Esophageal squamous cell carcinoma (ESCC) is an

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1 GENERAL THORACIC Comparison of the 6th and 7th Editions of the American Joint Committee on Cancer Tumor-Node-Metastasis Staging System in Patients With Resected Esophageal Carcinoma Po-Kuei Hsu, MD, Yu-Chung Wu, MD, Teh-Ying Chou, MD, Chien-Sheng Huang, MD, and Wen-Hu Hsu, MD Department of Surgery, Chutung Veterans Hospital, Hsinchu county; Division of Thoracic Surgery, Department of Surgery, Taipei-Veterans General Hospital, Taipei; School of Medicine, National Yang-Ming University, Taipei; Institute of Clinical Medicine, National Yang-Ming University, Taipei; Department of Pathology, Taipei-Veterans General Hospital, Taipei; and School of Medicine, Taipei Medical University, Taipei, Taiwan Background. The 7th edition American Joint Committee on Cancer tumor-nodes-metastasis (AJCC TNM) staging system was published recently. We aim to evaluate its predictive ability and to compare the performance of the 6th and 7th editions of the AJCC TNM staging systems in esophageal cancer. Methods. A total of 392 esophageal squamous cell carcinoma patients receiving primary surgical resection between 1995 and 2006 were included. Patients were staged using the 6th and 7th edition staging systems. Survival analysis was performed with a Cox regression model. The homogeneity, discriminatory ability, and monotonicity of gradients of two staging systems were compared using linear trend 2, likelihood ratio 2 statistics, and Akaike information criterion calculation. Results. The overall five-year survival rate for the entire cohort was 27.1%. Female gender, T, N, and M classifications according to the 7th edition staging system definition were independent prognostic factors in multivariate analysis. But histology grade and cancer location had no significant influence on patient survival. The 7th edition staging system has the highest linear trend 2 and likelihood ratio 2 scores. Compared with the 6th edition, the 7th edition staging system also has a smaller Akaike information criterion value, which represented the optimum prognostic stratification. Conclusions. The strength of the 7th edition AJCC TNM staging system is the new descriptors for N and M classifications. However, we did not find histologic grade and cancer location to be significant prognostic factors in our cohort. Overall, the 7th edition AJCC TNM staging system has better performance than the previous edition. (Ann Thorac Surg 2010;89: ) 2010 by The Society of Thoracic Surgeons Esophageal squamous cell carcinoma (ESCC) is an aggressive disease with a dismal prognosis despite multimodality therapy [1, 2]. Although the current practice of incorporating chemoradiation into the treatment protocol, surgical resection remains the best chance for cure with a complete resection [3]. A complete surgical resection with radical lymphadenectomy also provides the information for accurate stage determination, which is very important in prognosis prediction and further therapy decision. The 6th edition American Joint Committee on Cancer tumor-nodes-metastasis (AJCC TNM) staging system was published in 2002 [4]. However, the descriptors for TNM classification and the stage grouping were not different from the previous one, which has been used since Many modifications to the 6th edition Accepted for publication Jan 13, Adddress correspondence to Dr Wen-Hu Hsu or Dr Yu-Chung Wu, Division of Thoracic Surgery, Department of Surgery, Taipei-Veterans General Hospital No. 201, Sec. 2, Shih-Pai Road, Taipei, Taiwan; whhsu@vghtpe.gov.tw. AJCC TNM system have been proposed. For example, the subdivision of M classification into M1A and M1B according to the presence of nonregional lymph node involvement is considered inappropriate due to lack of advantage in survival prediction [5 7]. Furthermore, subdivision of N classification based on the absolute number of involved lymph nodes instead of (or not only) the presence of regional lymph node involvement has been suggested for better survival stratification [5 8]. The 7th edition AJCC TNM staging system was released in 2009 [9, 10]. The major changes include the following. T4 is subclassified as T4A (resectable cancer invasion) and T4B (unresectable cancer invasion. N is subclassified based on the number of positive regional lymph nodes (N1: 1 to 2 nodes; N2: 3 to 6 nodes; and N3: 7 nodes). M classification is redefined based on the presence of distant metastasis, and the term nonregional lymph node is eliminated. Histologic grade and tumor location are incorporated by The Society of Thoracic Surgeons /10/$36.00 Published by Elsevier Inc doi: /j.athoracsur

