The significance of intraoperative pleural effusion during surgery for bronchogenic carcinoma

Abstract

Objectives: To analyze patients submitted to thoracotomy for lung carcinoma presenting with an intraoperative pleural effusion (PE). Methods: From 1993 to 1999, 1279 patients received thoracotomy with curative intent for primary lung carcinoma. Intraoperatively, 52 patients (4%) presented a PE ≫100 ml which was not diagnosed preoperatively. Of these, seven patients had received preoperative transthoracic fine-needle biopsy FNB and were excluded from the analysis. In the remaining 45 patients pleural fluid cytology was undertaken. In patients with cytology-negative PE, clinico-pathologic characteristics including intratumoral vascular invasion, intratumoral perineural invasion, peritumoral lymphocytic infiltrate, visceral, parietal and mediastinal pleural involvement, pTNM and survival were analyzed and compared with our total population of lung cancer patients operated on during the same period. Results: The mean amount of collected fluid was 210 ml (100–450 ml). Of the 45 patients with intraoperative PE, 16 (35%) received exploratory thoracotomy because of pleural carcinosis or major involvement of mediastinal structures; eight (18%) received resection of the tumor, although the cytologic examination of the pleural fluid eventually resulted positive for neoplastic cells. Median survival for the two groups was 6 and 9 months, respectively. Twenty-one patients (47%) received resection of the tumor with a cytology-negative pleural fluid. In this group, analysis of clinico-pathologic characteristics revealed that squamous cell type and mediastinal pleural involvement were significantly associated with the presence of intraoperative PE (P=0.01 and P=0.05, respectively); 3- and 5-year survivals of this group were similar to those observed in our total population of resected lung cancer patients (68 and 56% vs. 54 and 42%, P=0.27). Conclusions: The presence of a PE at thoracotomy during surgery for lung carcinoma is an infrequent occurrence. In more than 50% of the cases cytology is positive and prognosis is poor. In the remaining cases, however, cytology is negative and the PE should be considered as reactive; in these patients a curative resection can be accomplished with an anticipated chance of long-term survival.

Lung carcinoma, Pleural effusion, Exploratory thoracotomy

1 Introduction

The presence of a pleural effusion (PE) in a patient with bronchogenic carcinoma has long been considered an indicator of poor prognosis.

Approximately 15% of all patients diagnosed with lung cancer will have a PE [1]. Most PEs associated with lung cancer are due to the tumor and represent a pleural involvement in the form of pleural carcinosis or invasion of mediastinal structures. In the majority of the cases PE cytology is positive for neoplastic cells and the patient is classified as having a Stage IIIb disease with an associated 6–8% chance of long-term survival [2].

There are, however, cases in which small PEs are detected at the time of thoracotomy in patients with an apparently operable disease, in which the fluid is not evidenced at preoperative evaluation.

The role of these small intraoperatively detected PEs has not been considered previously and its significance on resectability and long-term prognosis has not yet been clarified.

The purpose of the present study was to evaluate the significance of the occurrence of intraoperative PE not preoperatively detected in the patients submitted to thoracotomy for a presumably resectable lung carcinoma.

2 Materials and methods

From January 1993 to December 1999 a total of 1279 patients were operated on with curative intent for bronchogenic carcinoma. There were 1087 men and 192 women ranging in age from 24 to 82 years with a mean age of 63 years.

Routine preoperative evaluation for patients with potentially resectable bronchogenic carcinoma included a complete history and physical examination, biochemical profile with blood cell count, electrocardiogram (EKG) with supplemental cardiologist's consultation when appropriate, chest radiograph, computed tomography (CT) of the chest and upper abdomen, fiberoptic bronchoscopy with cytological or histologic and microbiological specimens and pulmonary function tests (PFTs) with arterial blood gas analysis.

Brain CT scan and total body bone scan were performed selectively.

