Ann Thorac Surg 2006;81:298-304
© 2006 The Society of Thoracic Surgeons
Original article: General thoracic
Pleural Lavage Cytology Before and After Lung Resection in Non-Small Cell Lung Cancer Patients
Sotarou Enatsu, MD
a
,
c
,
*
,
Junji Yoshida, MD
a
,
Tomoyuki Yokose, MD
b
,
Mitsuyo Nishimura, MD
a
,
Yutaka Nishiwaki, MD
a
,
Takayuki Shirakusa, MD
c
,
Kanji Nagai, MD
a
a Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Japan
b Department of Pathology, National Cancer Center Research Institute East, Kashiwa, Japan
c Second Department of Surgery, Fukuoka University School of Medicine, Fukuoka City, Japan
Accepted for publication June 27, 2005.
* Address correspondence to Dr Enatsu, Second Department of Surgery, Fukuoka University School of Medicine, 7-45-1, Nanakuma, Jonan-ku, Fukuoka City, Fukuoka, 814-0180, Japan (Email: md040004{at}cis.fukuoka-u.ac.jp).
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Abstract
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BACKGROUND: The aim of this study was to analyze on a multivariate basis the prognostic significance of pre-resection and post-resection pleural lavage cytologies in surgically resected primary non-small cell lung cancer (NSCLC) patients, in relation to pathologic TNM factors in a large cohort of almost 1,200 patients.
METHODS: From August 1992 through March 2001, pleural lavage cytology (PLC) was performed in 1,214 NSCLC patients without pleural effusion or dissemination undergoing pulmonary resection. The cytologic evaluation was classified into three categories: negative, suggestive, and positive. To investigate the impact on patient survival, PLC results were analyzed with conventional clinicopathologic factors.
RESULTS: Definitive pre-resection PLC result was obtained in 1,194 patients and 38 had a positive result. The 5-year survival rates were 27% if pre-resection PLC was positive and 71% if negative. Of 1,198 patients 54 had a positive post-resection PLC result. The 5-year survival rates were 10% if post-resection PLC was positive and 73% if negative. On multivariate analysis, post-resection PLC was an independent prognostic factor as significant as established clinicopathologic factors.
CONCLUSIONS: Pre-resection and post-resection PLC should be recognized as an essential prognostic factor and should be performed in NSCLC patients without pleural effusion and dissemination. Post-PLC, compared with pre-PLC, had a greater and independent impact on survival and needs to be incorporated in the pathologic staging of NSCLC in the future.
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Introduction
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Pleural lavage cytology (PLC) has been reported to be a possible prognostic factor in patients with resected non-small cell lung cancer (NSCLC). However, many of the reports are that only PLC immediately after thoracotomy, before lung resection, (pre-PLC) has been studied in detail. The pre-PLC impact on patient outcome has been studied, chiefly, on a univariate basis and has not been studied in relation to the conventional pathologic TNM by multivariate analysis. Although pre-PLC has been reported to be a poor prognosis predictor, a positive result is currently not recognized as equivalent to T4 or a factor indicating incomplete resection. Although PLC after radical NSCLC resection, before chest closure, (post-PLC) has also been studied, significance of post-PLC remains controversial. Higashiyama and associates [1] performed pre-PLC and post-PLC in 325 lung cancer patients, but neither pre-PLC nor post-PLC results were an independent prognostic factor. Dresler and associates [2], who reported the pre-PLC and post-PLC analysis in 137 patients, stated that the 3-year survival rate was significantly better in negative post-PLC patients than in positive patients. We thought further analyses on post-PLC were needed. In the present study, we analyzed both pre-PLC and post-PLC on a multivariate basis, in relation to pathologic TNM factors in a large cohort of almost 1,200 patients.
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Material and Methods
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From August 1992 through March 2001, a total of 1,387 patients underwent surgical resection for primary NSCLC at the National Cancer Center Hospital East. Intraoperative PLC, which was approved for this observational study by the institutional review board, was prospectively performed in all patients without pleural effusion and dissemination, totaling 1,214 patients, and all were enrolled in this study. As the largest sample size for PLC study was 1,000 before this study, we aimed at accruing well more than 1,000 patients before analysis. Preoperative evaluation included a detailed history, physical examination, bronchoscopy, contrast-enhanced computed tomography (CT) of the chest, and distant metastasis screening (bone, brain, liver, and adrenals). Histologic typing was determined according to the World Health Organization classification [3]. Disease stages were determined based on the TNM classification of the International Union Against Cancer [4]. Immediately after thoracotomy, the pleural cavity was carefully washed with 500 mL physiologic saline before any pulmonary parenchyma manipulation. A sample of 50 mL was retrieved for cytologic evaluation (pre-PLC). We performed lung resection (segmentectomy or greater) and complete mediastinal lymph node dissection in 1,199 patients, and lung resection and mediastinal lymph node sampling in 15 patients. Before chest closure, a pleural cavity lavage sample was also retrieved (post-PLC) in the same fashion as pre-PLC. Samples were centrifuged at 1,500 rpm for 5 minutes. The sediment was stained using Papanicolaou's methods. A single cytologist blinded to the clinical-pathologic information evaluated the specimen and classified it into three categories: Papanicolaou classes I and II as negative, class III as suggestive, and classes IV and V as positive. In the survival analyses, we studied only cases with definitive cytologic diagnoses, excluding Papanicolaou class III. To investigate the impact on patient survival, the following conventional clinicopathologic factors were reviewed and analyzed: age, gender, smoking index (< 400 vs 
400), serum carcinoembryonic antigen (CEA) level (< 5.0 mg/mL vs 5.0 mg/mL), clinical T factor (cT: cT2-4 vs cT1), clinical lymph node status (cN: mediastinal node involvement as cN2 vs less extensive as cN0-1), histologic type of tumor (adenocarcinoma versus others), pleural involvement of surgical (sP0-1 vs sP2-3) and pathologic finding (p0 vs p1-3), lymphatic invasion (positive versus negative), vascular invasion (positive versus negative), pathologic N status (pN: pN2-3 vs pN0-1), degree of fibrotic scarring (scar grade 1-2 vs grade 3-4), nuclear atypia (grade 1 or 2 vs grade 3), mitotic activity (mitotic index 1 or 2 vs 3), and surgical resection completeness (incomplete versus complete). Complete resection was defined as negative surgical margin and no highest mediastinal lymph node involvement. Incomplete resection was defined as positive surgical margin or highest mediastinal lymph node involvement. The smoking index was defined as the product of the number of cigarettes smoked per day and the number of years of smoking. We defined cN2 as mediastinal lymph node(s) greater than 1.0 cm in the shortest dimension on preoperative conventional CT. Pleural involvement was classified according to the Japan Lung Cancer Society criteria: p0; tumor did not extend beyond the elastic pleural layer, p1; tumor invaded the visceral pleura elastic layer but was not exposed on the pleural surface, p2; tumor was exposed on the pleural surface and p3; tumor invaded the parietal pleura or chest wall. Surgeons determined pleural involvement (sP factor) macroscopically before resection. Pathologic pleural involvement (p factor) were diagnosed on the resected specimens by a single pathologist blinded to the surgeons' findings [5]. Lymphatic invasion and vascular invasion indicated tumor cells identifiable in the lymphatic and vascular vessel lumen, respectively. Scar grade was classified into 4 grades: grade 1; tumor had foci of alveolar collapse with resulting condensation of elastic fibers but no or minimal fibroblastic tissue with collagen, grade 2; tumor had fibroblastic tissue with a small amount of collagen fibers, grade 3; tumor had fibroblastic tissue with moderate or abundant amount of collagen fibers, and grade 4; tumor showed hyalinization [6]. Nuclear atypia categorization was based on the most atypical nuclei on sections and divided into 3 grades as follows: grade1; nuclei that were uniform in size and equal to or only slightly larger than those of reactive type II alveolar epithelial cells, grade 2; nuclei that were uniform in size and up to twice the size of those of reactive type II alveolar epithelial cells, and grade 3; presence of giant tumor cells. Mitotic index was classified into three grades based on the findings of several sections: index 1; up to 5 mitotic cells per 10 high-power fields (HPF), index 2; 6–15 mitotic cells per 10 HPF, and index 3; greater than 15 mitotic cells per 10 HPF [7]. The length of survival was defined as the interval in months between the day of surgical intervention and the date of death due to any cause or the last follow-up. An observation was censored at the last follow-up when the patient was alive or lost to follow-up. The survival rates were calculated by the Kaplan-Meier method [8] and univariate analyses were performed by means of the log-rank test. Multivariate analyses were performed using the Cox proportional hazards model [9]. Forward and backward stepwise procedures were used to determine the combination of prognostic factors (StatView: version 5.0; SAS Institute, Inc, Cary, NC). A p value less than 0.05 was taken to indicate a statistical significance.
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Results
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Patient clinicopathologic characteristics are shown in Table 1. There were 781 men and 433 women. Their ages ranged from 22 to 89, with a median of 65 years. Clinicopathologic characteristics for pre-PLC and post-PLC are shown in Tables 2 and 3,
respectively. For pre-PLC, definitive cytologic results were obtained in 1,194 patients, with a positive result in 38 (3.2%). Univariate analyses revealed significant differences between pre-PLC positive and negative patients in pathologic pleural involvement, pathologic N status, lymphatic permeation, vascular invasion, resection completeness, and scar grade. For post-PLC, definitive cytologic result was obtained in 1,182 patients, 54 (4.6%) of which showed a positive result. Significant differences were observed in pathologic stage, pathologic pleural involvement, pathologic N status, lymphatic permeation, vascular invasion, resection completeness, and scar grade between post-PLC positive and negative patients. The 5-year survival rate was 27% for positive pre-PLC patients, which was significantly worse than 71% for negative pre-PLC patients (Fig 1). The 10% 5-year survival rate for positive post-PLC patients was significantly worse 73% for negative post-PLC patients (Fig. 2).
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Fig 1. Survival curves of patients according to pre-PLC results. The 5-year survival rate was 27% for positive pre-PLC patients and was significantly worse (71%) for negative pre-PLC patients. The crosses indicate censored cases at the respective points. (PLC = pleural lavage cytology.)
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Fig 2. Survival curves of patients according to post-PLC results. The 5-year survival rate was 10% for positive post-PLC patients and was significantly worse (73%) for negative post-PLC patients. The crosses indicate censored cases at the respective points. (PLC = pleural lavage cytology.)
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Five-year survival rates for patients with negative pre-PLC and post-PLC (n = 1,094), positive pre-PLC and negative post-PLC (n = 21), negative pre-PLC and positive post-PLC (n = 37), and positive pre-PLC and positive post-PLC (n = 13) were 81, 50, 12, and 0%, respectively. Multivariate analyses revealed 6 independent prognostic factors when only factors available before lung resection were analyzed (Table 4): age, CEA level, cT factor, cN factor, sP factor, and pre-PLC result. When factors available after postoperative pathologic evaluation were included in multivariate analyses, however, 10 independent prognostic factors were recognized, but pre-PLC result was not (Table 5): Age, CEA level, cT factor, pT factor, pN factor, p factor, lymphatic invasion, vascular invasion, resection completeness, and post-PLC result.
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Comment
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The first report on PLC was in 1958 by Spjut and associates [10]. They reported the results of post-PLC in 49 patients with lung cancer undergoing surgical resection. The cytologic results were positive for malignant cells in 16 (33%) of them, but outcomes were not analyzed. In 1984, Eagan and colleagues [11] reported positive post-PLC in 12 (8.9%) of 135 patients. Lung cancer recurred in nine of the 12 patients, with only two in the ipsilateral pleural space. Eight patients died of lung cancer, one recurring locally and seven having distant metastases. They concluded the prognostic role of PLC needed further study. The first report on pre-PLC was by Kondo and associates in 1989 [12], followed by their expanded result analyses in 1993 [13]. They reported that 42 (9.0%) of 467 lung cancer patients undergoing surgery with little or no pleural effusion had a positive pre-PLC result. The 3-year survival rates of the patients with negative and positive cytology results were 68.7% and 22.9%, respectively. The prognosis of the positive cytology group was as poor as that of stage IIIB or IV patients. They concluded that pre-PLC was an important prognostic factor, indicating microscopic cancer cell exfoliation into the pleural cavity and subclinical malignant pleural effusion. Okada and associates [14] reported, based on 1,000 patients in 2003, that 45 (4.5%) patients had positive pre-PLC findings. Positive cytologic findings were observed more frequently in patients with adenocarcinoma, advanced stage, extended lymph node involvement, pleural involvement, lymphatic invasion, vascular invasion, high serum CEA level, and male gender. The survival rate at 5 years was 28% in patients with a positive result and 67% in negative patients (p < 0.001). Multivariate analysis demonstrated that pre-PLC was an independent prognostic determinant (p = 0. 0290). Higashiyama and associates [1] performed pre-PLC and post-PLC in 325 lung cancer patients without malignant pleurisy. Positive post-PLC patients especially with adenocarcinoma resulted in a poor outcome. The survival rate at 5 years was 71% in 250 patients with negative pre-PLC and post-PLC results, while it was 33% in 19 patients with positive results. However, in multivariate analyses, neither pre-PLC nor post-PLC result was an independent prognostic factor in their study. Dresler and associates [3] reported the pre-PLC and post-PLC analysis in 137 patients in 1999. The 3-year survival rates of the patients with negative and positive pre-PLC results were 55% and 0%, respectively (p = 0.088). The 3-year survival rates of the patients with negative and positive post-PLC results were 50% and 0%, respectively (p < 0.04). In the present study, we analyzed both pre-PLC and post-PLC in almost 1,200 patients, the largest cohort ever studied with regard to PLC. Both pre-PLC and post PLC were analyzed in a multivariable setting, together with conventional significant clinicopathologic prognostic factors we reported previously [15]. Although our study yielded results similar to previous studies and post-PLC proved to be an important prognostic predictor, we found no difference in PLC results in relation to histologic characteristics. There have been a considerable number of reports concluding positive pre-PLC to be a poor prognosis predictor since pre-PLC was first reported by Kondo and associates in 1989 [12]. However, positive pre-PLC is currently not recognized as equivalent to T4 or a factor indicating incomplete resection [16–18]. In our study, pre-PLC was an independent prognostic factor when analyzed with prognostic factors available before lung resection, but not when postoperative pathologic factors and post-PLC results were combined in analyses. Positive pre-PLC patient outcome, when post-PLC was negative, was not very poor, with the 5-year survival rate reaching almost 60%. Therefore, positive pre-PLC result alone does not contraindicate surgical resection. In contrast, post-PLC proved to be an independent prognostic factor as significant as other established prognostic factors, including pathologic TNM status. No positive post-PLC patients survived beyond 4 years. As the patient outcome was extremely poor when pre-PLC was also positive, adjuvant therapy may be needed in these patients. We conclude PLC should be recognized as an essential prognostic factor and should be performed in NSCLC patients without pleural effusion and dissemination. And post-PLC, compared with pre-PLC, had a greater and independent impact on survival and needs to be incorporated in the pathologic staging of NSCLC in the future. As Vicidomini and associates referred to in their recent article on PLC [19], the results of the American College of Surgeons Oncology Group's Z0040 trial, which has completed a 1,200 patient accrual, will further define the potential implications of PLC in the management of lung cancer.
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Acknowledgments
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We thank Professor J. Patrick Barron, International Medical Communications Center, Tokyo Medical University, for reviewing the English manuscript. This study was supported in part by a Grant-in-Aid for Cancer Research from the Ministry of Health and Welfare, Japan.
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Abstract
Introduction
