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Ann Thorac Surg 2003;76:1828-1832
© 2003 The Society of Thoracic Surgeons

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Original article: general thoracic

Discrepancy of computed tomographic image between lung and mediastinal windows as a prognostic implication in small lung adenocarcinoma

^a Department of Thoracic Surgery, Hyogo Medical Center for Adults, Akashi City, Japan

Accepted for publication June 5, 2003.

^* Address reprint requests to Dr Okada, Department of Thoracic Surgery, Hyogo Medical Center for Adults, Kitaoji-cho 13-70, Akashi City 673-8558, Hyogo, Japan
e-mail: morihito1217jp{at}aol.com

	Abstract

Top Abstract Introduction Patients and methods Results Comment References

 
BACKGROUND: There have been no proven preoperative indicators for postoperative survival of patients with an adenocarcinoma, the incidence of which has been increasing lately.

METHODS: Of 952 consecutive patients operated on for primary lung cancer between 1995 and 2002, 167 patients with a proven adenocarcinoma 3 cm or less in diameter underwent complete removal of the primary tumor. We examined their computed tomographic scans to estimate tumor shadow disappearance rate (TDR), which was defined as the ratio of the tumor area of the mediastinal window to that of the lung window, reviewed the clinical records, and evaluated their relation to prognosis.

RESULTS: On univariate analyses, size of the tumor (p = 0.0380), TDR (p = 0.0018), carcinoembryonic antigen (p = 0.0001) pathologic stage (p < 0.0001), nodal involvement (p < 0.0001), lymphatic invasion (p = 0.0001), and vascular invasion (p = 0.0017) were significantly associated with prognosis. Also, the outcomes of multivariate analyses for preoperative factors indicated that TDR (p = 0.0340) and carcinoembryonic antigen (p = 0.0047) are significant independent prognostic determinants. The 5-year survival was 48% in cases with a TDR of 0% to 25%, 87% in those with a TDR of 26% to 50%, 97% in those with a TDR of 51% to 75%, and 100% in those with a TDR of 76% to 100%. The incidence of lymphatic, vascular invasion, and nodal metastases was lower in patients with a higher TDR.

CONCLUSIONS: Small-sized adenocarcinomas with a higher TDR showed less lymphatic, vascular vessel invasion, or nodal involvement, and demonstrated longer survival, suggesting that TDR was associated with clinical-pathologic characteristics and tumor aggressiveness. Preoperative assessment of TDR may be useful to identify an appropriate candidate for a lesser pulmonary resection.

	Introduction

Top Abstract Introduction Patients and methods Results Comment References

 
The incidence of lung adenocarcinomas has been increasing during the last several decades, and now is the most common cell type [1, 2]. Routine clinical use of computed tomography (CT) has recently made detection of many small pulmonary nodules possible. Therefore, estimating the malignant potential behavior of small-sized adenocarcinomas is potentially valuable for treatment planning. However, it is not fully identified because heterogeneity is one of the unique characteristics of pulmonary adenocarcinomas, and many subtypes of adenocarcinomas have been advocated [3, 4]. For example, bronchioloalveolar carcinoma, a subset of adenocarcinomas, has a considerably better prognosis than other adenocarcinomas, implying that distinguishing between bronchioloalveolar carcinoma and conventional adenocarcinomas, akin to separating adenocarcinomas from other lung carcinomas, is essential to understand the biologic potential of a tumor. The identification of prognostic variables especially before operation is important to decide the operative procedure and adjuvant therapy as well as to detect the subsets of patients that are at higher or lower risk of having a cancer-related outcome, in particular elderly patients or those with poor lung function. However, there have been no clinically proven preoperative indicators for postoperative survival of patients with an adenocarcinoma as yet.

Takamochi and colleagues [5] proposed a radiologic variable, tumor shadow disappearance rate (TDR), that was determined from tumor shadows on both pulmonary and mediastinal window setting images on CT as a predictor of N0 disease in patients with an adenocarcinoma. Their data demonstrated that a higher TDR together with a lower concentration of serum carcinoembryonic antigen (CEA) were significant predictors of pathologic N0 disease, but the authors did not refer to their relationship to prognostic factors or survival on the long-term follow-up. Because little information regarding prognosis during the pretreatment state is available, new information is highly desired. In this study we analyzed the follow-up data in patients who had undergone complete resection of small-sized adenocarcinomas and estimated TDR as an independent preoperative prognostic determinant in such patients.

