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Eur J Cardiothorac Surg 2000;17:575-579
© 2000 Elsevier Science NL

Pleural lavage cytology in esophageal cancer without pleural effusions: clinicopathologic analysis

^a Hubei Cancer Hospital, Wuhan 430070, PR China
^b Division of Thoracic Surgery, University of Maryland Medical Center, 22 South Greene Street, Baltimore, MD 21201, USA

Corresponding author. Tel.: +1-410-328-6366; fax: +1-410-328-0693
e-mail: xjiao{at}smail.umaryland.edu

	Abstract

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion 5. Conclusions Appendix A Conference discussion References

 
Objective: The literature of pleural lavage cytology (PLC) is focused on lung cancer. We conducted this pilot study to determine the incidence of malignant pleural cytologies in patients without pleural effusions who undergo curative resection for esophageal cancer, and to evaluate the clinicopathologic significance of positive cytology. Methods: Forty-eight patients underwent esophagectomy for thoracic esophageal cancer in our unit from January 1998 to January 1999. After thoracotomy, pleural lavage was performed before any intrathoracic manipulation and cytologically evaluated. Results: There was one patient with stage I, 27 patients with stage II, and 20 patients with stage III cancer of the thoracic esophagus. The mean age was 55 years (range 41–77 years). Fifteen cases (31.3%) were found to have positive lymph nodes (N1). Squamous cell carcinoma was the dominant histopathologic type (91.7%). Positive lavage cytology in the whole group was found in 18.8% (9/48). There was no significant correlation to gender, age, clinical symptoms, histology, T or N status, TNM stage, or tumor location. Conclusions: The incidence of positive pleural lavage cytology in esophageal cancer is disconcertingly high. Positive cytology might suggest a more aggressive tumor biology. Future studies on its relation to survival and occult lymphatic metastasis are warranted.

Key Words: Esophageal cancer • Pleural lavage cytology

	1. Introduction

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion 5. Conclusions Appendix A Conference discussion References

 
In recent years, several reports from Europe, Japan and the United States have been published on the prognostic value of pleural lavage cytology (PLC) in lung cancer patients without a pleural effusion undergoing surgical resection [1–8]. Most authors suggested that a significant number of patients with otherwise early stage disease will have positive pleural cytology results and subsequently have a poorer prognosis than patients with negative cytology results. Some authors advocated that PLC should be added to TNM staging system of lung cancer. So far, however, the literature of PLC has been focused on lung cancer. We conducted this pilot study to determine the incidence of malignant pleural cytologies in patients without pleural effusions who undergo curative resection for thoracic esophageal cancer, and to evaluate the clinicopathologic significance of positive cytology.

	2. Materials and methods

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion 5. Conclusions Appendix A Conference discussion References

 
Forty-eight patients underwent esophagectomy for thoracic esophageal cancer in our unit at Hubei Cancer Hospital between January 1998 and January 1999. All had no evidence of pleural fluid on posteroanterior or lateral chest roentgenogram. Immediately after opening the pleura, 200 ml of warm physiologic saline solution was instilled into the pleural space before any further manipulation. The surgeon carefully washed the pleural cavity by hand for 1 min. The fluid was then aspirated and sent to cytology. All cytologic specimens were centrifuged. Smears and cytospins were alcohol fixed and stained with Papanicolaou's stain. Cytologic diagnosis was classfied as: class I, normal pattern, absence of atypical or abnormal cells; class II, benign abnormality, atypical but non-malignant cells present; class III, atypical cells consistent with dysplasia; class IV, suggestive of, but inconclusive for, malignancy; class V, conclusive for malignancy. To prevent any false positive result, Papanicolaou classes I–IV were considered as ‘negative lavage’, and only Papanicolaou class V was designated as ‘positive lavage’.

The primary tumor and lymph node status was classified according to the fourth edition of the Manual for Staging of Cancer of the American Joint Committee on Cancer (AJCC) [9]. Careful intraoperative staging at the time of surgical resection was performed by dissecting paraesophageal, subcarina, paragastric and celiac lymph nodes. Adenocarcinomas located at the gastro-esophageal junction were excluded since these tumors were considered as gastro-cardiac carcinomas in the unit.

The Fisher's exact test was used to evaluate the significance of the relationship between the cytologic result of intraoperative pleural lavage and the clinic and histopathologic findings.

