Journal of Surgical Oncology 2013;108:542–549
Extranodal Metastasis Is a Powerful Prognostic Factor in Patients With Adenocarcinoma of the Esophagogastric Junction HONG-DIAN ZHANG, MD,1 PENG TANG, MD,1 XIAO-FENG DUAN, MD,1 CHUAN-GUI CHEN, ZHAO MA, MD,1 YONG-YIN GAO, MD,2 HUA ZHANG, MD,3 AND ZHEN-TAO YU, MD1*
1 MD,
1
Department of Esophageal Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy of Tianjin City, Tianjin, China 2 Department of Gastrointestinal Medical Oncology, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy of Tianjin City, Tianjin, China 3 Department of Lung Cancer, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy of Tianjin City, Tianjin, China
Background and Objectives: The purpose of this study is to estimate the effect of extranodal metastasis (EM) on recurrence and survival in patients with adenocarcinoma of the esophagogastric junction (AEG) after curative resection. Methods: Clinical data from 284 node‐positive AEG patients who underwent curative resection were reviewed. Univariate and multivariate analyses were conducted to elucidate the effect of EM on recurrence‐free survival (RFS) and overall survival (OS). Results: EM was detected in 70 (24.6%) of the 284 cases. It had a significant correlation with tumor size, Lauren type, histopathological grading, depth of tumor invasion, number of metastatic nodes, lymph node ratio, and TNM stage. The 5‐year RFS and OS rates were 22.2% and 24.3%, respectively. Patients with EM had a significantly decreased RFS (16 vs. 36 months, P < 0.001) and OS (23 vs. 41 months, P < 0.001) compared with those without EM. Multivariate analyses identified EM as an independent prognostic factor (P ¼ 0.003 and 0.001, respectively). Conclusion: The presence of EM increases recurrence probability and reduces OS probability of AEG patients with lymph node metastasis. EM is a powerful prognostic factor reflecting a particularly aggressive biological behavior. Better understanding of EM status can help clinicians with regard to treatment decision and prognosis evaluation.
J. Surg. Oncol. 2013;108:542–549. ß 2013 Wiley Periodicals, Inc.
KEY WORDS: adenocarcinoma of the esophagogastric junction; extranodal metastasis; lymph node metastasis; recurrence; prognosis
INTRODUCTION
MATERIALS AND METHODS
Adenocarcinoma of the esophagogastric junction (AEG) is a special clinical disease characterized by pathologically different tumors developing in the border between the esophageal squamous epithelium and the gastric adenomatous epithelium. In the last decade, the incidence of AEG has increased compared with distal gastric cancer in many countries [1,2]. Due to its unique anatomical location, pathogenic processes, epidemiology, and biological behavior, the prognosis is often extremely poor [3,4]. Surgical resection with lymphadenectomy is the primary treatment for AEG in improving patient survival [5,6]. Lymphatic vessel invasion and lymph node metastasis are considered as the foremost important factors in determining the prognosis of AEG patients [7,8]. However, histological examination of the dissected nodal structures may exhibit spreading of cancer cells to the extramural soft tissue that was discontinuous with the primary lesion or the locoregional lymph nodes. This type of spreading has been reported as an independent negative prognosis factor in patients with head and neck [9–11], thyroid [12], esophageal [13], gastric [14,15], rectal [16], cervical [17], and bladder [18] cancers and so on. Such spreading probably reflects the invasiveness and aggressiveness of the primary tumor [19]. However, regarding AEG patients with lymph node metastasis, rare attention has been paid to the prognostic value of the presence of extranodal metastasis (EM) [20,21]. The objective of this study is to assess the incidence and prognostic significance of EM in a consecutive series of lymph node‐positive AEG patients after curative resection.
Patients
ß 2013 Wiley Periodicals, Inc.
