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. 2016 Jul 26;11(7):e0157518. doi: 10.1371/journal.pone.0157518

Prognostic Value of Pleural Lavage Cytology in Patients with Lung Cancer Resection: An Updated Meta-Analysis

Chun-Mei Wang 1, Zhou-Gui Ling 2,*, Yan-Bin Wu 3, Shuang-Qi Cai 3, Zhen-Ming Tang 2, Cong Wu 3, Yi-Qiang Chen 3
Editor: Rafael Rosell4
PMCID: PMC4961387  PMID: 27458805

Abstract

Objective

Pleural lavage cytology (PLC) is considered as a possible tool for assessing prognosis of lung cancer patients. We aimed to comprehensively review the prognosis value of PLC in patients undergoing surgical resection.

Methods

We searched 4 electronic databases for relevant studies comparing positive PLC and negative PLC. The primary outcomes included survival rate and recurrence rate at maximum follow-up.

Results

The meta-analysis included 28 studies, with a total of 20,714 patients. For the overall survival rate of all stages, the results demonstrated that positive pre-resection, post-resection and pooled PLC were associated with unfavorable survival: hazard ratio (HR) 2.89 (95% confidence interval [CI] 2.48–3.37), 2.70 (1.90–3.83), and 2.89 (2.52–3.31), respectively. For the stage I survival rate, the combined results also suggested that positive pre-resection, post-resection and pooled PLC were associated with unfavorable survival: HR 3.29 (95% CI 2.55–4.25), 4.85 (2.31–10.20), and 3.16 (2.53–3.94), respectively. Furthermore, a meta-analysis of 14 studies included 14,279 patients showed that positive pre-resection, post-resection and pooled PLC were associated with an increased risk of overall recurrence: risk ratio (RR) 2.45 (95% CI 1.91–3.15), 2.37 (1.11–5.09), and 2.37 (95% CI 2.00–2.80), respectively. Positive PLC was also associated with a high pleural recurrence (RR 4.77; 95% CI 3.13–7.26) or distant recurrence (RR 2.33; 95% CI 1.65–3.29).

Conclusions

Both positive pre- resection and post-resection PLC are associated with not only higher tumor recurrence but also unfavorable survival outcomes in patients with lung cancer resection. This technique can therefore act as a strong prognostic factor for tumor recurrence and adverse survival rates.

Introduction

Lung cancer is a major cause of cancer-related deaths in the Western world [1], and its prognosis closely depends on the disease stage at diagnosis. Early detection and surgical resection are regarded as the mainstay to reduce the mortality of lung cancer patients [2]. However, the recurrence rate remains significant even with complete resection for early stage non-small-cell lung cancer (NSCLC) [3, 4]. One reason might be the exfoliation from the tumor in the pleural cavity, which spreads at a microscopic level even in the early stages [2]. Gu et al.[5] have suggested that occult micrometastatic tumor cells have already spread to the lymph nodes and bone marrow at the time of surgery, even though current clinical staging examinations and conventional histopathologic methods do not detected this. Therefore, methods to detect microscopic spread in patients with lung cancer resection are needed. One of those is pleural lavage cytology (PLC), which is a simple method with the potential to detect microscopic spread.

PLC is a technique that obtains cancer cells from saline instilled into and retrieved from the chest cavity during surgery for non-small-cell lung cancer (patients without preoperative pleural effusion) [6]. A positive PLC indicates the spread of microscopic intrapleural cancer resulting from visceral pleural invasion, vascular invasion or lymphatic permeation of the primary lesion [7]. Since it was first reported by Spjut et al.[8] in 1958, many studies have reported that positive PLC is associated with a poorer prognosis than is negative PLC [9–13]. Two previous meta-analyses concluded that positive PLC is a strong prognostic factor for survival in patients with lung cancer, and patients with PLC-positive disease may be appropriate for upstaging by one T category [6,14]. However, neither of these meta-analyses evaluated the relationship between positive PLC and recurrence, and the study by Lim et al.[6] did not differentiate between pre-resection and post-resection PLC. Recently, another meta-analysis [15] published in 2012, showed that patients with positive pre-resection PLC were associated with not only unfavorable survival outcomes but also higher tumor recurrence; however, the data regarding positive PLC after lung resection were not assessed in this meta-analysis. Since that time, many relevant studies in this field have been published. Some of those included large numbers of patients but conveyed controversial results. Therefore, we performed an updated meta-analysis to comprehensively assess the value of positive PLC in predicting the survival and recurrence rates in patients presenting with lung cancer resection.

Methods

Search strategy and inclusion criteria

Relevant studies were obtained by searching the PubMed, Embase, Cochrane Library and Chinese Biomedical Literature on disc (CBM) databases through September 15, 2015. The search terms for all four databases included (lung cancer OR pulmonary cancer OR lung neoplasm OR non-small-cell lung cancer) AND “Pleural lavage”, AND (lung resection OR pulmonary resection) in the title, abstract and keywords. The search was expanded using the ‘related articles’ function and by considering reference lists of all studies, including review articles. The search results were limited to human subjects. Additional articles were also identified by manually searching the references cited in the articles. This process was performed repeatedly until no additional articles could be found. Initially there were no language restrictions, but the full-text review and final analysis were limited to articles published in English and Chinese. The review was limited to the published studies. If evidence indicated that some patients participated in multiple studies (e.g., two or more articles with the same authors, institutions, or period of study), only the most recent article and the best-quality study were selected. Two reviewers (CMW and ZGL) independently judged study eligibility while screening the citations. Disagreements were resolved by a consensus determination by the reviewers.

To be included in our meta-analysis, studies had to meet the following criteria: studies had to compare outcomes related to positive and negative PLC in patients with lung cancer resection and to report either recurrence data or results that would allow the calculation of survival data. Conference abstracts were excluded because of the limited data presented in them. Review articles and studies in which it was not possible to extract the primary outcome of interest were also excluded.

Data extraction and outcome measurements

Two investigators (CMW and ZGL) independently extracted the following data: first author, year of publication, location, number of patients, total number of positive versus negative PLCs, maximum follow-up, outcomes, and European Lung Cancer Working Party (ELCWP) score. The extracted data were gathered in a standardized Access 2010 (Microsoft Corp) file and checked by another author (YBW). If conflicting results were reported, the data were checked by two authors (CW and YQC) until the disagreement was resolved. If any information was missing from a study, we contacted the authors to obtain the missing data. Some data were extracted from two previous meta-analyses [14,15].

