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Ann Thorac Surg 1997;64:941-944
© 1997 The Society of Thoracic Surgeons

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Original Article: General Thoracic

Pleural Cytologies in Lung Cancer Without Pleural Effusions

Fox Chase Cancer Center, Philadelphia, Pennsylvania

	Abstract

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Background. Malignant pleural effusions significantly increase the stage of lung cancer with attendant worsening of prognosis. There is a paucity of literature evaluating malignant pleural lavage cytology in patients without pleural effusions. We propose to determine the incidence of malignant pleural cytologies in patients without pleural effusions who undergo curative resection for lung cancer and to identify any predictive risk factors for positive cytology.

Methods. Seventy-eight patients underwent curative resection for lung cancer. Lavage was performed before lung manipulation and after resection and cytologically evaluated.

Results. Twelve pneumonectomies, 64 lobectomies, and 2 wedge resections were performed on 40 men and 38 women with an average age of 65.7 years. Fourteen percent had positive lavage cytology before lung resection with an 11% (6 of 53) incidence in stage I. A significant correlation to adenocarcinoma compared with squamous cell was found (p = 0.03) but not to stage, T or N status, grade, pleural invasion, or preoperative transthoracic needle biopsy.

Conclusions. The incidence of positive pleural cytology in otherwise stage I patients is disconcertingly high. Positive cytology may be a prognosticator of a more aggressive tumor biology.

	Introduction

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
See also page 944.

A presumptive diagnosis of lung cancer and the presence of a pleural effusion mandates at least a thoracentesis to rule out malignant cells. The presence of a malignant pleural effusion significantly increases the stage of lung cancer with attendant worsening of prognosis and a predicted survival consistent with stage IIIB/IV disease. There is a paucity of literature evaluating the predictive value of a malignant pleural lavage cytology in patients without pleural effusions. The presence of malignant cells in the pleural cavity in patients without effusions before lung manipulation and resection may be attributed to either exfoliation from tumors at the pleural surface, thereby representing localized disease, or it may represent disseminated disease, which if found in otherwise early stage lesions would signify a much more aggressive tumor biology. Several papers have suggested the utility of performing intraoperative pleural lavage, either before or after resection to determine the importance of positive pleural cytology as a prognostic factor [1–5]. Three of these studies suggested that survival is decreased in patients without pleural effusions but with positive pleural lavage cytology [3–5]. However, despite these reports, pleural lavage in patients without an effusion who are undergoing potentially curative resection has not been established as a routine staging practice. In this study we propose to determine the incidence of malignant pleural cytologies in patients without pleural effusions who undergo curative resection for lung cancer and to identify any predictive risk factors for positive cytology.

	Material and Methods

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Patients
This study consisted of 115 consecutive patients who underwent thoracotomy for potentially curative resection of lung cancer at the Fox Chase Cancer Center between March 1996 and November 1996. Those patients who had evidence of pleural effusion by posteroanterior or lateral chest roentgenogram, prior thoracotomy or thoracostomy within the past 5 years, prior history of chemotherapy or chest radiation, or evidence of metastatic disease were excluded from the study.

Surgical Procedure
At operation, immediately after the pleura was incised, 250 mL of warm Ringer's lactate solution was instilled into the chest. The patient was gently rocked to assure good distribution. The washings were then aspirated and sent to cytology labeled as "Pre" lavage. There was no manipulation of the lung before or during this procedure. At the completion of the operation, before saline irrigation, the pleural lavage was repeated, again with 250 mL of warm Ringer's lactate solution. A fresh suction tip, tubing, and collection bag were used for this second washing. The specimen was labeled as "Post" lavage and sent to cytology.

Of the patients who underwent curative resection, those who were unresectable or were found to have positive surgical margins and those who were found to have benign or metastatic disease were excluded from the study.

Pathologic Examination
Pathologic stage, pathologic T status, pathologic N status, histology, grade, pleural invasion, and history of preoperative transthoracic needle biopsy were recorded. All patients were pathologically staged according to the American Joint Commission on Cancer for lung cancer (before the recent revision). Grade was recorded as well-differentiated, moderately differentiated, 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. Absence or presence of transthoracic needle biopsy was obtained to assess possible tumor spillage into the pleura cavity.

Statistics
Contingency table analysis was performed to test for association between first pleural lavage cytology and tumor stage, histology, grade, lymph node stage, degree of pleural involvement, clinical stage, and diagnosis obtained by percutaneous needle biopsy. Fisher's exact test was used when appropriate, otherwise the ² test of independence was employed. The critical level of significance was set to 5%.

	Results

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
A total of 78 patients were available for evaluation after 10 with benign, 15 with metastatic disease, and 12 with positive margins or unresectable disease were excluded.