	Patients and methods

Top Abstract Introduction Patients and methods Results Comment References

 
Between January 1995 and June 2002, 952 consecutive patients were operated on for primary lung cancer by the same surgical team. Of these, 167 patients with a proven adenocarcinoma 3 cm or less in diameter underwent complete removal of the primary tumor. Patients who had evidence of residual tumor at the surgical margin, malignant effusion, or N3 disease verified by intraoperative findings or postoperative pathologic examination were defined as having been subjected to an incomplete surgery and were excluded from this study [6]. The criteria, based on and modified from those of Martini and Melamed [7], have been used for the designation of multiple primary lung cancers [8]. Surgical-pathologic staging was done according to the New International Staging System for Lung Cancer [9].

Contrast-enhanced CT was performed on an X-force or an Asteion (Toshiba Medical Systems, Tokyo, Japan). All slices with 10-mm spacing were obtained from the apex of the lung to the base. The images were photographed using a window level of -600 to -550 Hounsfield units (HU) with a window width of 1,700 to 1,800 HU (lung windows) and a level of 25 to 70 HU with a width of 350 to 400 HU (mediastinal windows). All lesions were completely resected within 1 month after CT. The analyses were made on hard-copy films by three independent observers. The observers quantified the maximum dimension of the tumor (maxD) and the largest dimension perpendicular to the maximum axis (perD) on both lung and mediastinal windows. Discrepancies in evaluation among the observers were resolved by averaging the values determined by them. As previously reported [5], TDR was defined as the following:

The records of all patients were reviewed for age, sex, size of the tumor, preoperative serum CEA, pathologic stage, lymph node status (N factor), pleural involvement (P factor), lymphatic invasion (Ly factor), and vascular invasion (V factor). The normal limit for serum CEA assessed by immunoenzymometric assay was 5 ng/mL. In lymphatic and vascular invasion, adenocarcinoma cells were identifiable in the lymphatic and blood vessel lumen, respectively.

Survival was calculated by the Kaplan-Meier method, and differences in survival were determined by log-rank analysis. A multivariate analysis of several prognostic factors was carried out using Cox's proportional hazards regression model. Zero time was the date of pulmonary resection, and the terminal event was death attributable to cancer, noncancer, or unknown causes. Significance was defined as p less than 0.05.

	Results

Top Abstract Introduction Patients and methods Results Comment References

 
The clinical and pathologic findings of patients are summarized in Table 1. On the basis of the international staging system, 86% of the patients who underwent complete resection for an adenocarcinoma 3 cm or less in diameter had stage I disease, 5% had stage II disease, and 10% had stage III disease. Segmentectomy was the most common procedure and was performed in 83 patients (50%). Sixty-six lobectomies (39%) and 18 wedge resections (11%) were carried out. There was no significant difference in distribution of operative procedure among the following group comparisons. Overall follow-up ranged from 5 to 94 months, with a median of 42 months. There were 135 (81%) patients with an adenocarcinoma 2 cm or less in diameter among the 167 patients with an adenocarcinoma 3 cm or less in diameter. The incidence rates of advanced stage, nodal involvement, pleural involvement, invasion of lymphatic vessels, and invasion of vascular vessels in patients with an adenocarcinoma 2.1 to 3.0 cm in size tended to be higher than in those with an adenocarcinoma 2.0 cm or less in diameter. Table 2 shows the results of univariate analyses to detect prognostic indicators among age, sex, size of the tumor, TDR, CEA, pathologic stage, N factor, P factor, Ly factor, and V factor in patients with an adenocarcinoma 3.0 cm or less in diameter. On univariate analyses, size of the tumor (p = 0.0380), TDR (p = 0.0018), and CEA (p = 0.0001), as preoperative variables, and pathologic stage (p < 0.0001), N factor (p < 0.0001), Ly factor (p = 0.0001), and V factor (p = 0.0017), as postoperative variables, were significantly associated with postoperative prognosis. The outcomes of multivariate analyses just for preoperative factors are given in Table 3. These indicated that TDR (p = 0.0340) and CEA (p = 0.0047) are significant independent prognostic determinants.

