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Area of Nodal Metastasis and Radioisotope Uptake in Sentinel Nodes of Upper Gastrointestinal Cancer
Journal of Surgical Research 135, 250 –254 (2006) doi:10.1016/j.jss.2006.06.005
Area of Nodal Metastasis and Radioisotope Uptake in Sentinel Nodes of Upper Gastrointestinal Cancer Hideo Arima, M.D.,1 Shoji Natsugoe, M.D., Ph.D., Yoshikazu Uenosono, M.D., Ph.D., Takaaki Arigami, M.D., Katsuhiko Ehi, M.D., Shigehiro Yanagita, M.D., Hiroshi Higashi, M.D., Sumiya Ishigami, M.D., Ph.D., Shuichi Hokita, M.D., Ph.D., and Takashi Aikou, M.D., Ph.D. Department of Surgical Oncology and Digestive Surgery, Field of Oncology, Course of Advanced Therapeutics, Kagoshima University School of Medical and Dental Science, Kagoshima, Japan Submitted for publication July 12, 2005
Background. Sentinel node navigation surgery has been introduced for the treatment of gastrointestinal tumor. As few studies have examined relationships between metastatic area and radioisotope uptake in sentinel nodes, the present study examined this relationship for gastric and esophageal cancers. Methods. Subjects comprised 43 patients (esophageal cancer, n ⴝ 19; gastric cancer, n ⴝ 24) with <3 lymph node metastases in whom sentinel node mapping with radio-guided methods was performed. Radioisotope uptake was measured after surgery for all dissected lymph nodes. Metastatic area was calculated using the following formula: metastatic area (%) ⴝ (area of metastasis/total area of lymph node) ⴛ 100. Based on radioisotope uptake, lymph nodes were divided into RI(ⴚ) and RI(ⴙ) groups. Results. In 35 patients, >1 metastatic node was present among the sentinel nodes. In 1 patient, no sentinel nodes were detected. No lymph node metastasis was found in sentinel nodes in the remaining seven patients. Lymph nodes were diagnosed as metastatic using preoperative imaging. Mean (ⴞSD) metastatic area was significantly higher for RI(ⴚ) (68.3 ⴞ 20.5%) than for RI(ⴙ) (15.1 ⴞ 20.8%; P < 0.0001). Radioisotope uptake was decreased in lymph nodes with >60% metastatic area. Conclusions. The fact that radioisotope uptake is not detectable in some lymph nodes with >60% metastatic area must be considered when planning sentinel node navigation surgery. © 2006 Elsevier Inc. All rights reserved. 1 To whom correspondence and reprint requests should be addressed at Department of Surgical Oncology and Digestive Surgery, Field of Oncology, Course of Advanced Therapeutics, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan. E-mail: h-arima@m3. kufm.kagoshima-u.ac.jp.
0022-4804/06 $32.00 © 2006 Elsevier Inc. All rights reserved.
Key Words: metastatic area; radioisotope; sentinel node; esophageal cancer; gastric cancer.
INTRODUCTION
The sentinel node is considered to represent the lymph node in which metastasis first occurs via lymphatic drainage from a primary tumor. The sentinel node concept was initially proposed in penile cancer by Cabanas [1]. Sentinel node navigation surgery (SNNS) has been introduced for breast cancer and melanoma to reduce lymph node dissection and improve postoperative quality of life in cancer patients [2– 4]. The accuracy rate for sentinel node identification in breast cancer is reportedly 96 to 100% using both radioisotope and dye technique [5–7]. Accuracy rate in melanoma is similar, at 97 to 99.5% [8, 9]. However, clinical application of SNNS to gastrointestinal cancer using dye or radioisotope techniques remains controversial [10, 11]. Sentinel nodes are identified intra-operatively by the uptake of radioisotope or dye. However, even if macroscopically overt nodal metastasis is found during operation, radioisotope or dye is sometimes not contained in such nodes. Miwa et al. reported false-negative results in 4 of 211 early stage gastric patients using dye methods. All four patients with false-negative findings displayed a large clinical node [12]. The problem arises in the relationship between radioisotope count and lymphatic flow or nodal metastasis. At present, standard criteria for radioisotope uptake in the sentinel node have not been accurately defined. Some studies have examined relationships between radioisotope count in the sentinel node and presence of metastasis. Martin et al. [13] reported that
250
251
ARIMA ET AL.: METASTATIC AREA AND RI UPTAKE
TABLE 1 Clinicopathological Characteristics of Patients Esophageal cancer
Gastric cancer
19
24
17/2 63.6 ⫾ 8.6
15/9 62.5 ⫾ 13.1
9/1/9
17/6/1
10/6/3
15/6/3
