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10.1245/s10434-007-9367-y
Annals of Surgical Oncology 14:2028-2035 (2007)
© 2007 Society of Surgical Oncology
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Original Article

Efficacy of Different Technical Procedures for Sentinel Lymph Node Biopsy in Gastric Cancer Staging

Stephan Gretschel, MD1, Andreas Bembenek, MD1, Michael Hünerbein, MD1, Stefan Dresel, MD3, Wolfgang Schneider, MD, PhD2 and Peter M. Schlag, MD, PhD1

1 Department of Surgery and Surgical Oncology, Charité, University Medicine Berlin, Campus Buch, Robert-Rössle-Cancer Hospital, HELIOS Klinikum, Lindenberger Weg 80, Berlin, 13125, Germany
2 Institute of Pathology, HELIOS Klinikum, Berlin-Buch, Wiltbergstraße 50, Berlin, 13125, Germany
3 Division of Nuclear Medicine, Charité, Robert-Rössle-Cancer Hospital, HELIOS Klinikum, Lindenberger Weg 80, Berlin, 13125, Germany

Correspondence: Address correspondence and reprint requests to: Peter M. Schlag, MD, PhD; E-mail: pmschlag{at}charite.de


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: The clinical impact of sentinel lymph node biopsy (SLNB) in gastric cancer is controversial. We performed a prospective trial to compare different methods: radiocolloid method (RM), dye method (DM), and both methods simultaneously (dual method, or DUM) for reliability and therapeutic consequences.

Methods: RM and DM were applied in 35 gastric cancer patients. After endoscopic peritumoral injection of 99mTc-colloid and Patent Blue V, the positions of all blue sentinel lymph nodes (SLNs) were recorded, and the SLNs microscopically examined by hematoxylin and eosin, step sections, and immunohistochemistry.

Results: RM, DM, and DUM identified the SLNs in 34 (97%) of 35 patients. The sensitivity for the prediction of positive lymph node status for RM was 22 (92%) of 24, for DM 16 (66%) of 24, and for DUM 22 (92%) of 24. In 7 of 17 (RM), 5 of 15 (DM), and 7 of 17 (DUM) patients classified as N0 by routine hematoxylin and eosin staining, micrometastases or isolated tumor cells were found in the SLN (upstaging) after focused examination. If only a limited lymph node dissection of the SLN basins would have been performed in patients, residual lymph node metastases were left in 9 of 24 (RM), in 7 of 34 (DM), and in 5 of 24 (DUM) of patients with node-positive disease.

Conclusions: Use of RM was superior. DUM did not further increase the sensitivity. A limited lymph node dissection—i.e., lymphatic basin in patients with SLN-positive disease—is associated with a high risk of residual metastases. Patients with negative SLNs may be selected for a limited surgical procedure if they meet certain criteria.

Key Words: Gastric cancer • Sentinel lymph node biopsy • Dye method • Radiocolloid method


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Sentinel lymph node (SLN) studies in patients with gastric cancer have shown that both radiocolloid and dye methods are able to detect SLN in most patients.1–7 However, the sensitivities in predicting nodal status vary between 65% and 100% in the current literature.8–10 Few studies have applied both methods in the same gastric cancer patient.4,11,12 Based on the experience in breast cancer and melanoma patients, this approach may also be beneficial in gastric cancer.13 Even fewer studies discussed the possibility of upstaging of patients initially classified as N0 by routine hematoxylin and eosin (HE) examination with a more detailed examination of SLN.14 As a consequence, the role of SLN mapping in gastric cancer surgery is currently unclear.

The aim of the study was to compare the radio-colloid method (RM), the dye method (DM), and the combination of both methods (the dual method, or DUM), applied simultaneously, in terms of clinical feasibility and sensitivity on the detection of nodal metastasis. A more exact nodal staging of the disease could lead to a modified surgical procedure, particularly in regard to a limited lymph node dissection in patients with small gastric cancer or other small surgical or endoscopic procedures.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Study Population and Design
We conducted a prospective trial from June 2002 to June 2005. The internal review board and the ethical committee of the Charité approved the study. All patients signed written consent.

Eligibility
We included patients with primary gastric cancer. Exclusion criteria were age >85 years, prior gastric surgery, pregnancy and advanced tumor stages prohibiting resection, such as infiltration of surrounding organs (uT4), or distant metastases.

