Esophageal carcinoma is one of the most tedious

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1 Subcarinal Node Metastasis in Thoracic Esophageal Squamous Cell Carcinoma Jingeng Liu, MD,* YiHu,MD,* Xuan Xie, MD, and Jianhua Fu, MD Department of Thoracic Oncology, Cancer Center, Sun Yat-sen University, Guangzhou, People s Republic of China Background. Subcarinal node metastasis is common in patients with esophageal cancer. Some scholars have suggested that subcarinal nodes might not need to be sampled or dissected in patients with superficial squamous cell carcinoma of the thoracic esophagus. This research investigated the frequency of subcarinal node metastasis in patients with esophageal squamous cell carcinoma, identified the factors correlated to subcarinal node metastasis, and evaluated the clinical relevance of subcarinal node metastasis in thoracic esophageal squamous cell carcinoma. Methods. We retrospectively analyzed the clinical data of 1,812 consecutive patients with thoracic esophageal squamous cell carcinoma who underwent esophagectomy in the Cancer Center of Sun Yat-sen University. The surgical procedures included the left transthoracic procedure, Ivor-Lewis approach, and the cervical-thoracoabdominal procedure. Results. The frequency of subcarinal node metastasis was 10.0%. The univariate and multivariate analysis showed that longer tumor length, higher pathologic T metastases of other groups were associated with a higher frequency of subcarinal node metastasis (all p < 0.05). Patients with solitary subcarinal node metastasis had a significantly lower 5-year cumulative survival rate than those with solitary paraesophageal node metastasis (25.3% vs 39.6%, p < 0.05). Conclusions. Longer tumor length, higher pathologic T metastases of other groups are associated with a higher frequency of subcarinal node metastasis. Subcarinal node metastasis indicates worse prognosis of patients with thoracic esophageal squamous cell carcinoma compared with paraesophageal node metastasis. (Ann Thorac Surg 2012;93:423 8) 2012 by The Society of Thoracic Surgeons Esophageal carcinoma is one of the most tedious malignancies in the digestive system. In China, squamous cell carcinoma (SCC) accounts for 95% of esophageal cancer and mostly arises in the thoracic esophagus [1]. In contrast, the predominant pathologic diagnosis of esophageal cancer in the West is adenocarcinoma, and it commonly arises in the distal end of the esophagus or the gastroesophageal junction [2]. Lymph node metastasis is a common pathway for the spread of esophageal cancer, nodal stage is considered the most reliable predictor of survival after esophagectomy with lymphadenectomy in esophageal cancer patients without systemic metastasis, and the presence of nodal metastasis is indicative of high risk for disease recurrence [3 5]. Subcarinal node metastasis is common in patients with esophageal cancer. The frequency of subcarinal node metastasis in patients with esophageal squamous cell carcinoma (ESCC) ranges from 11.2% to 25.0% in published reports [6 9]. However, subcarinal nodes are very difficult to dissect in the transhiatal esophagectomy. Gotohda and colleagues [10] analyzed the patterns of lymph node metastasis in 65 patients who underwent Accepted for publication Oct 6, *Drs Jingeng Liu and Yi Hu contributed equally to this work. Address correspondence to Dr Fu, Department of Thoracic Oncology, Cancer Center, Sun Yat-sen University, 651 Dongfeng Rd E, Guangzhou , PR China; fujh@sysucc.org.cn. systematic three-field dissection for superficial SCC of the thoracic esophagus and found no subcarinal node metastasis in any of the patients. For this reason, the authors argued that subcarinal nodes might not need to be sampled or dissected in patients with superficial SCC of the thoracic esophagus [10]. Given this situation, we retrospectively analyzed the clinical data of 1,812 consecutive patients with thoracic ESCC who underwent esophagectomy in Cancer Center of Sun Yat-sen University. Our purpose was to further investigate the frequency of subcarinal node metastasis in patients with ESCC and identify the factors correlated to subcarinal node metastasis. We also evaluated the clinical relevance of subcarinal node metastasis in thoracic ESCC by comparing the prognosis of patients with solitary subcarinal node metastasis vs solitary paraesophageal node metastasis. Patients and Methods This retrospective study was approved by the Ethics Committee of Sun Yat-sen University Cancer Center. Study Cohort The records of all patients who underwent esophagectomy for ESCC at the Sun Yat-sen University Cancer Center from January 1997 to December 2008 were identified. We excluded patients with non-scc, cervical esophageal carci by The Society of Thoracic Surgeons /$36.00 Published by Elsevier Inc doi: /j.athoracsur

