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Ann Thorac Surg 2005;79:254-257
© 2005 The Society of Thoracic Surgeons
Department of Thoracic Surgery, Second University of Naples, Naples, Italy
Accepted for publication June 25, 2004.
* Address reprint requests to Dr Vicidomini, Chirurgia Toracica, Seconda Università di Napoli, Piazza Miraglia, 2, 80138 Napoli, Italy (E-mail: gmvicidomini{at}yahoo.it).
Presented at Fortieth Annual Meeting of The Society of Thoracic Surgeons, San Antonio, TX, Jan 26–28, 2004.
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Abstract |
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METHODS: We enrolled 84 patients (79 men, 5 women) aged between 36 and 81 years (mean age, 64.8 years) undergoing a major lung resection for NSCLC, with no preoperative evidence of pleural effusions. Intraoperatively, the patients were given a pre-resectional pleural lavage with physiologic saline solution. The fluid was aspirated and sent to cytology.
RESULTS: Pre-resectional pleural lavage was positive in 19 patients (22.6%). The lavage was positive in 7.3% in patients with early stage I disease (3/41) and 37.2% in patients with stage II/III disease. In the group of 16 patients with chest wall neoplastic involvement (T3), 9 had a positive lavage (56.2%; p = 0.05). No significant correlation was found between positive lavage and nodal status, visceral pleural involvement, or histologic findings. Patients with malignant cells in the pre-resectional lavage had a significantly shorter survival than patients with a negative lavage (p = 0.025).
CONCLUSIONS: A positive cytology finding of intraoperative pre-resectional pleural lavage could be an important prognostic factor in patients undergoing major lung resection for NSCLC. Patients with a positive lavage should be upstaged. However, larger series are needed to define accurately the role of this technique in early stage lung cancer.
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsCommentDISCUSSIONReferences |
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One of the potential prognostic factors that has been evaluated in recent years is the presence of neoplastic cells in pleural lavage performed after thoracotomy. Malignant pleural effusion in patients with lung cancer is classified as T4, stage IIIb. Such disease is considered locally advanced and associated with a very poor prognosis. Patients with malignant pleural effusion are excluded from surgery and treated with alternative therapy or observation.
Several studies have evaluated the prognostic value of malignant cells detected in the pleural lavage performed intraoperatively either before, after, or before and after lung resection. Some authors suggest that positive pleural lavage cytology (PLC) worsens the prognosis of patients and should be considered as T4 [2, 3]. Patients classified in early stages after surgery should therefore be upstaged because malignant cells are present in the pleural lavage. The prognostic significance of this procedure and the correlation with other prognostic factors is not completely clear, however, and other researchers believe that positive PLC increases only the risk of local recurrences [4]. Thus, intraoperative pleural lavage is not commonly accepted as a routine procedure.
We present our experience with this procedure. Our study evaluated the importance of PLC and its potential role in terms of the staging and prognosis of NSCLC. We also tried to determine if this technique is able to select subgroups of patients for whom adjuvant therapy could improve survival.
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsCommentDISCUSSIONReferences |
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All patients received a standard preoperative evaluation that comprised a detailed history, physical examination, blood biochemical profile, chest radiography, bronchoscopy, total body computed tomography (CT) scan, bone scintigraphy, and functional evaluation (spirometry, lung perfusion scintigraphy, diffusing lung capacity for carbon monoxide [DLCO] test). Mediastinoscopy was performed only in cases of enlarged mediastinal lymph nodes at CT scan. Transthoracic fine needle aspiration biopsy (FNAB) was not performed. No patient had preoperative evidence of pleural effusion or distant metastases.
After a posterolateral thoracotomy and opening of the pleura, and before any surgical manipulation of the lung, 250 mL of warm physiologic saline solution was flushed into the pleural space. The fluid was shaken for 1 minute and then suctioned off by a syringe. After that, lung resection was performed along with a standard mediastinal lymph node dissection.
The lavage specimens were sent to the laboratory for cytology. After centrifugation, they were stained by the Papanicolaou method. Cell blocks were stained with hematoxylin and eosin. The results of cytology were determined to be negative or positive. All surgical data were recorded. The primary tumor was staged according to the TNM international staging system [1]. Lymph nodes were numbered according to Naruke classification [5]. The histologic type of tumor was determined by applying the World Health Organization classification.
The statistical analysis was performed by the means of 
2 test of independence and Fisher's exact test, when appropriate. The survival rates were calculated to the Kaplan-Meier method, and p of less than 0.05 was considered as the significance limit.
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Results |
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The distribution of positive lavage in each pathologic N status was 21.4% in N0 patients (12/56), 12.5% in N1 (1/8), and 30% in N2 (6/20). No statistical association was noted between PLC and nodal status.
The frequency of positive PLC was 18.4% (9/49) in cases of squamous cell carcinoma, 32% (8/25) in adenocarcinomas, 20% (1/5) in large-cell carcinomas, and 20% (1/5) in other types of carcinoma. Although patients with adenocarcinoma showed the higher rate of positive PLC, the association between histologic type and PLC was not significant.
Positive PLC significantly predominated in the group with invasion of parietal pleura (9/16 patients, 56.2%); positive PLC frequency was 25% (2/8) in the group with visceral pleura invasion and 13.3% (8/60) in the group with no pleural invasion. Thus, the correlation between positive PLC and parietal T3 disease was statistically significant (p = 0.05). The rates of positive PLC according to the pathologic characteristics of patients are shown in Table 2.