The medical records of a consecutive series of 412 primary AEG patients who underwent curative surgical resection at Tianjin Medical University Cancer Institute and Hospital from January 2000 to December 2007 were reviewed retrospectively. AEG was defined as tumors with a center located within 5 cm oral and aboral of the anatomical esophagogastric junction. Before surgery, all patients had chest radiographs, an abdominal ultrasonography, or a CT scan for tumor staging. Upper gastrointestinal endoscopy and barium swallows were performed to determine the Siewert type [22,23]. The choice of operation was based on preoperative diagnosis and estimated length of esophageal invasion. None of these
Grant sponsor: National Natural Science Foundation of China; Grant number: 81071981. Conflict of Interest: The authors declare no conflict of interest. *Correspondence to: Zhen‐Tao Yu, MD, Department of Esophageal Cancer, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy of Tianjin City, Tianjin 300060, China. Fax: þ86‐22‐23359984. E‐mail:
[email protected] Received 13 June 2013; Accepted 05 August 2013 DOI 10.1002/jso.23430 Published online 9 September 2013 in Wiley Online Library (wileyonlinelibrary.com).
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cases received any kind of neoadjuvant therapy, including preoperative chemotherapy and/or radiotherapy. All patients underwent subtotal or total gastrectomy with lymphadenectomy in accordance with the principle outlined by the Japanese Gastric Cancer Association [24]. Postoperative adjuvant chemotherapy with fluoropyrimidine‐ or platinum‐based regimens with the optional addition of anthracycline or taxane was routinely prescribed to patients with more than stage II cancer. Several patients who satisfied the criteria but did not receive adjuvant chemotherapy, because of poor performance status or severe complications, or refusal by the patients, were also included in the study. All patients included in our study were retrospectively evaluated based on gender, age, tumor size, histological grading according to the World Health Organization (WHO) classifications, Lauren classifications [25], depth of tumor invasion, lymph node metastasis, lymph node ratios, TNM stage, type of operative methods, lymphadenectomy, and postoperative chemotherapy.
Pathological Examinations The pathological examination of the surgical specimens was conducted following standardized pathological procedure. Specimens and dissected lymph nodes which contained some amounts of surrounding fat tissues were fixed in 10% formalin, embedded in paraffin, and stained with hematoxylin–eosin (H&E). Each metastasis was re‐examined microscopically on slides for the presence of EM. In our study, EM was defined as the presence of tumor cells in extramural soft tissue that was discontinuous with the primary lesion or the locoregional lymph nodes. Deposits of metastatic adenocarcinoma into soft tissue without a recognizable lymph node were also considered as EM, unless these metastasis were associated with perineural and/or vessel involvement (Fig. 1). Three senior pathologists investigated all the sections of the primary tumors based on the seventh edition of the American Joint Committee on Cancer (AJCC) TNM classification system for esophagus and esophagogastric junction cancer [26,27]. Moreover, the clinicopathological findings were determined based on the criteria provided by the Japanese Classification of Gastric Carcinoma [28]. With regards to the WHO classification, well/moderately differentiated types and papillary types were classified as a differentiated group, while poorly differentiated adenocarcinoma, mucinous adenocarcinoma, signet‐ring cell carcinoma, and other types of carcinoma were classified as an undifferentiated group.
Follow‐Up After curative resection, all patients were followed up every 3 months for the first year, every 6 months for the second year, and then every year until death or the last follow‐up. Clinical and laboratory examinations, as well as imaging studies, were obtained during each visit. Recurrence of the disease was diagnosed on clinical grounds. When recurrence was suspected, further investigations were conducted, such as enhancement computed tomography (CT). The type of recurrence was classified as locoregional, hematogenous, or peritoneal seeding based on imaging studies or intraoperative and biopsy findings in reoperated cases. Only the first site of relapse was taken into consideration. Follow‐up extended until May 2012. Recurrence‐free survival (RFS) was defined as the period from the first day after surgery to disease recurrence or to the date of death or last follow‐up. Overall survival (OS) was described as the period from the first day after surgery to the date of death or last follow‐up.