2 424 LIU ET AL Ann Thorac Surg SUBCARINAL NODE METASTASIS IN ESCC 2012;93:423 8 noma, or gastroesophageal junction carcinoma, and patients who underwent surgical exploration but without esophagectomy. Neoadjuvant chemotherapy or radiotherapy, or both [8, 11], other concurrent malignant diseases, or previous primary cancers might affect the status of the subcarinal nodes, therefore patients with these conditions were also excluded. Tumor, node, and metastasis descriptors, as well as the staging classification used for this analysis, were those defined in the American Joint Committee on Cancer Staging Manual (7th edition). Surgical Procedure Surgical procedures included primary tumor resection and lymph node dissection. The most commonly used surgical approaches included the left transthoracic procedure, the Ivor-Lewis approach, and the cervical-thoracoabdominal procedure. The left transthoracic procedure and Ivor-Lewis procedure with anastomosis of the upper chest were performed for all tumors of the lower thoracic esophagus and some tumors of the middle thoracic esophagus. The cervical-thoracoabdominal procedure was used for all tumors of the upper thoracic esophagus and some tumors of the middle thoracic esophagus. In this cohort of patients, en bloc lymph node dissection was performed, including the subcarinal, paraesophageal, pulmonary ligament, diaphragmatic, and paracardial lymph nodes, as well as those located along the lesser gastric curvature, the origin of the left gastric artery, the celiac trunk, the common hepatic artery, and the splenic artery. In addition, the lymph nodes, such as aortopulmonary, anterior mediastinal, and left tracheobronchial nodes were removed when the left transthoracic procedure was used, and the right superior mediastinal lymph nodes and right tracheobronchial nodes were removed when Ivor-Lewis procedure or cervical-thoracoabdominal procedure were used. Cervical lymphadenectomy was not systematically undertaken. For patients with cervical anastomosis, the lymph nodes exposed in the cervical incision were also dissected. Figure 1 shows the schematic diagram of the extension of lymphadenectomy. The lymph nodes were grouped according to Casson s lymph node map of esophageal cancer [12]. The alimentary tract was reconstructed using the gastric pull-up technique; if the stomach was unavailable, a jejunal loop or the left colon was used. The surgeons identified the sites of the nodes during the operation. All resected specimens were submitted for pathologic examination. Follow-Up Assessment A follow-up examination was generally scheduled every 3 months for the first year, every 4 months for the second year, and twice yearly thereafter. The regular follow-up assessment included physical examination, blood chemistry analysis, tumor markers (carcinoembryonic antigen, SCC antigen), computed tomography scan, esophagography, ultrasonography, and endoscopy. However, examinations were performed sooner if the patient had specific symptoms. Operative death was defined as death within 30 days after operation or at any time postoperatively if the Fig 1. Schematic diagram shows the extension of lymphadenectomy. (2R right upper paratracheal nodes; 3P Posterior mediastinal nodes; 4R right lower paratracheal nodes; 5 aortopulmonary nodes; 6 anterior mediastinal nodes; 7 subcarinal nodes; 8M middle paraesophageal nodes; 8L lower paraesophageal nodes; 9 pulmonary ligament nodes; 10R right tracheobronchial nodes; 10L left tracheobronchial nodes; 15 diaphragmatic nodes; 16 paracardial nodes; 17 left gastric nodes; 18 common hepatic nodes; 19 splenic nodes; 20 celiac nodes.) patient did not leave the hospital alive. April 2011 was the last contact date for survival. The median time from the operation to the last contact date for the entire cohort was 78.0 months (range, 1.0 to months). Statistical Analysis Continuous variables were compared by independent samples t test. The mean values are described as mean standard deviation. The Pearson 2 test was used to determine the significance of differences between groups for dichotomous variables. Survival was calculated by the Kaplan-Meier method, and the log-rank test was used to assess differences in survival between groups. A twosided p was considered statistically significant.

