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Interact CardioVasc Thorac Surg 2009;8:321-324. doi:10.1510/icvts.2008.185702 © 2009 European Association of Cardio-Thoracic Surgery
Prognostic significance and possibility in guiding adjuvant therapy of the pleural lavage cytology in patients with non-small cell lung cancer
a Department of General Thoracic Surgery, Seirei Hamamatsu General Hospital, Japan Received 12 June 2008; received in revised form 31 October 2008; accepted 12 November 2008
*Corresponding author. Tel.: +81-53-474-2222; fax: +81-53-471-6050.
Pleural lavage cytology (PLC) has been reported to be a significant prognostic factor in patients with operable non-small cell lung cancer (NSCLC). PLC may detect micro metastasis in patients without apparent pleural effusion or dissemination. Although many studies have reported PLC as a good predictor of postoperative recurrence, its role in the staging of NSCLC and in determining adjuvant therapy is still controversial. From June 1999 through December 2006, PLC immediately after thoracotomy was performed in 284 NSCLC patients without effusion or dissemination. Cases with exploratory thoracotomy were excluded from this study. Results of PLC were evaluated with other clinicopathological factors, and the difference in survival according to PLC status was investigated. Thirteen patients with positive PLC showed a poorer disease-free survival (P<0.0001) compared to those with negative PLC. The difference in survival rate between patients with positive and negative PLC, was significant in stage I disease, but not in stage II and III disease. PLC is a useful predictive marker for postoperative recurrence and should be routinely evaluated in lung cancer surgery, especially, in stage I disease. PLC might also assist in guiding adjuvant therapy.
Key Words: Lung cancer; Diagnosis and staging; Adjuvant/neoadjuvant therapy
The clinical significance of intraoperative pleural lavage cytology (PLC) in non-small cell cancer (NSCLC) is still controversial, although many studies have suggested a prognostic role for PLC [1–7]. Since PLC may indicate occult disease in otherwise curable NSCLC, the clinical significance of PLC should be investigated in particular its role in staging and in determining the need for adjuvant therapy. We reviewed our experience to address these specific issues.
From July 1999 to December 2006, PLC was performed in 284 patients who underwent curative resection for NSCLC without apparent pleural effusion and/or dissemination. Cases with exploratory thoracotomy were excluded from this study. Median follow-up period was 955 days. PLC was performed in a uniform method. Before any surgical manipulation immediately after completion of the thoracotomy incision, physiological saline solution of 20 ml was injected into the thoracic cavity and recovered for cytological evaluation. The fluids were centrifuged at 1500 rpm for 5 min and stained by the Papanicolau, Gimza, and PAS methods. The cytological examination was evaluated as positive or negative for malignancy. Histological diagnosis was based on the WHO classification [8], and pathological staging was determined based on the TNM staging system of the International Union Against Cancer [9]. Pleural involvement was classified according to the Japan Lung Cancer Society criteria [10]; p0 as tumor that did not extend beyond the elastic layer, p1 as tumor invading the visceral pleura elastic layer but not present at the pleural surface, p2 as tumor present at the pleural surface and p3 as tumor invading the parietal pleura or chest wall. We defined that p0 and p1 as negative for pleural involvement, and p2 and p3 as positive. After surgery, patients were periodically observed at out-patient clinic every 3–4 months with physical examination and chest X-ray. Bone or computed tomographic scans were done annually or when indicated. Comparisons of categorical and numeral data between two groups were made by Fisher exact test and Mann–Whitney's U-test, respectively. Survival rates were analyzed using Kaplan–Meier methods, and the log-rank test was used to compare the survival curves. Univariate and multivariate analysis were performed using the Cox proportional hazard model. A P-value <0.05 was considered significant. Initial sites of recurrence were divided into distant and local. Local disease is defined as any recurrent disease within hemithorax including loco-regional relapse.
Positive PLC was obtained in 13 (4.6%) cases (Table 1). All patients with stage I A had negative PLC. There were no significant differences in age, gender, type of surgery, and histology between positive and negative PLC patients groups. Pathological stage, T factor, N factor, and P factor showed significant association with the result of PLC.
Postoperative recurrence was more common in the PLC positive group than in the negative group (Table 2). However, initial site of recurrence was not significantly different between both groups (Table 3).
There was a significant difference in disease-free survival between both groups (Fig. 1). Five-year disease-free survival was 66% and 12.3% for positive and negative PLC groups, respectively. More specifically, this statistical difference in survival was significant in pathological stage I disease (Fig. 2), but not in stage II and III (Fig. 3).
Univariate analysis of prognostic factor for postoperative recurrence showed pathological stage, histology, T factor, N factor, P factor and PLC as significant (Table 4). Among these factors, T factor, P factor and PLC were found to be significant by multivariate analysis (Table 5). These findings showed the prognostic significance of PLC for postoperative recurrence, especially for stage I disease.
The importance of PLC in the prognosis of NSCLC has generated many studies over the years. Because positive PLC cases showed a significant worse prognosis than negative ones, it has been thought to be an independent prognostic factor independent of TNM staging. And since positive PLC are not only associated with local failure but also distant metastasis, it may be a predictor of systemic microscopic metastasis at the time of surgery. Although past reports have demonstrated the prognostic significance of PLC in postoperative recurrence, there is no definitive agreement on how to incorporate PLC in the staging system or to use it in assessing postoperative therapy. Lim et al. reported that positive PLC should be upstaged to T4 [3]. However, many reports mentioned that PLC and malignant effusion should not be confused and the result of PLC alone should not determine the operability [1, 2, 4]. In our present study, patients with positive PLC showed higher recurrence rate and poorer prognosis than those of negative group in a multivariate analysis. Especially, survival difference was statistically significant in stage I disease. This finding is supported by other studies that have equally showed that positive PLC adversely affects survival of patients with stage I disease [1, 2, 5]. This constellation of studies suggests that positive PLC should result in upstaging of patients with presumed stage I disease. Until recently, adjuvant therapy has had minimal impact in patients with more advanced stage disease [11]. However, with the advent of new regimens and novel therapies, some studies are showing significant benefit to adjuvant therapy, including in patients with stage II disease [12–14]. Based on our study and others [6], stage I disease with positive PLC should be upstaged to stage II or more, and thus PLC play a role in assessing the need of adjuvant therapy. All the positive PLC results were found in adenocarcinoma in this study. Past studies also mentioned the relationship of histology and PLC, and most of them reported that adenocarcinoma cases are dominant. Because of a small sample size, we could not find the definitive correlation of histological type and PLC result. However, this may be merely influenced by the increased number of adenocarcinomas especially in Japan [15]. Multivariate analysis revealed both PLC and P factor as significant prognostic factors. This implies that the direct seeding of cancer cells from the pleural surface develop positive PLC, however, there might be another mechanism because of the fact that negative pleural invasion cases also revealed positive PLC (Table 1). Furthermore, part of P factor has been already adopted into the existing TNM-staging system as T factor; p2 and p3 can be translated into T2 and T3, respectively. This is why we insist upon the clinical significance of PLC other than the known prognostic factors.
PLC is easy to perform and, is a useful modality in assessing prognosis, particularly in stage I disease, and possibly a guide to further therapy. Thus, thoracic surgeons should routinely do PLC in lung cancer surgery. Furthermore, incorporating PLC into the present staging system should be discussed in light of the past studies.
We thank Dr Marie-Christine Aubry, Department of Laboratory Medicine and Pathology, Mayo Clinic for her proofreading of the manuscript.
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Abstract
1. Introduction