There were 40 men and 38 women with an average age of 65.7 years (range, 35 to 87 years). A total of 12 pneumonectomies, 64 lobectomies, and 2 wedge resections were performed (4 patients had both a wedge and lobe resection). Positive lavage cytology before resection was identified in 14% (11 of 78) of patients. Two patients had positive lavage cytology after resection with negative lavage cytology before resection. Of the 11 patients with positive lavage cytology before resection, 7 had positive lavage cytology after resection. The 13 patients with positive lavage cytology (before or after resection) are listed in Table 1.

Pathologic T Status
The frequency of positive lavage cytology in patients with T1, T2, T3 and T4 tumors was 11% (3 of 28), 15% (6 of 41), 13% (1 of 8), and 100% (1 of 1), respectively. The T4 lesion represented a patient with two separate nodules in different lobes who underwent a pneumonectomy. No statistically significant association was found between positive lavage cytology before resection and pathologic T status.

Pathologic N Status
The frequency of positive lavage cytology in patients with N0, N1, N2, and Nx was 12% (7 of 59), 14% (2 of 14), 50% (2 of 4), and 0% (0 of 1), respectively. No statistically significant association was found between positive lavage cytology before resection and pathologic N status.

Histology
The frequency of positive lavage cytology in patients with adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, and large cell carcinoma was 23% (8 of 35), 4% (1 of 27), 20% (1 of 5), and 17% (1 of 6), respectively. In addition, there were 2 patients with small cell carcinoma, 1 with adenoid cystic carcinoma, 1 with carcinoma tumor, and 1 with adeno/large cell carcinoma. When tumor histology was categorized as adenocarcinoma, squamous cell carcinoma, or other, the association between lavage cytology before resection and histology was not statistically significant (p = 0.097). Adenocarcinoma was the most common histologic subtype with positive cytology.

Tumor Grade
The frequency of positive lavage cytology in patients with well-differentiated, moderately differentiated, poorly differentiated, and undifferentiated tumors was 0% (0 of 5), 17% (6 of 36), 14% (5 of 36), and 100% (1 of 1), respectively. No statistically significant association was found between positive lavage cytology before resection and tumor grade.

Pleural Invasion
The frequency of positive lavage cytology in patients with no pleural invasion, invasion into but not through the pleura, and invasion through the pleura was 18% (8 of 45), 11% (2 of 18), and 7% (1 of 15), respectively. No statistically significant association was found between positive lavage cytology before resection and pleural invasion.

Preoperative Transthoracic Needle Biopsy
Of the 78 patients, 30 had preoperative, diagnostic transthoracic needle biopsy, and of these, 17% (5 of 30) had positive lavage cytology. No statistically significant association was found between lavage cytology before resection and transthoracic needle biopsy.

	Comment

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
The first report on pleural cavity cytology and lung cancer was in 1958 by Spjut and associates [1]. Although a positive pleural cytology was demonstrated in 46% of patients, neither pathologic nor survival data were recorded. In 1984, Eagan and colleagues [2], from the Mayo Clinic, performed pleural lavage after completion of pulmonary resection in 136 patients. The lavage cytology after resection was positive in 8.9% of the resections: 4.3% in stage I, 18.7% in stage II, and 18.5% in stage III. They found positivity of pleural lavage to be related to lymph node status, cell type (adenocarcinoma more than others), and T status. Survival data were not included in this study.

Three more recent studies have examined the predictive value of preresectional pleural lavage in patients without an effusion. In 1990, Buhr and associates [3] studied 59 patients undergoing curative resection for primary lung cancer. They identified a 45.7% positivity: 39.5% in stage I, 50% in stage II, and 71.4% in stage III. Positivity was correlated to T status but not to lymph node involvement and was more frequently seen in squamous cell carcinoma as compared with adenocarcinoma. The 2-year survival rate in patients with stage I non–small cell lung cancer who had positive cytology was 40% as compared with 97% for those with negative cytology.

Okumura and coworkers [4] reported on 164 patients with pleural lavage cytology after thoracotomy, immediately after the resection, and just before closure after irrigating the chest. Twenty-three patients had at least one positive lavage cytology (14%), with 13 of these having the first lavage cytology give positive results (8%). A positive lavage cytology was found in 13% (10 of 70) in stage I patients, 3.7% (1 of 27) in stage II, 21% (9 of 44) in stage IIIA, and 43% (3 of 7) in stage IIIB. Positive cytology correlated with pathologic T stage, pleural invasion, and pathologic stage but not with lymph node status or histology, although adenocarcinoma was the most common type (15 of 23). The 3-year overall survival for patients with positive lavage cytology was 39% versus 69% for those with negative cytology. They found a higher recurrence rate for positive lavage cytology in patients with stage I and II cancers. They also examined the effect of diagnostic preoperative needle aspiration for cytology and found no correlation to resultant pleural cytology indicating that TTNB did not seed the pleural cavity.