Preoperative Staging
All patients underwent upper endoscopy, endoscopic ultrasonography, and abdominal computed tomographic scan. Patients with a tumor diameter of >5 cm were deemed ineligible. Patients with disease with an infiltration depth of uT1 to uT3 in endoscopic ultrasonography, and without extensive lymphatic metastases by computed tomographic scan or endoscopic ultrasonography were included.

Surgical Treatment and Lymph Node Dissection
All patients were scheduled for total gastrectomy and D2 lymphadenectomy with curative intent. Lymph node positions 1 to 12 (according to the second edition of the Japanese Gastric Cancer Association) were removed.15 Patients who had undergone an incomplete D2 lymphadenectomy were excluded from the study.

Lymph Node Basins and Lymph Compartments
For this study, the lymph compartment was divided into five basins according to the classification of Miwa et al.10: left gastric artery, right gastric artery, left gastroepiploic artery, right gastroepiploic artery, and posterior gastric artery. According to the Japanese Gastric Cancer Association,15 lymph node compartment I comprises the dissection of lymph node positions 1 to 6, and lymph node compartment II comprises positions 7 to 12.

Mapping Technique and Sentinel Lymph Node Biopsy
Radiocolloid Method
One day before surgery, 0.4 mL of 99mTc-marked colloidal rhenium sulfide with a particle size of 100 µm (Nanocis; CIS Bio-international, Gif-sur-Yvette, France) was endoscopically injected into the submucosal layer directly adjacent to the tumor in four portions, oral, aboral, and bilateral to the tumor. After 16 to 18 hours, radiocolloid scintigraphy was performed preoperatively with a gamma camera with a high-resolution collimator (140 keV). At laparotomy, the radioactive SLN were identified with a handheld gamma probe (Gammafinder, World of Medicine, Berlin, Germany) and marked with a suture. Lymph nodes with a count rate more than 10-fold above baseline (obtained over the middle chest) were defined as radiocolloid-positive SLN (R-SLN). In cases with a strong overlapping signal from the primary tumor (shine-through phenomenon), the R-SLN was identified ex vivo. After completion of the gastrectomy with D2 lymphadenectomy, the abdomen was scanned for residual activity, focusing on the remaining D3 lymph node positions. Ex vivo, the specimen was examined for the previously marked radiocolloid-containing ("hot") lymph nodes (R-SLN). R-SLN were excised after exact documentation of the lymph node position and submitted for selective histopathological lymph node examination.

Dye Method
Before injection, the lesser sac was opened to assess the retrogastric lymphatic drainage. Patent Blue V (1.2 mL in four portions of 0.3 mL) was injected endoscopically into the quadrants of the submucosa around the tumor, similar to the radioactive method, while the duodenum was clamped. Subsequently, lymphatic drainage was observed for up to 10 minutes after injection. Lymph nodes that showed blue staining within 10 minutes after dye injection were defined as dye SLN (D-SLN). Blue-stained lymph nodes (D-SLN) in the regions of the planned dissection (D1 + D2 compartments) were marked with a suture. In case of juxtaregional staining (a SLN outside of the D2 compartment), a separate excision was performed. Ex vivo, marked D-SLN were excised after their exact positions were documented, and they were submitted for selective histopathological lymph node examination.

Histopathological Lymph Node Assessment of SLN
All lymph nodes, both SLN and non-SLN, underwent the following pathological evaluation: lymph nodes up to 10 mm in diameter were bisected, and larger lymph nodes were sectioned in slices of approximately 2 mm thickness. The specimens were processed in paraffin blocks for HE staining. The HE staining was not performed intraoperatively on frozen sections, to avoid loss of diagnostic accuracy. If the processed SLN did not reveal metastases, the 2-mm slices were divided into 250-µm subslices. From each slice, serial sections were cut at 5 µm thickness, with at least one section undergoing immunohistochemistry (IHC). If no tumor cells were found by HE staining, at least four serial sections per lymph node were stained with IHC (pan-cytokeratin antibody MNF116 [Dako, Germany] with streptavidin-AP). Equivocal findings by HE staining were evaluated similarly by IHC. To exclude false-positive results of nonspecific signals of perifollicular reticulum cells or plasma cells, CK-positive cells were only considered as isolated tumor cells or micrometastasis if they met strict cytomorphological criteria of tumor cells after counterstaining with hemalum. On the basis of the simplified model of spherically configured metastases and mathematical statistical calculations, this approach enabled the pathologist to identify metastases up to a diameter of 0.25 mm with a probability of 100% and up to a diameter of 0.1 mm with a probability of 50%.16