N Sex Male/Female Age pT factor T1/T2/T3 Number of nodal metastases 1/2/3
highest radioisotope count was not predictive of nodal involvement for sentinel nodes in breast cancer. Analysis of correlation between metastatic area and radioisotope uptake in sentinel nodes is thus considered important. The present study investigated the critical problem of whether radioisotope count reflects metastatic area in sentinel nodes for esophageal and gastric cancer, to decrease false negative rates in the identification of sentinel nodes using radioisotope tracers. MATERIALS AND METHODS Patients Subjects initially comprised 274 consecutive patients (esophageal cancer, n ⫽ 79; gastric cancer, n ⫽ 195) who underwent SNNS at Kagoshima University Hospital between August 2000 and January 2005. Histologically, all esophageal cancers were squamous cell carcinoma and all gastric cancers were adenocarcinoma. Informed consent was obtained from all patients before operation. No patients received radio- or chemotherapy before surgery. Of these cases, 88 patients (esophageal cancer, n ⫽ 43; gastric cancer, n ⫽ 45) displayed lymph node metastasis. Patients with ⬎3 nodal metastases were excluded from analysis because our clinical experience has indicated that ⱕ3 lymph nodes can be identified by sentinel node navigation [14]. A small number of lymph node metastases identified by sentinel node navigation were considered to more accurately reflect the relationship between metastatic area and radioisotope uptake. Thus, 43 patients with ⱕ3 lymph node metastases (esophageal cancer, n ⫽ 19; gastric cancer, n ⫽ 24) were enrolled in the present study. In cases with 2 to 3 metastatic lymph nodes, the lymph node with highest radioisotope count was recognized as the sentinel node for the other
lymph nodes. Total number of lymph nodes was 43 (Table 1). Clinicopathological findings of the 43 cases are summarized in Table 2.
Radioisotope Injection and Lymph Node Mapping Solutions of 99mTc and tin were mixed at a ratio of 1:2 to make a particle size of approximately 100 nm. At 1 d before surgery, 0.5 mL (0.75 mCi) of 99mTc-tin colloid was endoscopically injected into the submucosa at 4 sites around the tumor using a MAJ-75 disposable 23-gauge needle (Olympus, Tokyo, Japan). During surgery, radioisotope uptake into each lymph node was measured using a Navigator GPS (Tyco Healthcare, Tokyo, Japan) with a window setting of ⬎95 keV and measuring time of 1 s. After surgery, all dissected lymph nodes were mapped and radioisotope uptake in each lymph node was measured again. In this study, lymph nodes in which radioisotope uptake was measurable were defined as sentinel nodes. Based on radioisotope uptake, lymph nodes were divided into two groups: RI(⫺); and RI(⫹).We defined absence of RI-uptake as RI(⫺) group and presence of RI-uptake as RI(⫹).
Evaluation of Metastatic Area Each lymph node was cut at the plane of largest dimension, then fixed in 10% formaldehyde and embedded in paraffin. Paraffin sections (3-m thick) were stained using hematoxylin and eosin. Presence or absence of metastasis was then examined microscopically in one representative section including the node hilus. Total area of the lymph node and area comprising metastatic cancer cells were measured using NCC Volumetrer version 2.03 area calculation software. Metastatic area was then calculated using the following formula: metastatic area (%) ⫽ (area of metastasis/total area of lymph node) ⫻ 100.
Statistical Analysis Correlations between metastatic area and radioisotope uptakes were analyzed using Mann-Whitney’s t test. Simple regression analyses were used for estimation of statistical significance. Value of P ⬍ 0.05 were considered statistically significant.
RESULTS Distribution of Lymph Node Metastasis
Sentinel nodes included ⱖ1 metastatic node in 35 patients (esophageal cancer, n ⫽ 14; gastric cancer, n ⫽ 21). In one patient with esophageal cancer (case 4), no lymph nodes were identified in sentinel node navigation. The remaining seven patients (esophageal cancer,
TABLE 2 Cases Without Lymph Node Metastasis in Sentinel Nodes Case
Cancer
Age
pT factor
Number of metastatic LNs
LN size (mm)
Metastatic area (%)
1 2 3 4* 5 6 7 8
Esophagus Esophagus Esophagus Esophagus Esophagus Stomach Stomach Stomach
39 67 52 69 68 68 75 66
pT1 pT3 pT3 pT3 pT3 pT3 pT2 pT2
1 2 2 1 1 2 2 1
10 10 15 9 13 10 9 5
85.2 85.1 79.0 73.0 62.0 77.8 61.1 22.8
* Lymph node was not identified by sentinel node navigation in case 4.