View larger version (15K): [in this window] [in a new window]   Fig 1. Cumulative survival curves of patients after complete resection of lung adenocarcinomas of 3 cm or less in diameter according to degree of tumor shadow disappearance rate (TDR).

	Comment

Top Abstract Introduction Patients and methods Results Comment References

Recently, some investigators reported that preoperative CT findings were related to the pathologic features and clinical results after resection of the tumor [10–12]. The ratio of ground-glass opacity (GGO), defined as a hazy increase in lung attenuation without obscuring the underlying vascular marking on CT [10, 13], was associated with the histologic type of the tumor, which sequentially was connected to the risk of nodal metastases and survival. Kodama and colleagues [11] demonstrated that the 3-year relapse-free survival in patients with an adenocarcinoma 2 cm or less containing a GGO greater than 50% was 100%. In addition, Matsuguma and coworkers [12] reported that all the cancers 2 cm or smaller in which the ratio of GGO was 50% or greater were bronchioloalveolar carcinomas without nodal involvement and did not recur after resection. However, characterizing and quantifying GGO was subjective and based on visual estimation by individuals, resulting possibly in much discrepancy in evaluation among the observers. Therefore, a more reliable and useful indicator that can possibly minimize the inconsistency is desired to predict the patient's prognosis preoperatively.

Takamochi and associates [5] proposed TDR as a new preoperative radiologic variable that is calculated from the tumor shadow on both pulmonary and mediastinal window setting on CT. Their analyses showed that a higher TDR was indeed a significant predictor of no pathologic nodal involvement in lung adenocarcinomas. The extent of GGO correlated well with that of bronchioloalveolar growth of adenocarcinomas, and GGO was observed as a hazy increased density area on the pulmonary window setting of CT, which would vanish on the mediastinal window setting. That is why the value of TDR could represent the proportion of GGO area to the whole tumor. Therefore, the patients with a higher TDR would be considered prone to survive longer because their tumors probably have indolent biologic behaviors. In this study, we attempted to examine the relation of TDR not only to nodal status but also to lymphatic invasion, vascular invasion, and survival, and to assess TDR as an independent prognostic determinant in patients with a small-sized adenocarcinoma. Lymphatic and vascular vessel invasion, which are known to reflect tumor aggressiveness, correlated with a poorer prognosis in patients with non–small-cell lung cancer [14, 15]. Not surprisingly, lymphatic and vascular vessel invasion as well as nodal involvement and pathologic stage were significant prognostic determinants in our series. Interestingly, tumors with a greater TDR showed less lymphatic, vascular vessel invasion, or nodal involvement, and patients survived longer. The present study suggested that the value of TDR was associated with the clinical-pathologic characteristics of small-sized adenocarcinomas, could indicate tumor aggressiveness, and might be of use for identifying patients suitable for a lesser resection. Some adenocarcinomas in which the postoperative pathologic examination revealed a greater part of bronchioloalveolar carcinoma were underestimated as less proportion of GGO on preoperative CT findings because of mucus production by their tumor cells in the alveolar lumina. It is of great interest to note that these underestimations have seldom occurred on the assessment of TDR. Although these data constituted just part of an emerging body of study that correlates findings on images with pathologic features and clinical outcome, they strongly suggested that a limited pulmonary resection could be an acceptable treatment strategy for these small-sized adenocarcinomas. In addition, calculating TDR is more objective than evaluating the ratio of GGO, which can have a high interobserver variability.

Takamochi and associates [5] showed another predictor of pathologic N0 disease was a normal serum concentration of CEA, and cases of pathologic N0 disease could be predicted more correctly by combining serum CEA with TDR. In this series, preoperative serum CEA was a significant independent prognostic indicator in addition to TDR. On the other hand, the size of the tumor on CT was a significant prognostic indicator but not independent. Preoperative assessment on the basis of serum CEA and TDR, not only CT size, may prove valuable to recognize a suitable candidate for a lesser pulmonary resection. However, the outcomes of the current study need to be verified in larger studies.

	References

Top Abstract Introduction Patients and methods Results Comment References

 

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Noriaki Tsubota Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Okada, M. Articles by Tsubota, N. Search for Related Content PubMed PubMed Citation Articles by Okada, M. Articles by Tsubota, N. Related Collections Lung - cancer