2 Ann Thorac Surg HSU ET AL 2010;89: ESOPHAGEAL CANCER TNM STAGE COMPARISON Table 1. Staging Groupings for Esophageal Squamous Cell Carcinoma in the Seventh Edition AJCC TNM Staging System Stage T N M G Location IA Any IB Any Lower IIA Upper/middle Lower IIB Upper/middle Any Any IIIA Any Any Any Any 4A 0 0 Any Any IIIB Any Any IIIC 4A Any Any 4B Any 0 Any Any Any 3 0 Any Any IV Any Any 1 Any Any 1025 conducted with palliative purpose rather than curative intent; thus, a radical lymph node dissection might not be completed. Therefore, we included patients who underwent triincisional esophagectomy only. The principle of tumor resection and the extent of lymphadenectomy were similar in all patients. A triincisional approach included right side thoracotomy for en bloc esophagectomy and radical mediastinal lymph node dissection, midline laparotomy for esophageal substitute mobilization and intraabdominal lymph node dissection, and left side cervicotomy for anastomosis and cervical lymph node sampling. The systematic mediastinal lymphadenectomy, including recurrent nerve nodes, paratracheal nodes, posterior and anterior mediastinal nodes, subcarinal nodes, paraesophageal nodes, and inferior pulmonary ligament nodes, was performed. Intraabdominal lymph node dissection included paracardial nodes and enlarged celiac axis nodes. A cervical lymph node was removed when enlargement was found during cervical incision for anastomosis. GENERAL THORACIC G histologic grade; G1 well differentiated; G2 moderately differentiated; G3 poorly differentiated; M metastasis; N node; T tumor. Stage groupings are redefined and separate stage groupings are used for squamous cell carcinoma and adenocarcinoma (Table 1) [9, 10]. In this study we aim to evaluate the predictive ability of the 7th edition AJCC TNM staging system and to compare the 6th and 7th editions of the AJCC TNM staging systems in a cohort of patients who underwent primary surgical resection for ESCC. Patients and Methods Patients The Institutional Review Board of Taipei-Veterans General Hospital approved this study and granted a waiver of the informed consent process. A total of 392 ESCC patients receiving primary surgical resection through the triincisional approach between 1995 and 2006 in Taipei- Veterans General Hospital were included in this study. The diagnosis workup and surgical procedures were as described previously [8]. In brief, all patients received preoperative studies, including physical examination, laboratory tests, esophagogastroduodenoscopy, flexible bronchoscopy, barium esophagography, computed tomography scans from neck to upper abdomen, ultrasound of the abdomen, and radionuclide bone scans. Surgical Procedures The triincisional approach is the mainstay for a curative esophageal cancer resection in our hospital. Only a minority of patients received a transhiatal approach due to poor cardiopulmonary reserve or a left side thoracoabdominal approach due to surgeon s preference. In these two approaches, the surgical intervention was Pathologic Examination The specimens were labeled by the surgeon and sent for pathologic examination after overnight preservation in 10% neutral buffered formalin. Description of the tumor (appearance, invasion depth, differentiation) and the lymph nodes (number of involved and examined lymph node in each station) were recorded. The histologic grade was determined by the extent to which a tumor resembled the nearby normal tissue. Grade was expressed in a qualitative assessment of differentiation from well-differentiated (grade 1), moderately-differentiated (grade 2), and poorly-differentiated (grade 3) to least differentiated (grade 4) by pathologists. All lymph nodes were cut in 5- m thickness at several levels along the longest axis, embedded in paraffin, and