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Ann Thorac Surg 2007;83:204-208
© 2007 The Society of Thoracic Surgeons

Original Articles: General Thoracic

Clinical Relevance of Intraoperative Pleural Lavage Cytology in Non-Small Cell Lung Cancer

Tatsuo Nakagawa, MD*, Norihito Okumura, MD, Yujiro Kokado, MD, Kentaroh Miyoshi, MD, Tomoaki Matsuoka, MD, Kotaro Kameyama, MD

Department of Thoracic Surgery, Kurashiki Central Hospital, Okayama, Japan

Accepted for publication July 18, 2006.

* Address correspondence to Dr Nakagawa, Department of Thoracic Surgery, Kurashiki Central Hospital, 1-1-1 Miwa, Kurashiki, Okayama 710-8602, Japan (Email: tn8336{at}kchnet.or.jp).


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Comment
 References
 
BACKGROUND: Intraoperative pleural lavage cytology for patients with lung cancer has been reported to be useful in detecting subclinical pleural dissemination. However, this procedure is not necessary for the staging of lung cancer in the current TNM staging system.

METHODS: Clinical records of 1025 patients with non-small cell lung cancer who underwent surgery were retrospectively reviewed and evaluated for the clinical relevance of intraoperative pleural lavage cytology.

RESULTS: Specimens of 37 patients (3.6%) were positive for pleural lavage cytology (PLC). Patients were categorized into three groups: positive PLC group, 27 patients with positive PLC without malignant pleural effusion or pleural dissemination; pleural dissemination (PD) group, 21 patients with malignant pleural effusion or PD; negative PLC group, 977 patients with negative PLC or negative PLC without PD. The positive PLC group had a significantly higher ratio of adenocarcinomas than the negative PLC group (p = 0.014). There was a significant difference in distribution of pleural factors between the positive and negative PLC groups (p < 0.001). Survival in the positive PLC group was significantly worse than in the negative PLC group (p = 0.007), especially in pathologic stage I (p = 0.001), but significantly better than in the PD group (p = 0.038). PLC status was found to be a significant independent prognostic factor in the multivariate analysis (p = 0.016).

CONCLUSIONS: The present study demonstrates the clinical relevance of intraoperative PLC in early stage non-small cell lung cancer. The result of intraoperative PLC should be involved in the staging system of lung cancer.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Comment
 References
 
Malignant pleural effusion in patients with lung cancer is regarded as T4 disease according to the TNM staging system. Patients with malignant pleural effusion or pleural dissemination (PD) have a poor prognosis, with a median survival of 2 to 4 months [1, 2], and are generally excluded from radical pulmonary resection. On the other hand, intraoperative pleural lavage cytology (PLC), a technique for detecting the subclinical dissemination of malignant cells in the pleural cavity, has been performed in various institutions, and the clinical relevance of PLC has been widely discussed [3–15]. Most of the studies revealed that positive PLC had a negative impact on postoperative survival of the patients with lung cancer; however, PLC is not regarded as an indispensable technique for the staging of lung cancer. Positive PLC by itself does not upgrade the stage of lung cancer according to the current TNM staging system. The reason for this controversy is probably the heterogeneous clinical outcome of the patients with positive PLC. Higashiyama and colleagues [13] reported that semiquantitative evaluation of tumor cell clusters in positive PLC was useful to predict postoperative recurrence. It is important to clarify whether radical resection is to be performed in patients with positive PLC who otherwise appear to have resectable tumors. In the present study, we retrospectively reviewed patients with non-small cell lung cancer (NSCLC) who underwent intraoperative PLC and evaluated the potential clinical role of this technique.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Comment
 References
 
From January 1993 to December 2005, thoracotomy was performed in 1092 patients with NSCLC at Kurashiki Central Hospital (Kurashiki, Japan). Intraoperative cytologic examination was performed as follows:

1 Inspection of the status of pleural effusion and dissemination was first performed immediately after thoracotomy.
2 When there was pleural effusion that could be collected by a syringe, a cytologic examination of the effusion was performed.
3 When there was no or minimal pleural effusion that was difficult to collect by a syringe, the pleural cavity was washed with 1000 mL of saline solution, and 10 mL of lavage was obtained for cytologic examination.
4 The sample was fixed onto glass slides using an auto-smear method (Sakura, Inc, Tokyo, Japan) and Papanicolaou-stained and reviewed by the cytologist.

Severe pleural adhesions precluded 67 patients from undergoing intraoperative cytologic examination of pleural lavage. They were excluded from this study, leaving 1025 eligible patients.

Clinical findings for each patient were obtained and reviewed from medical records. Pathologic typing and staging were determined according to the current guidelines from the Japan Lung Cancer Society [16], which are identical to the International System for Staging Lung Cancer [17].

Patients’ outcomes were confirmed by medical records or by telephone interviews. The median follow-up time was 22 months (range, 1 to 144 months). We preoperatively obtained the informed consent from the patients for the use of the clinical data, and our Institutional Review Board waived the need for the approval of the study.