Data Analysis
All SLNs that contained tumor cells (including macrometastases, micrometastases, or isolated tumor cells) were defined as positive SLN. If there was no evidence for tumor cells in the SLN, the lymph node was defined as negative. If the SLN was free of tumor cells but other lymph nodes (non-SLN) revealed metastases, the SLN was defined as false negative. The detection rate was defined as the number of successful identifications of one or more SLN in relation to the total number of sentinel lymph node biopsy (SLNB) procedures. The sensitivity was defined as the percentage of patients with positive SLN from the total number of patients with node-positive disease; the false-negative rate is the corresponding percentage of patients with node-positive disease with false-negative results. To analyze the feasibility of a limited lymph node dissection on the basis of SLNB results, where only SLN-positive basins are resected, we compared the distribution of lymph node metastases within resected and unresected basins.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Radiocolloid Method
Thirty-five patients with primary gastric cancer meeting all inclusion criteria were enrolled onto the study (Table 1Go). A total of 34 (97%) of 35 patients who underwent RM had at least one R-SLN. In 10 of 34 patients, the SLN was only retrievable ex vivo as a result of a strong background signal from the primary tumor. The median number of R-SLN detected per patient was 3 (range, 1–10). The most common locations of R-SLN according to the Japanese Gastric Cancer Association were position 6 in the subpyloric region with 22 SLN in 14 of 34 patients, position 7 on the left gastric artery with 14 SLN in 11 (32%) of 34 patients, and position 3 in the lesser curvature with 20 SLN in 10 (29%) of 34 patients. In 23 (68%) of 34 patients, the SLN were located in compartment I only, in 4 (12%) of 34 in compartment II only, and in 7 (20%) of 34 of the patients in both compartments. The distribution of R-SLN in relation to the tumor localization is shown in Fig. 1Go.


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  		TABLE 1. Patient characteristics
 

Figure 1
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  		FIG. 1. Lymphatic drainage and positions of sentinel lymph node (SLN) of 35 gastric cancer patients detected by the radiocolloid method (RM), dye method (DM), and dual method (DUM) in relation to the lymph node positions 1 to 12 of the Japanese Gastric Cancer Association depending on the tumor localization. Red dots indicates the SLN containing radiocolloid and dye, blue dots the SLN containing dye alone, and black dots the SLN containing radiocolloid alone. (A) Tumor localized in the upper third of the stomach (n = 5). (B) Tumor localized in the middle third of the stomach (n = 15). (C) Tumor localized in the lower third of the stomach (n = 15).

 
Lymph node metastases or nodes with tumor cells were found in 24 (71%) of 34 patients. Twenty-two patients had at least one tumor-involved R-SLN, corresponding to a sensitivity to predict a positive nodal status of 22 (92%) of 24 and a false-negative rate of 2 (8%) of 24 (Tables 2Go and 3Go). In 7 (32%) of 22 patients with correctly predicted positive nodal status, both SLN and non-SLN were involved, whereas in 15 (68%) of 22 of patients, the SLNs were the only positive lymph nodes.


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  		TABLE 2. Comparison of three methods for sentinel lymph node biopsy
 

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  		TABLE 3. Clinical and pathological characteristics of false-negative sentinel lymph nodes found by various methodsa
 
Table 4Go shows the lymphatic basins with tumor involved SLNs. Table 5Go and Fig. 2Go provide residual lymph node metastases after hypothetical lymph node dissections limited to the lymphatic basins in which R-SLN were found. Among the 18 patients whose disease was initially classified as pN0, two had nodal micrometastases and five had isolated tumor cells. Stepwise sections and IHC identified these metastases and tumor cells, corresponding to an upstaging rate of 7 (39%) of 18 patients in this group.


