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Ann Thorac Surg 2007;83:197-202
© 2007 The Society of Thoracic Surgeons

Original Articles: General Thoracic

Recurrence Patterns in Patients With Early Stage Non-Small Cell Lung Cancers Undergoing Positive Pleural Lavage Cytology

Yukitoshi Satoh, MD, PhDa,b,c,*, Rira Hoshi, CTb, Yuichi Ishikawa, MD, PhDc, Takeshi Horai, MD, PhDb, Sakae Okumura, MDa, Ken Nakagawa, MDa

a Department of Thoracic Surgical Oncology, Cancer Institute Hospital, the Japanese Foundation for Cancer Research, Tokyo, Japan
b Department of Cytology, Cancer Institute Hospital, the Japanese Foundation for Cancer Research, Tokyo, Japan
c Department of Pathology, Cancer Institute, the Japanese Foundation for Cancer Research, Tokyo, Japan

Accepted for publication August 14, 2006.

* Address correspondence to Dr Satoh, Department of Thoracic Surgical Oncology, Cancer Institute Hospital, 3-10-6 Ariake, Koto-ku, Tokyo 135-8550, Japan (Email: ysatoh{at}jfcr.or.jp).


   Abstract
Top
 Abstract
Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
BACKGROUND: Cytologic approaches such as pleural lavage cytology (PLC) are considered as possible aids to assessing prognosis of lung cancers. However, there is some controversy whether radical surgery is warranted based on the positive PLC findings with stage I non-small cell lung cancers (NSCLCs).

METHODS: From January 1991 to December 2002, PLC was performed before any manipulation or resection of the lung for 853 consecutive patients who had no macroscopic pleural effusion, dissemination, or diffuse adhesions and who subsequently underwent curative resection for NSCLCs. Results of PLC with reference to clinicopathologic characteristics, adjuvant therapy, 5-year survival, and recurrence patterns were analyzed.

RESULTS: PLC findings were positive in 41 patients (4.8%), rates being most frequent with adenosquamous carcinomas and adenocarcinomas. In the positive group, distant metastases (72%) and pleural recurrence (25%) (p = 0.0011) were often observed, and the survival rate was significantly poorer (p < 0.002), even for patients with stage I disease (p = 0.009). As adjuvant therapies in the positive group after resection, 6 patients received hypotonic cisplatin and 15 received a distilled water infusion into the pleural space. Although only 2 patients had pleural recurrence, these therapies did not improve long-term outcome.

CONCLUSIONS: PLC is a distinct prognostic factor for early stage lung carcinomas. Thus, we suggest that cytologic examination of PLC should be routine, even for patients with stage I NSCLCs before beginning lung resection. Moreover, curative resection, followed by adjuvant systemic therapy, could be necessary for improvement of outcome.


   Introduction
Top
 Abstract
 Introduction
Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
Despite improvements in detection and in surgical and medical treatment during the past two decades, the clinical behavior of non-small cell lung cancer (NSCLC) remains poor, with an unsatisfactory survival for even pathologic stage I adenocarcinomas [1]. The 5-year survival rates range from 70% for stage IA disease to 40% for stage IIB tumors after complete surgical resection in Western countries [2]. It is thus likely that many cancers diagnosed as early stage disease have already spread at the microscopic level [3].

Hundreds of papers have appeared in the past several decades proposing a variety of molecular markers or proteins and tumor-related biomarkers that may have prognostic significance for NSCLCs [4–6]. Cytologic approaches are considered useful as aids to assessing prognosis of early stage lung cancers [7]. Moreover, the presence of malignant cells on pleural lavage cytology (PLC) of patients with lung cancer is indicative of advanced disease [8–18].

In previous reports, rates for positive results of PLC before lung manipulation for NSCLC were 4% to 14% [8, 10, 19]. Patients with positive PLC findings, which might suggest an initial stage of carcinomatous pleuritis, have a poor survival rate because small amounts of malignant pleural effusion or a few minute pleural dissemination nodules might be easily overlooked at thoracotomy [18]. Positive cytologic findings without an effusion might be ascribed to exfoliation from tumors at the pleural surface, thereby representing localized disease, or might correspond to disseminated disease, implying a much more aggressive tumor biology [18].

The benefits of PLC procedures are under currently intensive investigation because findings appear increasingly clinically relevant to thoracic surgeons [18]. Indeed, recent studies indicated that information provided by PLC conveys important additional prognostic messages, leading to upstaging of patients to stage IIIB or greater [20, 21].

The present study, a prospective trial built on our experience with PLC in patients undergoing resection for NSCLCs and monitored for long-term outcome, was undertaken to analyze survival and the pattern of recurrence with particular reference to PLC findings with early stage lung cancers.


