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Ann Thorac Surg 1999;67:1435-1439
© 1999 The Society of Thoracic Surgeons

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Original Articles

Prognostic value of positive pleural lavage in patients with lung cancer resection

^a Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA

Accepted for publication October 26, 1998.

Address reprint requests to Dr Dresler, Medical Affairs for Smoking Control, SmithKline Beecham Consumer Healthcare, 1500 Littleton Rd, Parsippany, NJ 07054

	Abstract

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Background. Despite an early stage, lung cancer patients often have a poor survival, suggesting inaccurate staging. A pleural lavage demonstrating malignant cells at the time of operation may predict a poorer survival, particularly in patients with otherwise early disease.

Methods. Patients, with no preoperative evidence of pleural effusions and undergoing a surgical resection with curative intent, had a preresectional and postresectional lavage to be evaluated by cytology.

Results. Fourteen percent of patients with stage I disease had malignant cells in their preresectional lavage and had a significantly shorter survival than stage I patients with a negative lavage. Positivity of preresectional lavage was not correlated with nodal status, pleural or lymphatic involvement, or histologic findings.

Conclusions. Preoperative pleural lavage should become a standard technique intraoperatively to better characterize and stage patients undergoing lung cancer resections. Patients with malignant cells in their preoperative lavage should be upstaged.

	Introduction

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Although the lung cancer staging system recently has been revised, a significant number of recurrences and early deaths still occur in the early stages, resulting in poor survivals. Thus, the staging system does not adequately predict prognosis, particularly of the early stage patients. Several efforts are underway in various studies to better define and, therefore, discriminate prognostic factors in patients currently placed in early stages. This study built on our previously reported experience with pleural lavage in patients undergoing lung resection for lung cancer and followed them for survival outcome [1].

Approximately 15% of all patients diagnosed with lung cancer will have a pleural effusion [2]. Patients with known malignant cells in the pleural fluid would be categorized as T4 and placed in stage IIIb. Stage IIIb is considered advanced disease, and such patients are not appropriate for surgical resection. Usually their survival rate is poor with a median survival of 3 to 4 months [3].

There is a spectrum of disease, however, in patients presenting with the diagnosis of lung cancer and positive pleural fluid. Patients may have a large or small amount of fluid; it may be serous or serosanguinous; or there may be pleural metastases, pleural penetration, or no pleural involvement. Each of these distinctions may portend a different prognosis in an otherwise early stage malignancy. At the present time, all patients with a known cytologically positive effusion are treated as advanced disease, not as candidates for resection, and often may be relegated to palliative therapy or observation.

However, groups in Germany and Japan examined the prognostic value of pleural lavage in patients without a pleural effusion undergoing surgical resection [4–6]. These studies have suggested that a significant number of patients with otherwise early stage disease will have positive pleural cytology results and subsequently have a poorer prognosis than patients with negative cytology results. Presently, pleural lavage is not a generally performed procedure during the staging or resection of a patient with lung cancer, particularly in the United States. This paper describes the independent importance of the presence or absence of malignant cells in the pleural lavage, relative to other prognostic factors, in patients undergoing surgical resection for lung cancer.

	Material and methods

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Between March 1995 and December 1997, 137 patients underwent pleural lavage during thoracotomy for potentially curative resection of lung cancer at Fox Chase Cancer Center. Patients with evidence of pleural fluid on posteroanterior or lateral chest roentgenogram were excluded from this study. Immediately after opening the pleura, 250 mL of warm Ringer’s lactate solution was instilled into the pleural space. The patient was gently rocked to assure thorough distribution. The fluid was then aspirated and sent to cytology labeled as "PRE" lavage. There was no manipulation of the lungs before or during this procedure. After completion of the operation and before any saline irrigation, the pleural lavage was repeated with 250 mL of warm Ringer’s lactate solution using a new, clean suction apparatus and collection bag. This specimen was labeled as "POST" lavage and was sent to cytology. All cytologic specimens were centrifuged. Smears and cytospins were alcohol fixed and stained with Papanicolaou’s stain. Cell blocks were stained with hematoxylin and eosin.

Pathologic stage, pathologic N status, histology, grade, and evidence of pleural or lymphatic invasion were obtained from the synoptic pathology report. All patients were staged according to the recently revised American Joint Commission on Cancer (AJCC) system [7]. Grade was recorded as well, moderately, or poorly differentiated or undifferentiated. Pleural invasion was recorded as no invasion, invasion into but not through the visceral pleura, or invasion through the visceral pleura. For purposes of analysis, the latter 2 categories were grouped together.

Follow-up of patients was obtained from the patient’s medical record or from their primary care physician. Follow-up data were available on 129 of the 137 patients studied.

The association between lavage cytology findings and pathologic stage, pathologic N classification, histology, tumor grade, and pleural and lymphatic involvement was tested for statistical significance using the ² test and, when appropriate, the Cochran-Armitage trend test. Survival rates and median survival times were estimated according to the product-limit (Kaplan-Meier) method. The statistical significance of the difference between the survival curves associated with positive and negative cytology findings was evaluated by the generalized Wilcoxon test.