Fig. 1. Hematoxylin and eosin staining shows extranodal metastasis in adenocarcinoma of the gastroesophageal junction. Tumor cells are scattered into the adipose connective tissue distinct from the metastatic lymph node, arrow indicates the EM. A: Original magnification 100. B: Original magnification 400. Kaplan–Meier method and compared with log‐rank test. Univariate analyses were carried out to evaluate the significance of EM and other clinicopathological features as prognostic factors. Factors deemed as potentially important by univariate analyses (P < 0.05) were subjected to multivariate Cox proportional hazards model to identify independent prognostic factors. The 95% confidence interval (CI) was used to quantify the relationships between survival time and each independent factor. A two‐tailed P‐value of 0.28 TNM stagea I II III Mode of surgery Total gastrectomy Proximal gastrectomy Lymphadenectomy D1 D2
All patients
Negative, no. (%)
Positive, no. (%)
284
214 (75.4%)
70 (24.6%)
234 50
180 (76.9%) 34 (68.0%)
54 (23.1%) 16 (32.0%)
143 141
113 (79.0%) 101 (71.6%)
30 (21.0%) 40 (28.4%)
121 163
103 (85.1%) 111 (68.1%)
18 (14.9%) 52 (31.9%)
148 136
122 (82.4%) 92 (67.6%)
26 (17.6%) 44 (32.4%)
144 140
118 (81.9%) 96 (68.6%)
26 (18.1%) 44 (31.4%)
41 243
39 (95.1%) 175 (72.0%)
2 (4.9%) 68 (28.0%)
97 106 81
79 (81.4%) 84 (79.2%) 51 (63.0%)
18 (18.6%) 22 (20.8%) 30 (37.0%)
142 142
118 (83.1%) 96 (67.6%)
24 (16.9%) 46 (32.4%)
1 46 237
1 (100%) 42 (91.3%) 171 (72.2%)
0 (0%) 4 (8.7%) 66 (27.8%)
64 220
46 (71.9%) 168 (76.4%)
18 (28.1%) 52 (23.6%)
131 153
101 (77.1%) 113 (73.9%)
30 (22.9%) 40 (26.1%)
EM, extranodal metastasis; AEG, adenocarcinoma of esophagogastric junction. P < 0.05, significant differences between two groups. a According to the American Joint Committee on Cancer staging manual, 7th edition. b The median value of lymph node ratio was 0.28.
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x2
P‐Value
1.766
0.184
2.087
0.149
10.839
0.001
8.342
0.004
6.835
0.009
8.878
0.003
9.497
0.009
9.176
0.002
9.633
0.008
0.538
0.463
0.400
0.527
Extranodal Metastasis of Adenocarcinoma of the Esophagogastric Junction (P ¼ 0.002), and advanced TNM stage (P ¼ 0.008). In addition, Lauren type (P ¼ 0.004) was significantly associated with EM. The median value of positive lymph nodes in patients with EM was 5.5 (range: 1–67) and 3.5 (range: 1–17) in patients without EM. A significant difference was found in the number of metastatic lymph nodes between the two groups (t ¼ 4.150, P < 0.001; Fig. 2).
Association of EM to Clinical Outcomes The overall median follow‐up period was 36 months (range: 3–108 months). The median follow‐up period for EM‐negative patients was 48 months (range: 6–108 months) and 24 months (range: 3–84 months) for EM‐positive patients. During the follow‐up period, recurrence of the disease occurred in 41.2% (117/284) of the 284 patients. The median values of RFS and OS for all patients were 17 months and 21 months, respectively. The 5‐year RFS rate was 22.2%, and the 5‐year OS rate was 24.3%. Of the 117 cases with recurrence disease, 41.0% (48/117) had locoregional recurrence, 22.2% (26/117) had hematogenous recurrence, and 36.8% (43/117) had peritoneal seeding. The rate of recurrence for patients without EM (75/214) was significantly lower than in patients with EM (42/70; P < 0.001). The rate of peritoneal recurrence between patients with and without EM (12.1% vs. 24.3%, P ¼ 0.014) was significantly different. However, no significant difference was noted in the rates of hematogenous recurrence (7.9% vs. 12.9%, P ¼ 0.216) and locoregional recurrence (15.0% vs. 22.9%, P ¼ 0.126) between the two groups. The 5‐year RFS rate and the median survival time in the EM‐positive group were significantly lower than those in the EM‐negative group (7.1% vs. 27.1% [16 months vs. 36 months], HR: 2.078, 95% CI: 1.550– 2.786, P < 0.001; Fig. 3A). The 5‐year OS rate was 7.2% for the EM‐ positive group and 29.9% for the EM‐negative group, and the median survival time was 23 and 41 months, respectively (HR: 2.157, 95% CI: 1.607–2.896, P < 0.001; Fig. 3B). To obtain a more comprehensive understanding of the clinical significance of EM, we analyzed the survival of all patients by stratification according to the median number of metastatic lymph nodes (patients with one to four metastatic nodes and patients with more than four metastatic nodes). For patients with one to four involved lymph nodes, the differences in RFS (P ¼ 0.001) and OS (P ¼ 0.004) were statistically significant (Fig. 4A,B). For patients with more than four positive lymph nodes, the differences in RFS (P ¼ 0.001) and OS (P < 0.001) were also statistically significant (Fig. 4C,D). However, for patients with one to four involved nodes with EM and patients with more
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than four involved lymph nodes without EM, the prognoses were equally poor for RFS (P ¼ 0.186) and OS (P ¼ 0.209).
