World J Surg DOI 10.1007/s00268-014-2573-4
Sentinel Node Mapping in Adenocarcinoma of the Esophagogastric Junction Tatsuo Matsuda • Hiroya Takeuchi • Shinichi Tsuwano • Tadaki Nakahara Makio Mukai • Yuko Kitagawa
•
Ó Socie´te´ Internationale de Chirurgie 2014
Abstract Background The incidence of adenocarcinoma of the esophagogastric junction (AEG) is increasing, but the surgical strategy for AEG remains controversial. We hypothesized that sentinel node (SN) mapping for AEG could be validated to avoid unnecessary lymphadenectomy and permit minimally invasive surgery. We examined the feasibility of SN mapping for AEG. Methods We enrolled 15 patients with preoperatively diagnosed cT1 N0 M0 primary AEG (Siewert type I, N = 3; Siewert type II, N = 12) lesions measuring \4 cm in diameter. The dual tracer method employing radioactive colloid and blue dye was used to detect SNs. The distribution of SNs was compared with that of metastatic lymph nodes in 52 patients who were surgically treated without SN mapping. Results SNs were successfully identified in all the patients. Two patients with lymph node metastasis had positive SNs identified via an intraoperative pathological examination, and the diagnostic sensitivity and accuracy based on the SN status were both 100 %. For Siewert type
T. Matsuda H. Takeuchi (&) S. Tsuwano Y. Kitagawa Department of Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan e-mail: [email protected] T. Nakahara Department of Radiology, Keio University School of Medicine, Tokyo, Japan M. Mukai Division of Diagnostic Pathology, Keio University School of Medicine, Tokyo, Japan
II AEG, the SNs were not detected in the lower mediastinum by intraoperative gamma probing. Thus, all surgical procedures were performed via a transhiatal approach. No patient without SN metastasis experienced cancer recurrence during a 38-month median follow-up. The distribution of SNs was similar to that of lymph node metastasis in the patients who were surgically treated without SN mapping. Conclusions We achieved 100 % SN detection. Our results suggested that SN mapping is feasible for AEG and highly sensitive and accurate in diagnosing lymph node metastasis. SN mapping may clarify the necessity of mediastinal lymph node dissection and individualize minimally invasive surgery.
Introduction The incidence of adenocarcinoma of the esophagogastric junction (AEG) is increasing in developed countries [1–3]. The Siewert classification of AEG has been widely accepted [4]. This classification divides AEG into three subtypes: types I, II, and III. Because AEG is located along the borderline between the mediastinum and abdomen, it can metastasize to both cavities. Siewert et al. [5] reported that R0 resection was a prognostic factor in patients with AEG. In addition, the reported occurrence of mediastinal lymph node metastasis in AEG is 7–40 % [6–12]. Prophylactic mediastinal nodal dissection may be necessary for AEG. To perform an appropriate prophylactic mediastinal nodal dissection, a thoracic approach is absolutely imperative. However, this invasive procedure may increase morbidity and markedly reduce patient quality of life after surgery. Thus, the necessity of mediastinal nodal dissection remains controversial.
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Sentinel node (SN) mapping represents a promising method to detect mediastinal lymph node metastasis in AEG. The SN is defined as the first lymph node that receives lymphatic drainage from the primary tumor site. The SN is believed to be the first possible site of micrometastasis along the route of lymphatic drainage from the primary tumor. Thus, the SN status may predict the pathological status of all regional lymph nodes. If the SNs are detected and confirmed to be negative for cancer metastasis, then unnecessary lymph node dissection may be avoided. We previously reported the availability of SN navigation surgery for early gastric cancer and observed a high detection rate and sensitivity for the diagnosis of metastasis [13–15]. SN navigation surgery for gastric cancer has been validated in a prospective multicenter trial [16]. To the best of our knowledge, SN mapping for AEG has not been established. We hypothesized that SN mapping for AEG could be validated to avoid unnecessary lymphadenectomy and permit minimally invasive surgery with adequate radical oncological resection. This study demonstrated the feasibility, diagnostic sensitivity, and accuracy of SN navigation surgery in 15 patients with cT1 N0 M0 AEG.