sectioned for hematoxylin and eosin staining. The lymph node number was counted under low power field microscope and two pathologists examined all slides individually. Patients were staged using the 6th and 7th editions of the AJCC TNM staging systems [4, 9]. Follow-Up Surviving patients were followed regularly at our outpatient department every three to six months for the first five years, than annually. The follow-up protocol includes history, physical examination, and chest computer tomographic scan. Endoscopic examination and wholebody positron emission tomographic scan were obtained as clinically indicated. Overall patient survival, defined as the time from operation to death or last follow-up, was used as a measure of prognosis. Statistics Survival analysis was performed using the Cox regression model and survival curves were plotted by the Kaplan-Meier method. In accordance with Ueno and colleagues [11], the criteria for evaluating the perfor-

3 GENERAL THORACIC 1026 HSU ET AL Ann Thorac Surg ESOPHAGEAL CANCER TNM STAGE COMPARISON 2010;89: mance of the staging systems were the following: (1) homogeneity within subgroups (small differences in survival among patients within same stage); (2) discriminatory ability between different groups (greater differences in survival among patients in different stages); (3) monotonicity of gradients shown in the association between stages and survival rates (patients with earlier stages have longer survival than those in later stages within the same system). The likelihood ratio 2 test related to the Cox regression model was used for measuring the homogeneity. The discriminatory ability and monotonicity of gradients assessments were measured with the linear trend 2 test. For the potential bias in comparing prognostic systems with different number of stages, the Akaike information criterion (AIC) within the Cox proportional hazard regression model was used [12, 13]. The AIC statistic was defined by AIC 2 log maximum likelihood 2 the number of parameters in the model. A smaller AIC value indicated a better model for predicting outcome. All calculations were performed using SPSS 14.0 software (SPSS Inc, Chicago, IL) and a p value of less than 0.05 was considered significant. Table 2. Demographics and Univariate Survival Analysis Results Variables Number 5-Year Survival (%) Median Survival, Months (95% CI) p Value Age, mean (ranges) 63.8 (30 88) ( ) Sex a Male ( ) Female ( ) Surgical approach Triincisional 392 Substitute organ Stomach ( ) Colon (0 12.7) Reconstruction route Retrosternal ( ) Posterior mediastinal (0 40.1) Subcutaneous Anastomosis site Neck 392 T a ( ) ( ) ( ) ( ) N a ( ) ( ) ( ) ( ) M a ( ) ( ) Tumor length, mean SD a Grade Well differentiated (G1) ( ) Moderately differentiated (G2) ( ) Poorly differentiated (G3) ( ) Location Upper third ( ) Middle third ( ) Lower third ( ) Adjuvant treatment With chemoradiation ( ) Without chemoradiation ( ) a A p value less than 0.05 was considered significant. CI confidence interval; M metastasis; N node; T tumor; SD standard deviation.

4 Ann Thorac Surg HSU ET AL 2010;89: ESOPHAGEAL CANCER TNM STAGE COMPARISON Results 1027 Mean follow-up time was 32.8 months (median follow-up time, 17.0 months). Overall five-year survival rate was 27.1 % with median survival of 20 months. In Table 2 the patient characteristics are summarized. The majority of patients had reconstruction with a gastric tube through the retrosternal route. The substitute organ and reconstruction route had no impact on patient survival (p and 0.642, respectively). Nine patients were incidentally found to have distant metastasis (lung, liver, or omentum) during the operation and were classified as M1. The T, N, and M classifications, according to the 7th edition staging system, all predicted survival significantly (Fig 1A C). However, it seems that further GENERAL THORACIC Fig 1. Kaplan-Meier survival curves for patients stratified by tumor T (A), node N (B), and metastasis M (C) classifications. Survival differences were analyzed using Cox regression model. Fig 2. Kaplan-Meier survival curves for patients stratified by histology grade (A) and cancer location (B). Survival differences were analyzed using Cox regression model. (G grade.)