	3. Results

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion 5. Conclusions Appendix A Conference discussion References

 
Table 1 describes patient sex, age, procedure performed, histology, and stage. PLC in the whole group was found in nine patients (18.8%, 9/48) who are listed in Table 2. Fifteen cases (31.3%) of esophageal cancer were found to have positive lymph nodes (N1). Forty-four (91.7%) patients had squamous cell carcinoma. The relationship between PLC with gender, age, clinical symptoms, histology, T or N status, TNM stage, tumor length or tumor location are shown in Table 3.

3.2. Pathology
There was no significant difference of the positivity of PLC between the different histologic types.

PLC positivity in early T stage (T1 and T2) and advanced T stage (T3 and T4) were 22.2% (2/9) and 17.9% (7/39), respectively (not significant). PLC positivity in N1 patients was 13.3% (2/15), which was lower than that in N0 patients (21.2%, 7/33), yet the difference is not significant. There was only one patient with stage I disease, the comparision of the positivity of PLC between stage II and stage III showed no significant difference (22.2 vs. 15%).

	4. Discussion

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion 5. Conclusions Appendix A Conference discussion References

 
In 1958 Spjut and associates first reported the results of pleural cavity washings on 49 patients undergoing thoracotomy for lung cancer [10]. In 1984 Eagan and colleagues reported their results with pleural lavage cytology after pulmonary resection for lung cancer [11]. However, both reports performed cytology exam after the operation had been performed, and did not consider its prognostic value. In 1989, Kondo et al. reported their preliminary results on PLC before pulmonary resection [1]. Since then, several large series have studied the prognostic value of PLC of lung cancer (see Table 4) [2–8,12]. The positive rate of PLC for lung cancer patients without pleural effusion varied widely from 3.7 to 38.6%, a difference which might be due to different stage of patients enrolled and different techniques or diagnostic standards used. Although the results of the relationship between positive PLC and clinicopathological factors like invasion of the visceral pleura, T stage, N stage, TNM stage, and histologic type remained controversial, most authors suggested that for surgically-treated lung cancer patients, positive PLC might be a prognosticator of a more aggressive tumor biology, a high risk of recurrence and a poorer survival [1,2,4,6,13]. Some authors advocated that PLC should be added to the TNM staging system for lung cancer in order to stratify patients more accurately [4,6,12,13].

The first case report of pleural lavage in carcinoma of the esophagus was published as a letter to the editor in 1974. The patient was found to have positive pleural lavage incidentally [15]. However, no systemic study had been done since then. As PLC appeared to be a prognosticator in lung cancer, we began this prospective study in esophageal cancer. Our results showed a high positive rate of 18.8% of pleural lavage cytology. The detection of malignant cells in pleural lavage fluid before resection proves that tumor cells have spread into the pleural cavity, even in the early stages of esophageal cancer. Although the statistical analysis showed no significant correlation to gender, age, clinical symptoms, histology, T or N status, TNM stage, tumor location or tumor length, we noted that the positive rate of PLC in patients younger than 60 years was almost three times to that in those older (22.9 vs. 7.7%). Whether this result suggests that esophageal cancer in young patients tends to be more aggressive is unknown. Persistent chest or back pain in esophageal cancer patients is usually a symptom indicating invasion of adjacent structures, a factor associated with a high likelihood of exfoliation. However, the positive rate of PLC in the group of patients with pain was only slightly higher than that of the group without pain (22.2 vs. 17.9%), and did not show a significant difference. For lung cancer patients, positive PLC usually is more prevalent in adenocarcinoma than in squamous cell carcinoma. Our results shown a high PLC positive rate in a group of patients with esophageal cancer with a dominant histologic type of squamous cell carcinoma.