PLC was performed immediately after thoracotomy and before closure of the thoracic cavity in the patients with no pleural effusions or apparent dissemination, then positive and negative pre- or post-resection PLC was compared. To explore the survival rate and recurrence rate of positive PLC, we only extracted data from the maximum follow-up. The outcomes of interest included overall survival rate of all stages, survival rate of stage I, overall recurrence of positive and negative PLC. Survival rates on the graphical representation of survival curves were determined by Engauge Digitizer version 4.1, three independent researchers (CMW, ZGL and ZMT) read the curves to reduce the imprecision in the reading variations.

Quality assessment

A methodological quality assessment of the included studies was performed by two investigators (CMW and ZGL), who were blinded to the study identities, using the European Lung Cancer Working Party (ELCWP) scale [16]. The description of methods was obtained from one article [14].

Statistical analysis

The impact of PLC on survival outcome was measured by hazard ratio (HR), which resulted from the survival rate at maximum follow-up. An HR >1 implied a worse survival outcome for the group with positive PLC. The recurrence rate was expressed as a risk ratio (RR) with 95% confidence interval (CI). An RR >1 implied a higher probability of recurrence for the positive PLC group. Heterogeneity of the included studies was evaluated using an I2 statistic, and sensitivity analysis was performed to further explore heterogeneity. If there was homogeneity of the individuals, a fixed-effect model was used. When the P-value of the heterogeneity test was <0.1, a random-effect model was used.

To assess the publication bias, we investigated the influence of a single study on the summary effect by omitting the outliers in each turn. The HR was calculated as described previously [17,18], and Log HRs, SE and their variations were then calculated by Review Manager Version 5.3. (The Cochrane Collaboration, Oxford, UK). Analyses were tested using Review Manager version 5.3 and SPSS version 16.0 meta-analysis software. A P-value <0.05 was judged as statistically significant.

Results

Study identification and selection

After an initial independent search, we identified 282 potentially relevant publications and excluded 101 duplicates. After reviewing the titles and abstracts, we excluded 127 publications because they did not meet the inclusion criteria. Among the remaining 54 full-text articles, 6 were excluded because the same authors published several reports on the same patients, and only the best-quality study was considered [2,19–23]; 3 were excluded because no outcomes of interest were reported [24–26]; 8 were excluded because they were meeting abstracts[27–34]; and 8 were excluded because they were non-English or non-Chinese publications [35–42]. One article was excluded because lavage cytology was not performed in the pleural cavity [43]. Finally, 28 articles were included in the present analysis [7,9,10,12,13,44–66]. The selection process is shown in Fig 1.

Fig 1. Selection process for the meta-analysis.

Fig 1

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Study characteristics

The meta-analysis included 28 studies involving 20,714 patients in which PLC was performed, and the baseline characteristics of these 28 trials are shown in Table 1. These studies were published between 1990 and 2015. The sample size of the included trials ranged from 84 to 4,171 individuals. Among these studies, 6 were conducted in Europe [10,45,47,49,52,65]; 20 in Japan [7,9,12,13,44,46,50–51,53–57,59–64,66]; and one each in the USA and China [48,58]. Among the 28 studies included here, 22 reported the survival rate of positive PLC versus negative PLC before resection, 5 reported the survival rate after resection, and 2 had PLC data from both pre- and post-resection. There were 14 studies that reported the stage I survival rate of positive PLC versus negative PLC (Table 1), and 14 reported the recurrence rate of positive PLC versus negative PLC (Table 2).

Table 1. Survival outcomes of PLC in the meta-analysis.

Author/Year Location Patients (N) Pos/Neg PLC Maximum follow-up (year) Overall survival rate (%) HR Stage I survival rate (%) HR ELCWP score
Pos/Neg p-Value Pos/Neg p-Value
Pre-resection PLC
Kondo/1993 Japan 467 42/425 3 22.9/68.7 <0.0001 7.39 NA 70.3
Buhr /1997 Germany 342 132/210 4 24.0/52.0 0.007 3.43 35.0/69.0 0.037 4.13 81.3
Higashiyama/1997 Japan 303 41/262 5 NA NA 72.8
Hillerdal/1998 Sweden 138 17/121 3 41.2/60.2 >0.05 2.16 NA 56.5
Dresler/1999 USA 124 17/107 2 31.0/63.0 0.088 3.79 48.0/82.0 0.009 4.94 72.8
Lim/2004 UK 292 13/279 3 28.2/ 64.5 0.002 4.63 NA 78.0
Tomita/2005 Japan 150 16/134 5 56.8 / 75.3 0.15 2.32 NA 79.8
Vicidomini/2005 Italy 84 19/65 3 30.0/ 65.0 0.025 4.33 NA 77.8
Nakagawa/2007 Japan 1004 27/977 5 37.0 /69.4 0.007 3.86 21.8/ 86.5 0.001 22.98 84.5
Tomita/2008 Japan 122 9/113 5 33.3/ 83.2 0.001 9.92 NA 79.8
Higashiyama/2009 Japan 679 89/590 5 43.0/66.0 <0.0001 2.57 57.0/ 80.0 <0.0001 3.02 72.8
Kawachi/2009 Japan 568 41/527 5 34.4 / 64.0 0.0001 3.39 NA 81.3
Nakamura/2009 Japan 284 13/271 5 12.3/ 66.0 <0.0001 13.84 NA 76.3
Shintani/2009 Japan 1249 67/1182 5 44.1 / 58.3 0.039 1.77 NA 81.3
Wang/2009 China 172 47/125 5 26.1/ 49.2 <0.001 2.74 NA 67.5
Taniguchi/2009 Japan 281 14/267 5 45.0/ 72.0 0.047 3.14 67.0/ 82.0 0.004 2.24 77.5
Aokage/2010 Japan 2135 65/2070 5 CI:1.71–3.20 2.34 NA 80.0
Hanagiri/2011 Japan 322 13/309 5 54.7/79.0 0.098 3.12 NA 72.5
Kaneda/2012 Japan 3231 148/3083 5 48.6 73.2 <0.001 2.89 56.8/77.0 0.01 2.55 80.0
Baba/2013 Japan 386 17/369 5 38.0/84.0 <0.01 8.57 NA 82.5
Yanagawa/2014 Japan 428 19/409 5 NA 46.6/76.5 <0.004 3.73 86.3
Mazza/2014 Italy 414 15/399 5 35.9/57.8 0.004 2.45 42.9/69.4 0.001 3.02 78.8
Hokka/2015 Japan 1317 46/1271 5 28.0/61.0 <0.0001 4.02 39.5 /77.3 <0.0001 5.22 75.8
Nakao/2015 Japan 1572 56/1516 5 50.6/78.0 <0.001 3.46 50.6 /88.9 <0.001 7.82 72.5
Overall 16,064 983/15081
Post-resection PLC
Dresler/1999 USA 121 14/107 2 43.0/58.0 0.04 1.67 67.0/80.0 0.97 1.97 72.8
Higashiyama/1997 Japan 306 44/262 5 NA NA 72.8
Kotoulas/2001 Greece 85 8/77 2 52.0/90.0 0.0081 8.31 NA 66.5
Maruyama/2004 Japan 143 49/94 5 55.1/ 5.1 0.02 2.46 75.0/ 89.9 0.02 2.97 68.3
Taniguchi/2009 Japan 293 26/267 5 32.0/76.0 <0.0001 6.73 33.0/86.0 <0.0001 12.47 77.5
Aokage/2010 Japan 2140 70/2070 5 22.0/ 9.0 <0.001 7.89 NA 80.0
Overall 3088 211/2877
Combination of pre- and post-resection PLC
Okumura/1991 Japan 158 23/135 3 38.8/69.2 <0.05 3.54 NA 64.5
Kameyama/2014 Japan 4171 217/3954 5 44.5/72.8 <0.0001 3.34 61.5/77.1 0.0062 2.11 66.3
Overall 4,329 240/4089
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HR = [p0/(1-p0)]/[p1/(1-p1)], p0 = the maximum follow-up survival rate in negative PLC group, p1 = the maximum follow-up survival rate in positive PLC group; PLC = pleural lavage cytology; ELCWP = European Lung Cancer Working Party; NA = not available; Pos/Neg = positive/negative; CI = confidence interval.