Analysis of Independent Prognosis Factors To determine whether EM was an independent factor associated with RFS and OS in AEG patients with lymph node metastasis. We used the Kaplan–Meier survival analysis to assess 12 possible prognostic factors: gender, age, tumor size, Lauren type, histopathological grading, depth of tumor invasion, N stage, lymph node ratio, EM, operative methods, lymphadenectomy, and postoperative chemotherapy. In the univariate analysis for RFS, tumor size (P ¼ 0.033), histopathological grading (P ¼ 0.026), depth of tumor invasion (P ¼ 0.002), N stage (P < 0.001), lymph node ratio (P ¼ 0.004), lymphadenectomy (P ¼ 0.039), and EM (P < 0.001) were found to be significant prognosis factors. In addition, the univariate analysis for OS indicated that tumor size (P ¼ 0.020), Lauren type (P ¼ 0.007), histopathological grading (P ¼ 0.012), depth of tumor invasion (P < 0.001), N stage (P < 0.001), lymph node ratio (P ¼ 0.006), operative methods (P ¼ 0.033), lymphadenectomy (P ¼ 0.009), and EM (P < 0.001) were important prognostic indicators. Table II shows the results of the univariate analyses for RFS and OS. Subsequent multivariate analyses using the Cox proportional hazards model were carried out to evaluate all significant prognostic factors found in the univariate analyses for survival. It was found that depth of tumor invasion (P ¼ 0.029, HR ¼ 1.621), N stage (P ¼ 0.002, HR ¼ 1.441), and EM (P ¼ 0.003, HR ¼ 1.610) were independent factors associated with RFS. Furthermore, the multivariate analysis showed that depth of tumor invasion (P ¼ 0.013, HR ¼ 1.762), N stage (P ¼ 0.002, HR ¼ 1.445), lymphadenectomy (P ¼ 0.004, HR ¼ 0.657), and EM (P ¼ 0.001, HR ¼ 1.699) were independent prognostic indicators for OS. Table III shows the results of the multivariate analyses for RFS and OS.
The Effect of EM on the Survival of Patients After Recurrence After recurrent disease was detected, patients were treated with second‐line chemotherapy or the best supportive care. All recrudescent patients were considered to determine whether EM had a prognostic effect on patient survival after recurrence. We found that, the median survival time after recurrence in the EM‐positive group was 4 months and that in the EM‐negative group was 8 months, there was a significant difference between the two groups (P ¼ 0.035).
