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Ann Thorac Surg 2001;72:1160-1164
© 2001 The Society of Thoracic Surgeons

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Original article: general thoracic

Significance of lymphangiosis carcinomatosa at the bronchial resection margin in patients with non-small cell lung cancer

^a Department of Thoracic Surgery, Askepios Fachkiniken Müchen-Gauting, University of Munich, Munich, Germany
^b Department of Pathology, Asklepios Fachkliniken München-Gauting, Munich, Germany
^c Department of Surgery, University of Munich, Munich, Germany

Address reprint requests to Dr Passlick, Department of Surgery, University of Munich, Klinikum Innenstadt, Nussbaumstr 20, 80336 Munich, Germany
e-mail: passlick{at}lrz.uni-muenchen.de

Presented at the Poster Session of the Thirty-seventh Annual Meeting of The Society of Thoracic Surgeons, New Orleans, LA, Jan 29–31, 2001.

	Abstract

Top Abstract Introduction Patients and methods Results Comment Acknowledgments References

 
Background. Treatment options for patients with microscopic residual disease at the bronchial margin (R1-resection) after resection for non-small cell lung cancer include observation, radiotherapy, reoperation, or even systemic therapy. The present study was performed to identify a parameter that would estimate the prognosis of these patients more precisely to permit a well-founded treatment recommendation for the individual patient.

Methods. A total of 1,162 patients with resected nonsmall cell lung cancer were analyzed in this retrospective study. Fifty-four patients (4.6%) had R1-resections at the bronchial margin. Type of residual disease (mucosal, extramucosal, or involvement of the entire bronchial wall) and occurrence of tumor cells in the lymphatic vessels (lymphangiosis carcinomatosa) were recorded as distinct parameters and analyzed by univariate and multivariate analyses (Log rank test; Cox regression model).

Results. Lymphangiosis carcinomatosa at the bronchial margin was detected in 22 patients (40.7%) and was associated with a significantly shortened survival (median survival with lymphangiosis carcinomatosa, 13.3 months; without lymphangiosis carcinomatosa, 20.1 months; p = 0.026). Early stage patients (stage I–II) without lymphangiosis carcinomatosa showed a median survival of 49 months. Multivariate analysis revealed that lymphangiosis carcinomatosa at the resection margin is an independent prognostic parameter (p = 0.038). Even after postoperative radiotherapy the prognosis was still poor if a lymphangiosis carcinomatosa was detected (median survival, 17.1 months). All other parameters (T-stage, N-stage, tumor histology, type of bronchial wall involvement) were not of prognostic significance in R1-resected patients.

Conclusions. Lymphangiosis carcinomatosa at the bronchial resection margin predicts a poor prognosis in patients with non-small cell lung cancer. It is more than questionable whether these patients would benefit from local treatment options like radiotherapy.

	Introduction

Top Abstract Introduction Patients and methods Results Comment Acknowledgments References

 
According to the TNM system classification, microscopic residual disease at the resection margin is defined as R1 disease [1]. In a larger series of patients with non-small cell lung cancer (NSCLC) R1 disease at the bronchial margin was diagnosed in a substantial number of the patients (range, 2.6% to 17%) [2–7].

A generally accepted view is that residual tumor affects the prognosis adversely. However, a recent study that analyzed the postoperative outcome following "incomplete resections" of NSCLC showed that the R-status (R0 versus R1 resection) was not of prognostic impact [4]. Other authors reported that R1-resected NSCLC subgroups with different prognoses can be observed: tumor histology (adenocarcinomas versus squamous cell carcinomas) and type of R1 disease (mucosal versus extramucosal) were reported to be of predictive value in R1-resected NSCLC [2, 5, 6, 8]. However, these prognosticators statistically were not significant or the number of patients appeared to be too small to draw definitive conclusions.

Our assumption is that the current definition of R1-resection covers too many different conditions to allow a clear prognostic assessment of the individual patient. Therefore, the present study analyzed the influence of different parameters on survival of NSCLC patients with an R1-resection at the bronchial resection margin. The parameters included standard clinicopathological factors (T-stage, N-stage), type of R1-disease (mucosal, extramucosal, whole bronchial wall), and based on the work of Soorae and Stevenson [9], detection of tumor cells in the lymphatic vessels of the bronchial margin (lymphangiosis carcinomatosa).

	Patients and methods

Top Abstract Introduction Patients and methods Results Comment Acknowledgments References

 
Patients
Patients with microscopic residual disease at the bronchial margin were identified by screening the database of 1,162 patients who had undergone operations for NSCLC at our department of thoracic surgery from January 1988 through December 1997. In total, 54 patients (4.6%) had R1-resections at the bronchial margin. The median age of the 9 female and 45 male patients was 62 years (range, 46–79). Intraoperative frozen section examination of the bronchial margin was not performed in all patients, either because the distance between primary tumor and resection was considered to be safe or because the functional reserve of the patients excluded a further extension of the resection.