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Comment |
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TopAbstractIntroductionPatients and MethodsResultsCommentDISCUSSIONReferences |
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In the years since the first report by Spjut and associates [6] in 1958, several studies tried to define the potential prognostic role of pleural lavage. The results of the research on this subject are still inconclusive. In the first studies, pleural lavage was performed after lung resection [6, 7]; then, some authors performed the pleural washings before and after lung resection [3, 4]. The significance of postoperative PLC seems difficult to evaluate; the surgical manipulations influence significantly the positive PLC rate, and the results of the study from Dresler and colleagues [8] suggest that postoperative PLC does not add prognostic information or change postoperative treatment strategy. As have other research groups [2, 9, 10], we only performed pleural lavage before surgical maneuvers.
The frequency in the literature of positive pre-resectional PLC varies from 4.5% [11] to 14.6% [8]. We found positive PLC in 22.6% of our small series. As in other studies [9, 11], patients with adenocarcinoma showed the higher rate of PLC, but in our series the correlation was not statistically significant. Only 3 of 41 patients (7.3%) with stage I disease had positive PLC, whereas patients with stage II/III disease showed positive PLC in 37.2% of cases; the difference between these two groups was significant.
The results of the study from Kotoulas and colleagues [12] supported the hypothesis that malignant cells spreading from infiltrated mediastinal lymph nodes were the main cause of PLC. In our study, no statistical correlation was found between positive PLC and nodal status. Probably, the surgical manipulations can cause the seeding of cells from lymph nodes.
Kondo and colleagues [9] found a correlation between positive PLC and visceral pleural involvement. Our study did not confirm these findings. Despite the results of other authors [10], we found a correlation between the neoplastic involvement of chest wall (parietal T3 disease) and positive pre-resectional PLC. These data suggest that parietal pleural involvement may increase the risk of tumor cell desquamation in the pleural space.
Another main question is the potential influence of positive PLC on patient survival. Some researchers [13] support the position that positive PLC is only correlated with an increased rate of local recurrences. Okada and colleagues [11] observed distant metastases more frequently than local recurrences, supporting PLC status as an independent prognostic factor after lung resection for cancer.
We did not find a correlation between locoregional recurrences and positive PLC. In our series, the analysis of survival data showed a significant difference between patients with positive PLC and those with negative PLC. This correlation between positive PLC and survival was not confirmed when we excluded the subgroup of patients with parietal T3 disease. These data support that the presence of malignant cells in pleural washings should be considered as a subclinical malignant pleural effusion and classified as T4 disease.
One potential objective of PLC is to exclude patients from useless surgery. In the future, the preoperative performance of this procedure by the means of video-assisted thoracoscopy could allow a better selection of patients for surgery.
The American College of Surgeons Oncology Group (ACOSOG) Z0040 trial could improve our understanding of the PLC significance. This prospective multi-institutional study, which has recently closed the registration phase, is evaluating the prognostic role of occult metastases in 1,200 patients with NSCLC. The primary objective of this trial is to define the relationships between each of three indicators of occult metastases—pleural lavage cytology examination, immunohistochemistry assay of lymph node micrometastases, and immunohistochemistry assay of bone marrow micrometastases—and overall survival. The study should also clarify the relationships between these indicators and the site of first recurrence.
In conclusion, pleural lavage performed immediately after thoracotomy in patients with resectable lung cancer is an easy procedure that is associated with a negligible increase of the operation time. It appears to be an important prognostic factor, able to detect patients with a high risk of relapses and thus, with a poorer prognosis. We believe that the main cause of positive PLC is the exfoliation of malignant cells from the tumor, particularly when it reaches the parietal pleura. In the near future, the results of ACOSOG Z0040 could define the potential implications of this method in the postoperative management of lung cancer.
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DISCUSSION |
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TopAbstractIntroductionPatients and MethodsResultsCommentDISCUSSIONReferences |
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DR VICIDOMINI: There was no statistically significant difference between local recurrences and the metastases in these patients. There was just a slightly higher number of distant metastases, but the difference was not significant.
DR MILTON SAUTE (Petach-Tikva, Israel): For the patients with stage I who had positive lavage, would you recommend any adjuvant therapy?
DR VICIDOMINI: Obviously the small number of our patients prevents us from concluding in one sense or another. I think that if this conclusion is confirmed from a larger series of patients, maybe it would be better to put these patients in a adjuvant regimen after surgery.
DR KENNETH M. STEINGLASS (New York, NY): I have a question regarding past practices. Quite a few years ago, I remember during my training, when we encountered a peripheral lesion, we would irrigate the pleural space with sterile water, not saline, at the time of surgery in an attempt to lyse free cells. Your findings are intriguing and surely deserve further study. In the meantime, do you think that such irrigation would be a reasonable adjunct at the time of surgery? It surely takes no time at all, and if there really are shed cells that might be of prognostic significance, a little sterile water irrigation of the pleural space is easy and also costs nothing.
DR VICIDOMINI: We do not have experience with this procedure. However, I think it can be an option.
DR NASSER K. ALTORKI (New York, NY): I enjoyed your presentation. You have shown that positive pleural lavage is a marker for disease progression. Is there any reason to believe that it is more important than stage? Have you done a regression model to see if pleural cytology is an independent prognostic of outcome independent of stage?
DR VICIDOMINI: I think, again, that the series is not large enough in order to conclude this. However, our analysis suggests on the basis of this study that this is an independent prognostic factor.
DR DANIEL L. MILLER (Atlanta, GA): Just a comment. The Z40 trial, which is through ACOSOG, is looking at this very question with regards to micrometastasis, and that will be closed sometime this spring, so hopefully we will know the answer in regards to positive cytology within the next 6 to 12 months.
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