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Metastatic area (%) 100
Metastatic area (%) 100
P < 0.0001
80
80
60
60
40
40
20
20
0
RI(+)
RI(-)
P < 0.0001
0
RI(+)
RI(-)
FIG. 1. Metastatic area in esophageal cancer. Metastatic area was significantly higher for the RI(⫺) group (76.9 ⫾ 9.7%) than for the RI(⫹) group (25.9 ⫾ 26.2%; P ⫽ 0.0006).
FIG. 3. Metastatic area in all patients. Metastatic area was significantly higher for the RI(⫺) group (67.9 ⫾ 20.8%) than for the RI(⫹) group (15.1 ⫾ 20.8%; P ⬍ 0.0001).
n ⫽ 4; gastric cancer, n ⫽ 3) displayed no lymph node metastasis in sentinel nodes. These seven cases were identified as false negatives (Table 2).
RI(⫹) nodes were ⱖ60%. Mean diameter of metastatic nodes was approximately 10 mm. In one patient with esophageal cancer, no lymph nodes were identified using SNNS. In four patients with esophageal cancer and three patients with gastric cancer, no lymph node metastasis was detected in any sentinel node, so these seven patients were considered to display falsenegative results. All patients displayed either tumors deeper than the submucosal layer or metastatic area ⬎60% (Table 2). However, these lymph nodes were diagnosed as metastatic by preoperative imaging. Regarding relationships between radioisotope count and metastatic area, higher metastatic area tended to be associated with lower radioisotope counts, although statistical correlation was not found between them (P ⫽ 0.083). In particular, radioisotope uptake was difficult to detect in lymph nodes with metastatic area ⬎60% (Fig. 4).
Metastatic Area and Radioisotope Uptake in Sentinel Nodes
Mean (⫾SD) metastatic area was significantly higher in RI(⫺) (76.9 ⫾ 9.7%) than in RI(⫹) (25.9 ⫾ 26.2%; P ⫽ 0.0006) for patients with esophageal cancer (Fig. 1). Similarly, mean metastatic area was significantly higher in RI(⫺) (53.9 ⫾ 28.2%) than in RI(⫹) (7.8 ⫾ 12.2%; P ⬍ 0.0001) for gastric cancer (Fig. 2). Mean metastatic area was significantly higher in RI(⫺) (68.3 ⫾ 20.5%) than in RI(⫹) (15.1 ⫾ 20.8%; P ⬍ 0.0001) for all cases (Fig. 3). When comparing metastatic area and radioisotope uptake in cases without lymph node metastasis in sentinel nodes, metastatic area was ⬍60% in only one of the eight RI(⫺) nodes (Table 2). Thus, if metastatic area was divided into ⱖ60% or ⬍60%, only two of 35
RI count 400 (CPS)
Metastatic area (%)
300
100
P < 0.0001
200 100
80
a a
80
60
60
40
40 20
20
0
0
RI(+)
RI(-)
FIG. 2. Metastatic area in gastric cancer. Metastatic area was significantly higher for the RI(⫺) group (52.8 ⫾ 30.0%) than for the RI(⫹) group (7.8 ⫾ 12.2%; P ⬍ 0.0001).
0
20
40
60
80
100
Metastatic area (%)
FIG. 4. Correlation between radioisotope count and metastatic area. Higher metastatic area was inversely associated with lower radioisotope count, but no significant correlation was identified (P ⫽ 0.083).
