Thoracoscopic and laparoscopic lymph node staging in esophageal cancer: do clinicopathological factors affect the outcome?

Thoracoscopic and Laparoscopic Lymph Node Staging in Esophageal Cancer: Do Clinicopathological Factors Affect the Outcome? Mark J. Krasna, MD, Xiaolong Jiao, MD, Joshua R. Sonett, MD, Ziv Gamliel, MD, Afshin Eslami, MD, Yael Raefaly, MD, and Yousheng Mao, MD Division of Thoracic Surgery, University of Maryland Medical System, Baltimore, Maryland

Background. This study was performed to evaluate the pattern of lymphatic metastases found by combined thoracoscopic (TS) and laparoscopic (LS) lymph node staging in esophageal cancer, and ascertain whether clinicopathologic factors may be used to guide the clinical practice of combined TS and LS staging. Methods. A retrospective study was performed in a series of 76 esophageal cancer patients who had undergone both TS and LS staging before treatment. The correlation of TS and LS lymph node metastases with clinicopathologic factors was analyzed, including the clinical T stage, clinical N stage, tumor location, and histology. Results. Thirty-one patients (40.8%) were found to have lymphatic metastasis by TS and LS staging. Among them, 22 patients had abdominal lymph node metastases, 7 patients had mediastinal lymph node metastases, and 2 patients had both. Patients with advanced T stage (T3 to T4) or adenocarcinoma had a higher frequency of abdom-

inal lymphatic metastases than patients with early T stage (T1 to T2) (39% vs 16%; p ⴝ 0.04) or squamous cell carcinoma (39% vs 20%; p ⴝ 0.079), respectively. Patients with clinical abdominal N1 stage had a higher incidence of positive laparoscopic finding than patients with clinical abdominal N0 stage (67% vs 23%; p ⴝ 0.001). There was no significant correlation between lymphatic metastases and the location of the primary tumor. Conclusions. Clinicopathologic factors, including the histologic type, the clinical T stage, and abdominal N stage, may affect the outcome of TS and LS lymph node staging in esophageal cancer patients. This clinicopathologic impact may play a role for the selection of candidates for TS and LS staging, and also allows surgeons to focus their attention on the most likely high-yield biopsy targets.

E

addition, there is no pathologic verification for lymph node metastasis diagnosis by these methods [2–5]. With recent advances in combined TS and LS techniques, minimally invasive surgery has been used for pretreatment staging of EC with encouraging results [6]. The feasibility and safety of TS and LS staging for EC patients was recently described by a national multi-institutional trial (CALGB 9380) [7]. Furthermore we recently demonstrated that a sensitivity of 62.5% and a specificity of 100% for diagnosis of N1 disease in the chest can be achieved by TS staging, and a sensitivity of 84.6% and a specificity of 100% for diagnosis of N1 disease in the abdomen can be achieved by LS staging [8]. One remaining question, however, is whether clinicopathologic factors including clinical T stage, N stage, tumor location, and histology will affect the yield of this minimally invasive staging approach. This retrospective analysis was performed to illuminate whether clinicopathologic factors can be used to guide the clinical practice of TS and LS staging in the individual patient.

sophageal cancer (EC) remains a desperate disease with a poor prognosis. More than 12,000 patients will die of this disease annually in the United States. Although multimodality treatment has been developed to improve both local and systemic control, the results remain controversial because of the lack of precise pretreatment staging information and various treatment regimens used [1]. Accurate TNM staging at the time of the initiation of treatment is essential in evaluating the results of therapy, and may subsequently identify a subgroup of patients who might benefit from preoperative chemotherapy, or preoperative radiotherapy, or both. Noninvasive staging techniques, including computed tomography (CT), magnetic resonance imaging, and esophageal ultrasonography (EUS), are commonly used in EC patients. Their accuracy in diagnosing lymphatic metastases is limited because they are not able to distinguish normal lymph nodes from metastatic lymph nodes; inflammatory nodules from metastatic nodules. In

Presented at the Video Session of the Forty-eighth Annual Meeting of The Southern Thoracic Surgical Association, San Antonio, Texas, Nov 8 –10, 2001. Address reprint requests to Dr Krasna, Division of Thoracic Surgery, University of Maryland Medical Center, 22 S Greene St, Baltimore, MD 21201; e-mail: [email protected].