Preoperative mediastinal lymphnodal sampling by means of mediastinoscopy or anterior parasternal mediastinotomy were performed selectively in case of enlarged (≫1.5 cm) mediastinal lymphnodes at CT scan.

Preoperative transthoracic fine-needle biopsy (FNB) was performed in the case of peripheral lesions in which bronchoscopy resulted negative.

The types of operation performed included 859 lobectomies, 197 pneumonectomies, 98 sublobar resections, 45 bilobectomies and 80 exploratory thoracotomies.

2.1 PE group

All patients who presented with a PE greater than 100 ml at operation which was not diagnosed at preoperative evaluation were included in the study. Patients who presented predisposing conditions for minor PE including preoperative FNB, recent (4–6 weeks) preoperative pleurisy or pneumonia were recorded and excluded from the analysis.

In all patients with an intraoperative PE, a careful evaluation was undertaken by a senior surgeon in order to identify exclusion criteria for resection, including pleural carcinosis, major involvement of the mediastinal structures, extracapsular mediastinal lymphnodal metastases.

The pleural fluid was collected entirely, measured and sent to the pathologist for cytological examination. The cytological evaluation was carried out by simple staining and subsequent immunohistochemistry in order to evaluate if the neoplastic cells detected were or not of the same type of the concomitant lung neoplasm. No tumor markers were measured and biochemical profile of the fluid was not detected. A small amount of the pleural fluid was also sent to the laboratory for microbiological examination. If no contraindications to resection were evidenced, resection was accomplished and associated in all cases with hilar and mediastinal lymphadenectomy.

Among patients with resected tumors, clinico-pathologic characteristics including intratumoral vascular invasion, intratumoral perineural invasion, peritumoral lymphocytic infiltrate, associated in situ carcinoma, visceral, parietal and mediastinal pleural involvement, staging and survival were analyzed and compared with the total population of resected bronchogenic carcinomas operated on in the same period.

2.2 Statistics

Differences between frequencies when all expected cell frequencies were greater or equal to 5 were tested using the chi-square statistics; otherwise, Fisher's exact test was used. Survival rates were computed using the Kaplan–Meier method [3]; the log–rank test was used to compare survival curves.

A probability value less than 5% (P≪0.05) was regarded as significant.

Data were analyzed with the use of STATISTICA '99 edition software (Statsoft, Tulsa, OK, USA).

3 Results

Fifty-two patients were found to present an intraoperative PE (≫100 ml) which was undetected preoperatively. This represents 4% of the entire population of patients submitted to thoracotomy for bronchogenic carcinoma at our Institution in the same period. Of these, seven patients had received preoperative FNB and were not considered for the analysis.

The total amount of the fluid in the pleural space ranged from 100 to 450 ml (mean 210 ml) and the macroscopic appearance was serous or serous/hematic in all cases.

Of the 45 patients with intraoperative PE and without previous FNB, 16 (35%) received only exploratory thoracotomy because of pleural carcinosis or major involvement of mediastinal structures which precluded a radical resection.

Eight patients (18%) received resection of the tumor, although the cytological examination of the pleural fluid eventually resulted positive for neoplastic cells.

Overall, in our series the presence of an intraoperative PE not detected preoperatively was in more than 50% of the cases a sign of advanced disease which is not benefited by surgery.

Finally, 21 patients (47%) received resection of the tumor with a cytology-negative pleural fluid in absence of predisposing factors for PE: this population forms the basis of further analysis.

3.1 Surgery, histologic characteristics and staging in the cytology-negative PE group

Among the 21 patients with cytology-negative PE and resectable tumors, there were 14 pneumonectomies (two right and 12 left), one bilobectomy and six lobectomies (three right and three left) (Table 1 ). The prevalence of pneumonectomies was significantly higher in the PE group as compared with our total population of resected bronchogenic carcinoma in the same period (P=0.00001).