The only postoperative death was a patient who died of an adult respiratory distress syndrome of the contralateral lung at the 28th postoperative day following pneumonectomy. Two patients developed a bronchial stump insufficiency. One patient was reoperated successfully, and the other patient suffering from a late empyema was treated by open thoracostomy.

Methods
For this study the pathological specimens from all 54 patients were reassessed by our pathologist (AM-H) and the type of residual disease was divided into three groups: (1) mucosal disease, (2) extramucosal disease, and (3) involvement of the entire bronchial wall. In addition, the occurrence of tumor cells in the lymphatic vessels of the bronchial resection margin (lymphangiosis carcinomatosa) was recorded as a distinct parameter.

Generally, postoperative radiotherapy was recommended for patients with a bronchial R1-resection. However, postoperative radiotherapy was completely performed in only 39 (72%) of 54 patients. In 6 patients (including one early postoperative death) the overall condition of the patient was considered to be too poor to perform postoperative radiotherapy, and in the remaining 9 patients radiotherapy was either incomplete or the patients had denied further treatment.

Follow-up information was obtained from all patients. The median observation time was 43 months (range, 24–77).

Statistical analysis
Differences in the relative frequency of events were compared by using the ² test. Kaplan-Meier survival curves were calculated and the observed differences in survival were compared by log rank test. For multivariate statistical analysis all variables were dichotomized and Cox proportional hazard models were applied. The analyses were performed using the SPSS statistical software package (SPSS Software, Chicago, IL).

	Results

Top Abstract Introduction Patients and methods Results Comment Acknowledgments References

 
Patient population
The study population consisted of 54 patients with R1-status who had undergone operation for NSCLC from January 1988 through December 1997. The disease was located on the right side in 36 patients (67%) and on the left side in 18 patients (33%). In 25 patients the primary tumor was located in the upper lobe, in 5 patients in the middle lobe, and in 15 patients in the lower lobe. In 9 patients the tumor was located centrally with an involvement of more than one lobe. The histopathological analysis disclosed 16 adenocarcinomas (30%), 35 squamous cell carcinomas (65%), two large cell carcinomas (4%), and one undifferentiated carcinoma (1%). Pathological staging showed the following results: stage IA: 2 (3.7%); stage IB: 3 (5.6%); stage IIB 9 (16.7%); stage IIIA: 20 (37.0%); and stage IIIB: 20 (37.0%). Resections included 20 lobectomies, six bilobectomies, 24 pneumonectomies, two bronchial sleeve lobectomies, one combined bronchial/vascular sleeve lobectomy, and one anatomic segmentectomy.

Incidence of lymphangiosis carcinomatosa
The histopathological analysis showed lymphangiosis carcinomatosa at the bronchial resection margin in 22 of 54 NSCLC patients with R1 resections (40.7%) (Table 1). The type of bronchial stump involvement was classified as mucosal residual disease in 8 patients (14.8%), extramucosal disease in 34 patients (63%), and the entire bronchial wall in 12 patients (22.2%). The occurrence of lymphangiosis carcinomatosa did not correlate with the type of R1 disease or the type of resection performed. However, involvement of the lymphatic vessels was significantly more frequent in patients with adenocarcinomas (68.8%) compared with patients who had squamous cell carcinomas (28.6%; p = 0.01). Interestingly, lymphangiosis carcinomatosa was even detected in 29.2% of the patients without lymph node involvement (pN₀) and in 44% of the patients with pT_1-2 tumors (Table 1).

View larger version (14K): [in this window] [in a new window]   Fig 1. Kaplan-Meier curves of patients (n = 54) with (n = 22; continuous line) or without (n = 32; interrupted line) lymphangiosis carcinomatosa (LC) at the bronchial resection margin. The difference in survival is significant with p = 0.026 (log rank test).

	Comment

Top Abstract Introduction Patients and methods Results Comment Acknowledgments References

 
It is a commonly accepted view that residual tumor at the resection margin adversely affects outcome in NSCLC [6, 10]. However, some authors doubt that a positive bronchial resection margin is an independent prognostic factor, whereas others suppose that there might be subgroups of patients with bronchial R1-disease that differ in their long-term prognosis [4, 7, 9, 11]. The pioneer in this field is T. W. Shield, who in 1974 showed that, despite R1-resection, patients may survive for a long time, especially those with squamous cell carcinomas [11]. Similar results were reported by Soorae and Stevenson [9]. However, at that time, tumor classification systems were not routinely used, systematic mediastinal lymphadenectomy was not performed in all cases, and NSCLCs and small cell lung cancers were grouped together.

The aim of the present study was to analyze a cohort of NSCLC patients with bronchial R1-status in greater detail to identify prognostic subgroups of patients as precisely as possible by using simple pathological methods. In addition to standard clinicopathological parameters, such as T-stage and N-stage, the type of residual disease (mucosal, extramucosal, entire bronchial wall) and the occurrence of tumor cells in the lymphatic vessels of the bronchial stump were analyzed. Similar to previous studies [2, 5, 6], the present analysis showed no prognostic significance for routinely assessed parameters like T-stage and N-stage, tumor histology (adenocarcinomas/squamous cell carcinomas), and type of R1-disease. The only significant prognosticator was lymphangiosis carcinomatosa at the bronchial resection margin (Table 2; Fig 1). In a multivariate analysis, the risk for cancer-related death in patients with lymphangiosis carcinomatosa was doubled compared with patients without lymphangiosis carcinomatosa (Table 3).