Table 2. Recurrence data of PLC in the meta-analysis.

Author/Year Location Patients(N) Pos/Neg PLC Maximum follow-up (year) Overall recurrence (n/N) Pleural recurrence (n/N) Distant recurrence (n/N)
Pos Neg Pos Neg Pos Neg
Pre-resection PLC
Buhr /1997 Germany 342 132/210 4 96/132 35/210 22/132 4/210 78/132 23/210
Higashiyama/1997 Japan 303 41/262 5 21/41 88/262 2/41 5/262 12/41 63/262
Higashiyama/2009 Japan 679 89/590 5 56/89 NA/590 21/89 14/590 32/89 NA
Kawachi/2009 Japan 568 41/527 5 24/41 141/527 7/41 31/527 13/41 69/527
Nakamura/2009 Japan 284 13/271 5 10/13 66/271 4/13 48/271 6/13 18/271
Shintani/2009 Japan 1249 67/1182 5 32/67 384/1182 3/67 7/1182 24/67 324/1182
Taniguchi/2009 Japan 281 14/267 5 9/14 53/267 2/14 19/267 4/14 23/267
Kaneda/2012 Japan 3231 148/3083 5 NA NA 26/148 86/3083 NA NA
Yanagawa/2014 Japan 428 19/409 5 7/19 52/409 2/19 6/409 2/19 21/409
Mazza/2014 Italy 414 15/399 5 9/15 122/399 4/15 59/399 5/15 63/399
Nakao/2015 Japan 1572 56/1516 5 40/56 387/1516 10/56 18/1516 28/56 292/1516
Overall 9,351 635/8716 248/398 1328/5043 103/635 297/8716 204/487 896/5043
Post-resection PLC
Higashiyama/1997 Japan 306 44/262 5 24/44 88/262 5/44 5/262 13/44 63/262
Taniguchi/2009 Japan 293 26/267 5 18/26 53/267 4/26 19/267 6/26 23/267
Overall 599 70/529 42/70 141/529 9/70 24/529 19/70 86/529
Combination of pre- and post-resection PLC
Okumura/1991 Japan 158 23/135 3 16/23 47/135 2/23 0/135 9/23 34/135
Kameyama/2014 Japan 4171 217/3954 5 141/217 1155/3954 NA NA NA NA
Overall 4329 240/4089 157/240 1202/4089 2/23 0/135 9/23 34/135
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PLC = pleural lavage cytology;NA = not available; Pos = positive; Neg = negative.

Quality assessment

The mean global quality score was 75.2%, with a range of 56.5 to 86.3% (Table 1). The design subscore had the lowest value, with only three studies that were prospective but non-randomized, and the remaining studies were retrospective. The most poorly described PLC methods included studies that did not define blinding or include a description of lavage sample conservation. The correlation was not significant between the global score and the number of patients included in the study (Spearman correlation coefficient rs = 0.348, p = 0.051). The global score was not statistically significantly different between the 20 studies performed in Japan and the 8 studies performed in other countries (mean 76.3% versus 72.4%, p = 0.133 by the two-sample t test).

Meta-analysis

Overall survival rate of all stages

Twenty-seven studies that included 19,677 patients (1,434 (7.3%) of whom were positive) reported overall survival rate of all stages. A meta-analysis demonstrated that positive pre-resection, post-resection and pooled PLC were associated with unfavorable survival: HR 2.89 (95% CI 2.48–3.37), 2.70 (1.90–3.83), and 2.89 (2.52–3.31), respectively. The test for heterogeneity was low among all studies (I2 = 21%, P = 0.16) (Fig 2). However, the heterogeneity in post-resection PLC was significant (I2 = 67%, P = 0.02). Subsequently, we performed sensitivity analyses to explore potential sources of heterogeneity. The study conducted by Dresler and colleagues [48] showed a strange CI in the forest plot, so we excluded the study and resolved the heterogeneity but did not change the results (HR 4.51, 95% CI 2.72 to 7.48; P<0.00001; P for heterogeneity = 0.21; I2 = 33%). We also performed a meta-analysis of the effect of positive PLC stratified by different study locations. The positive PLC patients conducted in Japan (19/27) showed a poor survival survival time (HR 3.04; 95% CI 2.69-0-3.57; P<0.00001), which similar to the experiences of remaining 8 countries (HR 2.52; 95% CI 1.94–3.28; P<0.00001).

Fig 2. Effect of positive PLC on the overall survival rate of all stages.