ARIMA ET AL.: METASTATIC AREA AND RI UPTAKE
DISCUSSION
According to the sentinel node concept, lymph node metastasis occurs first in the sentinel node. Although SNNS has actually been performed for melanoma and breast cancer, lymphatic flow differs between upper gastrointestinal tract cancers and melanoma and breast cancer [15, 16]. Thus, when performing sentinel node detection using radioisotope methods for upper gastrointestinal tract cancer, some fundamental problems are encountered: 1) suitable size of colloid particles; 2) ready movement of radioisotope colloid from lymphatics to lymph nodes; and 3) inflow and stasis of radioisotope colloid in lymph nodes. To resolve these problems, we have performed various basic research and clinical studies. Various sizes of radioisotope colloid are available, such as 99mTc-tin colloid, 99mTcphytate, 99mTc-serum albumin, 99mTc-sulfur colloid, and 99m Tc-rhenium colloid. In SNNS, 99mTc-tin colloid and 99m Tc-phytate are usually used to detect sentinel nodes [11, 17-19]. We have previously reported that particle size for tin and phytate colloids is controllable by manipulating the conditions under which the colloid forms [20]. We have also examined relationships between colloid size and radioisotope uptake in gastric cancer. In the three sizes of 99mTc-tin colloid (500, 100, or 50 nm), radioisotope uptake in sentinel nodes was highest for 100-nm particles [14]. Even with suitably sized radioisotope colloid injected without technical error, radioisotope uptake was not identified in some lymph nodes with metastasis that was thought to represent sentinel nodes. In SNNS, accurate detection of lymph node metastasis is essential. The present study examined relationships between metastatic area and radioisotope uptake. Radioisotope uptake was correlated with metastatic area in both esophageal and gastric cancer. As metastatic area increased, radioisotope uptake decreased. These results suggest that tin-colloid particles of 100 nm in diameter experience difficulty-entering lymph nodes in which metastatic area is ⬎60%. In lymph nodes with high metastatic area, numerous afferent lymphatics might be blocked by cancer cells. Conversely, radioisotope uptake might be countable in such nodes if smaller colloid particles were used. We have previously examined relationships between metastatic area and radioisotope uptake using 99mTc-rhenium colloid, with particles smaller than 99mTc-tin colloid [21]. In 99mTcrhenium colloid, radioisotope uptake was counted for lymph nodes in which almost the entire node was replaced by cancer cells. However, because of the small particle size, radioisotope uptake was detected in numerous lymph nodes, both regional and distant. Selecting a suitable colloid size and metastatic area is thus important for detecting sentinel nodes. When performing SNNS in cases of upper gastrointestinal cancer, attention is required to the fact that
253
radioisotope uptake may not be countable in lymph nodes with high metastatic area. Regarding relationships between radioisotope count and metastatic area, higher metastatic area was associated with lower radioisotope counts (Fig. 4). The reason why statistical correlation was not found between them (P ⫽ 0.083) was sparse of distribution of lymph node with metastatic area ⬍60%. In this series, such nodes were diagnosed as metastatic using preoperative imaging. Clinical diagnosis of lymph node metastasis is thus essential before SNNS [22]. If such nodal metastases are not detected preoperatively, lymph node metastasis should be examined by inspection and palpation. Because metastatic area of these nodes is ⬎60%, most such nodes would be detectable by swelling and hardness. In the present series, lymph node metastasis was detectable in ⱖ1 sentinel node in all except eight cases. If lymph node metastasis is found in sentinel nodes, standard lymphadenectomy should thus be performed, as ⱖ2 nodal metastases may be present without any count for radioisotope uptake. The present study demonstrated the close relationship between metastatic area and radioisotope uptake in metastatic nodes during esophageal and gastric cancer. The presence of lymph node metastasis without radioisotope uptake count should be borne in mind, particularly for lymph nodes with metastatic area ⬎60%. Diagnosis of lymph node metastasis using both preoperative imaging and sentinel node detection is thus important. REFERENCES 1.
Cabanas RM. An approach for the treatment of penile carcinoma. Cancer 1977;39:456.
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Morton DL, Wen DR, Wong JH, et al. Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch Surg 1992;127:392.
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Krag DN, Weaver DL, Alex JC, Fairbank JT. Surgical resection and radiolocalization of the sentinel lymph node in breast cancer using a gamma probe. Surg Oncol 1993;2:335.
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Giuliano AE, Kirgan DM, Guenther JM, Morton DL. Lymphatic mapping and sentinel lymphadenectomy for breast cancer. Ann Surg 1994;220:391.
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Sabel MS, Zhang P, Barnwell JM, Winston JS, Hurd TC, Edge SB. Accuracy of sentinel node biopsy in predicting nodal status in patients with breast carcinoma. J Surg Oncol 2001;77:243; doi:10.1002/jso. 1103.
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Vuylsteke RJ, van Leeuwen PA, Statius Muller MG, Gietema HA, Kragt DR, Meijer S. Clinical outcome of stage I/II melanoma patients after selective sentinel lymph node dissection: Long-term follow-up results. J Clin Oncol 2003;21:1057; doi:10. 1200/JCO. 2003.07.170.
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Morton DL, Hoon DS, Cochran AJ, et al. Lymphatic mapping and sentinel lymphadenectomy for early-stage melanoma: Therapeutic utility and implications of nodal microanatomy and molecular staging for improving the accuracy of detection of nodal micrometastases. Ann Surg 2003;238:538. 10. Aikou T, Higashi H, Natsugoe S, Hokita S, Baba M, Tako S. Can sentinel node navigation surgery reduce the extent of lymph node dissection in gastric cancer? Ann Surg Oncol 2001; 8:90S. 11. Wilhelm AJ, Mijnhout GS, Franssen EJ. Radiopharmaceuticals in sentinel lymph-node detection: An overview. Eur J Nucl Med 1999;26:S36.