DISCUSSION
Fig. 2. The correlation between metastatic lymph nodes and the occurrence of extranodal metastasis. Journal of Surgical Oncology
Several studies have confirmed that pathological evidence of regional nodal metastases is associated with a marked decrease in overall and disease‐specific survival. In the present study, it identified that the histopathological detection of EM was related to tumor aggressive behavior and could be a powerful prognostic factor in predicting recurrence and OS in AEG patients with lymph node metastasis. EM is well known as an important pathological factor contributing to poor prognosis in several types of cancers. For breast carcinoma, EM was determined to be a prognosticator of disease‐free survival [29] and had been considered as the separate pN1biii subcategory in the last edition of the TNM classification for malignant tumors [30]. However, this parameter was omitted in the recent edition of the aforementioned classification scheme. Additionally, in cervical cancer and bladder carcinoma, EM was associated with a high rate of local failure and reduced RFS and OS [17,18]. Conventional reports of EM in these tumors could be used to improve patient counseling and to change follow‐up plans and treatment strategies regarding adjuvant therapies. However, research on the effect of EM on patients with AEG was rare [20]. In the present study involving 284 surgically treated nodal‐
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Fig. 3. The survival curves of the patients with AEG determined by Kaplan–Meier method (log‐rank test). A: The 5‐year recurrence‐free survival rate was significantly lower in EM(þ) group (7.1%) than that of EM() group (27.1%; P < 0.001). B: The 5‐year overall survival rate was significantly lower in EM(þ) group (7.2%) than that of EM() group (29.2%; P < 0.001). EM, extranodal metastasis; AEG, adenocarcinoma of the gastroesophageal junction.
Fig. 4. The survival curves of the patients with AEG by Kaplan–Meier method according to metastatic nodes and EM status (log‐rank test). A: RFS curves according to EM status of patients with one to four metastatic nodes. B: OS curves according to EM status of patients with one to four metastatic nodes. C: RFS curves according to EM status of patients with more than four metastatic nodes. D: OS curves according to EM status of patients with more than four metastatic nodes. EM, extranodal metastasis; AEG, adenocarcinoma of the gastroesophageal junction; RFS, recurrence‐ free survival; OS, overall survival. Journal of Surgical Oncology
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TABLE II. Univariate Analysis of RFS and OS for 284 Node‐Positive AEG Patients Recurrence‐free survival Variable Gender Age Tumor size Lauren type Histopathological grading Depth of tumor invasion N stage Lymph node ratio EM status Type of gastrectomy Lymphadenectomy Postoperative chemotherapy
Overall survival
HR
95%CI
P‐Value
HR
95%CI
P‐Value
1.319 1.282 1.345 1.247 1.349 1.955 1.521 1.479 2.078 0.771 0.755 0.828
0.945–1.840 0.985–1.670 1.023–1.767 0.957–1.625 1.036–1.758 1.286–2.971 1.277–1.811 1.134–1.930 1.550–2.786 0.565–1.053 0.579–0.986 0.634–1.080
0.104 0.065 0.033 0.102 0.026 0.002 0.000 0.004 0.000 0.101 0.039 0.164
1.352 1.267 1.388 1.445 1.413 2.180 1.523 1.456 2.157 0.714 0.699 1.897
0.968–1.890 0.969–1.656 1.053–1.830 1.105–1.890 1.079–1.848 1.413–3.365 1.274–1.820 1.113–1.907 1.607–2.896 0.525–0.973 0.534–0.914 0.631–1.083
0.077 0.084 0.020 0.007 0.012 0.000 0.000 0.006 0.000 0.033 0.009 0.166
HR, hazard ratio; CI, confidence interval; OS, overall survival; RFS, recurrence‐free survival; EM, extranodal metastasis; AEG, adenocarcinoma of esophagogastric junction. P < 0.05, significant differences between two groups.