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  		TABLE 4. Distribution of lymph node basins and positive sentinel lymph nodes detected by the different methods is showna
 

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  		TABLE 5. Analysis of hypothetical limited resection of lymphatic basin with resulting residual lymph node metastases
 

Figure 2
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  		FIG. 2. Positions of lymph node metastases in relation to tumor localization: A1, upper third (3 patients); B1, middle third (9 patients); C1, lower third of stomach (12 patients). Positions of residual lymph node metastases after hypothetical lymph node dissections limited to the sentinel lymph node basins after radiocolloid method are as follows: A2, upper third (1 patient); B2, middle third (3 patients); C2, lower third of stomach (5 patients).

 
Dye Method
In the 35 patients undergoing SLNB by DM, at least one D-SLN was identified in 34 (97%) of 35 patients. The minimum time needed for the detection of blue-stained lymph nodes was 2 minutes. The median number of detected D-SLN was 3 (range, 1–6). D-SLN were most commonly found in lymph node position 6 with 24 SLN in 14 (41%) of 34 patients, in position 7 with 17 SLN in 12 (35%) of 34 patients, and in position 3 with 20 SLN in 10 (29%) of 34 patients. In 20 (59%) of 34 patients, the SLN were located only in compartment I, in 5 (15%) of 34 only in compartment II, and in 9 (26%) of 34 in both compartments. The distribution of D-SLN in relation to the tumor localization is shown in Fig. 1Go.

A total of 24 (71%) of 34 patients had lymph node metastases or isolated tumor cells. Sixteen were correctly predicted by the examination of the D-SLN, corresponding to a sensitivity of 16 (66%) of 24 for predicting the positive lymph node status and a false-negative rate of 8 (33%) of 24 (Table 2Go). In 7 (44%) of 16 patients with a correctly predicted positive nodal status, both SLN and non-SLN showed metastases, and in 9 (56%) of 16 patients, the SLN were the only metastatic lymph nodes.

Table 3Go lists clinicopathological characteristics of eight false-negative cases. Table 4Go lists the lymphatic basins with stained SLNs. Table 5Go and Fig. 2Go provide an overview of residual lymph node metastases after hypothetical lymph node dissections limited to the lymphatic basins in which we found stained D-SLN. Within the 18 patients with pN0 disease, additional micrometastases (one case) and isolated tumor cells (four cases) were found in the SLN by focused examination with IHC, corresponding to a upstaging rate of 5 (28%) of 18.

Dual Method
The detection rate was 34 (97%) of 35. In 18 (53%) of 34 patients, the SLN were located only in compartment I, in 2 (6%) of 34 only in compartment II, and in 14 (41%) of 34 in both compartments. The distribution of SLN in relation to the tumor localization is shown in Fig. 1Go. A total of 24 (71%) of 34 patients had lymph node metastases. Of these, 22 (92%) of 24 showed at least one tumor-involved SLN (blue, hot, or both). The eight false-negative results of the DM were correctly reversed with RM. Thus, the DUM showed a sensitivity of 22 (92%) of 24 in predicting a positive lymph node status and a false-negative rate of 2 (8%) of 24, respectively (Table 2Go). Table 3Go shows clinicopathological characteristics of the two patients with falsely negative results. Table 4Go shows the lymphatic basins with hot and/or stained SLNs. Table 5Go and Fig. 2Go provide an overview of residual lymph node metastases after hypothetical lymph node dissections limited to the lymphatic basins in which we found hot R-SLN, stained D-SLN, or both hot and stained SLN. The rate of upstaging was 7 (39%) of 18.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
At least one SLN was present in 97% of the patients. The lymph flow showed a certain pattern depending on tumor localization. Tumors located in the middle third of the stomach drained along the lesser curvature (lymph node positions 3 and 7), tumors in the lower third drained along the subpyloric region (lymph node position 6). There is no agreed rule of lymphatic drainage, and the registered SLN positions varied considerably (Fig. 1Go). We rarely found SLNs in compartment II exclusively (8%). However, these were present often only in compartment I (44%) or in both compartments (48%). This finding corresponds to those of others that identified a low probability (2% to 5%) of lymph node drainage exclusively in compartment II. They also showed a relative low impact of skip metastases.5,17 Lymph node drainage from compartment I to compartment II seems to be consistent, although within each compartment, the drainage is individually different.