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Miwa K, Kinami S, Taniguchi K, Fushida S, Fujimura T, Nonomura A. Mapping sentinel nodes in patients with early-stage gastric carcinoma. Br J Surg 2003;90:178; doi:10.1002/bjs. 4031.
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Martin RC, Fey J, Yeung H, Borgen PI, Cody HS 3rd. Highest isotope count does not predict sentinel node positivity in all breast cancer patients. Ann Surg Oncol 2001;8:592; doi: 10.1007/s10434-001-0592-5.
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Uenosono Y, Natsugoe S, Higashi H, et al. Evaluation of colloid size for sentinel nodes detection using radioisotope in early gastric cancer. Cancer Lett 2003;200:19; doi:10.1016/ S0304-3835(03)00389-6.
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Maruyama K, Sasako M, Kinoshita T, Sano T, Katai H. Can sentinel node biopsy indicate rational extent of lymphadenectomy in gastric cancer surgery? Fundamental and new information on lymph-node dissection. Langenbecks Arch Surg 1999;384:149. Siewert JR, Sendler A. Potential and futility of sentinel node detection for gastric cancer. Recent Results Cancer Res 2000; 157:259. Tsopelas C. Particle size analysis of (99m)Tc-labeled and unlabeled antimony trisulfide and rhenium sulfide colloids intended for lymphoscintigraphic application. J Nucl Med 2001;42:460. Davis MA, Jones AG, Trindade H. A rapid and accurate method for sizing radiocolloids. J Nucl Med 1974;15:923. Warbick A, Ege GN, Henkelman RM, Maier G, Lyster DM. An evaluation of radiocolloid sizing techniques. J Nucl Med 1977; 18:827. Higashi H, Natsugoe S, Uenosono Y, et al. Particle size of tin and phytate colloid in sentinel node identification. J Surg Res 2004;121:1; doi:10.1016/j.jss. 2004.02.011. Natsugoe S, Tanabe G, Baba M, Aikou T, Shimazu H. Measurement of RI uptake in regional lymph nodes-application of lymph flow study. Japn J Lymphol 1986;9:219. Natsugoe S, Yoshinaka H, Morinaga T, et al. Ultrasonographic detection of lymph-node metastases in superficial carcinoma of the esophagus. Endoscopy 1996;28:674.
Area of Nodal Metastasis and Radioisotope Uptake in Sentinel Nodes of Upper Gastrointestinal Cancer Hideo Arima, M.D.,1 Shoji Natsugoe, M.D., Ph.D., Yoshikazu Uenosono, M.D., Ph.D., Takaaki Arigami, M.D., Katsuhiko Ehi, M.D., Shigehiro Yanagita, M.D., Hiroshi Higashi, M.D., Sumiya Ishigami, M.D., Ph.D., Shuichi Hokita, M.D., Ph.D., and Takashi Aikou, M.D., Ph.D. Department of Surgical Oncology and Digestive Surgery, Field of Oncology, Course of Advanced Therapeutics, Kagoshima University School of Medical and Dental Science, Kagoshima, Japan Submitted for publication July 12, 2005
Background. Sentinel node navigation surgery has been introduced for the treatment of gastrointestinal tumor. As few studies have examined relationships between metastatic area and radioisotope uptake in sentinel nodes, the present study examined this relationship for gastric and esophageal cancers. Methods. Subjects comprised 43 patients (esophageal cancer, n ⴝ 19; gastric cancer, n ⴝ 24) with <3 lymph node metastases in whom sentinel node mapping with radio-guided methods was performed. Radioisotope uptake was measured after surgery for all dissected lymph nodes. Metastatic area was calculated using the following formula: metastatic area (%) ⴝ (area of metastasis/total area of lymph node) ⴛ 100. Based on radioisotope uptake, lymph nodes were divided into RI(ⴚ) and RI(ⴙ) groups. Results. In 35 patients, >1 metastatic node was present among the sentinel nodes. In 1 patient, no sentinel nodes were detected. No lymph node metastasis was found in sentinel nodes in the remaining seven patients. Lymph nodes were diagnosed as metastatic using preoperative imaging. Mean (ⴞSD) metastatic area was significantly higher for RI(ⴚ) (68.3 ⴞ 20.5%) than for RI(ⴙ) (15.1 ⴞ 20.8%; P < 0.0001). Radioisotope uptake was decreased in lymph nodes with >60% metastatic area. Conclusions. The fact that radioisotope uptake is not detectable in some lymph nodes with >60% metastatic area must be considered when planning sentinel node navigation surgery. © 2006 Elsevier Inc. All rights reserved. 1 To whom correspondence and reprint requests should be addressed at Department of Surgical Oncology and Digestive Surgery, Field of Oncology, Course of Advanced Therapeutics, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan. E-mail: h-arima@m3. kufm.kagoshima-u.ac.jp.
