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Ann Thorac Surg 2003;75:353-355
© 2003 The Society of Thoracic Surgeons

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Original article: general thoracic

Visceral pleura invasion and pleural lavage tumor cytology by lung cancer: a prospective appraisal

^a Service de Chirurgie Thoracique Hôpital Européen Georges Pompidou, 20-40 rue Leblanc, 75015 Paris, France
^b Laboratoire d’Anatomo-Pathologie, Hôpital Européen Georges Pompidou, Paris, France

Accepted for publication September 5, 2002.

* Address reprint requests to Dr Riquet, Service de Chirurgie Thoracique, Hôpital Européen Georges Pompidou, 20-40 rue Leblanc, 75015 Paris, France.
e-mail: marc.riquet{at}hop.egp.ap-hop-paris.fr

	Abstract

Top Abstract Introduction Patients and methods Results Comment References

 
BACKGROUND: Despite an early-stage diagnosis, lung cancer presenting with visceral pleura invasion (VPI) or malignant pleural lavage cytology (PLC) has a poor prognosis. The purpose of this study was to correlate VPI to malignant PLC.

METHODS: One hundred forty-three consecutive patients scheduled for surgical lung resection having undergone preresectional pleural lavage cytology were reviewed. There were 121 malignant and 22 nonmalignant lesions. All cases were studied by pathology, histology, previous transthoracic puncture, VPI, and presence of pleural lymphatic involvement.

RESULTS: PLC was positive (n = 13) or suspected (n = 5) for malignant cells in, respectively, 10.7% and 4.1% of patients with lung cancer. There was no positive PLC in cases of nonmalignant disease. PLC was positive only in pT2 tumors and almost always when the tumor was exposed on the pleural surface, thus possibly exfoliating within the pleural space (12/17 patients, 70.6%; p < 0.01). Positive PLC was obtained whatever the histology but did not appear related to previous transthoracic puncture or involvement of pleural lymphatics by tumor cells.

CONCLUSIONS: VPI and positive PLC are linked, and the appearance of tumor cells within the pleural cavity can be explained by tumor desquamation. The role that visceral pleura involvement and parietal pleura reabsorption play in lung cancer is of paramount importance and deserves further research. A better understanding of their relationship could have major implications in the therapeutic management of non–small cell lung cancer.

	Introduction

Top Abstract Introduction Patients and methods Results Comment References

 
Visceral pleura invasion (VPI) by non–small cell lung cancer (NSCLC) is a specific entity in the TNM classification: a tumor of any size that invades the visceral pleura is classified as T2 [1]. Thus, VPI is a factor of poor prognosis [2]. Its frequent association with extensive N2 involvement supports the hypothesis that exfoliated tumor cells are drained from pleural lymphatics to the mediastinal lymphatic pathways and then into the blood stream [2, 3]. Okumura [4] and Kondo [5] and colleagues have noticed that prognosis was significantly aggravated when pleural lavage performed after thoracotomy and before lung resection revealed malignant cytology. These authors also noticed that pleural lavage cytology (PLC) was positive significantly more often in cases of VPI. The purpose of our study was to further define how VPI and positive PLC are correlated.

	Patients and methods

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Patients
This study consisted of 143 consecutive patients scheduled for thoracotomy in view of a lung resection at the Georges Pompidou European Hospital, Paris, France between February 2001 and July 2002. Patients with neoadjuvant therapy, diffuse pleural adhesions, suspected pleural effusion, pulmonary metastases, and central or T4 NSCLC were excluded. Patients included 41 women and 102 men aged 19 to 85 years (mean, 60.3 years). Pulmonary resection consisted of pneumonectomy (n = 18), lobectomy (n = 104), bilobectomy (n = 9), and wedge resections (n = 12). There were 22 miscellaneous lung diseases (MLD) and 121 NSCLC. MLD consisted of three tuberculomas, four typical carcinoïds, six bronchiectases, two hamartochondromas, one sequestration, four pseudo inflammatory diseases, one subpleural lymph node, and one hydatid cyst. Malignant disease consisted of 121 NSCLCs, three of which with synchronous lung cancers, accounting for 124 tumors: adenocarcinoma (n = 61), squamous cell carcinoma (n = 44), large cell carcinoma (n = 8), large cell neuroendocrine carcinoma (n = 4), adenosquamous (n = 4), and basaloid carcinoma (n = 2). The pTNM stage was Ia (n = 23), Ib (n = 49), IIa (n = 3), IIb (n = 24), and IIIa (n = 25).