A 1993 report by Kondo and colleagues [5] described a similar study in lung cancer patients in which pleural lavage before lung manipulation was performed using 50 mL of normal saline solution. Nine percent of 467 patients had positive lavage cytology: 3.7% (7 of 191) in stage I, 3.2% (2 of 26) in stage II, 11% (14 of 124) in stage IIIA, and 21% (7 of 33) in stage IIIB, with correlation to visceral pleural involvement and lymphatic involvement, but not to lymph node status. There was a significant difference in survival between patients with positive pleural cytology and those with negative cytology: 3-year overall survival of 23% versus 69%, respectively. This study also examined the effect of preoperative needle aspiration for cytology and found no correlation to resultant pleural cytology.

In our study of 78 patients we found a 14% (11 of 78) incidence of positive lavage cytology before resection overall and an 11% (6 of 53) incidence in stage I patients, 17% (3 of 21) in stage II, 18% (2 of 11) in stage IIIA, and 100% (1 of 1) in stage IIIB. There was no significant association between cytology and pathologic stage, pathologic T status, pathologic N status, histology, grade, or pleural invasion. This study also evaluated the theoretical risk of tumor seeding with pleural cavity contamination imposed by transthoracic needle biopsy. No association between positive lavage cytology and diagnostic preoperative transthoracic needle biopsy was identified in our study. These findings are consistent with the results presented by Okumura and associates [4] and Kondo and colleagues [5] who also evaluated the potential seeding with transthoracic needle biopsy.

Two of the patients had negative lavage cytology before resection but positive lavage cytology after resection. Both of these patients had invasion of the tumor through the visceral pleura, suggesting the possibility that lung manipulation resulted in exfoliation of cells into the pleural cavity. This underscores the importance of minimizing lung manipulation and the possible utility of irrigation at the completion of the procedure.

Our findings of the disconcertingly high incidence in otherwise stage I patients were also seen in the studies examining lavage before resection [3–5]. The etiology of the malignant pleural cells is unclear. both Okumura and colleagues [4] and Kondo and coworkers [5] found an association with pleural invasion, possibly suggesting cell exfoliation; however, this was not seen in our study. Dissemination by lymphatic spread is another plausible mechanism; however, neither the previous studies [3–5] nor our study found any association between positive cytology and lymph node involvement, although Kondo and associates [5] did find an association between positive cytology and lymphatic permeation as well as vascular involvement.

Survival data from this group will be important. Pleural cytology will be a significant prognosticator of a survival benefit if found in the negative lavage cytology group. Buhr and coworkers [3] reported an overall 2-year survival rate in stage I non–small cell lung cancer of 97% for negative cytology compared with 40% for the positive cytology group. Both Okumura and associates [4] and Kondo and colleagues [5] reported 3-year overall survival rates of 69% for their negative cytology groups compared with 39% and 23%, respectively, for their positive cytology groups. If these results are reproducible, indicating the utility of pleural lavage before resection as a prognosticator, then pleural lavage cytology before resection should be added to our staging armamentarium. This staging procedure is easily performed at the time of the operation with very minimal impact on the duration of the procedure. A large, national study is being planned to address these issues.

	Acknowledgments

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
We acknowledge Andre Rogatko, PhD, for his assistance in the statistical analysis of our data.

	Footnotes

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Presented at the Poster Session of the Thirty-third Annual Meeting of The Society of Thoracic Surgeons, San Diego, CA, Feb 3–5, 1997.

Address reprint requests to Dr Dresler, Fox Chase Cancer Center, 7701 Burholme Ave, Philadelphia, PA 19111.

	References

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 

1. Spjut JH, Hendrix VJ, Ramirez GA, Roper CL. Carcinoma cells in pleural cavity washings. Cancer 1958;11:1222–5.[Medline]
2. Eagan RT, Bernatz PE, Payne WS, et al. Pleural lavage after pulmonary resection for bronchogenic carcinoma. J Thorac Cardiovasc Surg 1984;88:1000–3.[Abstract]
3. Buhr J, Berghauser KH, Morr H, Dobroschke J, Ebner HJ. Tumor cells in intraoperative pleural lavage—an indicator for the poor prognosis of bronchogenic carcinoma. Cancer 1990;65:1801–4.[Medline]
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/Free Full Text]
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;106:1092–7.[Abstract]

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This Article Abstract 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): Sten I. Kjellberg Carolyn M. Dresler Melvyn Goldberg Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kjellberg, S. I. Articles by Goldberg, M. Search for Related Content PubMed PubMed Citation Articles by Kjellberg, S. I. Articles by Goldberg, M. Related Collections Related Article