0022-4804/06 $32.00 © 2006 Elsevier Inc. All rights reserved.
Key Words: metastatic area; radioisotope; sentinel node; esophageal cancer; gastric cancer.
INTRODUCTION
The sentinel node is considered to represent the lymph node in which metastasis first occurs via lymphatic drainage from a primary tumor. The sentinel node concept was initially proposed in penile cancer by Cabanas [1]. Sentinel node navigation surgery (SNNS) has been introduced for breast cancer and melanoma to reduce lymph node dissection and improve postoperative quality of life in cancer patients [2– 4]. The accuracy rate for sentinel node identification in breast cancer is reportedly 96 to 100% using both radioisotope and dye technique [5–7]. Accuracy rate in melanoma is similar, at 97 to 99.5% [8, 9]. However, clinical application of SNNS to gastrointestinal cancer using dye or radioisotope techniques remains controversial [10, 11]. Sentinel nodes are identified intra-operatively by the uptake of radioisotope or dye. However, even if macroscopically overt nodal metastasis is found during operation, radioisotope or dye is sometimes not contained in such nodes. Miwa et al. reported false-negative results in 4 of 211 early stage gastric patients using dye methods. All four patients with false-negative findings displayed a large clinical node [12]. The problem arises in the relationship between radioisotope count and lymphatic flow or nodal metastasis. At present, standard criteria for radioisotope uptake in the sentinel node have not been accurately defined. Some studies have examined relationships between radioisotope count in the sentinel node and presence of metastasis. Martin et al. [13] reported that
250
251
ARIMA ET AL.: METASTATIC AREA AND RI UPTAKE
TABLE 1 Clinicopathological Characteristics of Patients Esophageal cancer
Gastric cancer
19
24
17/2 63.6 ⫾ 8.6
15/9 62.5 ⫾ 13.1
9/1/9
17/6/1
10/6/3
15/6/3
N Sex Male/Female Age pT factor T1/T2/T3 Number of nodal metastases 1/2/3
highest radioisotope count was not predictive of nodal involvement for sentinel nodes in breast cancer. Analysis of correlation between metastatic area and radioisotope uptake in sentinel nodes is thus considered important. The present study investigated the critical problem of whether radioisotope count reflects metastatic area in sentinel nodes for esophageal and gastric cancer, to decrease false negative rates in the identification of sentinel nodes using radioisotope tracers. MATERIALS AND METHODS Patients Subjects initially comprised 274 consecutive patients (esophageal cancer, n ⫽ 79; gastric cancer, n ⫽ 195) who underwent SNNS at Kagoshima University Hospital between August 2000 and January 2005. Histologically, all esophageal cancers were squamous cell carcinoma and all gastric cancers were adenocarcinoma. Informed consent was obtained from all patients before operation. No patients received radio- or chemotherapy before surgery. Of these cases, 88 patients (esophageal cancer, n ⫽ 43; gastric cancer, n ⫽ 45) displayed lymph node metastasis. Patients with ⬎3 nodal metastases were excluded from analysis because our clinical experience has indicated that ⱕ3 lymph nodes can be identified by sentinel node navigation [14]. A small number of lymph node metastases identified by sentinel node navigation were considered to more accurately reflect the relationship between metastatic area and radioisotope uptake. Thus, 43 patients with ⱕ3 lymph node metastases (esophageal cancer, n ⫽ 19; gastric cancer, n ⫽ 24) were enrolled in the present study. In cases with 2 to 3 metastatic lymph nodes, the lymph node with highest radioisotope count was recognized as the sentinel node for the other
lymph nodes. Total number of lymph nodes was 43 (Table 1). Clinicopathological findings of the 43 cases are summarized in Table 2.
Radioisotope Injection and Lymph Node Mapping Solutions of 99mTc and tin were mixed at a ratio of 1:2 to make a particle size of approximately 100 nm. At 1 d before surgery, 0.5 mL (0.75 mCi) of 99mTc-tin colloid was endoscopically injected into the submucosa at 4 sites around the tumor using a MAJ-75 disposable 23-gauge needle (Olympus, Tokyo, Japan). During surgery, radioisotope uptake into each lymph node was measured using a Navigator GPS (Tyco Healthcare, Tokyo, Japan) with a window setting of ⬎95 keV and measuring time of 1 s. After surgery, all dissected lymph nodes were mapped and radioisotope uptake in each lymph node was measured again. In this study, lymph nodes in which radioisotope uptake was measurable were defined as sentinel nodes. Based on radioisotope uptake, lymph nodes were divided into two groups: RI(⫺); and RI(⫹).We defined absence of RI-uptake as RI(⫺) group and presence of RI-uptake as RI(⫹).