5 GENERAL THORACIC 1028 HSU ET AL Ann Thorac Surg ESOPHAGEAL CANCER TNM STAGE COMPARISON 2010;89: Table 3. Multivariate Survival Analysis Results Variables HR 95% CI p Value Age Sex a Tumor length Histologic grade Cancer location Adjuvant treatment T a N a M a A p value less than 0.05 was considered significant. CI confidence interval; HR hazard ratio; M metastasis; N node; T tumor. subclassification of seven or greater positive lymph nodes as N3 is unnecessary because its survival was similar with N2 patients (Fig 1B). Another prognostic factor was tumor length. When examined as a continuous variable in the Cox regression model, it significantly predicted survival (hazard ratio: 1.092; 95% confidence interval to 1.145; p 0.001). However, histology grade and cancer location were not significant prognostic factors in our analysis (p and 0.353, respectively). The survival curves based on grade or location did not show any discriminatory ability (Fig 2). During the study period we did not have a standardized protocol for postoperative chemotherapy and (or) radiotherapy. Adjuvant therapy was suggested to all patients with T3-T4 classification or positive lymph node involvement; however, only 81 (20.7%) patients completed the adjuvant treatments. Without reaching a significant level, the patients with adjuvant treatment group showed a poorer five-year survival rate and median survival time. This probably reflects the selection bias because adjuvant therapy was offered to more advanced stage patients. The multivariate Cox regression model was performed with the incorporation of age, sex, tumor length, grade, location, adjuvant chemoradiation, and TNM (Table 3). Female gender, T, and N remained independent prognostic factors. Tumor length, which was a significant prognostic factor in univariate analysis, did not have significant influence on survival in multivariate analysis. Table 4 lists the patient distribution and stage specific survival rates. In the 6th edition staging system, the Kaplan-Meier plot showed overlapped survival curves among stages IIB, III, and IV (Fig 3A). Even classified as four major stages (I, II, III, IV), the survival curves of stages III and IV were similar (Fig 3B). According to the 6th edition staging system, most patients of stage IV were due to nonregional lymph node metastasis, whereas stage IIB (T1-2N1M0) and stage III (T3N1M0 and T4N0-1M0) consisted of patients with regional lymph node metastasis. Because these stages had similar survival, our results indicated that to identify nonregional lymph node metastasis and label as M1A or M1B is unnecessary. In the 7th edition staging system, when classified as all eight substages, there were similar survival curves between stages IIA and IIB, and between stages IIIB and IIIC (Fig 4A). But when classified as four major stages, the Kaplan- Meier plot showed a good discriminatory ability among stages I through IV (Fig 4B). According to the 7th edition staging system, T2-3N0M0 could be classified as stages IB, IIA, or IIB depending on the histologic grade and cancer location. However, as shown before, we did not recognize grade and location as significant prognostic factors in survival analysis. Therefore, the discriminatory ability was supposed to be worse among stages IB, IIA, and IIB. The majority of stage IIIC in our database was of N3 lesions (40 of 61, 65.6%). Because our database demonstrated similar survival between N2 and N3 patients, it was not surprising that there was no significant survival difference between stage IIIB (T3N2M0) and IIIC patients. The performance of the 6th and 7th edition staging systems, assessed by the linear trend 2, likelihood ratio 2, and the AIC test is described in Table 5. The 7th Table 4. Cross Table of the 6th Edition by the 7th Edition AJCC TNM Staging System With Patient Distribution and Stage-Specific Survival 6th Edition I IIA IIB III IV Survival According to the 7th Edition System 7th edition IA ( ) IB ( ) IIA ( ) IIB ( ) IIIA ( ) IIIB ( ) IIIC ( ) IV ( ) Survival according to 6th edition system 70.0 ( ) 35.0 ( ) 24.0 ( ) 13.0 ( ) 12.0 ( ) Survival median survival, months (95% confidence interval).

6 Ann Thorac Surg HSU ET AL 2010;89: ESOPHAGEAL CANCER TNM STAGE COMPARISON 1029 subdivided into N0 to N3. Therefore, a standardized extent of lymph node dissection and pathologic examination should be made in order to prevent the bias caused by inadequate lymph node evaluation. However, the evidence for routine three-field lymph node dissection is lacking. How extensive should lymph node dissection be for the thoracic esophageal cancer staging remains an important issue [14]. In our study, the prin- GENERAL THORACIC Fig 3. Kaplan-Meier survival curves for patients stratified by the 6th edition staging system. (A) Classified as all five substages. (B) Classified as four major stages. edition staging system had better homogeneity (highest likelihood ratio 2 score), discriminatory ability, and monotonicity of gradients (highest linear trend 2 score). Compared with the 6th edition staging system the 7th edition staging system had a smaller AIC value, which represented the optimum prognostic stratification. Comment The 7th edition staging system strengthens the role of positive lymph nodes, by which the N classification is Fig 4. Kaplan-Meier survival curves for patients stratified by the 7th edition staging system. (A) Classified as all eight substages. (B) Classified as four major stages.