Methods
After thoracotomy and immediately after opening of the pleura, 25 mL of warm physiologic saline solution was instilled into the pleural space. The patient was gently rocked to assure thorough distribution. The fluid was then aspirated by means of a syringe and sent to the laboratory for cytology. At the laboratory, pleural cavity aspirations were centrifuged. For each sample, four cytocentrifuge preparations were performed and stained with the Papanicolaou method and Wright-Giemsa stain. When possible, cell blocks were fixed in 10% buffered formalin for paraffin embedding, sectioning, and staining by hematoxylin and eosin. Samples were classified as benign, suspicious, or neoplastic. The major practical problem encountered was the amount of red blood cells, cell debris, and the distinction between reactive mesothelial cells and cancer cells. In ambiguous samples, an additional immunostaining with calretinine and BerEP4 antibodies was used [6]. To analyze the relationship of the tumor and the pleura, for each pulmonary resection (lobectomy or pneumonectomy), careful inspection of the pleural surface and palpation of lung parenchyma was performed. For tumors distal to the pleura, only one sample was submitted in order to detect lymphatic embolism. For tumors close to the pleura, multiple samples were taken. In these latter cases, in order to document tumor extension to or through the pleura, two or three sections at a right angle to the pleura were performed. These sections were taken in areas where the tumor was closest to the pleura, and in particular in retracted areas. In case of a sharp retraction of the pleura, a perpendicular section of the pleural margin including this area was performed. On microscopic analyses, when pleural invasion (VPI) was difficult to assess on hematoxylin and eosin stain, serial sections of the paraffin block and elastic stain were performed.

VPI was classified according to Hammar’s diagram [7]: px and p0 = tumor with no pleural involvement or reaching the visceral pleura but not extending beyond its elastic layer; p1 = tumor extending beyond the elastic layer of the visceral pleura but not exposed on the pleural surface; p2 = tumor exposed on the pleural surface but not involving the parietal pleura; and p3 = tumor invading the visceral and parietal pleura, corresponding to a subgroup of T3 in the pTNM. There were 62 p0, 31 p1, 17 p2, and 14 p3. Total p1 + p2 (n = 48; 38.7%) corresponded to VPI.

All cases were studied according to pathology, histology, VPI, previous transthoracic puncture, presence of visceral pleural lymphatic involvement by tumor cells, and tumor size.

All statistical analysis were performed using computerized software (JMP; SAS Institute, Cary, NC), with a p value of less than 0.05 considered as significant.

	Results

Top Abstract Introduction Patients and methods Results Comment References

 
PLC was positive (n = 13) or suspected (n = 5) for malignant cells in, respectively, 10.7% and 4.1% of patients with NSCLC. There was no positive PLC in cases of nonmalignant disease. There was no positive PLC after transthoracic puncture (n = 13) or in case of pT1 or pT3 disease. Positive PLC was significantly demonstrated in pT2 tumors (p < 0.02), but was independent of tumor size in case of T2 disease. Results according to histology and VPI are presented in Table 1. Positive PLC significantly predominated in the p2 group (12/17 cases, 70.59%; p < 0.01). This p2 group appeared to consist of three subgroups. In 11 cases (subgroup 1), p2 corresponded to its definition of a free tumor exposed on the pleural surface; all were PLC positive. In two cases (subgroup 2), the p2 tumor was exposed on the pleural surface and crossed a lung fissure; only one was PLC positive. In four cases (subgroup 3), the tumor was thought to be p3 at surgery and was excised with a partial parietal pleurectomy performed; these ended up being p2 tumors exposed on the visceral surface but contained within its adhesion to the parietal pleura; none had positive PLC.