	Results

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Table 1 describes patient sex, age, procedure performed, histology, and stage.

Stage
The frequency of positive preoperative and postoperative cytology findings in each of pathologic stages I, II, and IIIa are given in Table 2. Although the overall association between stage and PRE and POST cytology was not statistically significant, the trend toward increasing frequency of positive POST cytology findings as the stage progresses from I to IIIa was significant at the 10% level (p = 0.09).

View larger version (14K): [in this window] [in a new window]   Fig 1. Survival in Stage I patients based on PRE lavage being positive or negative.

View larger version (14K): [in this window] [in a new window]   Fig 2. Survival in all stages based on PRE lavage being positive or negative.

	Comment

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The first report on pleural cavity cytology was in 1958 by Spjut and associates [8]. They demonstrated a 46% positive pleural cytology findings (obtained after resection), but they did not analyze the patients for survival. A report from Eagan and colleagues [9], from the Mayo Clinic in 1984, found an 8.9% postresection lavage positivity in 136 patients; 4.3% of the patients with a positive lavage result were otherwise in stage I.

More recently, in 1990 Buhr and coworkers [4] studied 59 patients undergoing a curative resection who had a PRE lavage with normal saline solution. They found a 46% positivity: 40% were in stage I, 50% in stage II, and 71% were in stage IIIa. They did not find positivity related to lymph node involvement, but did find it most related to squamous cell carcinomas rather than adenocarcinoma. Their 2-year survival in the stage I patients with positive PRE cytology findings was 22% as compared with 95% with negative cytology results. Kondo and associates in 1993 [5] also reported a pleural lavage study and again found a significant survival difference between positive and negative lavage results. In this study, they found a correlation between positive lavage results and visceral pleural involvement and lymphatic involvement, but not to lymph node status.

In the present study, 14.6% of patients had a positive PRE lavage finding. The most important finding, however, is that the 14% of stage I patients with malignant cells in their preoperative lavage had a significantly shorter survival than stage I patients with a negative lavage finding. These patients have a survival curve akin to stage III disease, and thus appear to be inadequately characterized under the current staging system. Moreover, this is a group of patients who may be appropriate for trials of adjuvant therapy.

This study did not find a correlation between positive PRE lavage findings and pathologic nodal status, differentiation, pleural involvement, or lymphatic involvement. In our series, PRE lavage positivity was higher in patients with adenocarcinoma rather than squamous cell or the other histologic classifications.

The importance of positive postoperative cytology results is difficult to determine. In this study, POST lavage cytology findings trended toward increasing positivity as the stage progressed from stage I to IIIa. Similarly, POST lavage positivity increased as nodal status went from N0 to N2 or when the pleural was involved. In addition, POST lavage cytology results statistically predicted poorer survival when all stages were analyzed together. However, because these findings correlate closely with standard components of the current staging system, it is less likely that postoperative cytology examination adds any significant prognostic information. From a therapeutic standpoint, because combined modality treatment is increasingly accepted in locally advanced stages of non–small cell lung cancer, positive postoperative cytology findings will not significantly change current treatment strategies.

The importance of this study is the demonstration of the statistically significant decrease in survival in otherwise early stage patients who are found to have malignant cells in their preresectional lavage. This is an important prognostic factor that should be amalgamated into the staging system and, therefore, become a routine aspect of staging, similar to the evaluation of nodal status.

The more difficult question is what to do with these patients once they are identified. Are they candidates for adjuvant therapy? In the present study, neither T (pleural involvement) nor N (nodal status) predicted the result of lavage. Should all early stage patients have preresectional evaluation of their pleural space? In the near future, a large surgical trial will address the issue of such micrometastatic in early stage lung cancer. Perhaps when this trial is completed these difficult questions may be addressed.

	Acknowledgments

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Grateful acknowledgment is given to Melyvn Goldberg, MD, for performing pleural lavage on the patients he resected for lung cancer.

	References

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 

1. Dresler C.M., Kjellberg S.I., Goldberg M. Pleural cytologies in lung cancer without pleural effusions. Ann Thorac Surg 1997;64:941-944.[Abstract/Free Full Text]
2. Johnston W.W. The malignant pleural effusion: a review of cytopathologic diagnoses of 584 specimens from 472 consecutive patients. Cancer 1985;56:905-909.[Medline]
3. Cohen S., Hossain S. Primary carcinoma of the lung: a review of 417 histologically proved cases. Dis Chest 1966;49:67-73.
4. Buhr J., Berghauser K.H., Morr H., Dobroschke J., Ebner H.J. Tumor cells in intraoperative pleural lavage—an indicator for the poor prognosis of bronchogenic carcinoma. Cancer 1991;65:1801-1804.
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6. 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 prognostic analysis. Ann Surg Oncol 1997;4:409-415.[Medline]
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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): Carolyn M. Dresler Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Dresler, C. M. Articles by Babb, J. Search for Related Content PubMed PubMed Citation Articles by Dresler, C. M. Articles by Babb, J.