7 GENERAL THORACIC 1030 HSU ET AL Ann Thorac Surg ESOPHAGEAL CANCER TNM STAGE COMPARISON 2010;89: Table 5. Comparison of the Performance of the 6th and 7th Editions of the American Joint Committee on Cancer Staging System (AJCC) TNM Staging System Figure Model Linear Trend 2 Likelihood Ratio 2 AIC 6th edition 3A I, IIA, IIB, III, IV B I, II, III, IV th edition 4A IA, IB, IIA, IIB, IIIA, IIIB, IIIC, IV B I, II, III, IV AIC Akaike information criterion; TNM tumor-node-metastasis. ciple of tumor resection and the extent of lymphadenectomy were similar in all patients. The mean number of dissected nodes was 23.6 in this study and more than 70% patients had 15 or more nodes examined, which indicated an adequate lymph node evaluation according to the National Comprehensive Cancer Network recommendation [3]. The clinical N stage, according to the 7th edition staging system, would be difficult to determine because counting the positive lymph node number depends on the postoperative pathologic examination. A precise clinical staging before a radical surgical intervention is nearly impossible. Although endoscopic ultrasound is the tool of choice in detecting regional lymph node involvement in esophageal cancer [15] it provides anatomic information only, without regarding the number of lymph nodes. To overcome this problem the positron emission tomographic scan, which provides the quantitative, functional assessment by standard uptake value, may be superior to endoscopic ultrasound in evaluation of the severity of lymph node involvement. In our previous work there was a significant relationship between the maximal standard uptake value of regional lymph nodes and the number of positive lymph nodes [16]. This correlation might help identifying patients with advanced lymph node preoperatively. The 7th edition staging system incorporates the histology grade and cancer location to subclassify T2-3N0M0 patients into stages IB, IIA, and IIB. However, the roles of histology grade and cancer location in esophageal cancer patient survival were controversial in the literature. Although histology grade is a strong predictor of survival in perijunctional esophagogastric carcinoma [17], its role in thoracic esophageal carcinoma yielded conflicting results [18 20]. In a 292 patient-based study, Wijnhoven and colleagues [21] showed grade of differentiation as a prognostic factor in univariate analysis but not in Cox regression multivariate analysis. When focusing on the squamous cell carcinoma-predominant databases, tumor differentiation was not significantly related with survival in the report by Roder and colleagues [22]. As for the cancer location, the results were also inconsistent [20, 21, 23]. Although many studies showed that survival improves as the tumor moves distally in the esophagus, these studies included a large portion of adenocarcinoma in distal-intraabdominal esophagus, and the results may not reflect the exact effect of tumor location in thoracic ESCC prognosis [19, 23]. To investigate this issue, Doki colleagues had analyzed 501 thoracic esophageal cancer cases (92% were ESCC). They reported that the upper, middle, or lower locations of thoracic esophageal cancer had similar five-year and ten-year disease-free survival [24]. In our study no prognostic role of these two variables was found. However, we could not exclude the possibility that the discrepancy was due to the sample size. Although our sample size was relatively small compared with the worldwide esophageal cancer collaboration database, we represented a single institution experience. The surgical procedures, pathologic examinations, and patient follow-up were uniform throughout the whole study period. In contrast, the previous published worldwide esophageal cancer collaboration data were assembled from 13 centers and the era spanned nearly 30 years; bias may be inevitable [20]. Furthermore, the squamous cell carcinoma histologic type constituted less than one half of the database, making further external validation necessary. Cancer staging is a dynamic process. With the improvement in understanding of the cancer biology, the staging system will need to be revised. The strength of the 7th edition AJCC TNM staging system includes elimination of the term nonregional lymph node and the new descriptors for N classification based on the positive lymph node number. Based on analysis of 392 ESCC patients who underwent primary surgical resection, we provided an external validation of the new AJCC TNM staging system. However, we did not find histologic grade and cancer location to be significant prognostic factors in our database. 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