The source of the malignant pleural cells is still unclear. There are two ways to explain positive PLC of lung cancer patients: exfoliation and lymphatic spread. Three reports form Japan found an association with pleural invasion, possibly suggesting cell exfoliation [2,4,12]. Higashiyama and Kondo also reported an association between positive cytology and lymphatic permeation as well as vascular involvement, suggesting the existence of lymphatic spread [4,12]. This was further supported by Buhr who performed tissue cultures for initially tumor-free lung parenchyma around lung cancer, and found tumor cell in lymphatic vessels after incubation [6]. Preformed stomas that connect subpleural lymphatics with the pleural space could account for the tumor cell dissemination [16,17]. Exfoliation and lymphatic spread are also two plausible mechanisms to explain the etiology of positive PLC of esophageal cancer, considering its locally invasive properties and rich lymphatic drainage. In our study, positive PLC was found in 22.2% (2/9) of patients with no apparent invasion of adventitia (T1,T2), and 17.9% (7/39) of patients with involvement of adventitia or adjacent structures (T3,T4). There was no significant difference between these two groups. This result suggested that in esophageal cancer, lymphatic spread may happen in early stage. Mucosal and submucosal lymphatic esophageal networks with connections to the epiesophageal lymph nodes in the adventitial layer and then to the periesophageal lymph nodes of the mediastinum could be the anatomic basis for the malignant spread.

What is the real significance of PLC in TNM stage of esophageal cancer? If the two way theory of the etiology of malignant tumor cells spread in pleural fluid, i.e. exfoliation and lymphatic spread, is true, one can speculate that for early T stage esophageal cancer (T1,T2), lymphatic spread might be the main pathological path way for positive PLC. For advanced T stage (T3,T4), both exfoliation and lymphatic spread might play a role in positive PLC. This may mean that for T1 and T2 tumors, positive PLC might reflect an early lymphatic spread, or occult N1, while for T3 and T4 tumors, positive PLC might reflect either pleural metastasis or lymphatic spread. We hope to answer this question in the future by analyzing the prognostic value of positive PLC and the relationship between positive PLC and ‘occult’ lymphatic metastasis detected by molecular markers [18–21].

Since this is a small series, the initial results on the relationship between PLC and clinicopathology are not yet conclusive. However, these data have shown that as in lung cancer, the incidence of positive pleural lavage cytology in esophageal cancer is disconcertingly high. Our findings on pleural cavity micrometastasis, like other investigators’ findings on lymphatic micrometastasis and bone marrow micrometastasis [22], support the concept of esophageal cancer as a systemic disease and provide circumstantial evidence for the strategy of multimodality therapy in this disease.

	5. Conclusions

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion 5. Conclusions Appendix A Conference discussion References

 
As in lung cancer, the incidence of positive pleural lavage cytology in esophageal cancer is disconcertingly high. Positive cytology might suggest a more aggressive tumor biology. Future studies on its relation to survival and occult lymphatic metastasis are warranted.

	Footnotes

 
Presented at the 13th Annual Meeting of the European Association for Cardio-thoracic Surgery, Glasgow, Scotland, UK, September 5–8, 1999.

¹ UICC Fellow – ICRETT Grant #805.

	Appendix A Conference discussion

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion 5. Conclusions Appendix A Conference discussion References

 
Mr K. Jeyasingham (Bristol, UK): In your analysis were you able to quantitatively assess the cell content of the pleural fluid as opposed to detecting the cells? I have a feeling that this may have a prognostic value rather than just a detection.

Secondly, micrometasteses and breakdown product markers may indicate the cells have been broken down, not necessarily be still effective for metastatic disease. Would you have any comments on that?

Dr Krasna: Those are two excellent points. No, we did not have numbers on the number of cells. I should point out that if you include the class 4 Pap smears, which were included in all the reports from lung cancer, together with the class 5 Pap smears, actually the incidence would be higher, it would be about 23%. I think your question about the number of cells is an excellent one, and we don't do that.

In terms of your second question, I think this is a very exciting area. We are currently incorporating the PLC as part of our thoracoscopic staging protocol that we do at the University of Maryland. Upon entering the chest, we are flushing the chest first with saline before doing any manipulation and extruding all the fluid and then doing the cytology. One of the things that we are doing is on any cell, not dependent on a number of cells, doing PCR sequencing and IHC staining to identify whether the same tumor is actually identifiable or, as you suggest, this is breakdown or dead or nonviable tumor. I also think that we would like to correlate these findings with our intraoperative lymph node mapping at thoracoscopy to see if the other hypothesis is true, which is that it's microscopic occult metastases to lymph nodes, and then following that spread into the pleural fluid. But we have not yet done that.

	References

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion 5. Conclusions Appendix A Conference discussion References

 

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