Evaluation of Metastatic Area Each lymph node was cut at the plane of largest dimension, then fixed in 10% formaldehyde and embedded in paraffin. Paraffin sections (3-m thick) were stained using hematoxylin and eosin. Presence or absence of metastasis was then examined microscopically in one representative section including the node hilus. Total area of the lymph node and area comprising metastatic cancer cells were measured using NCC Volumetrer version 2.03 area calculation software. Metastatic area was then calculated using the following formula: metastatic area (%) ⫽ (area of metastasis/total area of lymph node) ⫻ 100.
Statistical Analysis Correlations between metastatic area and radioisotope uptakes were analyzed using Mann-Whitney’s t test. Simple regression analyses were used for estimation of statistical significance. Value of P ⬍ 0.05 were considered statistically significant.
RESULTS Distribution of Lymph Node Metastasis
Sentinel nodes included ⱖ1 metastatic node in 35 patients (esophageal cancer, n ⫽ 14; gastric cancer, n ⫽ 21). In one patient with esophageal cancer (case 4), no lymph nodes were identified in sentinel node navigation. The remaining seven patients (esophageal cancer,
TABLE 2 Cases Without Lymph Node Metastasis in Sentinel Nodes Case
Cancer
Age
pT factor
Number of metastatic LNs
LN size (mm)
Metastatic area (%)
1 2 3 4* 5 6 7 8
Esophagus Esophagus Esophagus Esophagus Esophagus Stomach Stomach Stomach
39 67 52 69 68 68 75 66
pT1 pT3 pT3 pT3 pT3 pT3 pT2 pT2
1 2 2 1 1 2 2 1
10 10 15 9 13 10 9 5
85.2 85.1 79.0 73.0 62.0 77.8 61.1 22.8
* Lymph node was not identified by sentinel node navigation in case 4.
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Metastatic area (%) 100
Metastatic area (%) 100
P < 0.0001
80
80
60
60
40
40
20
20
0
RI(+)
RI(-)
P < 0.0001
0
RI(+)
RI(-)
FIG. 1. Metastatic area in esophageal cancer. Metastatic area was significantly higher for the RI(⫺) group (76.9 ⫾ 9.7%) than for the RI(⫹) group (25.9 ⫾ 26.2%; P ⫽ 0.0006).
FIG. 3. Metastatic area in all patients. Metastatic area was significantly higher for the RI(⫺) group (67.9 ⫾ 20.8%) than for the RI(⫹) group (15.1 ⫾ 20.8%; P ⬍ 0.0001).
n ⫽ 4; gastric cancer, n ⫽ 3) displayed no lymph node metastasis in sentinel nodes. These seven cases were identified as false negatives (Table 2).
RI(⫹) nodes were ⱖ60%. Mean diameter of metastatic nodes was approximately 10 mm. In one patient with esophageal cancer, no lymph nodes were identified using SNNS. In four patients with esophageal cancer and three patients with gastric cancer, no lymph node metastasis was detected in any sentinel node, so these seven patients were considered to display falsenegative results. All patients displayed either tumors deeper than the submucosal layer or metastatic area ⬎60% (Table 2). However, these lymph nodes were diagnosed as metastatic by preoperative imaging. Regarding relationships between radioisotope count and metastatic area, higher metastatic area tended to be associated with lower radioisotope counts, although statistical correlation was not found between them (P ⫽ 0.083). In particular, radioisotope uptake was difficult to detect in lymph nodes with metastatic area ⬎60% (Fig. 4).
Metastatic Area and Radioisotope Uptake in Sentinel Nodes
Mean (⫾SD) metastatic area was significantly higher in RI(⫺) (76.9 ⫾ 9.7%) than in RI(⫹) (25.9 ⫾ 26.2%; P ⫽ 0.0006) for patients with esophageal cancer (Fig. 1). Similarly, mean metastatic area was significantly higher in RI(⫺) (53.9 ⫾ 28.2%) than in RI(⫹) (7.8 ⫾ 12.2%; P ⬍ 0.0001) for gastric cancer (Fig. 2). Mean metastatic area was significantly higher in RI(⫺) (68.3 ⫾ 20.5%) than in RI(⫹) (15.1 ⫾ 20.8%; P ⬍ 0.0001) for all cases (Fig. 3). When comparing metastatic area and radioisotope uptake in cases without lymph node metastasis in sentinel nodes, metastatic area was ⬍60% in only one of the eight RI(⫺) nodes (Table 2). Thus, if metastatic area was divided into ⱖ60% or ⬍60%, only two of 35
RI count 400 (CPS)
Metastatic area (%)
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100
P < 0.0001
200 100
80
a a
80
60
60
40
40 20
20
0
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FIG. 2. Metastatic area in gastric cancer. Metastatic area was significantly higher for the RI(⫺) group (52.8 ⫾ 30.0%) than for the RI(⫹) group (7.8 ⫾ 12.2%; P ⬍ 0.0001).