Fig 2

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Survival rate of stage I

There were 14 studies involving 14,129 patients (869 (6.2%) of whom were positive) included in the analyses of the stage I survival rate of PLC with lung cancer resection. Positive pre-resection, post-resection and pooled PLC were associated with unfavorable survival: HR 3.29 (95% CI 2.55–4.25), 4.85 (2.31–10.20), and 3.16 (2.53–3.94), respectively. The test for heterogeneity was low among all studies (I2 = 24%, P = 0.19) (Fig 3).

Fig 3. Effect of positive PLC on the survival rate of stage I lung cancer.

Fig 3

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Overall recurrence

Fourteen studies that included 14,279 patients reported overall recurrence data. The overall recurrence rate of positive PLC was 63.1% (447/708) and was 27.6% (2671/9661) in negative PLC. Positive pre-resection, post-resection and pooled PLC were associated with a higher likelihood of overall recurrence compared to negative PLC at maximum follow-up: RR 2.45 (95% CI 1.91–3.15), 2.37 (1.11–5.09), and 2.37 (95% CI 2.00–2.80), respectively. The test for heterogeneity was significant (I2 = 77%, P <0.00001) (Fig 4). In addition, the positive PLC patients conducted in Japan (12/14) showed a high recurrence (RR 2.37; 95% CI 2.03–2.78; P<0.0001), which consistent with the experiences of remaining 2 countries (RR 2.96; 95% CI 1.30–6.79; P = 0.01).

Fig 4. Effect of positive PLC on the overall recurrence.

Fig 4

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Pleural recurrence only

Fourteen studies including 10,108 patients reported pleural recurrence. The pooled RR was statistically significant at 4.77 (95% CI 3.13–7.26) with high heterogeneity (I2 = 64%, P = 0.0007) (Fig 5). Positive pre-resection PLC tended to have a higher impact on recurrence compared with positive post-resection PLC (RR 4.84 versus 3.39).

Fig 5. Effect of positive PLC on the pleural recurrence.

Fig 5

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Distant recurrence

Twelve studies including 6,201 patients reported distant recurrence. The pooled RR was statistically significant at 2.33 (95% CI 1.65–3.29) with high heterogeneity (I2 = 79%, P<0.0001). Positive pre-resection PLC was associated with an increased risk of distant recurrence (RR 2.62; 95% CI 1.72–4.00; P<0.00001), but positive post-resection PLC had no impact on distant recurrence (RR 1.70; 95% CI 0.80–3.62; P = 0.17) (Fig 6).

Fig 6. Effect of positive PLC on the distant recurrence.

Fig 6

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Publication bias

Fig 7 is a funnel plot including all studies (overall survival rate) and reveals one study [56] lying outside the 95% CI. After we removed the outlier, the shapes of the funnel plots became symmetrical and the overall survival outcomes for all patients (RR 2.84; 95% CI 2.48 to 3.26) were not altered significantly.

Fig 7. Funnel plots for publication bias for HR of overall survival rate.

Fig 7

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Discussion

NSCLC patients with positive PLC have a very poor prognosis. This meta-analysis aimed to comprehensively assess the HR of survival and the RR of recurrence for lung cancer patients having positive pre- or post-resection PLC compared to negative PLC. Our results suggest that both positive pre- and post-resection PLCs were associated not only with a higher recurrence rate but also with a poorer overall survival outcome at maximum follow-up compared with negative PLC. The HR of overall survival was 2.89 (95% CI 2.52–3.31) and the overall RR of recurrence was 2.37 (95% CI 2.00–2.80) for patients having positive PLC. In the analysis of studies that reported survival data for patients with stage I disease only, positive PLC both pre- and post-resection was also associated with unfavorable survival outcomes, and the pooled HR was 3.16 (95% CI 2.53–3.94). The recurrence and survival of positive PLC patients conducted in Japan were consistent with the experiences from other countries. The results of this meta-analysis showed that positive PLC can act as an adverse prognostic predictor for recurrence and survival in patients with lung cancer resection, regardless of whether it is performed before or after resection. However, a positive PLC result before lung resection tends to have a higher impact on survival than that of after resection, for the positive pre-resection PLC was associated with an increased risk of distant recurrence (RR 2.62; 95% CI 1.72–4.00; P<0.00001), which showed no impact on positive post-resection PLC (RR 1.70; 95% CI 0.80–3.62; P = 0.17).

The main finding of our meta-analysis was in agreement with the previously mentioned meta-analyses on this topic [6,14], which highlighted a link between unfavourable survival outcomes and positive pre-resection PLC. Our results also confirmed the findings of the meta-analysis by Saso et al,[15] which regarded pre-resection PLC were associated with not only unfavorable survival outcomes but also higher overall, local and distant recurrence. In detail, the updated meta-analysis included eight recently published articles on trials involving 11,841 patients, and some of them had large numbers of patients (>1,000). One study conducted by Kameyama et al.[63], published in 2014, involving 4,171 patients, and the authors found that 65% of patients with positive PLC and 29.2% of PLC-negative patients developed a recurrence within 5 years of surgery, which was statistically significant (P<0.0001). The 5-year survival rates were 44.5% for patients with positive PLC results and 72.8% for patients with negative PLC results (P<0.0001). In the present meta-analysis, the pooled data showed that positive pre- or post-resection PLC in patients at all stages had an unfavorable prognosis and a higher overall recurrence rate than did negative PLC. Although positive post-resection PLC was not associated with an increased risk of distant recurrence, it associated with an increased risk of higher overall and pleural recurrence compared to negative PLC. Therefore, positive pre- or post-resection PLC status was an independent factor for a poor prognosis.

The first line of treatment in patients with stage I cancer is complete lung or tumor resection, and the prognosis after resection in this category of patients is generally good. However, the survival outcome is poor if the PLC finding is positive during surgery. A previous meta-analysis [15] included nine studies showing that positive pre-resection PLC was associated with a poor survival outcome for patients with stage I cancer, and the HR was of statistical significance at 4.20. This updated meta-analysis included 14 studies (10 pre-resection and 3 post-resection). We also found that positive pre- or post-resection PLC in patients with stage I cancer had a poorer survival rate than did negative PLC, and it seems that positive post-resection PLC has a greater role in predicting survival than does positive pre-resection PLC (HR 4.85 versus 3.29). Similar results were reported by Satoh et al.[2], who found 5-year survival rates in stage I NSCLC patients of 60% in PLC-positive and 88% in PLC-negative patients. Nakagawa et al.[12] stratified their cohort of patients according to disease stage and determined that the different overall survival rate between PLC-positive and PLC-negative cases was only found in stage I NSCLC patients. The positive PLC findings seem to provide remarkable clinical information that might be used to identify a subset of stage I patients who might benefit from adjuvant treatments, including the use of local and systemic chemotherapy. Ogawa et al.[67] found that adjuvant chemotherapy after surgery tended to improve the 5-year recurrence-free survival rate by 30.9% compared with surgery alone in stage I patients with positive PLC findings. Baba et al.[62] determined that intrapleural chemotherapy with cisplatin could improve postoperative survival in PLC-positive NSCLC patients. However, these studies are small, retrospective, non-randomized, a large-scale, multi-centre, prospective randomized trial randomized-control trial is necessary.