Comparison between two groups was performed by the Pearson {chi}2 test for count data and the Student t test for continuous data if the distribution of the samples was normal, or by the Mann-Whitney U test if the distribution of samples was not normal. For univariate analysis, all the cumulative survival rates after the operation were calculated by the Kaplan-Meier method, and any differences were evaluated by the log-rank test. Multivariate analysis of independent prognostic factors was conducted by the Cox proportional hazards regression model (Wald stepwise backward elimination method). Differences were considered significant at p < 05. All statistical analyses were performed using the statistical software program package SPSS 13.0 (SPSS Inc, Chicago, Ill) for Windows (Microsoft Corp., Redmond, Wash).


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Comment
 References
 
Patient Background
Of the 37 patients (3.6%) whose specimens were positive for PLC, 10 (27.0%) had pathologically confirmed PD. A total of 21 patients had pathologically confirmed PD, 6 (28.6%) of whom had malignant pleural effusion (Fig 1). PLC status was categorized in the following three groups: positive PLC group, 27 patients with positive pleural lavage cytology without PD; PD group, 21 patients with malignant pleural effusion or PD; negative PLC group, 977 patients with negative PLC or negative pleural effusion cytology without PD. Of the 27 patients in the positive PLC group, 26 (96.3%) had adenocarcinoma, with a significantly higher ratio of adenocarcinoma compared with the negative PLC group (p = 0.014).


Figure 1
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  		Fig 1. Category of the patients classified according to the status of pleural involvement. (PLC = pleural lavage cytology; PEC = pleural effusion cytology; PD = pleural dissemination.)

 
As to the extent of pleural invasion, the distribution between the positive PLC and negative PLC group (p < 0.001) was significantly different. In the positive PLC group, p2 was more frequently observed than p3. The percentage of positive PLC was 23.4% (n = 15) in 64 patients with p2 disease and 2.1% (n = 2) in 95 patients with p3 disease. In contrast, the percentage of negative PLC was higher in patients with p3 disease than in patients with p2 disease (90.5% versus 65.6%). Comparison of clinicopathologic features between PD and negative PLC showed a significant difference in gender, surgical procedure, tumor size, and pleural invasion (Table 1).


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  		Table 1. Patient’s Clinicopathologic Background
 
Clinical Outcome
In the positive PLC group, 19 patients had recurrent disease: 6 had a local recurrence, 4 had a distant metastasis, and 9 had both local recurrence and distant metastasis. In the positive PLC group, 16 patients underwent chemical pleurodesis after surgery, and 21 patients received adjuvant chemotherapy. The 5-year survival rates were positive PLC group, 37.0%; PD group, 17.0%; and negative PLC group, 69.4% (p < 0.001). There was a significant difference in survival between the positive PLC and PD groups (p = 0.038), between the positive PLC and negative PLC groups (p = 0.007), and between the PD and negative PLC groups (p < 0.001) (Fig 2). When focusing on the PLC status, survival was compared between the positive and negative PLC groups and stratified according to pathologic stage. The survival of the positive PLC group was significantly worse than that of the negative PLC group in p-stage I (p = 0.001), whereas no significant difference was seen in p-stage II (p = 0.568), stage III (p = 0.224), or stage IV (p = 0.254) (Fig 3).


Figure 2
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  		Fig 2. Comparison of postoperative survival curves according to the category of pleural involvement. (PLC = pleural lavage cytology; PD = pleural dissemination.)

 

Figure 3
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  		Fig 3. Comparison of postoperative survival curves between positive and negative pleural lavage cytology (PLC) in stage I.

 
Multivariate Analysis
To elucidate independent prognostic factors in p-stage I, the six clinicopathologic factors of age, gender, surgical procedure, pathologic type (adenocarcinoma versus non-adenocarcinoma), tumor size (≤30 mm versus >30 mm), and PLC status were analyzed by multivariate analysis. The PLC status was found to be a significant independent prognostic factor (p = 0.016), as were age (p = 0.004), gender (p = 0.002), and pleural invasion (p < 0.001) (Table 2).


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  		Table 2. Multivariate Analysis of Prognostic Factors in Stage I a
 

   Comment
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
References
 
In the present study, we retrospectively analyzed the clinicopathologic background of patients with positive PLC and evaluated the clinical significance of PLC in patients with NSCLC. Positive rates of PLC vary among studies, from 3.7% to 38.6% [3–15]. In most studies, the positive ratio of PLC was much higher in adenocarcinoma than in squamous cell carcinoma. However, some articles reported a relatively higher positive ratio in squamous cell carcinoma and consequently a higher positive ratio of more than 20% for all [7, 15]. It was pointed out that, possibly, a large number of mesothelial cells grow as cell clusters in the pleural lavage and mimic squamous cell carcinomas [12]. Discrepancy in positive ratios among studies may partly depend on these false-positives in cytologic examination.

The most important result of our study is that patients with positive PLC had a significantly poorer prognosis than those with a negative PLC in p-stage I, which was confirmed by multivariate analysis of independent prognostic factors. The predictive value of PLC in relatively early stages of NSCLC has been reported in some articles [4, 5, 7, 10, 13]. It is acceptable that the impact of a positive PLC on prognosis was more clear in early stages rather than in advanced stages because the prognosis was so poor in the advanced stages that the negative impact of a positive PLC was difficult to detect.