positive AEG patients, the occurrence of EM was associated with an increased frequency of recurrence (60.0% vs. 35.5%, P < 0.001) and a significantly reduced 5‐year OS rate (7.2% vs. 29.9%). Etoh et al. [31] defined EM as the presence of cancer cells in soft tissue that was discontinuous with the primary lesion or the perinodal soft tissue which was distinct from the lymph node. According to the Union for International Cancer Control (UICC), this type of tumor spreading should be regarded as a lymph node metastasis if the nodule has the form and smooth contour of a lymph node; otherwise, it should be regarded as part of the primary tumor [30]. Although a number of studies have described the presence of EM in several cancer types, their morphological characteristics and clinical implications have not been demonstrated. EM may originate from extracapsular extensions of lymph node metastasis, overgrowth of cancers from invading lymphovascular bundles, and localized seeding nodules. Furthermore, in these reports, patients who were found lymph node negative were also
TABLE III. Multivariate Analysis of RFS and OS for 284 Node‐Positive AEG Patients
Variable RFS Tumor size Histopathological grading Depth of tumor invasion N stage Lymph node ratio EM status lymphadenectomy OS Tumor size Lauren type Histopathological grading Depth of tumor invasion N stage Lymph node ratio EM status Type of gastrectomy Lymphadenectomy
Wald value
P‐Value
HR
95%CI
0.149 1.640 4.782 9.804 1.319 8.576 3.740
0.700 0.200 0.029 0.002 0.251 0.003 0.053
1.059 1.199 1.621 1.441 0.682 1.610 0.761
0.790–1.421 0.908–1.584 1.051–2.498 1.146–1.811 0.355–1.311 1.171–2.214 0.576–1.004
0.049 0.706 0.774 6.169 9.830 1.435 10.479 2.791 8.188
0.825 0.401 0.379 0.013 0.002 0.231 0.001 0.095 0.004
1.035 1.141 1.153 1.762 1.445 0.665 1.699 0.754 0.657
0.766–1.398 0.839–1.552 0.840–1.582 1.127–2.755 1.148–1.820 0.341–1.297 1.233–2.342 0.541–1.050 0.492–0.876
HR, hazard ratio; CI, confidence interval; OS, overall survival; RFS, recurrence‐ free survival; EM, extranodal metastasis; AEG, adenocarcinoma of esophagogastric junction. P < 0.05, significant differences between two groups.
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included and investigated [20]. Due to most EM were found in node‐ positive cases, and lymph node status had an important effect on prognosis, thus, node‐negative patients were excluded in the present study, and only a consecutive series of node‐positive patients with AEG were considered to lessen the confounding effect. The results of the present study, which was consistent with a previous one, revealed that the incidence of EM was 70 (24.6%) in 284 patients. Moreover, EM incidence was significantly associated with large tumors, poorly and undifferentiated carcinomas, deeper tumor invasion, more lymph node metastases, higher lymph node ratio, and advanced TNM stage, which were all proven to indicate worse outcomes. Nakamura et al. [14] reported a significant correlation between the number of involved nodes and the occurrence of EM in gastric cancer, as reported by Tanabe et al. [13] in esophageal cancer. Simultaneously, in our study, EM occurrence exhibited a positive close correlation with the number of involved lymph nodes. Patients with more than four positive lymph nodes are more likely to have EM. Therefore, positive nodes should be re‐ examined carefully in patients with five or more lymph node metastases during pathological work‐ups to determine EM occurrence. To clarify the effect of EM itself on prognosis, multivariate analyses of the present clinical variables were conducted. We found that the presence of EM remained as an independent prognostic factor for AEG patients with postoperative recurrence and poor survival. This phenomenon was consistent with the finding as reported in previous studies that EM had a close correlation with cancer aggressiveness. Detection and quantification of EM in the surgical resection specimen may be helpful to individualize postoperative therapeutic strategies in the adjuvant setting. Nakamura et al. [14] classified EM according to the number of lymph nodes with EM, and found that an increasing number of positive lymph nodes with EM were associated with poorer outcomes. Etoh et al. [31] also reported that survival rate decreased as the number of EM increased. In our study, this histopathological feature identified a subgroup of patients with a significantly decreased chance of RFS and OS compared with patients without EM. In addition, we analyzed patient survival by stratifying the number of metastatic lymph nodes into two groups, as follows: (1) patients with one to four metastatic nodes and (2) patients with more than four metastatic nodes. In both groups, patients with EM had a significantly poorer outcome than patients without EM. Whereas, RFS and OS in patients with one to four lymph node metastases without EM were similar to those in patients with five or more metastatic nodes without EM. These results suggest that a tumor with EM is highly advanced and has high metastatic potential. Adjuvant chemoradiation along with intensive follow‐up after surgery may be effective to improve patient prognosis [32].