3 Ann Thorac Surg LIU ET AL 2012;93:423 8 SUBCARINAL NODE METASTASIS IN ESCC Survival time was measured from the date of the operation to the date of death or the last follow-up. Patients who were lost during the follow-up duration were censored at the last time of contact. Patients alive at the end of the study were also classified as censored for purpose of data analysis. The statistical analysis was performed with SPSS 17.0 software (SPSS, Chicago, IL). Results A total of 1,812 patients (1,384 men, 428 women) met the inclusion criteria and were included in the analysis. Patients were a mean age of 57.6 years (range, 30 to 88 years). The median number of resected lymph nodes for the entire cohort was 13 (range, 2 to 86). Among these, the median number of resected subcarinal nodes was 2 (range, 1 to 13). Lymph node metastases were observed in 841 patients (46.4%), and subcarinal node involvement Table 1. The Correlation Between Frequency of Subcarinal Node Metastasis and Clinicopathologic Characteristics of Patients Subcarinal Node Metastasis No. (%) a p Value Age, years 45 22/157 (14.0) /1,270 (9.5) 65 38/385 (9.9) Sex Male 143/1,384 (10.3) Female 38/428 (8.9) Tumor location Upper thoracic 28/330 (8.5) Middle thoracic 114/1,043 (10.9) Lower thoracic 39/439 (8.9) Tumor length, cm 3 11/299 (3.7) /1,048 (9.7) 5 68/465 (14.6) Pathologic T stage Tis 0/14 (0) T1a 0/49 (0) T1b 1/69 (1.4) T2 33/454 (7.3) T3 133/1,141 (11.7) T4a 9/60 (15.0) T4b 5/25 (20.0) Histologic grade G1 26/436 (6.0) G2 82/876 (9.4) G3 73/500 (14.6) Lymph node status of other groups Negative 40/1,011 (4.0) Positive 141/801 (17.6) a Percentage of patients with subcarinal node metastasis. Table 2. Logistic Regression Analysis of Factors Correlated to Subcarinal Node Metastasis Regression Coefficient OR (95% CI) p Value Tumor length ( ) Pathologic T stage ( ) Histologic grade ( ) Lymph node status of other groups ( ) CI confidence interval; OR odds ratio. was found in 181 (10.0%). The median number of positive lymph nodes was 2 (range, 1 to 40) in patients with lymph node metastases and 4 (range, 1 to 40) in patients with subcarinal node involvement. There were 24 operative deaths (1.3%) in the entire cohort of patients. Correlation analysis showed that longer tumor length, higher pathologic T stage, lower histologic grade, and positive lymph node metastases of other groups were associated with a higher frequency of subcarinal node metastasis (all p 0.05, Table 1). But no significant correlation was observed between subcarinal node metastasis and the clinicopathologic variables of age, sex, and tumor location (all p 0.05, Table 1). Logistic regression analysis showed tumor length, pathologic T stage, histologic grade, and lymph node status of other groups were independent factors correlated with subcarinal node metastasis (Table 2). Patients with subcarinal node metastasis had a 5-year cumulative survival of 22.5%, which was significantly lower than the 46.6% survival in those without subcarinal node metastasis (p 0.05, Fig 2). To evaluate the clinical relevance of subcarinal node metastasis in thoracic ESCC more accurately, we selected paraesophageal node metastasis as a reference. Two groups were identified and Fig 2. Kaplan-Meier estimates show for overall survival of subcarinal node metastasis for the positive (black line) and negative (gray line) groups. 425

4 426 LIU ET AL Ann Thorac Surg SUBCARINAL NODE METASTASIS IN ESCC 2012;93:423 8 compared: patients with solitary subcarinal node metastasis and patients with solitary paraesophageal node metastasis. We excluded patients with multiple or multigroup lymph node metastases, patients with operative death, and patients with adjuvant chemotherapy or radiotherapy, or both. Finally, we identified 29 patients with solitary subcarinal node metastasis and 96 with solitary paraesophageal node metastasis. No significant difference was found between the two groups in age, sex, tumor location, pathologic T stage, completeness of resection, histologic grade, and the number of resected lymph nodes (all p 0.05, Table 3). Patients with solitary subcarinal node metastasis had a 5-year cumulative survival of 25.3%, which was significantly lower than the 39.6% survival in those with solitary paraesophageal node metastasis (p 0.05, Fig. 3). Comment Subcarinal node metastasis is common in patients with esophageal cancer. The frequency of subcarinal node metastasis in patients with ESCC ranges from 11.2% to 25.0% [6 9]. Some scholars found that subcarinal node metastasis