© 2002 by The Society of Thoracic Surgeons Published by Elsevier Science Inc

(Ann Thorac Surg 2002;73:1710 –3) © 2002 by The Society of Thoracic Surgeons

Material and Methods A retrospective study was performed in a series of 76 EC patients who had undergone both TS and LS staging 0003-4975/02/$22.00 PII S0003-4975(02)03552-X

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before treatment. The pathology of the patients included squamous cell carcinoma (30 patients) and adenocarcinoma (46 patients). All were more than 18 years and had a performance status of 0 to 2. No patient had prior chemotherapy or radiotherapy within the past 5 years. Patient workup included esophagoscopy with biopsy, bronchoscopy for lesions adjacent to the carina or mainstem bronchi, conventional computed tomographic (CT) scan of the chest and upper part of the abdomen, magnetic resonance imaging when indicated, and EUS. Patients were then registered in the staging study and underwent TS and LS surgical staging using a technique previously described [9]. A right thoracoscopic staging procedure was generally used, whereas a left thoracoscopic procedure was indicated when imaging examination demonstrated suspicious lymph nodes at the aortopulmonary AP window or left paraesophageal region. The 1997 AJCC staging criteria were used. On CT and magnetic resonance imaging examinations, thickening of the esophageal wall was diagnosed as T3, and direct involvement of adjacent organs as T4 by contact greater than 90°. The normal esophageal wall was usually depicted as five layers by EUS. The outermost layer invaded by tumor was defined as the depth of tumor invasion in the EUS studies. Lymph nodes more than 10 mm in diameter and lymph nodes more than 5 mm in short-axis diameter with a clear, hypoechoic, round shape, were defined as node metastases on CT and EUS examinations, respectively. The clinical stage was determined by highest stage of the individual results of the different noninvasive imaging techniques. Patients were assigned a clinical T stage based on the current AJCC staging criteria using depth of penetration as determined either by radiograph or ultrasound [10]. Lymph node involvement was noted according to size criteria on CT as well as any EUS evidence of pathologic appearing nodes. The esophagus was divided into three portions (upper, middle, and lower) to define the location of the primary tumor. The upper portion of the thoracic esophagus extends from the thoracic inlet to the level of the tracheal bifurcation, approximately 24 cm from the upper incisor teeth. The middle portion is the proximal half of the esophagus between the tracheal bifurcation and the EG junction, approximately 32 cm from the upper incisor teeth. The lower portion is the distal half of the esophagus between the tracheal bifurcation and the esophagogastric junction. The abdominal portion and the esophagogastric junction are also included in the lower portion of this study. For surgical staging, the posterior mediastinal nodes (level 3p), lower paratracheal nodes (level 4), aortopulmonary window nodes (level 5), subcarinal nodes (level 7), paraesophageal nodes (level 8), pulmonary ligament nodes (level 9) and the thorax, paracardial lymph node (level 16), left gastric node (level 17), and celiac lymph node (level 20) in the abdomen were usually sampled. The correlation of TS and LS surgical N staging with clinicopathologic factors, including clinical T stage, N stage, tumor location, and histology, were evaluated by the ␹2 test.

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Table 1. Clinicopathological Characteristics and Thoracoscopic and Laparoscopic Staging Results in 76 Patients With Esophageal Cancer No. of Cases With Positive Metastastic Lymph Node Findings by TS and LS Staging at Anatomic Regions

Clinicopathologic Characteristics (No. of Patients) Location of primary tumor Upper (3) Middle (29) Lower (44)b Histology Squamous cell carcinoma (46) Adenocarcinoma (30) Clinical T stage T1-2 (25) T3-4 (51) Clinical N stage N0 (37) N1 (39) a b

Chest ⫹a

Abdomen ⫹a

Both ⫹a

Total

1 3 3

0 6 16

0 1 1

1 10 20

4

5

1

10

3

17

1

21

3 4

4 18

0 2

7 24

4 3

10 12

0 2

14 17

Positive signs stand for positive metastatic lymph node finding. This includes esophagogastric junction.