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Several studies have identified EM as an indicator of distant metastasis in patients with head, neck, or vaginal cancers [12,33]. Concerning to gastrointestinal cancer, it has been similarly reported the association of extranodal invasion with hepatic and peritoneal metastases in patients with gastric cancer that EM maybe indicated to M category [34,35], and indicates a high risk of local recurrence in patients with rectal cancer [36]. In our study, the initial recurrence pattern of tumor in patients with EM was different from those without EM, and no significant difference was observed in the rates of local and hematogenous recurrences. However, the rate of peritoneal recurrence was significantly higher in EM‐positive patients than in EM‐negative patients. This finding is similar to the result of the study by Nakamura on gastric cancer [14]. After recurrent disease was detected, patients were treated with second‐line chemotherapy or best supportive care. The survival time after recurrence of EM‐negative patients was higher than that of EM‐positive patients, which was not reported in other tumor types. This indicates that patients with EM should be regarded as a high‐ risk group for recurrence and aggressive combined therapy should be performed for patients with EM. Radical surgical resection is the primary method in the treatment of AEG cancer. However, the long‐term outcome in patients with lymph node metastasis is unsatisfactory. Effective neoadjuvent therapy and perioperative chemotherapy may improve these patients prognosis. For neoadjuvent therapy, the final results of the CROSS study in 2012 showed that chemoradiation therapy followed by surgical resection was significantly superior to surgery alone in treating gastroesophageal junction subset of gastric cancers [37]. Both the ACTS‐GC Study Group trial [38] and the MAGIC trial [39] have demonstrated that perioperative chemotherapy significantly improved PFS and OS. However, the MAGIC trial did not evaluate the role of preoperative treatment when a D2 lymph node resection was performed and only 11.2% of tumor site was located in the esophagogastric junction. In our study, the patients were selected from 2000 to 2007 when perioperative chemotherapy was not widely accepted, and neoadjuvent chemotherapy may affect EM and the relationship between EM and OS [39]. Therefore, we selected patients who did not undergo preoperative chemoradiation therapy/chemotherapy and perioperative chemotherapy as subjects to exclude the aforementioned influential factor. Future studies to assess the efficacy of perioperative chemotherapy should focus on the treatment of AEG. In recent years, endoscopic ultrasound (EUS) is being used increasingly in clinical staging of gastric cancer patients because of its superior accuracy for T and N staging compared with abdominal ultrasound or CT scans [40]. However, EUS was not widely used among patients involved in our study at that time, without convincing results about the diagnostic value about EUS on extranodal invasion. Further randomized prospective studies are needed to evaluate the actual role of EUS in predicting this extensive metastasis in a large number of patients in recent years. The limitation of the present study is that it is retrospective in nature, including a relatively small sample population and the presence of several confounding factors. There was a lack of standardized postoperative chemotherapy regimens during that period which may affect patient survival. Furthermore, positive peritoneal cytology has been included recently in the AJCC staging system as an M1 disease patients and it is an independent predictor for identifying patients with high risk of recurrence after curative resection in gastric cancer [41]. However, only a small fraction of patients were subjected to peritoneal cytology, thus several IV stage cases may involve in the present study. Despite these limitations, we believe that extranodal extension of AEG in regional lymph nodes is an important and adverse prognostic finding. Further investigations should be performed involve a larger sample size, randomized prospective cohorts, multicenter studies to evaluate the prognostic effect of EM and identify the underlying mechanism. In conclusion, the presence of EM was a statistically significant independent predictor of reduced RFS and OS in AEG patients with Journal of Surgical Oncology
lymph node metastasis after curative resection. EM was closely associated with cancer aggressiveness and poor prognosis. Therefore, further investigation on the biological mechanisms underlying this finding and the prognostic significance of EM would be highly significant. Pathologists should be aware of this clinically important feature and should carefully examine lymphadenectomy specimens from AEG patients to determine the presence of EM upon histological examination. The standard for aggressive multidisciplinary treatment should be low in the presence of EM.
ACKNOWLEDGMENTS This work was supported by National Natural Science Foundation of China (81071981). The authors thank Runfen Cheng and Huiqin Liu for their excellent technical assistance.
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