was rare in patients with superficial SCC of the thoracic esophagus and suggested that subcarinal nodes might not need to be sampled or dissected in patients with superficial SCC of the thoracic esophagus Table 3. Characteristics of Patients With Solitary Subcarinal Node Metastasis Versus Solitary Paraesophageal Node Metastasis Solitary Node Metastasis Subcarinal Paraesophageal p Value Age, mean SD years Sex, No. Male Female 5 16 Tumor location, No. Upper thoracic Middle thoracic Lower thoracic 7 20 Pathologic T stage, No. T T T4 3 3 Completeness of resection, No. R R1 2 4 R2 2 2 Histologic grade, No. G G G Resected lymph nodes, median (range) 14 (6 36) 13 (3 39) SD standard deviation. Fig 3. Kaplan-Meier estimates show overall survival of solitary subcarinal node metastasis group (black line) and solitary paraesophageal node metastasis group (gray line). [10]. Thus, further clarification is necessary to identify which factors correlated to subcarinal node metastasis and the clinical relevance of subcarinal node metastasis in thoracic ESCC. There are probably differences in the biologic behavior between adenocarcinoma and SCC and also in the prevalence and pattern of lymphatic spread [13, 14]. So in the present research, we enrolled patients with thoracic ESCC exclusively. In the current study, the frequency of lymph node metastasis was 46.4% for the entire cohort. This was in accordance with published reports in which the percentage of patients with lymph node metastasis was 40.9% to 58.4% [9, 15, 16]. In the 1,812 patients, subcarinal node involvement was found in 181 (10.0%). As found by the univariate and multivariate analysis, longer tumor length, higher pathologic T stage, lower histologic grade, and positive lymph node metastases of other groups were associated with a higher frequency of subcarinal node metastasis. Only 1 of 69 patients (1.4%) with T1b disease was found with subcarinal node metastasis, and no subcarinal node metastasis was found in the 63 patients with Tis/T1a disease. No significant correlation was observed between subcarinal node metastasis and the clinicopathologic variables of age, sex, and tumor location. Huang and colleagues [15] investigated the frequency of subcarinal node metastasis in patients with ESCC in different tumor locations, and found that it was 7.4% (4 of 54) in upper thoracic, 18.8% (128 of 680) in middle thoracic, and 10.5% (36 of 343) in lower thoracic locations. In the present study, we also found that the frequency of subcarinal node metastasis was the highest in the middle thoracic and the lowest in the upper thoracic locations, but this difference was not significant. In the entire cohort of this research, patients with subcarinal node metastasis had shorter survival than those without subcarinal node metastasis. Shimada and colleagues [7] also reported that the presence of subcarinal node metastasis was an independent risk factor for poorer survival. To evaluate the clinical relevance of

5 Ann Thorac Surg LIU ET AL 2012;93:423 8 SUBCARINAL NODE METASTASIS IN ESCC subcarinal node metastasis in thoracic ESCC more accurately, we selected paraesophageal node metastasis as a reference. Many scholars believed that the surgical outcomes in patients with thoracic esophageal cancer depended on the number, but not the site, of metastatic lymph nodes after curative esophagectomy [17, 18]. Moreover, the 7th edition of the American Joint Committee Cancer Staging Manual for esophageal carcinoma categorizes N stage according to the number of metastatic lymph nodes, irrespective of the site. By contrast, the 10th edition of the Japanese Classification of Esophageal Cancer categorizes N stage according to both the site and the number of metastatic lymph nodes [19]. The present research identified and compared two groups: patients with solitary subcarinal node metastasis and patients with solitary paraesophageal node metastasis. We excluded patients with multiple or multigroup lymph node metastases, patients with operative death, and patients with adjuvant chemotherapy or radiotherapy, or both. Patients with solitary subcarinal node metastasis had a significantly lower 5-year cumulative survival than those with solitary paraesophageal node metastasis. We tested the balance of the two groups for age, sex, tumor location, pathologic T stage, completeness of resection, histologic grade, and the number of resected lymph nodes. No significant difference was found. According to this result, we argued that the clinical relevance of