For the RM, we used Nanocis with a particle size of 100 nm, as recommended by Uenosono et al.18 We achieved a sensitivity of 92%, similar to previous studies in which the same tracer was used.7,19,20 By use of 500-nm thin colloids, a SLN was detected in a comparable range (81% to 100%) of cases.1,2,5,9,17,21

The DM with patent blue showed a low sensitivity of only 66% in our study. Several studies report sensitivity rates up to 100%,6,8,10,14,22–28 whereas others29,30 observed low sensitivity rates of 61% and 41%. Table 3Go shows possible reasons for false negative findings. Two patients with false-negative findings by RM and DUM and five of eight of the DM group had advanced disease (pT2, pT3). In our opinion, the SLN technique is unsuitable for advanced gastric cancer. However, three of eight patients in the false-negative DM group had pT1 tumors. Two of these had high body mass index (28 and 32). It is well known that obesity can lower the identification rate of SLNs.31,32 The third pT1 patient was underweight, with a body mass index of 18. The SLN was in position 7. In position 3, we detected isolated tumor cells with IHC (i+). It is not known whether radiocolloid injection before surgery has a detrimental effect on the intraoperative performance of the DM.

The current evidence of the DUM in gastric cancer is limited. Most notably, the number of patients with node-positive disease enrolled onto the study, which is pivotal for the determination of sensitivity and false-negative rate, is too low to validate the method. The number of patients with node-positive disease in the studies of Karube et al.,11 Hayashi et al.,4 and Tonouchi et al.12 was 13, 7, and 4 respectively. In our study, the sensitivity calculation was made on the basis of 24 patients with node-positive disease. The RM increased the overall sensitivity, whereas the DM did not. Both, DUM and RM revealed a sensitivity of 92% and a false-negative rate of 8%. It remains to be clarified whether the use of dye containing radioactive colloid increase the sensitivity.

We found that a focused examination of the SLN and IHC by stepwise sections led to the identification of micrometastases or isolated tumor cells in up to 39% of patients that was initially classified as pN0 by routine HE. Similar findings have been reported for malignant melanoma, and breast and colon cancer.33–37 The clinical significance of these small tumor deposits is not known, but recent studies of gastric cancer have postulated that this finding has prognostic significance.38–41

SLNB was developed to limit complete lymph node dissection. It is essential for clinical safety that SLNB has a reasonable sensitivity and a low false-negative rate. In our study, only the RM and therefore the DUM exhibited an adequate sensitivity and were able to reliably select patients with tumor-free lymph nodes. A major clinical dilemma of the SLN concept is the low validity of the intraoperative histopathological examination of the SLN to allow a correct intraoperative therapeutic decision. Current methods such as imprint cytology and frozen sections have a sensitivity ranging from 30% to 96%.8,42–50 We did not perform the histological evaluation of the SLNs intraoperatively and therefore did not change the extent of resection during surgery. Intraoperative rapid polymerase chain reaction of SLN is an interesting approach to increase the sensitivity.51–53 Another major limitation of the SLN concept in gastric cancer is the so-called shine-through phenomenon, where a strong radioactive signal from the primary tumor hinders the SLN detection with RM. In almost one third of our cases (10 of 34), the SLN was only retrievable ex vivo because a strong background signal from the primary tumor. This technical problem could be adressed with improved collimators or more focused gamma probes.

Our results demonstrate that approximately 38% to 62% (RM/DM) of the patients with node-positive disease had also lymph node involvement in positions other than the SLN. Thus, a limited dissection based on SLN basins, as proposed by Miwa et al.,10,54 would hypothetically have left behind lymph node metastases in 7 (29%) of 24 of patients by DM, in 9 (38%) of 24 of patients assessed by RM, and in 5 (21%) of 24 of patients assessed by DUM. Lymphatic basin dissection seems to be justified only for SLN-negative early cancer, but not for SLN-positive disease.

We conclude that all patients with evidence of tumor cells in the SLN should undergo standard lymph node dissection because of the high percentage of residual lymph node metastases that are outside the lymph node basin. Without further investigation of SLNB in well-designed prospective multicenter trials, limited lymph node dissection cannot be recommended in gastric cancer.

Received for publication August 13, 2006. Accepted for publication January 12, 2007.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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