Most cases of p-stage I are completely resectable, and the standard surgical procedure is lobectomy. The question is how a patient with stage I should be treated when the intraoperative PLC is positive. In the present study, there were 12 patients with a positive PLC in p-stage I, and lobectomy was performed in 9, segmentectomy in 2, and wedge resection in 1. No significant difference was found in recurrence rate among the surgical procedures (p = 0.670; data not shown), however, and the difference in survival (p = 0.353; data not shown) was not significant. Considering the high postoperative recurrence and mortality rate, standard lobectomy or pneumonectomy may not contribute to better prognosis than limited operation for patients with positive PLC, even when the stage is thought to be early.

Our study showed that patients with positive PLC had a more favorable prognosis than those with malignant pleural effusion or pleural dissemination, which is classified as the advanced stages pT4-stage IIIB or IV in the current TNM staging system. Okada and colleagues [13] reported a similar result in their study in a large population, suggesting that malignant pleural effusion could contribute to a worse prognosis compared with positive PLC. On the other hand, Kondo and colleagues [5] reported that the prognosis of patients with positive PLC was as poor as that of patients with stage IIIB or IV disease. It is acceptable that the PLC status should be involved in the staging system of lung cancer. However, there still seems to be controversy whether positive PLC should be considered the same as pleural dissemination.

The PLC status has a predictive value of clinical outcome and may give physicians a strategy for adjuvant therapy to patients with otherwise early stages of NSCLC. In the present study, 16 patients underwent chemical pleurodesis and 21 patients received adjuvant chemotherapy. Previously, the Japan Clinical Oncology Group conducted a phase III randomized trial to determine the efficacy of intraoperative intrapleural hypotonic cisplatin treatment for patients with positive PLC and revealed that the therapy was effective in suppressing the appearance of carcinomatous pleuritis [18]. However, survival between the treated and control group was not significantly different. Although it would not be easy to perform, a larger prospective study is needed to evaluate the efficacy of systemic adjuvant chemotherapy.

It is easy to explain why positive PLC was most frequently observed in pleural invasion in p2 disease in which the cancer cells invade the visceral pleura; however, positive PLC was observed even in p0 or p1 disease. Several studies have shown a strong correlation between positive PLC and lymphatic permeation. Although lymphatic invasion was histologically evaluated in only 79.7% of the patients (n = 817) because the evaluation was not routinely performed in the early period of the study, our data showed the same result, that is lymphatic invasion was detected in 55.6% of the positive PLC group and in 35.9% of the negative PLC group (p = 0.007).

Exfoliation of tumor cells through subpleural lymphatics to the pleural space can be speculated to be a cause of positive PLC [5, 11, 12]. On the other hand, it is intriguing that positive PLC was more frequent in p2 disease than in p3 disease. The same result was reported in previous articles [5, 11, 12]. Riquet and colleagues [12] reported that positive PLC was never observed in cases of p3 tumor or in cases where the parietal pleura was adherent in p2 tumors, even when the parietal pleura was not invaded. They suggested the possibility that adhesion to the parietal pleura prevents tumor desquamation to the pleural space.

In conclusion, our study demonstrates the clinical relevance of intraoperative PLC in early stages of NSCLC. Pleural dissemination is sometimes difficult to detect when the lesions are small and few in number. Recently, video-assisted thoracic surgery (VATS) has become popular for the surgical treatment of lung cancer. Intraoperative PLC is essential for the detection of microscopic exfoliation of tumor cells. It is possible that intraoperative PLC may also contribute to the detection of pleural dissemination. Such minimum lesions are difficult to detect because of limited surgical view in VATS. The American College of Surgeons Oncology Group conducted a phase III randomized trial (ACOSOG Z0040) for the evaluation of prognosis of occult metastases including positive PLC that finished in March 2004. The result of this study could confirm the clinical significance of PLC in patients with resectable NSCLC in the near future.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 References
 

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  4. Okumura M, Ohshima S, Kotake Y, Morino H, Kikui M, Yasumitsu T. Intraoperative pleural lavage cytology in lung cancer patients Ann Thorac Surg 1991;51:599-604.[Abstract]
  5. Kondo H, Asamura H, Suemasu K, et al. Prognostic significance of pleural lavage cytology immediately after thoracotomy in patients with lung cancer J Thorac Cardiovasc Surg 1993;106:1092-1097.[Abstract]
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  7. Buhr J, Berghauser KH, Gonner S, Kelm C, Burkhardt EA, Padberg WM. The prognostic significance of tumor cell detection in intraoperative pleural lavage and lung tissue cultures for patients with lung cancer J Thorac Cardiovasc Surg 1997;113:683-690.[Abstract/Free Full Text]
  8. Higashiyama M, Doi O, Kodama K, et al. Pleural lavage cytology immediately after thoracotomy and before closure of the thoracic cavity for lung cancer without pleural effusion and dissemination: clinicopathologic and prognostic analysis Ann Surg Oncol 1997;4:409-415.[Medline]
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