Table 1

Comparison of demographic, clinical and histologic characteristics between the group of patients with intraoperative cytology-negative PE and resectable tumors (N=21) and the total population of patients resected for bronchogenic carcinoma (N=1279)

The group of patients with cytology-negative PF and resected tumors were compared with the total population of patients with bronchogenic carcinoma resected in the same period with regard to the staging and the following histologic characteristics: histologic type, intratumoral vascular invasion, intratumoral perineural invasion, peritumoral lymphocytic infiltrate, associated in situ carcinoma and visceral, parietal and mediastinal pleural involvement (Table 2 ).

Table 2

Comparison of several histologic variables among patients with intraoperative cytology-negative PE and resectable tumors (N=21) and the total population of patients resected for bronchogenic carcinoma^a

Squamous cell type and mediastinal pleural invasion were significantly associated with the presence of intraoperative PE (P=0.01 and P=0.05, respectively).

3.2 Survival

Median survival of the 16 patients who received exploratory thoracotomy was 6 months (range 2–8).

Median survival of the eight patients with resectable tumors and cytology-positive PF was 9 months (range 2–10).

Three- and 5-year survival rates in the group of patients with resectable tumors and cytology-negative PF were 68 and 56%, respectively. The corresponding rates in the total population of patients resected for bronchogenic carcinoma in the same period were 54 and 42%. The difference between the two groups was not significant (P=0.27) (Fig. 1 ).

Fig. 1

Survival curves of patients with resected lung carcinoma and intraoperative cytology-negative PE vs. our total population of patients with resected lung carcinoma. Patients at risk at 3 years: 446 (total population)/7 (PE group). Patients at risk at 5 years: 133 (total population)/1 (PE group).

4 Discussion

Our study indicates that the finding of a PE at the time of thoracotomy in a patient with non-small cell lung carcinoma (NSCLC) is not always to be considered an indicator of poor prognosis.

The prevalence of an intraoperative PE out of our total population of resected lung carcinomas is small (45/1279, 3.5%) and the condition is therefore a quite unusual occurrence.

In the present series, cytology was positive in 53% of the cases (24/45 patients) and in these patients survival was poor either in resectable tumors or in explorative thoracotomies; median survival of these patients was similar to that of patients with Stage IV disease (6–9 months). We did not search for any influence of the number of the tumor cells on survival in this group of patients.

In the remaining 47% of the cases, however, (21/45 patients) cytology was negative and the survival of these patients was similar to those patients with corresponding stage without PE.

The presence of ipsilateral PE in patients with bronchogenic carcinoma is a rather frequent occurrence: it has been reported that about 15% of all patients with bronchogenic carcinoma has an associated PE. Since the introduction of the TNM staging system for lung cancer, the presence of PE has been considered an indicator of poor prognosis [4].

In the clinical practice, however, a PE in a patient with an associated lung carcinoma may assume different presentations: the effusion may be malignant or non-malignant, small to moderate to massive in size and it may be detected preoperatively with imaging techniques or alternatively it may be an unexpected finding at the time of thoracotomy. Each of these different situations is associated with a different Stage disease and a different prognosis. Every discussion about the significance of PE in a patient with an associated bronchogenic carcinoma should therefore take into account these clinical situations.

A PE is considered malignant if cytological examination of the fluid is positive for neoplastic cells or, if negative, if the fluid is exudative or bloody and clinically judged to be resultant from the underlying malignancy. Patients with malignant PE have long been considered at an advanced stage and in the most recent TNM classification are staged as T4 Stage IIIb disease with an associated 6 to 8% 5-year survival [2]. A recent study by Sugiura et al. [5] compared the survival of 197 patients with Stage IIIb disease, with or without PE and the patients with Stage IV disease. The authors conclude that survival of patients with Stage IIIb and PE is more similar to survival of patients with Stage IV than to survival of patients with Stage IIIb without PE. Further, no significant survival difference was found between Stage IIIb patients with cytologically positive and cytologically negative PE. Similar results have been reported by Mott and coworkers [6] on 120 patients and by Naruke et al. [7] on more than 2000 patients with M0 disease. There is therefore a convincing evidence that NSCLC patients with malignant PE should be approached in a similar way as patients with Stage IV disease and should therefore be treated primarily with chemotherapy [8].