With a mean score of 75.2%, the overall quality of all of the trials was not very good, and the main limitation of these studies is that a retrospective study design was used. On the other hand, although most studies were retrospective and only three trials were prospective, the result of the overall survival rate had low heterogeneity among the included studies. However, there was high heterogeneity within the results of recurrence, both pre-resection and post-resection, which potentially compromised the validity of our meta-analysis. The variations in inclusion criteria, patient characteristics, maximum follow-up, cytological techniques and experience of the pathologist may explain the heterogeneity.

Several potential limitations of the present meta-analysis should be taken into account. First, this meta-analysis included some clinical studies that had a small or modest sample size; for example, ten studies included no more than 200 patients each, which may cause an overestimation of the true effect compared to larger samples. Second, there was considerable heterogeneity among the studies. For example, most studies (20/28) were conducted in Japan, the number of patients varied greatly, and the maximum follow-up period and ELCWP score differed. The experience of surgeon may potentially influence the survival and recurrence outcomes, although the results from Japan were consistent with the experiences from other countries, these factors may have resulted in heterogeneity, with a potential impact on our results. Third, the inclusion of only studies published in English and Chinese may have resulted in publication bias. Furthermore, our review only included fully published studies. We did not include unpublished studies and conference abstracts because our methodology required data that was in available in full publications to perform the methodology assessment and meta-analysis.

Positive pre-resection PLC proved to be a strong independent adverse prognostic factor, positive post-resection PLC was also a strong predictor for a poor prognosis. Although 7.3% of lung cancer patients had a positive finding of PLC in our study, the presence of malignant cells in the pleural cavity without apparent pleural effusion indicates the aggressive biologic behavior of the tumor, including cell exfoliation, migration, and extravasation [60]. Therefore, we suggest that a cytological examination of PLC should be performed routinely in patients with lung cancer resection, whether before or after curative resection. A positive result may prove beneficial during the initial tumor staging process and thus subsequent management decisions. Indeed, larger tumor size, later stage, adenocarcinoma and pleural invasion were found more frequently in PLC-positive patients [7,48,64]. Since positive cytology was associated with a high pleural or distant recurrence, the adjuvant chemotherapy after surgery should focus on local (i.e. intrapleural chemotherapy) or systemic treatment according to the status of recurrence in patients with positive PLC.

In conclusion, positive pre- or post-resection PLC is associated with not only higher tumor recurrence but also unfavorable survival outcomes in all stages and particularly in stage I lung cancer patients. Positive PLC indicates subclinical dissemination of cancer cells into the pleural cavity; it means a greater possibility of recurrence or metastasis and is almost synonymous with malignant pleural effusion. Our results confirm that PLC findings are independent prognostic factors for all stages or particularly in early stage lung cancer. Further large-scale, multicenter, prospective randomized trials of ‘surgery’ versus ‘surgery and adjuvant chemotherapy’ in stage I patients with positive resection PLC may be needed.

Supporting Information

S1 Appendix. A PRISMA 2009 checklist for this meta-analysis.

(DOC)

Click here for additional data file. (64.5KB, doc)
S1 Table. Survival outcomes of PLC in the meta-analysis.

(DOCX)

Click here for additional data file. (39.6KB, docx)
S2 Table. Recurrence data of PLC in the meta-analysis.

(DOCX)

Click here for additional data file. (29.2KB, docx)

Abbreviations

PLC

pleural lavage cytology

HR

hazard ratio

CI

confidence interval

TNM

tumor nodes metastasis

NSCLC

non-small-cell lung cancer

ELCWP

European Lung Cancer Working Party

RR

risk ratio

BLC

bag lavage cytology

Data Availability

All relevant data are within the paper and its Supporting Information files.

Funding Statement

This study was supported by the research grant from National Natural Science Foundation of China (No. 81360018) to Dr. Cong Wu [http://www.nsfc.gov.cn]. The funders designed the study and resolved disagreements.