LS ⫽ laparoscopic;

TS ⫽ thoracoscopic.

Results There were 62 males and 14 females with a mean age of 63.5 years (range, 38 to 81 years). The TS and LS lymph node staging was successfully done in all patients. TS staging was performed through a right side approach in 66 patients and left side approach in 10 patients. There was no major morbidity and mortality for the TS and LS staging procedure. Thirty-one patients (40.8%; 31 of 76) were found to have lymphatic metastasis by TS and LS staging of which 22 patients had abdominal lymph node metastases, 7 had mediastinal lymph node metastases, and 2 had both. Details of clinicopathologic characteristics and TS and LS staging results are shown in Table 1. Patients with advanced T stage (T3 to T4) or adenocarcinoma had a higher frequency of abdominal lymphatic

Table 2. Correlation of Clinical T Stage With the Overall Thoracoscopic and Laparoscopic Surgical N Staging, and Surgical N Staging at Anatomic Regions Surgical N Staging at Anatomic Regions

Clinical T Stage (No. of Patients) T1–T2 (25) T3–T4 (51) p Value

Overall Surgical N1 Staging (%)

Chest Surgical N1 Staging (%)

Abdominal Surgical N1 Staging (%)

7 (28) 24 (47) 0.1

3 (12) 6 (12) 0.98

4 (16) 20 (39) 0.04

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Table 3. Correlation of the Primary Tumor Histology With the Overall Thoracoscopic and Laparoscopic Surgical N Staging, and Surgical N Staging at Anatomic Regions Surgical N Staging at Anatomic Regions

Histology (No. of Patients) Adenocarcinoma (46) Squamous cell carcinoma (30) p Value

Overall Surgical N1 Staging (%)

Chest Surgical N1 Staging (%)

Abdominal Surgical N1 Staging (%)

21 (46) 10 (33)

4 (9) 5 (17)

18 (39) 6 (20)

0.29

0.3

0.079

metastases than patients with early T stage (T1 to T2) (39% vs 16%; p ⫽ 0.04) or squamous cell carcinoma (39% vs 20%; p ⫽ 0.079) (Tables 2, 3). Patients with clinical abdominal N1 stage had a higher incidence of positive laparoscopic findings than patients with clinical abdominal N0 stage (67% vs 23%; p ⫽ 0.001) (Table 4). Patients with adenocarcinoma had a lower chance of having mediastinal lymphatic metastases, but the difference was not significant (9% vs 17%; p ⫽ 0.3) (Table 3). There was no significant correlation between lymphatic metastases and the location of the primary tumor (Table 5). The most common lymphatic metastasis sites in the thorax were lymph nodes at level 8 (7 patients), followed by level 3 (2 patients), and level 9 (1 patient). The most common lymphatic metastasis sites in the abdomen were lymph nodes at level 17 (12 patients), followed by level 16 (9 patients), level 20 (9 patients), and level 18 (1 patient). No lymph nodes at levels 4, 5, and 7 were found to have metastasis by TS and LS staging in this group of patients.

Comment The main advantage of the combined TS and LS staging procedure is that it provides greater accuracy in evaluation of regional and celiac lymph nodes. Such information is very important in patient stratification and selection of therapy, especially in the setting of new treatment Table 4. Correlation of the Overall Clinical N Stage and Clinical N Stage at Anatomic Regions With the Overall Thoracoscopic and Laparoscopic Surgical N Staging, and Surgical N Staging at Anatomic Regions Clinical N Stage (No. of Patients) Overall N0 (37) N1 (39) Chest N0 (45) N1 (31) Abdomen N0 (61) N1 (15)

Surgical N1 Staging (%)

p Value

14 (38) 17 (44)

0.6

5 (11) 4 (13)

0.8

14 (23) 10 (67)

0.001

protocols. The TS and LS staging also provides tissue samples for further molecular biological analysis to detect occult lymph node metastasis for a more accurate staging [11, 12]. Furthermore the histologic status of mediastinal and abdominal lymph nodes is critical for the design of the field for irradiation. It allows for maximizing dose delivery to areas of known disease, while minimizing dose to surrounding sensitive, normal tissue [13]. For all these reasons, TS and LS staging has been used as an important complement to CT and EUS staging for EC patients [14]. The combined TS and LS staging procedure has been shown to be feasible and safe. The correlation of clinicopathologic factors with this minimally invasive staging diagnosis, however, remains less clear. Because some reports have demonstrated that patients may have different lymph node metastases patterns based on the tumor location, histology, and clinical TNM stage [15–18], we performed this study to clarify if such patterns may affect the yield of our surgical staging procedure. We found that patients with adenocarcinoma or advanced T stage are more likely to have abdominal lymph node metastases, a result which is consistent with the above reports. Patients with clinical diagnosis of abdominal lymph node metastases had a higher incidence of laparoscopic N1 disease. This result may be attributed to the increased accuracy of clinical staging diagnosis by EUS for nonobstructing tumors. Nevertheless the fact that laparoscopy found N1 disease in 23% of patients with clinical abdominal N0 stage and N0 disease in 33% of patients with clinical abdominal N1 stage supports the use of laparoscopic staging in EC patients (Table 2). The location of the tumor did not have significant impact on the surgical staging outcome in this study, although patients with distal disease or disease at the esophagogastric junction had nearly a doubled percentage of abdominal lymph node metastases than patients with middle and upper disease. All these results suggest that the histologic type, the clinical T stage, and abdominal N stage, rather than the tumor location, may affect the outcome of TS and LS lymph node staging in EC patients. Such findings may play a role for selection of candidates for TS and LS staging, and also allows surgeons to focus their attention on the most likely high-yield biopsy targets. Although the accuracy and specificity of TS and LS Table 5. Correlation of the Primary Tumor Location With the Overall Thoracoscopic and Laparoscopic Surgical N Staging, and Surgical N Staging at Anatomic Regions

Tumor Location (No. of Patients) Lower (44)a Upper ⫹ middle (32) p Value a

Surgical N Staging at Anatomic Regions

Overall Surgical N1 Staging (%)

Chest sN1 (%)

Abdominal sN1 (%)

20 (45) 11 (34) 0.3

4 (9) 5 (16) 0.4

17 (39) 7 (22) 0.1

This includes esophagogastric junction.

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Fig 1. Staging algorithms for esophageal cancer at the University of Maryland Medical System: noninvasive staging methods, including computer tomography (CT) and positron emission tomography (PET), when indicated, are used first to screen patients to exclude distant metastases. These are followed by endoscopic ultrasound examination (EUS) and EUS-guided fine needle aspiration (FNA) of suspicious lymph nodes (LN). If EUS FNA is negative, thoracoscopy/laparoscopy (TS and LS) staging is done to further define the stage categories. If lymphatic metastases are found by EUS FNA or the combined TS and LS staging procedure, multimodality treatment will be considered for the patient. (EGD ⫽ esophagoscopy; ? ⫽ any suspicious metastases.)

staging is superior to other noninvasive staging methods in our previous study [8], the cost and surgical intervention before definitive treatment remains significant [19]. Recently, EUS-guided fine needle aspiration (EUS FNA) has been used for pretreatment staging of EC patients with encouraging results [20, 21]. Positron emission tomography (PET) scanning was also found to be more accurate than CT in detecting distant metastases in EC patients [22]. Considering these advances and our research findings, we have now changed our staging algorithms to include EUS FNA, as well as PET scan, when applicable (Fig 1). Noninvasive staging methods are used to screen patients first, followed by EUS FNA. If EUS FNA is negative, TS and LS staging is done to further define the stage categories. We believe the combination use of these staging tools can provide a more efficient and cost-effective way to obtain complete and accurate staging information on EC patients. TS and LS staging can provide complete and accurate staging in EC patients. Clinicopathologic factors, including the histologic type, the clinical T stage, and abdominal N stage, rather than the tumor location, may affect the outcome of TS and LS lymph node staging in EC patients. A biopsy should be taken at least of lymph nodes at level 8 in the chest, and level 16, 17, or 20 in the abdomen because they are the most common sites for metastases. The combinational use of different staging tools may provide a more efficient and cost-effective way to obtain complete and accurate staging information in EC patients.

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