Most PEs associated with lung carcinoma are detected preoperatively with plain chest radiograph, CT scan, magnetic resonance imaging (MRI) or PET. In the presence of a preoperatively detected PE associated with lung carcinoma, further investigations are mandatory before proceeding to thoracotomy and resection. Video-assisted thoracoscopy (VATS) has recently been proposed as a useful procedure for staging before resection [9]; an alternative procedure which could help in the evaluation of these patients is the ultrasound-guided aspiration of the fluid. The finding of a PE preoperatively, in the absence of predisposing conditions including atelectasis or previous transthoracic FNB, recent pleurisy or pneumonia, is almost invariably a sign of advanced disease which precludes any curative surgery. A recent report from a Spanish group addresses this issue [10]. The authors performed VATS in 76 patients with NSCLC and ipsilateral PE was preoperatively diagnosed: pleural fluid cytology was positive in 55 patients and negative in 21. Only five patients were judged to have a potentially resectable tumor at VATS; these patients were eventually submitted to thoracotomy but in none of them a curative resection could be accomplished due to mediastinal involvement.

A small proportion of patients with NSCLC have an associated PE not diagnosed preoperatively: in these patients the PE represents an unexpected finding at the time of thoracotomy. The size of PE is usually small (≪400 ml). There is very little mention of this occurrence in the literature, with only one report from a Japanese group in 1990 [11] and a brief comment on a 1997 report from Naruke et al. [7]. In the report of Naruke, a PE was identified at thoracotomy in 364 out of 2055 patients with M0 disease (17%). Of these, 290 patients had a non-malignant PE and 74 patients had a malignant PE. Five-year survival rates of patients with non-malignant effusion was similar to survival of all M0 patients without PE (42 vs. 45%), whereas patients with malignant PE had a significantly lesser survival rate (16%). The authors conclude that a lung cancer associated with malignant PE is staged T4 and is incurable by surgery. However, lung cancer patients with PE and normal results of cytological study behave like M0 patients of corresponding stage.

Our results are similar to Naruke's. Our prevalence of intraoperative PE out of the total population of resected lung cancer patients is less than Naruke's (3.5 vs. 17%). We have excluded in our study patients who received preoperative FNB, which might theoretically induce a iatrogenic small-size PE. Contrary to Naruke, about half of our patients with intraoperative PE have a pleural fluid cytology positive for neoplastic cells: of these, in two-third of the cases pleural carcinosis, major mediastinal involvement or extracapsular mediastinal lymphoadenopathy precluded resection; in the remaining one-third of the cases, tumor was resected. In both cases, however, median survival was extremely poor resembling that of patients with Stage IV disease. In the remaining half of the patients, PE was cytology negative and the patients survived in a similar way as the M0 patients of the corresponding stage. The percentage of lung cancer patients with non-malignant PE is extremely low (21/1279 in our series, 290/2055 in Naruke's) but nonetheless these patients are worth being identified because a curative resection is feasible. Presently, however, there does not seem to be any possibility to preoperatively identify the patients with small intraoperative PE cytology positive in whom thoracotomy or resection is of no benefit. The role of PET scan is under study although preliminary results seem encouraging [12]. In our series, mediastinal pleural involvement, squamous cell type and pneumonectomy were associated with the presence of intraoperative PE. A possible explanation may be that pleural involvement may induce production of pleural fluid either reactive or with exfoliation of neoplastic cells as a result of pleural carcinosis. As for histology, it has been demonstrated that squamous cell carcinoma most often presents a picture of obstructive pneumonitis, pulmonary collapse, parenchymal consolidation with hilar involvement; it may therefore be hypothesized that these characteristics may all be associated with production of pleural fluid, either reactive or malignant. As for the type of operation, it is possible that tumors requiring pneumonectomy are more likely to present hilar and mediastinal involvement, which predispose to pleural fluid production. All these findings, however, need confirmation by further studies on a larger number of patients.

In conclusion, the presence of a PE identified at thoracotomy in patients with a potentially resectable lung carcinoma is a rare occurrence. We might suggest that intraoperative cytological analysis should be of help in these cases in order to correctly stage the underlying neoplasm. Cytology is positive in about half of the cases and these patients are to be considered as Stage IV disease, irrespective of the resectability of the tumor. In the remaining half of the cases, however, cytology is negative, and the PE should be considered as reactive. In these patients a curative resection can be accomplished with a reasonable chance of long-term survival. Although not done in the present study, it may be interesting to investigate the presence of subpleural neoplastic cells in the parietal pleura in this subgroup of patients.

Appendix A Conference discussion

Mr D. Waller (Leicester, UK): Could you comment on the use of VATS in these patients prior to doing a thoracotomy?

Dr Cristofori: We didn't use thoracoscopy in these patients because the pleural effusion was not previously detected at radiological examination, so we couldn't expect a minimal pleural effusion. We discovered this pleural effusion ahead of thoracotomy.

Mr Waller: So you do cytology in the theater?

Dr Cristofori: We didn't do an intraoperative cytological examination. In fact, we performed that at pulmonary resection. But we collected the pleural effusion ahead of thoracotomy, and so we invited the sample for a definitive cytological examination.

Mr Waller: So what would you do in the future now, how would you modify what you do?

Dr Cristofori: There is in the literature several works. In fact there is the work of an American group that includes PET examination for detecting these small pleural effusions. These small pleural effusions with PET examination positive seem to be a cytologically positive pleural effusion in this case and do not perform intervention.

Mr Waller: So you would advocate doing PETs on everybody? You do PET scans on all patients?

Dr Cristofori: I don't understand.

Mr Waller: Would you do PET scans on all patients?

Dr Cristofori: We didn't do –

Mr Waller: No, but in the future how will you prevent this happening again?

Dr Cristofori: In the future, I don't know, in the future we perform a better examination for detecting pleural effusions, although we can't perform a thoracoscopy in all patients for a resection of lung cancer before thoracotomy.

Mr Waller: Why not? I would suggest that that is a good idea. We found that very useful.

Mr G. Ladas (London, UK): There are several publications in the literature regarding unsuspected positive intraoperative lavage, and Kondo's series from Japan was the largest, with more than 450 patients. But even ourselves at the Royal Brompton we have reported our results a couple of years ago at the Ninth World Conference on Lung Cancer. Prospectively over 5 years we found an incidence of 7% positive lavage cytology at the time of operation, which is obviously different than a pleural effusion. This has been reported to be linked to a lower survival but not as low as you reported today. A 3-year survival of around 30% is what you usually find in the largest series for patients with unsuspected positive lavage cytology.

So my question to you is, how did you stage these patients? You said you couldn't identify any effusion preoperatively or during your investigations. Did you perform CT scans on each and every one?

Dr Cristofori: Yes, yes, we performed the CT scans, but the pleural effusion was in a volume of 100 and 400 ml. We do not recognize this small entity a pleural effusion at CT examination.

Mr Ladas: I think it is well recognized that if you identify a pleural effusion, albeit a small one, preoperatively, you should definitely exclude this being a malignant effusion. If you manage to identify the 5% of patients with paramalignant effusions, i.e. lung cancer, and a cytologically negative-proven effusion preoperatively, then, yes, you should go on and perform an operation.

If you have got an effusion, and you perform aspiration and the cytology is negative, you should do a VATS pleural biopsy. If that is negative, well, yes, you should go to a thoracotomy. So only if you have no pleural effusion preoperatively or you find one and you prove it to be cytologically negative should you proceed with thoracotomy. If you do that and then find a positive lavage cytology, the outlook is worse but it will still not be as bad as what you have shown today.