcome was excellent (5-year survival, 100%). Limited surgical resection would be enough for this population. A clinical trial Table 4. The 5-Year Survival Rates in Subgroups of Peripheral Adenocarcinoma of the Lung Based on the s a Subgroup No. Hazard Ratio 95% Confidence Interval p Value The size of central collapse/ 2.263 1.213 4.220 0.010 fibrosis (cm) a positive 3.041 1.159 7.974 0.024 vs negative positive vs negative 2.698 1.143 6.366 0.024 a Entered as a continuous variable into the logistic regression model. 5-Year Survival (%) 2 p Value b CF 5 mm, no vascular invasion, and no lymph node involvement With all of the factors 16 100...... c With one or two of the 67 76.4 12.978 0.0003 factors With none of the factors 17 43.1 CF 10 mm, no vascular invasion, and no lymph node involvement With all of the factors 36 93.4 23.496 0.0001 With one or two of the 50 69.7 factors With none of the factors 14 38.6 a Prognostic factors denote the following three factors: the size of central collapse/fibrosis, vascular invasion, and lymph node metastasis. b p Value in the log rank test. c p Value could not be evaluated because of no events in the subgroup with all of the factors. CF the size of central collapse/fibrosis (mm). Table 5. Relationship Between Conventional Prognostic Factors and the Size of Central Collapse/Fibrosis Region Among Lung Adenocarcinoma 2.0 cm or Less in Size Size of Central Collapse/Fibrosis Region (mm) 5 5 p Value a Positive 0 9 0.039 Negative 10 17 Positive 1 9 0.223 Negative 9 17 a p value in Fisher s exact test. to determine the feasibility of limited surgical resection for selected small adenocarcinomas is now ongoing in our institute. The pathogenesis of peripheral lung adenocarcinoma is unknown. Although the concept of in situ central squamous cell carcinoma of the lung has been well accepted [15], that of in situ peripheral adenocarcinoma of the lung is still controversial. Many researchers recently reported that atypical adenomatous hyperplasia is a possible precursor to adenocarcinoma of the lung [16]. Although the concomitant occurrence of atypical adenomatous hyperplasia does not have prognostic significance [17], some investigators have reported that K-ras activation has already occurred in some of these lesions, indicating their potential for malignant transformation [18]. Furthermore, very recently we found that atypical adenomatous hyperplasia is of monoclonal origin [19]. Combined with these facts, some atypical adenomatous hyperplasias would progress to localized bronchioloalveolar carcinoma (BAC) without central fibrotic regions, and then to BAC with central fibrotic foci, so-called sclerosing BAC [3]. The concept of scar cancer of the lung had been accepted for some decades, but has not been so recently except for rare cases. Shimosato and colleagues [2] proposed that the central fibrosis in most scar carcinomas was a secondary phenomenon rather than a precursor to the carcinoma. Thereafter several investigators have reported the prognostic significance of the central fibrosis [1, 3 5]. The characteristics of central fibrosis, such as the presence of active fibroblasts, the pattern of stromal elastosis, and the interface pattern, have been confirmed to be significant prognostic factors in these reports. In contrast there have been no reports on the size of central fibrosis. Although the pathogenesis of central fibrosis in adenocarcinoma of the lung remains unknown, some investigators reported the concept of an adenoma carcinoma sequence of the lung, which suggested that some atypical adenomatous hyperplasias would progress to localized BAC without central collapse or fibrotic regions, and then to BAC with central fibrotic foci, so-called sclerosing BAC [3, 16, 20]. Therefore, the size of central fibrosis could be a prognostic factor, in addition to

Ann Thorac Surg SUZUKI ET AL 2000;69:893 7 CENTRAL FIBROSIS IN LUNG ADENOCARCINOMA 897 the characteristics of central fibrosis. This contention is corroborated by the present results. The size of central fibrosis should be evaluated preoperatively to use this prognostic factor to decide on the type of surgical resection. Some researchers have reported that ground glass opacity or hazy attenuation on HRCT could be an adenocarcinoma of the lung and represent pathologic lepidic tumor growth [9, 10]. Furthermore, Jang and colleagues [10] reported that a focal area of ground glass attenuation on HRCT is an early sign of localized BAC. These findings support our suggestion that a peripheral small adenocarcinoma showing a focal area of ground glass attenuation could be a candidate for limited surgical resection, although this must be confirmed in a clinical trial. Although we attempted to evaluate the prognostic significance of ground glass opacity on HRCT directly, because the median follow-up of patients with adenocarcinoma evaluated by HRCT is less than 2 years in our institute, we considered it was inappropriate to attempt to evaluate the prognostic significance of ground glass opacity on HRCT at present. Therefore, we evaluated central fibrosis regions pathologically among lung cancer patients who had undergone resection more than 5 years previously. Although the feasibility of limited surgical resection versus lobectomy for T1 lung cancer was not confirmed in a phase III trial [7], we consider that some small adenocarcinomas in situ adenocarcinoma of the lung could be cured with an appropriate limited surgical resection. To make it possible to implement this strategy, preoperative clinical, rather than surgical or pathologic, criteria for such in situ adenocarcinomas of the lung need to be established. In this respect, HRCT could be a useful tool to preoperatively define in situ adenocarcinoma of the lung. Of course, new diagnostic methods, such as molecular diagnosis and positron emission tomography, may become more helpful to define the in situ characteristics of peripheral lung carcinoma in the future. The authors thank Prof J. Patrick Barron, International Medical Communications Center, Tokyo Medical University, for reviewing the English manuscript. The study was supported in part by a Grant-in-Aid for Cancer Research from the Ministry of Health and Welfare, Japan. References 1. Yamashiro K, Yasuda S, Nagase A, Hirata T, Nojima T, Nagashima K. Prognostic significance of an interface pattern of central fibrosis and tumor cells in peripheral adenocarcinoma of the lung. Hum Pathol 1995;26:67 73. 2. Shimosato Y, Suzuki A, Hashimoto T, et al. Prognostic implications of fibrotic focus (scar) in small peripheral lung cancers. Am J Surg Pathol 1980;4:365 73. 3. 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