Materials and methods
Table 1 Patient clinical parameters Parameter
SN mapping (N = 15)
Without SN mapping (N = 52)
Age, years (mean ± SD)
63.8 ± 10.7
64.0 ± 12.0
p value 0.816
Sex (male/female)
12/3
41/11
0.923
Siewert classification (type I/II)
3/12
7/45
0.531
Preoperative clinical TNM classification \0.001
cT factor cT1a
5
0
cT1b
10
7
cT2
0
24
cT3
0
20
cT4a cT4b
0 0
1 0
cN0
15
28
cN1
0
12
cN2
0
9
cN3
0
3
cM0
15
52
cM1
0
0
cN factor
0.013
cM factor
–
SD standard deviation, SN sentinel lymph node, TNM tumor, node, metastasis
Patients Between November 2000 and August 2011, a total of 15 patients who were preoperatively diagnosed with cT1 N0 M0 primary AEG tumors (Siewert type I, N = 3; Siewert type II, N = 12) measuring \4 cm in diameter at Keio University Hospital (Tokyo, Japan) were enrolled in the study. SN mapping was performed in the 15 patients with AEG (12 men and 3 women) with a mean age of 63.9 years (Table 1). Four patients were also diagnosed with Barrett’s esophagus (Siewert type I, 3/3; Siewert type II, 1/12). All the patients underwent SN mapping after providing written informed consent. Before surgery, the patients underwent esophagogastrography, esophagogastroscopy, and abdominal computed tomography and ultrasonography. Clinical staging and pathological examination of resected specimens were performed according to the Japanese Classification of Esophageal Cancer by the Japan Esophageal Society [17] and the tumor, node, metastasis (TNM) classification proposed by the American Joint Committee on Cancer. The Japanese classification scheme, which identifies lymph nodes by number, was used to describe identified lymph node stations. We also compared the distribution of SNs with lymph node metastasis in 52 patients with AEG (type I, N = 7;
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type II, N = 45) who were surgically treated without SN mapping at Keio University Hospital during the same period. SN mapping procedures Instead of using the conventional blue dye-only method, a dual tracer method that employs radioactive colloid and blue dye was used to detect SNs as previously described [18, 19]. In brief, 1 day prior to surgery, 2.0 mL of technetium-99m tin colloid solution (150 MBq) was injected into four quadrants of the submucosal layer around the primary tumor with an endoscopic puncture needle. For intraoperative SN detection [15], blue dye (1 % isosulfan blue or indocyanine green) was injected at the beginning of surgery via intraoperative endoscopy in the same manner as the preoperative injection of radioactive tracer. Blue-stained lymphatic vessels and nodes could be identified within 15 min of dye injection. A hand-held gamma probe was simultaneously used to locate the radioactive SNs (Fig. 1). Intraoperative gamma probing is feasible using a gamma detector (GPS Navigator; RMD Instruments LLC, Watertown, MA, USA), which is introducible via either a trocar port or incisional wound. The
World J Surg Fig. 1 Intraoperative gamma probing was performed to identify sentinel nodes in the lower mediastinum
nodes identified as SNs by either blue staining or radioactivity in the resected specimens were carefully investigated using the gamma probe, and all the SNs were sent for intraoperative pathological examination. After lymph node dissection, the absence of SNs, especially the lower mediastinal lymph nodes, was carefully confirmed by the gamma probe through either the incisional wound or laparoscopy ports. For the intraoperative pathological diagnosis, two frozen sections were examined by hematoxylin and eosin (H&E) staining. The sections were obtained from two different slices (one slice around the largest dimension and the other slice after cutting deeper into half of the node) in each SN. After surgery, another paraffin section from the residual lymph node was also examined for permanent diagnosis by H&E staining. In addition, we observed the aforementioned three sections by immunohistochemical staining with a mouse monoclonal anticytokeratin (1:50; AE1/AE3; Dako, Glostrup, Denmark) performed by an immunoperoxidase method. We categorized the final pathological results as macrometastasis, micrometastasis, or isolated tumor cells. The macrometastases were defined as tumors [2 mm in length and micrometastases as tumors between 0.2 and 2 mm in length. Tumors \0.2 mm in length were defined as isolated tumor cells.
Surgical SN navigation strategy for AEG Siewert type I Transthoracic esophagectomy was performed in all the patients with extended regional lymph node dissection (at least D2 dissection according to the Japanese Classification of Esophageal Cancer) [17]. We believe that a transthoracic approach is necessary to perform R0 resection for Siewert type I AEG. After lymph node dissection, the absence of SNs in the mediastinum or abdominal cavity was carefully confirmed using a gamma probe through the incisional wound or thoracoscopic and laparoscopic ports.
Siewert type II The operation was begun with a transhiatal approach in all the Siewert type II patients. If the SN was detected in the lower mediastinum and was positive for cancer metastasis, then mediastinal nodal dissection was performed with a thoracic approach. If the positive SN was detected only among the abdominal regional lymph nodes, then total gastrectomy with D2 lymphadenectomy was performed according to the 2010 Gastric Cancer Treatment Guidelines of the Japanese Gastric Cancer Association [20]. If all SNs were negative for metastasis, then proximal gastrectomy with at least D1 ? nodal dissection was performed. Statistical analysis Statistical analyses were conducted using SPSS Version 20 (IBM, Armonk, NY, USA). Clinical and pathological variables were analyzed using Pearson’s chi-squared test and the Mann–Whitney U test. A p \ 0.05 was considered statistically significant.
Results For all the patients with Siewert type I AEG (N = 3), transthoracic esophagectomy with gastric tube reconstruction was performed, including two cases of video-assisted thoracoscopic surgery. For all the patients with Siewert type II AEG (N = 12), proximal gastrectomy with transhiatal resection of the abdominal esophagus was performed, including six cases of laparoscopic surgery. The surgical pathological findings of the patients are shown in Table 2. SN detection was successful in all the 15 patients (100 %). The mean number of identified SNs per patient was 5.5 (Table 3). A total of 56 % of SNs were detected by only radioactivity, 20 % of SNs were detected by only blue dye, and 24 % of SNs were detected by both radioactivity and blue dye. Positive SNs were identified in two patients
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World J Surg Table 2 Surgical pathological findings in patients with adenocarcinoma of the esophagogastric junction Parameter
SN mapping (N = 15)
Without SN mapping (N = 52)
p value
\0.001
Surgical procedure Laparoscopy-assisted proximal gastrectomy with transhiatal approach
6
0
Open proximal gastrectomy with transhiatal approach
6
8
Open proximal gastrectomy with left thoracoabdominal approach
0
1
Open total gastrectomy with transhiatal approach Open total gastrectomy with left thoracoabdominal approach
0
24
0
1
Video-assisted thoracoscopic esophagectomy with gastric tube reconstruction
2
9
Transthoracic esophagectomy with gastric tube reconstruction
1
9
pT factor pT1a
7
2
pT1b
7
8
pT2
1
12
pT3
0
29
pT4a
0
1
pT4b
0
0
Postoperative diagnosis \0.001
pN factor
0.008
pN0
13
20
pN1
2
12
pN2
0
14
pN3
0
6
21.3 ± 7.9
34.9 ± 21.2
0.004
24.1 ± 9.3
46.4 ± 19.8
\0.001
3.0 (0–55)
19.0 (0–63)
0.03
Number of dissected lymph nodes, mean ± SD Tumor length (mm), mean ± SD Distance of proximal tumor border from the junction (mm), median (range)
SD standard deviation, SN sentinel lymph node
Table 3 Results of the sentinel node mapping Detection rate (%)
100 (15/15)
Number of dissected SNs (mean ± SD)
5.5 ± 3.8
Sensitivity (%)
100 (2/2)
Accuracy (%)
100 (15/15)
SD standard deviation, SN sentinel lymph node
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with lymph node metastasis via intraoperative pathological examination. Therefore, the diagnostic sensitivity and accuracy based on the SN status were both 100 %. The location of the identified SNs was analyzed in all the 15 patients (Fig. 2). In the patients with Siewert type II AEG (N = 12), most SNs were located in the lesser curvature area, including stations 3 (75 %), 1 (50 %), 7 (42 %), and 9 (17 %). SNs were also identified at the greater curvature side of the cardia (No. 2; 33 %). SNs were not identified in the lower mediastinum by intraoperative gamma probing. Therefore, all surgical procedures were performed using a transhiatal approach instead of a thoracic approach. After 2007, all five patients underwent laparoscopy-assisted proximal gastrectomy. Similarly, as observed in the patients with Siewert type II AEG, most SNs were located in the lesser curvature area in the patients with Siewert type I AEG (N = 3), including stations 1 (100 %), 3 (100 %), and 7 (33 %). In addition, SNs were also detected in the mediastinum including station 108 (66 %), 109 (33 %), and 110 (33 %). No severe intraoperative or postoperative complications occurred in any of the patients. Only one patient developed recurrence after surgery. This patient had Siewert type I with three metastatic lymph nodes. None of the patients without SN metastasis experienced cancer recurrence during a median follow-up of 38 months (range 27 * 77). Two patients exhibited lymph node metastasis. One patient had Siewert type I AEG with three metastatic lymph nodes (one positive SN each at stations 108 and 3, and one positive non-SN at station 3). These three lymph nodes were 10.1 (SN No. 108), 4.2 (SN No. 3), and 4.3 mm (non-SN No. 3) in diameter. All three lymph nodes displayed macrometastases that nearly occupied the entire lymph node diffusely. Another patient had Siewert type II AEG with two metastatic lymph nodes (one positive SN at station 7 and one positive non-SN at station 9). These lymph nodes were 13.5 (No. 7) and 14.3 mm (non-SN No. 9) in diameter. The two lymph nodes also had macrometastases that nearly occupied the entire lymph node diffusely. This patient had strongly requested laparoscopyassisted proximal gastrectomy regardless of the presence of node metastasis. Therefore, we performed laparoscopyassisted proximal gastrectomy after obtaining preoperative informed consent. The locations of lymph node metastasis and surgical pathological findings were analyzed in 52 patients with AEG (type I, N = 7; type II, N = 45) who were surgically treated without SN mapping (Table 2 and Fig. 3). These 52 patients represented more advanced cases than the 15 SN mapping cases because our SN mapping indication was limited to cT1 N0 M0 primary adenocarcinoma with a tumor diameter \4 cm. Two of ten patients (20 %) with pT1 tumors had lymph node metastasis. One patient had
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Fig. 2 Distribution of the identified sentinel nodes in the 15 patients. * Number of patients with a detectable sentinel node at the lymph node station. Thoracic lymph nodes: No. 105: upper thoracic paraesophageal lymph nodes; No. 106recL: left recurrent nerve lymph nodes; No. 106recR: right recurrent nerve lymph nodes; No. 108: middle thoracic paraesophageal lymph nodes; No. 110: lower thoracic paraesophageal lymph nodes; No. 111: supradiaphragmatic
lymph nodes. Abdominal lymph nodes: No. 1: right cardiac lymph nodes; No. 2: left cardiac lymph nodes; No. 3: lymph nodes along the lesser curvature; No. 7: lymph nodes along the left gastric artery; No. 8a: lymph nodes along the common hepatic artery anterosuperior group; No. 9: lymph nodes along the celiac artery; No. 10: lymph nodes at the splenic hilum; No. 11p: lymph nodes along the proximal splenic artery. SN sentinel node
Fig. 3 Distribution of the lymph node metastasis in the 52 patients with adenocarcinoma of the esophagogastric junction (type I, N = 7; type II, N = 45) surgically treated without sentinel node mapping. *Number of patients with detectable lymph node metastasis at the lymph node station
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Siewert type I AEG with three metastatic lymph nodes at stations 1, 3, and 7. Another patient had Siewert type II AEG with one metastatic lymph node at station 4sa. The distribution of SNs was similar to that of lymph node metastasis. The metastatic lymph nodes were mainly located in the lesser curvature area, including stations 1, 3, and 7. Mediastinal lymph node metastasis was present in seven of the 52 patients (type I, 2/7; type II, 5/45).
Discussion In the present study, we investigated the feasibility of SN mapping in the surgical treatment of patients with AEG. SN mapping was successful in all the 15 patients (100 %). Two patients with lymph node metastasis displayed positive SNs as identified by intraoperative pathological examination. Therefore, the diagnostic sensitivity and accuracy based on the SN status were both 100 %. SNs were not detected in the mediastinum in patients with Siewert type II AEG; therefore, all surgical procedures were performed by a transhiatal approach. All the patients without SN metastasis were free from cancer recurrence for a median follow-up of 38 months. In addition, the distribution of SNs was similar to that of lymph node metastasis in 52 patients who were surgically treated without SN mapping. Thus, we believe that SN mapping is feasible for AEG. Two major trials were performed in the Netherlands and Japan to investigate the optimal surgical approach for AEG. Hulscher et al. [21, 22] conducted a multicenter randomized controlled trial in the Netherlands to compare transhiatal approach esophagectomy versus right thoracic approach esophagectomy with extended en bloc lymphadenectomy in 205 patients with AEG (type I, N = 90; type II, N = 115). The 5-year survival rate was not significantly different between the transhiatal and right thoracic approach groups. However, in the subgroup analysis of the patients with Siewert type I, a survival benefit of 14 % was observed with the right transthoracic approach (51 vs. 37 %). In addition, an overall survival benefit for either surgical approach was not observed in the patients with Siewert type II AEG. They concluded that the transhiatal approach is better for patients with Siewert type II AEG, whereas thoracotomy is better for patients with Siewert type I AEG. The Japan Clinical Oncology Group (JCOG) conducted a multicenter randomized controlled trial in Japan (JCOG 9502) to compare the left thoracoabdominal approach (LTA) with the abdominal transhiatal approach in 165 Siewert types II and III patients (type II, N = 95; type III, N = 70) [23]. The 5-year overall survival rate was 52.3 % in the transhiatal approach group and 37.9 % in the LTA group. The hazard ratio of death for the LTA compared
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with the transhiatal approach was 1.36 (95 % confidence interval 0.89–2.08; p = 0.92). Morbidity was worse for the LTA than for the transhiatal approach. Thus, they concluded that the LTA approach cannot be justified to treat Siewert type II or III AEG if the length of esophageal invasion is B3 cm. The Hulscher and JCOG trials concluded that the transhiatal approach is better for patients with Siewert type II AEG [21–23]. However, the surgical strategy for patients with Siewert type II AEG remains controversial owing to the high frequency of lower mediastinal lymph node metastasis. Therefore, methods to identify patients with AEG at high risk of mediastinal lymph node metastasis are needed. Burkhard et al. reported that SN mapping helps to individualize the extent of lymphadenectomy required [24]. This is particularly important because lymphadenectomy is a major factor contributing to postoperative morbidity and mortality. Although SN procedures represent an attractive modality for AEG, only a few reports have been published [25, 26]. These reports identified an SN detection rate of 85–98 % and a relatively high false-negative rate (15 %). There are two reasons why our study achieved a 100 % SN detection rate and a 0 % false-negative rate. One reason is that the dual tracer method with radioactive colloid and blue dye was used for all the patients. Another reason is that our indication for the SN procedure was limited to cT1 N0 M0 primary adenocarcinoma tumors with a diameter \4 cm. This indication is the same as that previously used for gastric cancer [27]. cT1 N0 AEG tumors with diameters \4 cm do not have a high risk of mediastinal lymph node metastasis. However, Andrew et al. [28] reported that 18 % of patients with pT1b esophageal or esophagogastric junction adenocarcinoma had lymph node metastasis, and 6 % of the patients had mediastinal lymph node metastasis. We think that SN mapping is useful for identifying high-risk patients with mediastinal lymph node metastasis and detecting metastatic lymph nodes. In addition, Omloo et al. [22] reported that AEG patients with one to eight metastatic lymph nodes appear to benefit from extended transthoracic esophagectomy. Therefore, if the positive SN with metastasis was detected in the lower mediastinum, we believe that mediastinal nodal dissection should be performed with a thoracic approach. We previously reported laparoscopy-assisted proximal gastrectomy with SN mapping as a feasible minimally invasive surgical procedure with minimal morbidity and postoperative reflux esophagitis in patients with early-stage gastric cancer in the upper third of the stomach [27, 29]. We also consider laparoscopy-assisted proximal gastrectomy with SN mapping to be feasible for patients with Siewert type II AEG. In the present study, SNs or metastatic lymph nodes were not located in the pyloric region
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(Figs. 2 and 3). Therefore, if SNs are identified only in the abdominal area and are pathologically negative in patients with cT1 N0 M0 Siewert type II AEG, the patient should be treated by laparoscopy-assisted proximal gastrectomy without extensive mediastinal lymph node dissection. After 2007, all the five patients with cT1 N0 M0 Siewert type II AEG in our study underwent laparoscopy-assisted proximal gastrectomy. We believe that a combination of laparoscopic SN biopsy and endoscopic submucosal dissection (ESD) for early AEG is an attractive option as a whole stomach-, esophagus-, and esophagogastric junction-preserving, minimally invasive approach [30, 31]. If all SNs are pathologically negative for cancer metastasis, theoretically, ESD instead of surgery may be sufficient for the curative resection of cT1 AEG beyond the ESD criteria. To confirm the theory, we first attempted to confirm the feasibility of SN mapping in patients with early AEG in this study. This study had some limitations. First, the sample size was small. Second, the follow-up period was not particularly long. Third, we searched mediastinal SNs via transhiatal approach alone in patients with Siewert type II AEG. Both transhiatal and transthoracic approaches may be better for identifying mediastinal SNs than the transhiatal approach alone. However, we used the transhiatal approach alone for two reasons. One reason is the higher invasiveness of the transthoracic approach than the transhiatal approach. Another reason is that we believe that we can sufficiently search for mediastinal SNs by using the dual tracer methods even in the transhiatal approach alone. Essentially, we could point the gamma probe in the mediastinal direction through the esophageal hiatus to search for mediastinal SNs. In addition, we carefully confirmed the absence of lower mediastinal SNs by using the gamma probe after the lymph node dissection. We also confirmed the absence of bluestained lymphatic vessels and nodes in the lower mediastinum by the transhiatal approach.
Conclusion SN mapping procedures are feasible in AEG. SN mapping allows for the identification of patients with AEG at high risk of mediastinal lymph node metastasis and helps to determine the necessity of mediastinal lymph node dissection with a thoracic approach. Therefore, minimally invasive surgery with adequate radical oncological resection can be individualized for each patient with AEG.
Conflicts of interest The authors declare no conflicts of interest. This study received no grant support.
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Sentinel Node Mapping in Adenocarcinoma of the Esophagogastric Junction Tatsuo Matsuda • Hiroya Takeuchi • Shinichi Tsuwano • Tadaki Nakahara Makio Mukai • Yuko Kitagawa
•
Ó Socie´te´ Internationale de Chirurgie 2014
Abstract Background The incidence of adenocarcinoma of the esophagogastric junction (AEG) is increasing, but the surgical strategy for AEG remains controversial. We hypothesized that sentinel node (SN) mapping for AEG could be validated to avoid unnecessary lymphadenectomy and permit minimally invasive surgery. We examined the feasibility of SN mapping for AEG. Methods We enrolled 15 patients with preoperatively diagnosed cT1 N0 M0 primary AEG (Siewert type I, N = 3; Siewert type II, N = 12) lesions measuring \4 cm in diameter. The dual tracer method employing radioactive colloid and blue dye was used to detect SNs. The distribution of SNs was compared with that of metastatic lymph nodes in 52 patients who were surgically treated without SN mapping. Results SNs were successfully identified in all the patients. Two patients with lymph node metastasis had positive SNs identified via an intraoperative pathological examination, and the diagnostic sensitivity and accuracy based on the SN status were both 100 %. For Siewert type
T. Matsuda H. Takeuchi (&) S. Tsuwano Y. Kitagawa Department of Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan e-mail: [email protected] T. Nakahara Department of Radiology, Keio University School of Medicine, Tokyo, Japan M. Mukai Division of Diagnostic Pathology, Keio University School of Medicine, Tokyo, Japan
II AEG, the SNs were not detected in the lower mediastinum by intraoperative gamma probing. Thus, all surgical procedures were performed via a transhiatal approach. No patient without SN metastasis experienced cancer recurrence during a 38-month median follow-up. The distribution of SNs was similar to that of lymph node metastasis in the patients who were surgically treated without SN mapping. Conclusions We achieved 100 % SN detection. Our results suggested that SN mapping is feasible for AEG and highly sensitive and accurate in diagnosing lymph node metastasis. SN mapping may clarify the necessity of mediastinal lymph node dissection and individualize minimally invasive surgery.
Introduction The incidence of adenocarcinoma of the esophagogastric junction (AEG) is increasing in developed countries [1–3]. The Siewert classification of AEG has been widely accepted [4]. This classification divides AEG into three subtypes: types I, II, and III. Because AEG is located along the borderline between the mediastinum and abdomen, it can metastasize to both cavities. Siewert et al. [5] reported that R0 resection was a prognostic factor in patients with AEG. In addition, the reported occurrence of mediastinal lymph node metastasis in AEG is 7–40 % [6–12]. Prophylactic mediastinal nodal dissection may be necessary for AEG. To perform an appropriate prophylactic mediastinal nodal dissection, a thoracic approach is absolutely imperative. However, this invasive procedure may increase morbidity and markedly reduce patient quality of life after surgery. Thus, the necessity of mediastinal nodal dissection remains controversial.
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Sentinel node (SN) mapping represents a promising method to detect mediastinal lymph node metastasis in AEG. The SN is defined as the first lymph node that receives lymphatic drainage from the primary tumor site. The SN is believed to be the first possible site of micrometastasis along the route of lymphatic drainage from the primary tumor. Thus, the SN status may predict the pathological status of all regional lymph nodes. If the SNs are detected and confirmed to be negative for cancer metastasis, then unnecessary lymph node dissection may be avoided. We previously reported the availability of SN navigation surgery for early gastric cancer and observed a high detection rate and sensitivity for the diagnosis of metastasis [13–15]. SN navigation surgery for gastric cancer has been validated in a prospective multicenter trial [16]. To the best of our knowledge, SN mapping for AEG has not been established. We hypothesized that SN mapping for AEG could be validated to avoid unnecessary lymphadenectomy and permit minimally invasive surgery with adequate radical oncological resection. This study demonstrated the feasibility, diagnostic sensitivity, and accuracy of SN navigation surgery in 15 patients with cT1 N0 M0 AEG.
Materials and methods
Table 1 Patient clinical parameters Parameter
SN mapping (N = 15)
Without SN mapping (N = 52)
Age, years (mean ± SD)
63.8 ± 10.7
64.0 ± 12.0
p value 0.816
Sex (male/female)
12/3
41/11
0.923
Siewert classification (type I/II)
3/12
7/45
0.531
Preoperative clinical TNM classification \0.001
cT factor cT1a
5
0
cT1b
10
7
cT2
0
24
cT3
0
20
cT4a cT4b
0 0
1 0
cN0
15
28
cN1
0
12
cN2
0
9
cN3
0
3
cM0
15
52
cM1
0
0
cN factor
0.013
cM factor
–
SD standard deviation, SN sentinel lymph node, TNM tumor, node, metastasis
Patients Between November 2000 and August 2011, a total of 15 patients who were preoperatively diagnosed with cT1 N0 M0 primary AEG tumors (Siewert type I, N = 3; Siewert type II, N = 12) measuring \4 cm in diameter at Keio University Hospital (Tokyo, Japan) were enrolled in the study. SN mapping was performed in the 15 patients with AEG (12 men and 3 women) with a mean age of 63.9 years (Table 1). Four patients were also diagnosed with Barrett’s esophagus (Siewert type I, 3/3; Siewert type II, 1/12). All the patients underwent SN mapping after providing written informed consent. Before surgery, the patients underwent esophagogastrography, esophagogastroscopy, and abdominal computed tomography and ultrasonography. Clinical staging and pathological examination of resected specimens were performed according to the Japanese Classification of Esophageal Cancer by the Japan Esophageal Society [17] and the tumor, node, metastasis (TNM) classification proposed by the American Joint Committee on Cancer. The Japanese classification scheme, which identifies lymph nodes by number, was used to describe identified lymph node stations. We also compared the distribution of SNs with lymph node metastasis in 52 patients with AEG (type I, N = 7;
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type II, N = 45) who were surgically treated without SN mapping at Keio University Hospital during the same period. SN mapping procedures Instead of using the conventional blue dye-only method, a dual tracer method that employs radioactive colloid and blue dye was used to detect SNs as previously described [18, 19]. In brief, 1 day prior to surgery, 2.0 mL of technetium-99m tin colloid solution (150 MBq) was injected into four quadrants of the submucosal layer around the primary tumor with an endoscopic puncture needle. For intraoperative SN detection [15], blue dye (1 % isosulfan blue or indocyanine green) was injected at the beginning of surgery via intraoperative endoscopy in the same manner as the preoperative injection of radioactive tracer. Blue-stained lymphatic vessels and nodes could be identified within 15 min of dye injection. A hand-held gamma probe was simultaneously used to locate the radioactive SNs (Fig. 1). Intraoperative gamma probing is feasible using a gamma detector (GPS Navigator; RMD Instruments LLC, Watertown, MA, USA), which is introducible via either a trocar port or incisional wound. The
World J Surg Fig. 1 Intraoperative gamma probing was performed to identify sentinel nodes in the lower mediastinum
nodes identified as SNs by either blue staining or radioactivity in the resected specimens were carefully investigated using the gamma probe, and all the SNs were sent for intraoperative pathological examination. After lymph node dissection, the absence of SNs, especially the lower mediastinal lymph nodes, was carefully confirmed by the gamma probe through either the incisional wound or laparoscopy ports. For the intraoperative pathological diagnosis, two frozen sections were examined by hematoxylin and eosin (H&E) staining. The sections were obtained from two different slices (one slice around the largest dimension and the other slice after cutting deeper into half of the node) in each SN. After surgery, another paraffin section from the residual lymph node was also examined for permanent diagnosis by H&E staining. In addition, we observed the aforementioned three sections by immunohistochemical staining with a mouse monoclonal anticytokeratin (1:50; AE1/AE3; Dako, Glostrup, Denmark) performed by an immunoperoxidase method. We categorized the final pathological results as macrometastasis, micrometastasis, or isolated tumor cells. The macrometastases were defined as tumors [2 mm in length and micrometastases as tumors between 0.2 and 2 mm in length. Tumors \0.2 mm in length were defined as isolated tumor cells.
Surgical SN navigation strategy for AEG Siewert type I Transthoracic esophagectomy was performed in all the patients with extended regional lymph node dissection (at least D2 dissection according to the Japanese Classification of Esophageal Cancer) [17]. We believe that a transthoracic approach is necessary to perform R0 resection for Siewert type I AEG. After lymph node dissection, the absence of SNs in the mediastinum or abdominal cavity was carefully confirmed using a gamma probe through the incisional wound or thoracoscopic and laparoscopic ports.
Siewert type II The operation was begun with a transhiatal approach in all the Siewert type II patients. If the SN was detected in the lower mediastinum and was positive for cancer metastasis, then mediastinal nodal dissection was performed with a thoracic approach. If the positive SN was detected only among the abdominal regional lymph nodes, then total gastrectomy with D2 lymphadenectomy was performed according to the 2010 Gastric Cancer Treatment Guidelines of the Japanese Gastric Cancer Association [20]. If all SNs were negative for metastasis, then proximal gastrectomy with at least D1 ? nodal dissection was performed. Statistical analysis Statistical analyses were conducted using SPSS Version 20 (IBM, Armonk, NY, USA). Clinical and pathological variables were analyzed using Pearson’s chi-squared test and the Mann–Whitney U test. A p \ 0.05 was considered statistically significant.
Results For all the patients with Siewert type I AEG (N = 3), transthoracic esophagectomy with gastric tube reconstruction was performed, including two cases of video-assisted thoracoscopic surgery. For all the patients with Siewert type II AEG (N = 12), proximal gastrectomy with transhiatal resection of the abdominal esophagus was performed, including six cases of laparoscopic surgery. The surgical pathological findings of the patients are shown in Table 2. SN detection was successful in all the 15 patients (100 %). The mean number of identified SNs per patient was 5.5 (Table 3). A total of 56 % of SNs were detected by only radioactivity, 20 % of SNs were detected by only blue dye, and 24 % of SNs were detected by both radioactivity and blue dye. Positive SNs were identified in two patients
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World J Surg Table 2 Surgical pathological findings in patients with adenocarcinoma of the esophagogastric junction Parameter
SN mapping (N = 15)
Without SN mapping (N = 52)
p value
\0.001
Surgical procedure Laparoscopy-assisted proximal gastrectomy with transhiatal approach
6
0
Open proximal gastrectomy with transhiatal approach
6
8
Open proximal gastrectomy with left thoracoabdominal approach
0
1
Open total gastrectomy with transhiatal approach Open total gastrectomy with left thoracoabdominal approach
0
24
0
1
Video-assisted thoracoscopic esophagectomy with gastric tube reconstruction
2
9
Transthoracic esophagectomy with gastric tube reconstruction
1
9
pT factor pT1a
7
2
pT1b
7
8
pT2
1
12
pT3
0
29
pT4a
0
1
pT4b
0
0
Postoperative diagnosis \0.001
pN factor
0.008
pN0
13
20
pN1
2
12
pN2
0
14
pN3
0
6
21.3 ± 7.9
34.9 ± 21.2
0.004
24.1 ± 9.3
46.4 ± 19.8
\0.001
3.0 (0–55)
19.0 (0–63)
0.03
Number of dissected lymph nodes, mean ± SD Tumor length (mm), mean ± SD Distance of proximal tumor border from the junction (mm), median (range)
SD standard deviation, SN sentinel lymph node
Table 3 Results of the sentinel node mapping Detection rate (%)
100 (15/15)
Number of dissected SNs (mean ± SD)
5.5 ± 3.8
Sensitivity (%)
100 (2/2)
Accuracy (%)
100 (15/15)
SD standard deviation, SN sentinel lymph node
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with lymph node metastasis via intraoperative pathological examination. Therefore, the diagnostic sensitivity and accuracy based on the SN status were both 100 %. The location of the identified SNs was analyzed in all the 15 patients (Fig. 2). In the patients with Siewert type II AEG (N = 12), most SNs were located in the lesser curvature area, including stations 3 (75 %), 1 (50 %), 7 (42 %), and 9 (17 %). SNs were also identified at the greater curvature side of the cardia (No. 2; 33 %). SNs were not identified in the lower mediastinum by intraoperative gamma probing. Therefore, all surgical procedures were performed using a transhiatal approach instead of a thoracic approach. After 2007, all five patients underwent laparoscopy-assisted proximal gastrectomy. Similarly, as observed in the patients with Siewert type II AEG, most SNs were located in the lesser curvature area in the patients with Siewert type I AEG (N = 3), including stations 1 (100 %), 3 (100 %), and 7 (33 %). In addition, SNs were also detected in the mediastinum including station 108 (66 %), 109 (33 %), and 110 (33 %). No severe intraoperative or postoperative complications occurred in any of the patients. Only one patient developed recurrence after surgery. This patient had Siewert type I with three metastatic lymph nodes. None of the patients without SN metastasis experienced cancer recurrence during a median follow-up of 38 months (range 27 * 77). Two patients exhibited lymph node metastasis. One patient had Siewert type I AEG with three metastatic lymph nodes (one positive SN each at stations 108 and 3, and one positive non-SN at station 3). These three lymph nodes were 10.1 (SN No. 108), 4.2 (SN No. 3), and 4.3 mm (non-SN No. 3) in diameter. All three lymph nodes displayed macrometastases that nearly occupied the entire lymph node diffusely. Another patient had Siewert type II AEG with two metastatic lymph nodes (one positive SN at station 7 and one positive non-SN at station 9). These lymph nodes were 13.5 (No. 7) and 14.3 mm (non-SN No. 9) in diameter. The two lymph nodes also had macrometastases that nearly occupied the entire lymph node diffusely. This patient had strongly requested laparoscopyassisted proximal gastrectomy regardless of the presence of node metastasis. Therefore, we performed laparoscopyassisted proximal gastrectomy after obtaining preoperative informed consent. The locations of lymph node metastasis and surgical pathological findings were analyzed in 52 patients with AEG (type I, N = 7; type II, N = 45) who were surgically treated without SN mapping (Table 2 and Fig. 3). These 52 patients represented more advanced cases than the 15 SN mapping cases because our SN mapping indication was limited to cT1 N0 M0 primary adenocarcinoma with a tumor diameter \4 cm. Two of ten patients (20 %) with pT1 tumors had lymph node metastasis. One patient had
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7 7
Fig. 2 Distribution of the identified sentinel nodes in the 15 patients. * Number of patients with a detectable sentinel node at the lymph node station. Thoracic lymph nodes: No. 105: upper thoracic paraesophageal lymph nodes; No. 106recL: left recurrent nerve lymph nodes; No. 106recR: right recurrent nerve lymph nodes; No. 108: middle thoracic paraesophageal lymph nodes; No. 110: lower thoracic paraesophageal lymph nodes; No. 111: supradiaphragmatic
lymph nodes. Abdominal lymph nodes: No. 1: right cardiac lymph nodes; No. 2: left cardiac lymph nodes; No. 3: lymph nodes along the lesser curvature; No. 7: lymph nodes along the left gastric artery; No. 8a: lymph nodes along the common hepatic artery anterosuperior group; No. 9: lymph nodes along the celiac artery; No. 10: lymph nodes at the splenic hilum; No. 11p: lymph nodes along the proximal splenic artery. SN sentinel node
Fig. 3 Distribution of the lymph node metastasis in the 52 patients with adenocarcinoma of the esophagogastric junction (type I, N = 7; type II, N = 45) surgically treated without sentinel node mapping. *Number of patients with detectable lymph node metastasis at the lymph node station
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Siewert type I AEG with three metastatic lymph nodes at stations 1, 3, and 7. Another patient had Siewert type II AEG with one metastatic lymph node at station 4sa. The distribution of SNs was similar to that of lymph node metastasis. The metastatic lymph nodes were mainly located in the lesser curvature area, including stations 1, 3, and 7. Mediastinal lymph node metastasis was present in seven of the 52 patients (type I, 2/7; type II, 5/45).
Discussion In the present study, we investigated the feasibility of SN mapping in the surgical treatment of patients with AEG. SN mapping was successful in all the 15 patients (100 %). Two patients with lymph node metastasis displayed positive SNs as identified by intraoperative pathological examination. Therefore, the diagnostic sensitivity and accuracy based on the SN status were both 100 %. SNs were not detected in the mediastinum in patients with Siewert type II AEG; therefore, all surgical procedures were performed by a transhiatal approach. All the patients without SN metastasis were free from cancer recurrence for a median follow-up of 38 months. In addition, the distribution of SNs was similar to that of lymph node metastasis in 52 patients who were surgically treated without SN mapping. Thus, we believe that SN mapping is feasible for AEG. Two major trials were performed in the Netherlands and Japan to investigate the optimal surgical approach for AEG. Hulscher et al. [21, 22] conducted a multicenter randomized controlled trial in the Netherlands to compare transhiatal approach esophagectomy versus right thoracic approach esophagectomy with extended en bloc lymphadenectomy in 205 patients with AEG (type I, N = 90; type II, N = 115). The 5-year survival rate was not significantly different between the transhiatal and right thoracic approach groups. However, in the subgroup analysis of the patients with Siewert type I, a survival benefit of 14 % was observed with the right transthoracic approach (51 vs. 37 %). In addition, an overall survival benefit for either surgical approach was not observed in the patients with Siewert type II AEG. They concluded that the transhiatal approach is better for patients with Siewert type II AEG, whereas thoracotomy is better for patients with Siewert type I AEG. The Japan Clinical Oncology Group (JCOG) conducted a multicenter randomized controlled trial in Japan (JCOG 9502) to compare the left thoracoabdominal approach (LTA) with the abdominal transhiatal approach in 165 Siewert types II and III patients (type II, N = 95; type III, N = 70) [23]. The 5-year overall survival rate was 52.3 % in the transhiatal approach group and 37.9 % in the LTA group. The hazard ratio of death for the LTA compared
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with the transhiatal approach was 1.36 (95 % confidence interval 0.89–2.08; p = 0.92). Morbidity was worse for the LTA than for the transhiatal approach. Thus, they concluded that the LTA approach cannot be justified to treat Siewert type II or III AEG if the length of esophageal invasion is B3 cm. The Hulscher and JCOG trials concluded that the transhiatal approach is better for patients with Siewert type II AEG [21–23]. However, the surgical strategy for patients with Siewert type II AEG remains controversial owing to the high frequency of lower mediastinal lymph node metastasis. Therefore, methods to identify patients with AEG at high risk of mediastinal lymph node metastasis are needed. Burkhard et al. reported that SN mapping helps to individualize the extent of lymphadenectomy required [24]. This is particularly important because lymphadenectomy is a major factor contributing to postoperative morbidity and mortality. Although SN procedures represent an attractive modality for AEG, only a few reports have been published [25, 26]. These reports identified an SN detection rate of 85–98 % and a relatively high false-negative rate (15 %). There are two reasons why our study achieved a 100 % SN detection rate and a 0 % false-negative rate. One reason is that the dual tracer method with radioactive colloid and blue dye was used for all the patients. Another reason is that our indication for the SN procedure was limited to cT1 N0 M0 primary adenocarcinoma tumors with a diameter \4 cm. This indication is the same as that previously used for gastric cancer [27]. cT1 N0 AEG tumors with diameters \4 cm do not have a high risk of mediastinal lymph node metastasis. However, Andrew et al. [28] reported that 18 % of patients with pT1b esophageal or esophagogastric junction adenocarcinoma had lymph node metastasis, and 6 % of the patients had mediastinal lymph node metastasis. We think that SN mapping is useful for identifying high-risk patients with mediastinal lymph node metastasis and detecting metastatic lymph nodes. In addition, Omloo et al. [22] reported that AEG patients with one to eight metastatic lymph nodes appear to benefit from extended transthoracic esophagectomy. Therefore, if the positive SN with metastasis was detected in the lower mediastinum, we believe that mediastinal nodal dissection should be performed with a thoracic approach. We previously reported laparoscopy-assisted proximal gastrectomy with SN mapping as a feasible minimally invasive surgical procedure with minimal morbidity and postoperative reflux esophagitis in patients with early-stage gastric cancer in the upper third of the stomach [27, 29]. We also consider laparoscopy-assisted proximal gastrectomy with SN mapping to be feasible for patients with Siewert type II AEG. In the present study, SNs or metastatic lymph nodes were not located in the pyloric region
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(Figs. 2 and 3). Therefore, if SNs are identified only in the abdominal area and are pathologically negative in patients with cT1 N0 M0 Siewert type II AEG, the patient should be treated by laparoscopy-assisted proximal gastrectomy without extensive mediastinal lymph node dissection. After 2007, all the five patients with cT1 N0 M0 Siewert type II AEG in our study underwent laparoscopy-assisted proximal gastrectomy. We believe that a combination of laparoscopic SN biopsy and endoscopic submucosal dissection (ESD) for early AEG is an attractive option as a whole stomach-, esophagus-, and esophagogastric junction-preserving, minimally invasive approach [30, 31]. If all SNs are pathologically negative for cancer metastasis, theoretically, ESD instead of surgery may be sufficient for the curative resection of cT1 AEG beyond the ESD criteria. To confirm the theory, we first attempted to confirm the feasibility of SN mapping in patients with early AEG in this study. This study had some limitations. First, the sample size was small. Second, the follow-up period was not particularly long. Third, we searched mediastinal SNs via transhiatal approach alone in patients with Siewert type II AEG. Both transhiatal and transthoracic approaches may be better for identifying mediastinal SNs than the transhiatal approach alone. However, we used the transhiatal approach alone for two reasons. One reason is the higher invasiveness of the transthoracic approach than the transhiatal approach. Another reason is that we believe that we can sufficiently search for mediastinal SNs by using the dual tracer methods even in the transhiatal approach alone. Essentially, we could point the gamma probe in the mediastinal direction through the esophageal hiatus to search for mediastinal SNs. In addition, we carefully confirmed the absence of lower mediastinal SNs by using the gamma probe after the lymph node dissection. We also confirmed the absence of bluestained lymphatic vessels and nodes in the lower mediastinum by the transhiatal approach.
Conclusion SN mapping procedures are feasible in AEG. SN mapping allows for the identification of patients with AEG at high risk of mediastinal lymph node metastasis and helps to determine the necessity of mediastinal lymph node dissection with a thoracic approach. Therefore, minimally invasive surgery with adequate radical oncological resection can be individualized for each patient with AEG.
Conflicts of interest The authors declare no conflicts of interest. This study received no grant support.
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