References

  • 1.American Cancer Society. Cancer Facts and Figures 2011.Atlanta: American Cancer Society; 2011. [Google Scholar]
  • 2.Hanagiri T, Baba T, So T, Yasuda M, Sugaya M, Ono K, et al. Time trends of surgical outcome in patients with non-small cell lung cancer. J Thorac Oncol. 2010;5:825–9. 10.1097/JTO.0b013e3181d5e47f [DOI] [PubMed] [Google Scholar]
  • 3.Mountain CF. Revisions in the international system for staging lung cancer. Chest. 1997;111:1710–7. [DOI] [PubMed] [Google Scholar]
  • 4.Martini N, Bains MS, Burt ME, Zakowski MF, McCormack P, Rusch VW, et al. Incidence of local recurrence and second primary tumors in resected stage I lung cancer. J Thorac Cardiovasc Surg. 1995;109:120–9. [DOI] [PubMed] [Google Scholar]
  • 5.Gu CD, Osaki T, Oyama T, Inoue M, Kodate M, Dobashi K, et al. Detection of micrometastatic tumor cells in pN0 lymph nodes of patients with completely resected nonsmall cell lung cancer:impact on recurrence and survival. Ann Surg 2002;235:133–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Lim E, Clough R, Goldstraw P, Edmonds L, Aokage K, Yoshida J, et al. Impact of positive pleural lavage cytology on survival in patients having lung resection for non-small-cell lung cancer: An international individual patient data meta-analysis. The Journal of thoracic and cardiovascular surgery. 2010;139:1441–6. 10.1016/j.jtcvs.2009.05.048 [DOI] [PubMed] [Google Scholar]
  • 7.Nakao M, Hoshi R, Ishikawa Y, Matsuura Y, Uehara H, Mun M, et al. Prognosis of non-small-cell lung cancer patients with positive pleural lavage cytology. Interactive cardiovascular and thoracic surgery. 2015;20:777–82. 10.1093/icvts/ivv047 [DOI] [PubMed] [Google Scholar]
  • 8.Spjut HJ, Hendrix VJ, Ramirez GA, Roper CL. Carcinoma cells in pleural cavity washings. Cancer 1958;11:1222–5. [DOI] [PubMed] [Google Scholar]
  • 9.Kondo H, Asamura H, Suemasu K, Goya T, Tsuchiya R, Naruke T, et al. Prognostic significance of pleural lavage cytology immediately after thoracotomy in patients with lung cancer. The Journal of thoracic and cardiovascular surgery. 1993;106:1092–7. [PubMed] [Google Scholar]
  • 10.Lim E, Ali A, Theodorou P, Nicholson AG, Ladas G, Goldstraw P. Intraoperative pleural lavage cytology is an independent prognostic indicator for staging non-small cell lung cancer. The Journal of thoracic and cardiovascular surgery. 2004;127:1113–8. [DOI] [PubMed] [Google Scholar]
  • 11.Riquet M, Badoual C, Le Pimpec Barthes F, Lhote FM, Souilamas R, Hubsch JP, et al. Visceral pleura invasion and pleural lavage tumor cytology by lung cancer: a prospective appraisal. Ann Thorac Surg. 2003;75:353–5. [DOI] [PubMed] [Google Scholar]
  • 12.Nakagawa T, Okumura N, Kokado Y, Miyoshi K, Matsuoka T,Kameyama K. Clinical relevance of intraoperative pleural lavage cytology in non-small cell lung cancer. Ann Thorac Surg.2007;83:204–8. [DOI] [PubMed] [Google Scholar]
  • 13.Aokage K, Yoshida J, Ishii G, Enatsu S, Hishida T, Nishimura M,et al. The impact on survival of positive intraoperative pleural lavage cytology in patients with non-small-cell lung cancer.J Thorac Cardiovasc Surg. 2010;139:1246–52. 10.1016/j.jtcvs.2009.07.049 [DOI] [PubMed] [Google Scholar]
  • 14.Li YN, Shi HZ, Liang QL, Yang HB, Huang GM. Prognostic significance of pleural lavage cytology in patients with lung cancer: a meta-analysis. Lung cancer (Amsterdam, Netherlands). 2008;60:183–92. [DOI] [PubMed] [Google Scholar]
  • 15.Saso S, Rao C, Ashrafian H, Ghaem-Maghami S, Darzi A, Athanasiou T. Positive pre-resection pleural lavage cytology is associated with increased risk of lung cancer recurrence in patients undergoing surgical resection: a meta-analysis of 4450 patients. Thorax. 2012;67:526–32. 10.1136/thoraxjnl-2011-200424 [DOI] [PubMed] [Google Scholar]
  • 16.Steels E, Paesmans M, Berghmans T, Branle F, Lemaitre F, Mascaux C, et al. Role of p53 as a prognostic factor for survival in lung cancer: a systematic review of the literature with a meta-analysis. Eur Respir J 2001;18:705–19. [DOI] [PubMed] [Google Scholar]
  • 17.Liu SJ. Meta-analysis of survival data:in:Zhang TS, Zhong WZ. Applied methodology for evidence-based medicine. 1th ed Changsha:Central-south university press;2012: 161. [Google Scholar]
  • 18.Tierney JF, Stewart LA, Ghersi D, Burdett S, Sydes MR. Practical methods for incorporating summary time-to-event data into meta-analysis. Trials. 2007;8:16 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.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. [DOI] [PubMed] [Google Scholar]
  • 20.Okada M, Tsubota N, Yoshimura M, Miyamoto Y, Maniwa Y. Role of pleural lavage cytology before resection for primary lung carcinoma. Annals of surgery. 1999;229:579–84. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Okada M, Sakamoto T, Nishio W, Uchino K, Tsuboshima K, Tsubota N. Pleural lavage cytology in non-small cell lung cancer: lessons from 1000 consecutive resections. The Journal of thoracic and cardiovascular surgery. 2003;126:1911–5. [DOI] [PubMed] [Google Scholar]
  • 22.Ding ZP, Shen-tu Y, Han WB, Zhou YZ, Wang KQ. Clinical value of pleural lavage cytology during operation for lung cancer. Tumor.2003;23:431–3. [Google Scholar]
  • 23.Enatsu S, Yoshida J, Yokose T, Nishimura M, Nishiwaki Y, Shirakusa T, et al. Pleural lavage cytology before and after lung resection in non-small cell lung cancer patients. The Annals of thoracic surgery. 2006;81:298–304. [DOI] [PubMed] [Google Scholar]
  • 24.Ding ZP, Shen-tu Y, Han WB, Zhou YZ, Wang KQ. The assessment value of pleural lavage cytology during operation for the patient's 3-year-survival rate with lung cancer. Chinese Journal of Clinical Rehabilitation. 2003;7:2513–4. [Google Scholar]
  • 25.Ichinose Y, Tsuchiya R, Yasumitsu T, Koike T, Yamato Y, Nakagawa K, et al. Prognosis of non-small cell lung cancer patients with positive pleural lavage cytology after a thoracotomy: results of the survey conducted by the Japan Clinical Oncology Group. Lung cancer (Amsterdam, Netherlands). 2001;31:37–41. [DOI] [PubMed] [Google Scholar]
  • 26.Higashiyama M, Kodama K, Yokouchi H, Takami K, Nakayama T, Horai T. Clinical value of pleural lavage cytological positivity in lung cancer patients without intraoperative malignant pleuritis. Recurrent pattern based on semiquantitative analysis of tumor cells in pleural lavage. The Japanese journal of thoracic and cardiovascular surgery. 2000;48:611–67. [DOI] [PubMed] [Google Scholar]
  • 27.Kaneda M. Value of examining pleural lavage cytology at the operation for primary lung cancer in clinical practice. Chest. 2010;138(4). [Google Scholar]
  • 28.Mazza F, Maineri P, Ferrari E, Alloisio A, Piras MT, Ratto GB. Positive pleural lavage cytology is a predictor of poor prognosis in resected NSCLC. Journal of Thoracic Oncology. 2011;6(6):S603–4. [Google Scholar]
  • 29.Shiba M, Nagato K, Iida T, Kunimatsu E. Cytodiagnosis of subclinical pleural effusion found at thoracotomy in surgically treated NSCLC patients. Cytopathology. 2012;23:69. [Google Scholar]
  • 30.Kakihana M, Usuda J, Kajiwara N, Ohira T, Ikeda N. Clinical value of intraoperative pleural lavage cytology in non-small cell lung cancer patients. Chest. 2012;142(4). [Google Scholar]
  • 31.Hokka D, Maniwa Y, Tauchi S, Tane S, Uchino K, Tane K, et al. Pleural lavage cytology is a significant prognostic factor for stage i lung adenocarcinoma patients. European Journal of Cancer. 2013;49:S809. [Google Scholar]
  • 32.Kobayashi Y, Yatabe Y, Takahashi O, Mizuno T, Kuroda H, Sakakura N, et al. The risk factor of late recurrence in patients with completely resected non-small cell lung cancer. Journal of Thoracic Oncology. 2013;8:S515–6. [Google Scholar]
  • 33.Saito M, Chiba N, Sakaguchi Y, Ishikawa S, Nakagawa T. A clinical relevance of intraoperative pleural lavage cytology in non-small lung cancer. Journal of Thoracic Oncology. 2013;8:S1217. [Google Scholar]
  • 34.Shiba M, Toyoda T, Fujiwara T, Iida T, Kunimatsu E, Matsuzaki O. Prognostic implication of cytodiagnosis of minute pleural effusion found at thoracotomy in NSCLC patients. Journal of Thoracic Oncology. 2013;8:S818. [Google Scholar]
  • 35.Buhr J, Berghauser KH, Morr H, Dobroschke J. Determining the prognosis of bronchial carcinoma by intraoperative pleural lavage. Deutsche Medizinische Wochenschrift. 1989;114:1597–601. [DOI] [PubMed] [Google Scholar]
  • 36.Kameyama M, Higashiyama M, Nakamori S, Kodama K, Imaoka S, Doi O, et al. Relationship between intraoperative pleural lavage cytology and recurrence in pleural cavity after resection of lung metastasis from colorectal cancer. Japanese Journal of Cancer and Chemotherapy. 1995;22:1616–8. [PubMed] [Google Scholar]
  • 37.Buhr J, Berghauser KH, Gonner S, Schaffer R, Padberg WM. Intrapulmonary tumor cell dissemination and intraoperative pleural lavage as prognostic factors in bronchial carcinoma. Zentralblatt fur Chirurgie. 1996;121:90–5. [PubMed] [Google Scholar]
  • 38.Buhr J, Berghäuser KH, Gonner S, Schäffer R, Padberg WM. Intrapulmonary tumor cell spread and intraoperative pleural lavage as prognostic factors in bronchial carcinoma? Langenbecks Archiv fur Chirurgie Supplement Kongressband Deutsche Gesellschaft fur Chirurgie Kongress. 1996;113:798–804. [PubMed] [Google Scholar]
  • 39.Oishi H, Saito Y, Abe J, Hasumi T. Recurrence patterns and prognosis in lung cancer patients with positive pleural lavage cytology at surgery. Kyobu geka The Japanese journal of thoracic surgery. 2008;61:1085–8; discussion 9–91. [PubMed] [Google Scholar]
  • 40.Araki K, Takagi Y, Tokushima T. Clinical and cyto-pathological implications of intraoperative pleural lavage cytology in stage I adenocarcinoma of the lung. Japanese Journal of Lung Cancer. 2009;49:1027–31. [Google Scholar]
  • 41.Funakoshi Y, Takeuchi Y, Nojiri T, Kimura T, Maeda H. Pleural lavage cytology immediately after thoracotomy in non-small cell lung cancer. Japanese Journal of Lung Cancer. 2009;49:1006–10. [Google Scholar]
  • 42.Araki O, Chida M, Karube Y, Hayama M, Tamura M, Kobayashi S, et al. Positive pleural lavage cytology results highly related to local recurrence: Institutional report and pooled analysis findings. Chirurgia (Turin). 2011;24:251–5. [Google Scholar]
  • 43.Nakano T, Tetsuka K, Endo T, Kanai Y, Otani S, Tsubochi H, et al. Extraction bag lavage cytology during video-assisted thoracoscopic surgery for primary lung cancer. Interactive cardiovascular and thoracic surgery. 2014;18:770–4. 10.1093/icvts/ivu032 [DOI] [PubMed] [Google Scholar]
  • 44.Okumura M, Ohshima S, Kotake Y, Morino H, Kikui M, Yasumitsu T. Intraoperative pleural lavage cytology in lung cancer patients. The Annals of thoracic surgery. 1991;51:599–604. [DOI] [PubMed] [Google Scholar]
  • 45.Buhr J, Berghauser KH, Gonner S, Kelm C, Burkhardt EA, Padberg WM, et al. The prognostic significance of tumor cell detection in intraoperative pleural lavage and lung tissue cultures for patients with lung cancer. Journal of Thoracic and Cardiovascular Surgery. 1997;113:683–90. [DOI] [PubMed] [Google Scholar]
  • 46.Higashiyama M, Doi O, Kodama K, Yokouchi H, Tateishi R, Horai T, et al. Pleural lavage cytology immediately after thoracotomy and before closure of the thoracic cavity for lung cancer without pleural effusion and dissemination: clinicopathologic and prognostic analysis. Annals of surgical oncology. 1997;4:409–15. [DOI] [PubMed] [Google Scholar]
  • 47.Hillerdal G, Dernevik L, Almgren SO, Per-Arne K, Gustafsson G. Prognostic value of malignant cells in pleural lavage at thoracotomy for bronchial carcinoma. Lung cancer. 1998;21:47–52. [DOI] [PubMed] [Google Scholar]
  • 48.Dresler CM, Fratelli C, Babb J. Prognostic value of positive pleural lavage in patients with lung cancer resection. The Annals of thoracic surgery. 1999;67:1435–9. [DOI] [PubMed] [Google Scholar]
  • 49.Kotoulas C, Lazopoulos G, Karaiskos T, Tomos P, Konstantinou M, Papamichalis G, et al. Prognostic significance of pleural lavage cytology after resection for non-small cell lung cancer. European journal of cardio-thoracic surgery. 2001;20:330–4. [DOI] [PubMed] [Google Scholar]
  • 50.Maruyama R, Shoji F, Okamoto T, Miyamoto T, Miyake T, Nakamura T, et al. Prognostic value of visceral pleural invasion in resected non-small cell lung cancer diagnosed by using a jet stream of saline solution. The Journal of thoracic and cardiovascular surgery. 2004;127:1587–92. [DOI] [PubMed] [Google Scholar]
  • 51.Tomita M, Shimizu T, Matsuzaki Y, Hara M, Ayabe T, Onitsuka T. Prognostic significance of carcinoembryonic antigen level in pleural lavage fluid for patients with lung adenocarcinoma. The Annals of thoracic surgery. 2005;80:276–81. [DOI] [PubMed] [Google Scholar]
  • 52.Vicidomini G, Santini M, Fiorello A, Parascandolo V, Calabrò B, Pastore V. Intraoperative pleural lavage: Is it a valid prognostic factor in lung cancer? Annals of Thoracic Surgery. 2005;79:254–7. [DOI] [PubMed] [Google Scholar]
  • 53.Tomita M, Shimizu T, Hara M, Ayabe T, Onitsuka T. Serum carcinoembryonic antigen level and pleural lavage cytology in woman with non-small cell lung cancer. The Thoracic and cardiovascular surgeon. 2008;56:422–5. 10.1055/s-2008-1038781 [DOI] [PubMed] [Google Scholar]
  • 54.Higashiyama M, Oda K, Okami J, Maeda J, Kodama K, Takenaka A, et al. Prognostic value of intraoperative pleural lavage cytology for lung cancer without carcinomatous pleuritis: importance in patients with early stage disease during long-term follow-up. European Journal of Cardio-thoracic Surgery. 2009;35:337–42. 10.1016/j.ejcts.2008.10.013 [DOI] [PubMed] [Google Scholar]
  • 55.Kawachi R, Nakazato Y, Masui K, Takei H, Koshi-ishi Y, Goya T. Clinical significance of pleural lavage cytology for non-small cell lung cancer: is surgical resection valid for patients with positive pleural lavage cytology? Interactive cardiovascular and thoracic surgery. 2009;9:265–8. 10.1510/icvts.2009.202010 [DOI] [PubMed] [Google Scholar]
  • 56.Nakamura T, Suzuki K, Mochizuki T, Ohde Y, Kobayashi H, Nakamura H, et al. Prognostic significance and possibility in guiding adjuvant therapy of the pleural lavage cytology in patients with non-small cell lung cancer. Interactive cardiovascular and thoracic surgery. 2009;8:321–4. 10.1510/icvts.2008.185702 [DOI] [PubMed] [Google Scholar]
  • 57.Shintani Y, Ohta M, Iwasaki T, Ikeda N, Kanou T, Tomita E, et al. Intraoperative pleural lavage cytology after lung resection as an independent prognostic factor for staging lung cancer. The Journal of thoracic and cardiovascular surgery. 2009;137:835–9. 10.1016/j.jtcvs.2008.09.027 [DOI] [PubMed] [Google Scholar]
  • 58.Wang C, Hao R, Liu J, Chen Z, Jin M, Wang W. The prognostic value of examining pleural lavage cytology during surgery for lung cancer patients. Chinese Journal of Clinical Oncology. 2009;36:1027–30. [Google Scholar]
  • 59.Taniguchi Y, Nakamura H, Miwa K, Adachi Y, Fujioka S, Haruki T, et al. Prognostic significance of pleural lavage cytology after thoracotomy and before closure of the chest in lung cancer. Interactive cardiovascular and thoracic surgery. 2009;9:102–6. 10.1510/icvts.2009.206045 [DOI] [PubMed] [Google Scholar]
  • 60.Hanagiri T, Takenaka M, Oka S, Baba T, Shigematsu Y, Nagata Y, et al. Pleural lavage cytology immediately after thoracotomy in patients with completely resected non-small cell lung cancer. International surgery. 2011;96:171–5. [DOI] [PubMed] [Google Scholar]
  • 61.Kaneda M, Yokoi K, Ito S, Niwa H, Takao M, Kondo R, et al. The value of pleural lavage cytology examined during surgery for primary lung cancer. European journal of cardio-thoracic surgery: official journal of the European Association for Cardio-thoracic Surgery. 2012;41:1335–41. [DOI] [PubMed] [Google Scholar]
  • 62.Baba T, Uramoto H, Kuwata T, Takenaka M, Chikaishi Y, Oka S, et al. Intrapleural chemotherapy improves the survival of non-small cell lung cancer patients with positive pleural lavage cytology. Surgery today. 2013;43:648–53. 10.1007/s00595-012-0281-y [DOI] [PubMed] [Google Scholar]
  • 63.Kameyama K, Okumura N, Miyaoka E, Asamura H, Yoshino I, Tada H, et al. Prognostic value of intraoperative pleural lavage cytology for non-small cell lung cancer: the influence of positive pleural lavage cytology results on T classification. The Journal of thoracic and cardiovascular surgery. 2014;148:2659–64. 10.1016/j.jtcvs.2014.07.090 [DOI] [PubMed] [Google Scholar]
  • 64.Yanagawa N, Shiono S, Abiko M, Abe M, Watanabe K, Watanabe I, et al. Positive intraoperative pleural lavage cytology is a predictive marker of disease recurrence in stage I lung adenocarcinoma. Interactive cardiovascular and thoracic surgery. 2014;18:621–5. 10.1093/icvts/ivu015 [DOI] [PubMed] [Google Scholar]
  • 65.Mazza F, Ferrari E, Maineri P, Dozin B, Ratto GB. Pleural lavage cytology predicts recurrence and survival, even in early non-small cell lung cancer. Surgery today. 2015;45:322–8. 10.1007/s00595-014-0915-3 [DOI] [PubMed] [Google Scholar]
  • 66.Hokka D, Uchino K, Tane K, Ogawa H, Tane S, Tanaka Y, et al. Pleural lavage cytology as an independent prognostic factor in non-small-cell lung cancer patients with stage I disease and adenocarcinoma. Molecular and clinical oncology. 2015;3:244–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 67.Ogawa H, Uchino K, Tanaka Y, Shimizu N, Okuda Y, Tane K, et al. Efficacy of adjuvant chemotherapy for lung adenocarcinoma patients with positive pleural lavage cytology findings. Interactive cardiovascular and thoracic surgery. 2015;21:34–9. 10.1093/icvts/ivv098 [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

S1 Appendix. A PRISMA 2009 checklist for this meta-analysis.

(DOC)

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S1 Table. Survival outcomes of PLC in the meta-analysis.

(DOCX)

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S2 Table. Recurrence data of PLC in the meta-analysis.

(DOCX)

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Data Availability Statement

All relevant data are within the paper and its Supporting Information files.

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