subcarinal node metastasis was not equivalent to paraesophageal node metastasis, and subcarinal node metastasis meant a worse prognosis. Some researchers performed similar research and yielded the opposite results. No significant difference was found in survival concerning different stations of lymph node metastasis [20], and even distant lymph node metastasis was not a risk factor for poor survival [21]. In summary, longer tumor length, higher pathologic T metastases of other groups are associated with a higher frequency of subcarinal node metastasis. Subcarinal node metastasis indicates a worse prognosis for patients with thoracic ESCC compared with paraesophageal node metastasis. The authors thank all of the patients included in this research. References 1. Guo M, Zhao Y, Yang H, Yan X. Analysis of clinicopathological characteristics for 5406 cases of esophageal neoplasm [in Chinese]. Chin J Cancer Prev Treat 2008;15: Daly JM, Fry WA, Little AG, et al. Esophageal cancer: results of an American College of Surgeons Patient Care Evaluation Study. J Am Coll Surg 2000;190: Altorki N, Skinner D. Should en bloc esophagectomy be the standard of care for esophageal carcinoma? Ann Surg 2001; 234: Hulscher JB, van Sandick JW, de Boer AG, Wijnhoven BP, Tijssen JG, Fockens P. Extended transthoracic resection compared with limited transhiatal resection for adenocarcinoma of the esophagus. N Engl J Med 2002;347: Koenig AM, Prenzel KL, Bogoevski D, et al. Strong impact of micrometastatic tumor cell load in patients with esophageal carcinoma. Ann Surg Oncol 2009;16: Hsu CP, Hsu NY, Shai SE, Hsia JY, Chen CY. Pre-tracheal lymph node metastasis in squamous cell carcinoma of the thoracic esophagus. Eur J Surg Oncol 2005;31: Shimada H, Okazumi S, Matsubara H, et al. Long-term results after dissection of positive thoracic lymph nodes in patients with esophageal squamous cell carcinoma. World J Surg 2008;32: Castoro C, Scarpa M, Cagol M, et al. Nodal metastasis from locally advanced esophageal cancer: how neoadjuvant therapy modifies their frequency and distribution. Ann Surg Oncol 2011;18: Chen J, Liu S, Pan J, et al. The pattern and prevalence of lymphatic spread in thoracic oesophageal squamous cell carcinoma. Eur J Cardiothorac Surg 2009;36: Gotohda N, Nishimura M, Yoshida J, Nagai K, Tanaka N. The pattern of lymphatic metastases in superficial squamous cell carcinoma of the esophagus. Hepatogastroenterology 2005;52: Bollschweiler E, Besch S, Drebber U, et al. Influence of neoadjuvant chemoradiation on the number and size of analyzed lymph nodes in esophageal cancer. Ann Surg Oncol 2010;17: Casson AG, Rusch VW, Ginsberg RJ, et al. Lymph node mapping of esophageal cancer. Ann Thorac Surg 1994;58: Siewert JR, Stein HJ, Feith M, Bruecher BL, Bartels H, Fink U. Histologic tumor type is an independent prognostic parameter in esophageal cancer: lessons from more than 1,000 consecutive resections at a single center in the Western world. Ann Surg 2001;234: Stein HJ, Feith M, Bruecher BL, Naehrig J, Sarbia M, Siewert JR. Early esophageal cancer: pattern of lymphatic spread and prognostic factors for long-term survival after surgical resection. Ann Surg 2005;42: Huang W, Li B, Gong H, et al. Pattern of lymph node metastases and its implication in radiotherapeutic clinical target volume in patients with thoracic esophageal squamous cell carcinoma: a report of 1077 cases. Radiother Oncol 2010;95: Mariette C, Piessen G, Briez N, Triboulet JP. The number of metastatic lymph nodes and the ratio between metastatic and examined lymph nodes are independent prognostic factors in esophageal cancer regardless of neoadjuvant chemoradiation or lymphadenectomy extent. Ann Surg 2008; 247: Kunisaki C, Makino H, Kimura J, et al. Impact of lymphnode metastasis site in patients with thoracic esophageal cancer. J Surg Oncol 2010;101: Tachimori Y, Nagai Y, Kanamori N, Hokamura N, Igaki H. Pattern of lymph node metastases of esophageal squamous cell carcinoma based on the anatomical lymphatic drainage system. Dis Esophagus 2011;24: Japanese Society for Esophageal Disease. Japanese classification of esophageal cancer. 10th ed. Tokyo: Kanehara Co., Ltd; Xu QR, Zhuge XP, Zhang HL, Ping YM, Chen LQ. The N-classification for esophageal cancer staging: should it be based on number, distance, or extent of the lymph node metastasis? World J Surg 2011;35: Shimada H, Okazumi S, Matsubara H, et al. Location and clinical impact of solitary lymph node metastasis in patients with thoracic esophageal carcinoma. Am J Surg 2006;192: