Japanese Journal of Clinical Oncology 33:68-72 (2003)
© 2003 Foundation for Promotion of Cancer Research
Sentinel Lymph Node Detection with Tc-99m Tin Colloids in Patients with Esophagogastric Cancer
1 Department of Surgery, 2 Department of Pathology and 3 Department of Radiology, Tokai University School of Medicine, Isehara, Kanagawa, Japan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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Background: The aim of this study was to determine by radioisotope use whether the sentinel lymph node concept is applicable to esophagogastric cancers. In addition, we examined radioactivities of hot nodes and compared them with the sensitivity of a gamma probe.
Methods: The subjects were 44 patients, 23 with esophageal cancer and 21 with gastric cancer. The day before surgery, patients underwent endoscopic submucosal injection of 184 MBq of Tc-99m tin colloids into sites surrounding the tumor. Radioisotope activities of lymph nodes dissected at surgery were measured with a well-typed gamma detector and each lymph node was categorized as a hot or cold node. Histopathology of the lymph nodes was examined by hematoxylin and eosin staining. Radioisotope activities and histopathological results were compared to determine whether radioisotope flow reflects lymphatic flow to regional lymph nodes. The sensitivity of a gamma probe was measured in a laboratory study and the relation between the radioisotope activities of hot nodes and the detection sensitivity of the gamma probe was examined.
Results: Histopathological examination revealed lymph node metastasis in 18 of the 44 patients. In 15 of these 18 patients, metastatic foci were recognized in at least one hot node. Subsequent analysis was performed on the 36 patients in whom tumor invasion was confined to the muscle layer and in whom endoscopic clippings had not been applied. Lymph node metastases were observed in 12 of these 36 patients. In these 12 patients, at least one hot node was positive for metastasis. The laboratory study revealed that the gamma probe was able to detect radioisotope activities of 
0.02 µCi. Thirty-two of 63 (51%) esophageal cancer hot nodes and 16 of 86 (19%) gastric cancer hot nodes showed radioisotope activities below the detection sensitivity of the gamma probe.
Conclusion: The sentinel lymph node concept is applicable to patients with esophageal and gastric cancers; however, further studies are necessary to identify hot nodes accurately using gamma probes.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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It remains unclear whether the sentinel lymph node (SLN) technique can be applied to patients with gastrointestinal cancer. An early study used the dye method and showed negative results in patients with colorectal cancer (1), whereas more recent studies have shown favorable results in patients with colorectal cancer (2) and gastric cancer (3). The radioisotope (RI) method has been investigated with favorable results in patients with esophageal, gastric and colorectal cancers (4). Our preliminary study also suggested that Tc-99m tin colloids can be used for lymphatic mapping in patients with esophagogastric cancer if the tumor invasion is limited to the muscle layer (5). We increased the number of patients in our study to confirm our previous observations. In the SLN technique with the RI method, an intraoperative gamma probe is used to identify hot nodes. We examined the RI activities of hot nodes in our patients and compared them with the sensitivity of the intraoperative gamma probe to determine whether the probe could accurately detect RI activities.
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PATIENTS AND METHODS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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Patient Study
The study included 44 patients, 23 with esophageal cancer and 21 with gastric cancer, who had no apparent signs of LN metastases on preoperative imaging studies and who underwent standard surgeries with extended LN dissections: three-field dissection in patients with esophageal cancer and D2 dissection (6) in patients with gastric cancer.
On the day before surgery, 0.5 ml (46 MBq, 1.25 mCi) of Tc-99m tin colloids was injected endoscopically into four submucosal sites surrounding the tumor. Injections were performed with 23-gauge endoscopic injection sclerotherapy needles (Create Medic, Yokohama, Japan). The amount injected into each patient was 184 MBq (5 mCi). Immediately after surgery, all dissected LNs were placed in test-tubes and RI activities were measured with a well-typed gamma detector (Aloka ARC-300, Auto Well Gamma System, Tokyo, Japan). Each LN was categorized as a hot or cold node according to radioactivity count rates. In each patient, hot nodes were defined as follows: (1) LNs with maximum count rates, (2) LNs with more than one-tenth of the patient’s maximum count rate and (3) LNs with count rates exceeding the rates of other LNs, even if the high count rates were less than one-tenth of the patient’s maximum count rate. Metastatic status was determined for each LN by routine hematoxylin and eosin (H&E) preparations. The RI activity and histopathological result for metastatic status were compared for each LN. The study was approved by the Tokai University Ethics Committee. Informed consent was obtained from all patients prior to the study.
Laboratory Study
Gamma Probe Sensitivity
The laboratory study was conducted with a commercially available intraoperative gamma probe (neo2000, Neoprobe, Dublin, OH). A detachable collimator was used during the study. Tc-99m solutions of 0.5 ml were prepared as RI sources. A total of 22 RI sources with different radioactivities from 736 to 0.0004 µCi, each diluted by half, were put into test-tubes. Each RI source was placed in contact with the center of the probe head and count rates in counts per second (cps) were measured.
Hot Node RI Activity
Additional Tc-99m solutions of 0.5 ml were made to act as RI sources. A total of 20 sources with different radioactivities from 618 to 0.0012 µCi, each diluted by half, were put into test-tubes. RI activities were measured with the gamma detector for 1 min in counts per minute (cpm). A calculation equation was obtained to read radioactivity levels from the count rates given by the gamma detector.
To evaluate hot nodes, we selected 36 patients in whom tumor invasion was confined to the muscle layer and in whom endoscopic clippings had not been applied. There was a total of 149 hot nodes in these 36 patients: 63 hot nodes in 15 patients with esophageal cancer and 86 hot nodes in 21 patients with gastric cancer. Intraoperative RI activities for each hot node were calculated with the calculation equation from the count rates obtained by the gamma detector considering the half-life of Tc-99m (6 h). We determined whether the RI activity levels of the hot nodes were greater than the sensitivity of the gamma probe and thus could be detected by the instrument.
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RESULTS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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Patient Study
The number of LNs dissected at surgery was 46 ± 16 (mean ± SD) per patient in patients with esophageal cancer and 40 ± 10 in patients with gastric cancer. The number of hot nodes per patient was 4.0 ± 1.8 in esophageal cancer patients and 3.9 ± 1.5 in gastric cancer patients. Histopathological examinations revealed LN metastases in 18 of 44 patients. In these 18 patients, the number of metastatic LNs ranged from 1 to 11 (3.6 ± 2.7). In 15 of these 18 patients, metastatic foci were recognized in at least one hot node (Table 1). The presence of metastatic foci in hot nodes accurately indicated whether the patient had regional LN metastases. All hot nodes were negative for metastases in the remaining three patients. Two of these three discordant cases were patients with esophageal cancer whose tumor invasions extended beyond the muscle layer (pT3). The other discordant case was that of a patient with esophageal cancer in whom three endoscopic clippings were applied after RI injection just above the injection sites deep into the submucosa. Because the use of clippings may have disturbed the physiological lymphatic flow of the RI, such patients were excluded from further analysis. Subsequent analysis was performed on 36 patients in whom the tumor invasion was confined to the muscle layer and in whom clippings were not applied. LN metastases were observed in 12 of these 36 patients. In these 12 patients, at least one hot node was positive for metastasis (Table 2).
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Laboratory Study
Gamma Probe Sensitivity
Count rates from the gamma probe for each Tc-99m solution are shown in Fig. 1. The count rates were 2 cps at 0.02 µCi and 1 or 0 cps at RI activities <0.02 µCi. Therefore, we believed that the gamma probe could detect RI activities
0.02 µCi.
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Hot Node RI Activity
Count rates from the gamma detector for each Tc-99m source are shown in Fig. 2. The calculation equation was
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RI activity = 4 x 10–7 x CR1.0517
where CR = count rate by the gamma detector. RI activities for each hot node were calculated. Because intraoperative use of the gamma probe occurred ~6 h earlier than measurement with the well-type gamma detector, RI activities at the time of surgery were calculated to take into account the decay of Tc-99m.
Fig. 3 shows the results. Thirty-two of 63 (51%) esophageal cancer hot nodes and 16 of 86 (19%) gastric cancer hot nodes had measurable RI activities lower than the detection sensitivity of the gamma probe; these nodes could have been missed by intraoperative assessment with the gamma probe.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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In patients with gastrointestinal cancer, SLN detection is expected to have a clinical impact in less invasive surgery (3), selective lymphadenectomy (4) and staging (2,4). In the detection of SLN, blue dyes or RIs have been used. In our early study of patients with thoracic esophageal cancer, we tested a blue dye (isosulfan blue); however, it was difficult to differentiate blue nodes from anthracotic nodes. Furthermore, it was impossible to follow the spread of the dye from the thoracotomy field to the neck or abdomen. Therefore, we began to use RI instead of dye. We also applied this RI method to patients with gastric cancer.
Historically, RIs have been used to examine lymphatic flow from the intestinal wall. In an animal experiment in which Tc-99m sulfur colloid was injected into the submucosal layer of the stomach and colon, the uptake of injected radiocolloid was confined to the immediate regional LNs for 2.5 to at least 3 h after injection (7). In a human study, RIs were used to determine lymphatic drainage originating from the esophagus and stomach. After RIs had been injected into the lower esophagus, high RI uptake was common in both the mid-mediastinal and abdominal LNs. However, after RI was injected into the gastric cardia, high RI uptake was demonstrated only in the abdominal LNs (8). In another study of patients with esophageal cancer, metastasis was present more often in hot nodes than in cold nodes when Tc-99m rhenium sulfur colloid was injected into the submucosal layer (9).
Several radioactive colloids are currently used for the clinical detection of SLNs, including Tc-99m sulfur colloid, Tc-99m colloidal albumin and Tc-99m antimony sulfide colloid (10,11). These radiocolloids are unavailable commercially in Japan, whereas Tc-99m tin colloid is readily available and inexpensive. Therefore, we began to use Tc-99m tin colloid. In other institutions in Japan, Tc-99m stannous phytate has also been used (10).
The current study demonstrates that lymphatic drainage from the foci of the esophagus and stomach can be reliably traced by submucosal injection of Tc-99m tin colloids. The SLN concept is applicable to patients with esophageal and gastric cancers. In SLN biopsy with RI, however, hot nodes have to be identified and resected intraoperatively with gamma probes. It has been shown that SLNs are found among hot nodes and that an intraoperative gamma probe has been used successfully in patients with breast cancer (12). In our study of patients with esophageal and gastric cancers, however, hot node RI activities were lower than the detection sensitivity of the gamma probe in 51% of the esophageal cancer hot nodes and 19% of the gastric cancer hot nodes.
Unlike the technique used in melanoma or breast cancer, RI has to be injected through an endoscope in patients with esophageal or gastric cancer. It is commonly observed that part of the injected RI seeps into the bowel lumen through the injection hole just after needle removal. We think that the low RI activities of the hot nodes can be attributed to the seeping RI. The injection technique has to be refined. One method to prevent RI seepage is to compress the hole with the outer sheath of the injection needle just after withdrawal of the inner puncture needle. We are testing this method in an ongoing study. Another method may be to increase the amount of RI injected. Further studies are needed to ensure that all hot nodes are detected by intraoperative gamma probes.
Our criteria for defining hot nodes may not be generally accepted. At present, however, no standard criteria exist for defining hot nodes or SLNs. In one study, hot nodes were defined by counts obtained with gamma probes of at least 25 in 10 s (13). In another study, SLNs were defined as hot nodes when a 10:1 ex vivo gamma probe ratio of SLN to non-SLN was present (14). The SLN to background radioactivity ratio has several definitions, including 2:1 or 3:1 in vivo (before SLN excision) or 10:1 ex vivo (after SLN excision) (15). A node was considered to be an SLN if its removal resulted in a fourfold or greater reduction in background counts (16). Further studies are needed to establish standard criteria for hot nodes and SLNs.
A limitation of this study is that the histopathological examinations were done on only one section of each LN with H&E staining. Such routine histopathological examination has been reported to be inadequate to detect micrometastasis (10,17). More intensive methods such as immunohistochemistry and reverse transcriptase polymerase chain reaction might be needed. We are using serial sectioning with immunohistochemistry in our ongoing study.
Our study results show that the SLN concept is applicable to patients with esophageal and gastric cancer. Further studies are needed to identify hot nodes accurately using intraoperative gamma probes.
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Acknowledgments |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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This work was supported by the Foundation for Promotion of Cancer Research in Japan. We express special thanks to Shinjiro Nagayama for his professional assistance.
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FOOTNOTES |
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+ For reprints and all correspondence: Seiei Yasuda, Department of Surgery, Tokai University School of Medicine, Boseidai, Isehara, Kanagawa 259-1193, Japan. E-mail: yasuda@is.icc.u-tokai.ac.jp
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Received June 3, 2002; accepted November 26, 2002
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