0
20
40
60
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Metastatic area (%)
FIG. 4. Correlation between radioisotope count and metastatic area. Higher metastatic area was inversely associated with lower radioisotope count, but no significant correlation was identified (P ⫽ 0.083).
ARIMA ET AL.: METASTATIC AREA AND RI UPTAKE
DISCUSSION
According to the sentinel node concept, lymph node metastasis occurs first in the sentinel node. Although SNNS has actually been performed for melanoma and breast cancer, lymphatic flow differs between upper gastrointestinal tract cancers and melanoma and breast cancer [15, 16]. Thus, when performing sentinel node detection using radioisotope methods for upper gastrointestinal tract cancer, some fundamental problems are encountered: 1) suitable size of colloid particles; 2) ready movement of radioisotope colloid from lymphatics to lymph nodes; and 3) inflow and stasis of radioisotope colloid in lymph nodes. To resolve these problems, we have performed various basic research and clinical studies. Various sizes of radioisotope colloid are available, such as 99mTc-tin colloid, 99mTcphytate, 99mTc-serum albumin, 99mTc-sulfur colloid, and 99m Tc-rhenium colloid. In SNNS, 99mTc-tin colloid and 99m Tc-phytate are usually used to detect sentinel nodes [11, 17-19]. We have previously reported that particle size for tin and phytate colloids is controllable by manipulating the conditions under which the colloid forms [20]. We have also examined relationships between colloid size and radioisotope uptake in gastric cancer. In the three sizes of 99mTc-tin colloid (500, 100, or 50 nm), radioisotope uptake in sentinel nodes was highest for 100-nm particles [14]. Even with suitably sized radioisotope colloid injected without technical error, radioisotope uptake was not identified in some lymph nodes with metastasis that was thought to represent sentinel nodes. In SNNS, accurate detection of lymph node metastasis is essential. The present study examined relationships between metastatic area and radioisotope uptake. Radioisotope uptake was correlated with metastatic area in both esophageal and gastric cancer. As metastatic area increased, radioisotope uptake decreased. These results suggest that tin-colloid particles of 100 nm in diameter experience difficulty-entering lymph nodes in which metastatic area is ⬎60%. In lymph nodes with high metastatic area, numerous afferent lymphatics might be blocked by cancer cells. Conversely, radioisotope uptake might be countable in such nodes if smaller colloid particles were used. We have previously examined relationships between metastatic area and radioisotope uptake using 99mTc-rhenium colloid, with particles smaller than 99mTc-tin colloid [21]. In 99mTcrhenium colloid, radioisotope uptake was counted for lymph nodes in which almost the entire node was replaced by cancer cells. However, because of the small particle size, radioisotope uptake was detected in numerous lymph nodes, both regional and distant. Selecting a suitable colloid size and metastatic area is thus important for detecting sentinel nodes. When performing SNNS in cases of upper gastrointestinal cancer, attention is required to the fact that
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radioisotope uptake may not be countable in lymph nodes with high metastatic area. Regarding relationships between radioisotope count and metastatic area, higher metastatic area was associated with lower radioisotope counts (Fig. 4). The reason why statistical correlation was not found between them (P ⫽ 0.083) was sparse of distribution of lymph node with metastatic area ⬍60%. In this series, such nodes were diagnosed as metastatic using preoperative imaging. Clinical diagnosis of lymph node metastasis is thus essential before SNNS [22]. If such nodal metastases are not detected preoperatively, lymph node metastasis should be examined by inspection and palpation. Because metastatic area of these nodes is ⬎60%, most such nodes would be detectable by swelling and hardness. In the present series, lymph node metastasis was detectable in ⱖ1 sentinel node in all except eight cases. If lymph node metastasis is found in sentinel nodes, standard lymphadenectomy should thus be performed, as ⱖ2 nodal metastases may be present without any count for radioisotope uptake. The present study demonstrated the close relationship between metastatic area and radioisotope uptake in metastatic nodes during esophageal and gastric cancer. The presence of lymph node metastasis without radioisotope uptake count should be borne in mind, particularly for lymph nodes with metastatic area ⬎60%. Diagnosis of lymph node metastasis using both preoperative imaging and sentinel node detection is thus important. REFERENCES 1.
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