	Comment

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PLC was positive in 10.7% (13/121) of patients with malignant disease, confirming reports in the literature with a frequency varying from 7.9% [4], to 9% [5], to 13% [8]. Positive PLC was more frequently observed in cases of adenocarcinomas, in constrast to a report by Buhr and associates [9], for whom squamous cell carcinoma appeared to be as frequent. In our study, we always observed a large number of mesothelial cells growing as cell clusters with at times cytoplasmic vacuolization, or bizarre cells mimicking carcinoma, particulary squamous cells carcinomas. The exact diagnosis was obtained by additional immunostaining, except in five cases, where cytology remained suspicious: two of which were squamous cell carcinomas. In fact, we observed, a positive PLC whatever the histology. We observed positive PLC in cases of adenosquamous carcinomas, as did Kondo and associates [5] and Dresler and associates[8], and in cases of large cell carcinomas, as did Dresler and associates [8] and in large cell neuro-endocrine carcinomas in 2 patients. The findings of the above authors are consistent with our observations of a lower frequency of positive PLC in cases of squamous cell carcinoma [5, 8].

Fine-needle aspiration cytology for lung cancer has been reported by Sawabata and associates [10] to have a high potential of malignant spread through the tract within the pleural space. A positive PLC has never been significantly correlated with previous transpleural fine-needle aspiration [4, 5, 8]. However, of the 13 patients who underwent preoperative transthoracic fine-needle aspiration, 3 had a positive PLC, but all presented as p2 VPI subgroup 1. We suggest a search for p2 VPI disease in cases of pleural carcinosis observed after lung resection in patients previously having undergone transpleural fine-needle aspiration.

These tumor cells can enter the pleural cavity, either through the lymphatics by diapedesis through the visceral pleura or as the result of exfoliation of cancer cells [11].

Kondo and associates [5] observed that positive PLC was significantly associated with subpleural lymph vessel involvement. Buhr and associates [9] performed tissue culture of tumor-free parenchyma in 23 cases of lung cancer. In 16 patients (69.6%), they detected tumor cells in lung parenchyma between the 3rd and 36th day (median 15 days) after incubation. In all patients, tumor cells were found in lymphatic vessels. In 14 of these patients, intraoperative pleural lavage was positive (87.5%).

In our series, positive PLC was not correlated with subpleural lymph vessel involvement by tumor cells, as was also reported by Dresler and associates [8]. We believe that the most likely mode of tumor cell seeding within the pleural cavity is exfoliation of cancer cells. As demonstrated by our study, 12 out of 13 positive PLC were observed in cases of p2 tumors, as also is reported by Kondo and associates [5]. Positive PLC was also possible in cases of p1 tumors, but not as frequent. Ichinose and associates [12] demonstrated the possibility of detecting tumor cells in pleura lavage using a jet stream of saline solution, even in cases of p1 tumors not diagnosed as invading the visceral pleura at histology. Manipulation of the lung during this procedure may account for the positive PLC or, perhaps, the multiplication of histologic slices could have lessened the number of p1 in benefit of p2.

Positive PLC has also been reported by Kondo and associates[5] and Okumura and associates [4] in cases of p3 tumors (which corresponds to T3 tumors). Kondo and associates [5] included in their study patients with pleural effusion and cases with pleural dissemination, whereas Okumura and associates [4] included both pre– and post–lung resection PLC. In our study, we never observed the positive PLC in cases of p3 tumors. Furthermore, positive PLC was never present in our series in cases where the parietal pleura was adherent to p2 tumors, even when the parietal pleura was not invaded. We believe that T3 or p3 involvement prevents tumor desquamation with the pleural cavity.

In conclusion, positive PLC appears correlated with VPI and most particularily within the p2 VPI subgroup 1. The role that visceral pleura involvment and parietal pleura cell reabsorption may play in the evolution and prognosis of NSCLC is an attractive and interesting topic, deserving further study. A better understanding of this relationship may have important implications for the therapeutic management of NSCLC.

	References

Top Abstract Introduction Patients and methods Results Comment References

 

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