   Material and Methods
Top
 Abstract
 Introduction
 Material and Methods
Results
 Comment
 Acknowledgments
 References
 
This study was approved by our Institutional Review Board, and each patient gave written informed consent before treatment. From January 1991 to December 2002, PLC was performed before any manipulation or resection of the lung for 853 consecutive patients who had no macroscopic pleural effusions, dissemination, or diffuse adhesions and who subsequently underwent curative resection for primary NSCLCs. Curative resection was defined as complete resection of lung cancers with no evident cancer cells remaining based on surgical and pathologic findings, according to the Japanese Lung Cancer Society criteria [22]. Patients with macroscopic pleural effusions that could be collected with a syringe were excluded, as were patients who had been treated preoperatively with chemotherapy or radiotherapy and those who had undergone preoperative transthoracic needle aspiration biopsy.

Preoperative evaluation was based on a detailed history and physical examination, biochemical profile, chest roentgenogram, bronchoscopy, and computed tomography or magnetic resonance imaging, or both, of the chest, brain, and upper portion of the abdomen.

Immediately after thoracotomy, the pleural cavity was carefully washed with 100 mL of physiologic saline solution before any further manipulation of the pulmonary parenchyma. The surgeon avoided touching the pleural surface so that only desquamated cells were obtained. The fluid was removed and centrifuged at 1500 rpm for 5 minutes [18].

The obtained sedimented material was stained by the Papanicolaou method, and the results of cytologic examination were divided into three categories: negative, suggestive, and positive. Only those with positive findings were included in this study. Histologic diagnosis was based on the World Health Organization classification [23–25], and intraoperative staging was achieved by a careful postoperative examination of dissected intrapulmonary, hilar, and mediastinal lymph nodes.

The outcomes of histopathologic examination of the status of lymph node metastasis and pleural involvement were abbreviated as N and p factors [26]. The p factors were defined according to the Japanese Lung Cancer Society classification [22]: p0, tumor with no pleural involvement beyond the elastic layer; p1, tumor extension beyond the elastic layer of the visceral pleura but no exposure on the pleural surface; p2, tumor exposure on the pleural surface but no involvement of adjacent anatomic structures; and p3, involvement of adjacent anatomic structures. Briefly, p0 and p1 belong to T1 disease, p2 to T2, and p3 to T3 disease.

To investigate the impact on patient survival, the following clinicopathologic factors were reviewed and analyzed: gender, age (<65 versus ≥65), tumor location, histology, postoperative stage, T category, N category, and p status.

Cancer recurrence was divided into three categories according to the sites of initial recurrence: locoregional, pleural, and distant. Pleural recurrence was defined as any recurrent disease within the hemithoracic pleura.

Comparisons of categoric data between two groups were made using the {chi}2 test. Survival was calculated using the Kaplan-Meier method, and differences in survival were determined by means of log-rank analysis. Multivariate analyses were performed using the Cox proportional hazards model. A p < 0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Material and Methods
 Results
Comment
 Acknowledgments
 References
 
Studied were 353 women and 500 men, and their mean age was 62.7 years (range, 16 to 86 years). The findings of cytologic examination were not influenced by age (p = 0.84). Forty-one patients (4.8%), 25 men (5.0%) and 16 women (4.5%), had positive PLC findings. The cytologic outcomes of pleural lavage according to histologic type, pathologic stage, status of lymph node metastasis, pleural involvement of the tumor (p factors), gender, and age are summarized in Table 1.


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  		Table 1. Results of Pleural Lavage Cytology with Reference to Clinical and Pathologic Characteristics
 
Positive results were observed much more frequently in patients with adenosquamous carcinoma (15% [4/27]) or adenocarcinomas (5.7% [36/628]) and were lacking with squamous cell carcinomas and large cell carcinomas. All the tumors in positive patients were located in the lung periphery. Even with pathologic stage I disease, 12 (2.3%) of 523 patients were positive, and malignant cells were detected in the PLC of 9 (9.1%) of 99 patients with stage II and 18 (8.5%) of 211 with stage III disease. Thus, positive findings were seen more frequently with advanced stages. Among the stage I group with positive PLC, 2 patients had stage IA and 10 had stage IB. PLC was positive in 16 (2.7%) of 586 patients without nodal involvement, 11 (9.0%) of 122 with N1 disease, 10 (7.9%) of 127 with N2 disease, and 4 (22%) of 16 with N3 disease. The rates for positive cytologic findings with reference to pleural invasion were 1.2% (7/600) for the p0 group, 8.4% (10/119) for p1, 24% (23/95) for p2, and 2.6% (1/39) for p3, with statistically significant variation.

Univariate prognostic predictors were histology (p = 0.003), pathologic stage (p = 0.042), T status (p < 0.0001), N status (p = 0.0002), and pleural involvement (p < 0.0001), as summarized in Table 1. When factors available after postoperative pathologic evaluation were included in multivariate analyses, five independent prognostic factors—gender, age, T factor, N factor, and p status—were recognized, but the PLC result was not one of them (Table 2). Moreover, postoperative stage was recognized as a suggestive prognostic factor (p = 0.091; Table 2).


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  		Table 2. Results of Multivariate Analysis of Potential Prognostic Factors
 
Mean overall follow-up for patients still alive was 61 months (range, 4 to 159 months). The overall 5-year survival rate was 46% in patients with positive PLC findings and 76% in patients with negative results, the difference being statistically significant (p < 0.002; Fig 1). The 5-year survival rates of patients with stage I disease with negative and positive cytologic findings were 88% and 60% respectively, again with statistical significance (p = 0.009; Fig 2). In contrast, the 5-year survival rates of patients with stage II and III diseases negative and positive for PLC findings were 54% and 38%, the differences in these cases not being statistically significant (p = 0.093; Fig 3).


Figure 1
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  		Fig 1. Survival of patients with reference to results of pleural lavage cytology (PLC).

 

Figure 2
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  		Fig 2. Survival of patients with pathologic stage I disease with reference to results of pleural lavage cytology (PLC).

 

Figure 3
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  		Fig 3. Survival of patients with pathologic stage II and III diseases with reference to results of pleural lavage cytology (PLC).

 
Among 41 patients with positive PLC findings, 32 (78%) already had a recurrence, a pleural pattern being more frequently observed than in the negative PLC group (p = 0.0011; Table 3). Data for recurrence according to stage and PLC results are summarized in Table 4. Even among the 12 patients with stage I disease and positive PLC, 9 demonstrated a recurrence, consisting of pleural in 5 (56%), distant in 3 (33%), and locoregional in 1 (11%). In particular, the difference in pleural recurrence was statistically significant for stage I disease (p < 0.0008; Table 4). On the other hand, differences with all three recurrence patterns for stage II disease and pleural and locoregional recurrence patterns for stage III disease were not statistically significant.


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  		Table 3. Recurrence Patterns for Disease with Reference to Pleural Lavage Cytology Results
 

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  		Table 4. Recurrence Patterns for Each Stage With Reference to Pleural Lavage Cytology Results
 
Among the p0 and p1 groups, in which no exposure of the visceral pleural surface was evident pathologically, 17 patients had PLC-positive results (Table 1); only 4 of these had no lymph node metastasis. Among the remaining 13, cancer recurred in 10 after lung resection. The initial recurrence sites were distant organs in all but 1 patient. Among the p2 and p3 groups with tumor exposure on the pleural surface or involvement of adjacent anatomic structures, 24 patients had PLC-positive results (Table 1). Cancer recurred in 18 of these after lung resection: 11 with distant metastases, 6 with pleural recurrence, and 1 with locoregional recurrence.

As adjuvant therapies after lung resection for positive PLC patients, 6 received hypotonic cisplatin, 15 received distilled water infusion into the pleural space, and the others were not given any treatment. The 6 patients with hypotonic cisplatin treatment had registered for the phase III trial of intraoperative intrapleural hypotonic cisplatin treatment conducted by the Japanese Clinical Oncology Group [27]. Although 4 of these 6 patients with hypotonic cisplatin treatment had cancer recurrence, only one had pleural recurrence. In 15 patients with distilled water infusion into the pleural space, 12 had cancer recurrence, but only 1 had pleural recurrence. No significant differences were noted in clinical background, including age, gender, and stage, between the 21 patients receiving adjuvant therapy and the 20 without it. The 5-year survival rates for the two positive PLC groups with and without adjuvant therapy were 46% and 43% respectively. The difference was not statistically significant (p > 0.2; Fig 4).


Figure 4
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  		Fig 4. Survival of patients with reference to adjuvant therapies in the positive pleural lavage cytology (PLC) group.

 

   Comment
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
Acknowledgments
 References
 
Compared with data in other reports, the 5-year survival rate in the PLC-positive patients in our study was high [8–21]. This difference may have been caused by the stage distribution. The number of patients in our study with stage I disease was larger, accounting for 30% of the 41 patients with positive PLC. Inclusion of a relatively large number of patients with early disease clearly could result in increased survival rates.

In the present study, positive PLC results were associated with a higher pleural recurrence rate and a significantly poorer 5-year survival. Positive cytologic findings without an effusion could suggest more aggressive biologic behavior of the tumor. The cause of this presence might be ascribed to exfoliation from tumors at the pleural surface or cell diapedesis through the lymphatics, thereby representing localized disease, or it might correspond to dissemination [18, 21, 28]. Another cause might be exfoliation of malignant cells from metastatic mediastinal lymph nodes [21].

Patients with pathologic stage I disease (particularly stage IA disease) are generally assumed to have been cured after complete resection because of noninvolvement of lymph nodes. A considerable proportion of cases nevertheless demonstrate recurrence, however, and one reason might be the presence of cells with cytologic abnormality [1, 4, 7]. PLC is thought to be useful for prognostic assessment for patients of adenocarcinomas located in peripheral sites in the lung [8, 10–18]. Moreover, several studies have demonstrated that patients with a positive PLC in pathologic stage I or II demonstrate a poor 5-year survival rate [11, 29]. It is therefore important to show whether positive PLC results are associated with survival for each stage of NSCLC [29].

Positive PLC is currently not recognized as equivalent to T4 or a factor indicating incomplete resection [12, 14, 29]. Although a considerable number of studies have indicated that positive PLC results are independent predictors of prognosis, not all who point to poorer survival were able to confirm whether this was independent of stage [11, 15]. Thus, where and how PLC should be implemented into conventional lung cancer staging is still unclear. This problem partly stems from the small numbers of patients with positive PLC results and variable links with survival in each series [13, 20].

Recently, Lim and associates [20] described positive PLC results to be useful independent of the overall stage and, in particular, the nodal status. They recommended that cytologic results of pleural and peritoneal washing should be considered separately from the classification of isolated tumor cells and micrometastases [20]. PLC might, therefore, need to be incorporated for pathologic staging of NSCLCs. Although our study provided evidence that PLC is a prognostic indicator, this was not independent of postoperative pathologic factors; therefore, a positive PLC result alone does not contraindicate surgical resection.

Kondo and associates [11] earlier revealed a correlation between positive PLC and visceral pleural involvement. The rates for positive cytologic findings in our series also demonstrated statistically significant variation with reference to pleural invasion. As confirmed here for the p2 and p3 groups, the rates for distant metastasis were higher with positive PLC compared with pleural recurrence. The number of PLC-positive patients was small in the p0 and p1 groups, but 13 of the 17 had hilar or mediastinal nodal metastases, or both, and this could clearly impact survival.

In patients with stage I disease, including groups without lymph node metastasis or any pleural invasion, positive PLC results were associated with a higher pleural recurrence rate and a significantly poorer 5-year survival. This may therefore indicate a pre-stage of carcinomatous pleuritis, even with a stage I status [11, 18, 28]. There is still some controversy whether radical surgery is warranted based solely on positive PLC findings in stage I disease [11]; however, recent reports concerning small groups showed a better prognosis with use of intrapleural cisplatin after lung resection [27, 30]. Unfortunately, the phase III trial of intraoperative intrapleural hypotonic cisplatin treatment conducted by the Japanese Clinical Oncology Group had to be prematurely terminated because of the slow registration pace [27]. The number of patients enrolled in this randomized trial was small, but intraoperative intrapleural hypotonic cisplatin treatment was found to effectively suppress the appearance of carcinomatous pleuritis in resected patients with positive PLC findings [27].

In our series, only 2 of 21 patients with adjuvant therapy, including hypotonic cisplatin or distilled water infusion into the pleural space, showed pleural recurrence; however, we found no difference in the 5-year survival rates between the groups with or without such adjuvant therapy. Although consistent benefit for adjuvant chemotherapy to patients with surgically resected stage IB to II NSCLCs has been reported [31], the management of patients with resected stage III disease remains unclear [31]. Our results indicate that curative resection, followed by intrapleural adjuvant therapy, may contribute only to avoidance of pleural recurrence; therefore, other systemic adjuvant therapies could be necessary for improvement of prognosis with positive PLC disease.

In conclusion, although the numbers of patients with positive PLC results were limited, as in many other studies on this topic [11, 20, 21], our results confirm that PLC findings are distinct prognostic factors for early-stage lung cancers in particular. We thus suggest that cytologic examination of PLC should be performed routinely, even for patients with early stage NSCLCs, before beginning curative resection. Further studies of individual patient data, meta-analyses of published trials, examination of relapse patterns, and assessment of intraoperative or postoperative adjuvant therapy (cf. multi-institutional trials such as CALGB 159902 and ACOSOG Z0040) are clearly warranted.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
References
 
This study was supported by Grants-in-Aid from the Ministry of Education, Sports, Culture, Science and Technology, as well as grants from the Ministry of Health, Labour and Welfare, the Smoking Research Foundation, and the Vehicle Racing Commemorative Foundation. We thank Atsuko Minami, Masafumi Tsuzuku, Noriyuki Furuta, and Yuji Arai for their technical assistance; and Drs Satoshi Miyata, Masaru Ushijima, and Masaaki Matsuura, Bioinformatics Group, Genome Center, Japanese Foundation for Cancer Research, for helpful advice with the statistical analyses.


   References
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 

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Related Article

Invited commentary
Eric Lim
Ann. Thorac. Surg. 2007 83: 202-203. [Extract] [Full Text] [PDF]




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