Soorae and Stevenson [9] suggested previously, that the occurrence of tumor cells in the lymphatic vessels at the resection margin might be of predictive value. In a study with 64 patients they reported that 11 of 14 patients (78.6%) with a "lymphatic permeation" of the bronchial margin died within 1 year after surgery.

In the present study, lymphangiosis carcinomatosa was detected in about 40% of all patients. Interestingly, lymphangiosis carcinomatosa was observed not only in patients with advanced tumors, but also in 29% of the patients with pN₀ disease and 44% of the patients with small primary tumors (pT_1-2) (Table 1). Particularly in the early tumor stages, the examination for lymphangiosis carcinomatosa allowed discrimination between patients with favorable and unfavorable prognoses (Table 4). For example, 39% of the patients with pN₀, R1-disease survived more than 3 years after operation if the resection margin was free of lymphangiosis carcinomatosa, whereas none of the pN₀ patients with lymphangiosis carcinomatosa at the resection margin lived longer than 29 months postoperatively. Furthermore, patients with stage I–II disease but without lymphangiosis carcinomatosa had an excellent prognosis with a median survival of 49 months (Table 4). These data support the view that patients with R1-disease at the bronchial margin should be considered as a heterogeneous group depending on the involvement of the lymphatic vessels. Furthermore, the data might be helpful to explain why some recent publications failed to observe survival differences between R0- and R1-resections [4], because they did not consider these subgroups separately.

Currently there are no standard recommendations for further treatment of patients with a bronchial R1-resection. Classic options include simple observation, reoperation, and radiotherapy [12]. According to recently published studies (including the present series) most centers recommend postoperative chest irradiation for patients with residual disease at the bronchial margin [2, 5, 6]. This view is based mainly on the logic assumption that residual disease needs to be eradicated to provide a chance for long-term survival. However, there are no randomized trials concerning this strategy and some studies even doubt that immediate postoperative radiotherapy influences survival or the incidence of local recurrences [7, 10].

Recently, Massard and colleagues [12] suggested a more differentiated approach for patients with bronchial R1-disease. Based on the observation that patients with carcinoma in situ at the bronchial resection margin had an excellent prognosis per se, which might not be improved by radiotherapy, they suggested that only patients with a peribronchial infiltration should undergo adjuvant radiotherapy to gain better local disease control.

In our study, the majority of the patients received postoperative radiotherapy, and patients with early tumor stages I–II or squamous cell carcinomas had an acceptable outcome as long as no lymphangiosis carcinomatosa was detected (Table 4). Therefore, we would still recommend local therapy like reoperation or adjuvant radiotherapy in this subgroup of patients. Patients with a sufficient functional reserve in which frozen section analysis has not been performed, or in which false negative results have been found, might be candidates for reoperations. However, as in our study, the majority of patients are candidates for adjuvant radiotherapy for functional reasons.

In contrast, patients with a lymphangiosis carcinomatosa at the resection margin have an extremely poor outcome even with radiotherapy (Fig 2). Therefore, this group of patients should be considered as advanced disease irrespective of their actual TNM system stage and all therapeutic options including systemic chemotherapy should be discussed.

View larger version (14K): [in this window] [in a new window]   Fig 2. Kaplan-Meier curves of patients (n = 39) with postoperative adjuvant radiotherapy and with (n = 14; continuous line) or without (n = 25; interrupted line) lymphangiosis carcinomatosa (LC) at the bronchial resection margin. The difference in survival is significant with p = 0.020 (log rank test).

	Acknowledgments

Top Abstract Introduction Patients and methods Results Comment Acknowledgments References

	References

Top Abstract Introduction Patients and methods Results Comment Acknowledgments References

 

1. UICC. TNM Supplement 1993. A Commentary on uniform use. Berlin: Springer, 1993.
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8. Kaiser L.R., Fleshner P., Keller S., Martini N. Significance of extramucosal residual tumor at the bronchial resection margin. Ann Thorac Surg 1989;47:265-269.[Abstract]
9. Soorae A.S., Stevenson H.M. Survival with residual tumor on the bronchial margin after resection for bronchogenic carcinoma. J Thorac Cardiovasc Surg 1979;78:175-180.[Abstract]
10. Snijder R.J., de la Rivere A.B., Elbers H.J.J., van-den Bosch J.M.M. Survival in resected stage I lung cancer with residual tumor at the bronchial resection margin. Ann Thorac Surg 1998;65:212-216.[Abstract/Free Full Text]
11. Shields T.W. The fate of patients after incomplete resection of bronchial carcinoma. Surg Gynecol Obstet 1974;139:569-572.[Medline]
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