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The Sentinel Lymph Node in Gastric Cancer: third updating .

Romeo Giuli MD, resident.
School of General and Emergency Surgery.
University of Siena.   Italy.

October 2002.     Review Article.

To previous article about Sentinel Node in GC
To the first updating
To the second updating

The Hideki Hayashi et al study is the first article to their knowledge that has evaluated the double-tracer technique ( the dye-guided and gamma probe-guided techniques ) in a prospective manner.
Their data indicate the improved efficiency of the dual-mapping technique for SN identification in predicting the tumor status of an entire lymph node region. They recommend this dual method for SN biopsy in gastric cancer ( 1 ).

SN mapping using the dye-guided technique in gastric cancers was technically easier to perform than in breast cancers or melanomas. This is because visualization of the dye in the lymph nodes or lymph vessels through the peritoneum was easily attained immediately after injection. But there are two possible difficulties in performing the dye-guided technique. First, because the pericardial area or prepyloric area is rich in fat and lacking peritonea in part, skeletonization around vessels is often required to detect positive staining nodes. Second, identification and removal of SNs must be performed quickly because dye flows into non-SNs and staining of primary lymph nodes or lymph vessels diminishes in 2 or 3 hours ( 1 ).

Although preoperative lymphoscintigraphy was informative for cutaneous melanoma, breast, and other cancers, it was not useful for gastric cancer. In Hayashi series, HNs could be detected in only 1 of 15 patients who underwent lymphoscintigraphy .Two possible reasons were considered for this negative result. First, most of the lymph nodes are too close to the main tumor to distinguish on lymphoscintigram. Second, uptake of tracers in the lymph nodes might be much lower than in the main tumor. The relative uptake ratio of the tracer in lymph nodes versus main tumor was reported to be lower in the stomach compared with other anatomic sites ( 1, 2 ).
The anatomic properties of the stomach affect the performance of gamma probe detection of SNs during operations. Lymph nodes along the lesser curvature sometimes attach to the gastric wall. The shine-through phenomenon cannot be avoided in those cases. Small regions that were suspicious and adjacent to the main tumor often needed to be removed en bloc and dissected on the back table to identify HNs. In addition, radioactive tracer may remain in the small or large intestine if it leaked from the injection site. Alternatively, the tracer may accumulate in the liver because of the properties of tin colloids. These facts cause challenges in detecting SNs in gastric cancers.

In the Hayashi et al study with the combination of dye- and probe-guided techniques, complete correspondence between SN histopathology (absence or presence of metastases) and entire regional lymph node status was indicated. But when estimated for individual tracers, one false-negative case for the dye-guided technique and two false-negative cases for the gamma probe-guided technique were revealed ( 1 ).

Hiratsuka and associates reported 100% coincidence between the presence of tumor cells in SNs and the entire regional lymph nodes when using the dye-guided technique in patients with T1 tumors. They used indocyanine green instead of patent blue dye. Also, a larger volume of dye (5 mL) was administered to each patient. These differences may contribute to their high accuracy rate, but one false-negative result ( 3% ) was noted when patients with T2 tumors were involved ( 1, 3 ).

Kitagawa and coworkers showed 100% accuracy using the gamma probe-guided technique, although tumor status of the patients was not precisely described. Although the same kind of colloid reagent was used in their study as in Hayashi study, the size of colloidal particles prepared may have differed. Differences in conditions such as temperature, incubation period, relative ratio to physiologic saline, or degree of vibration are known to result in different sizes of tin colloid particles. Using the described method, more than 45% of the colloid particles prepared in the Hayashi conditioned setting were estimated to be greater than 1,000 nm (1, 4, 5, 6 ).
Smaller-particle radiotracers, such as 99m Tc sulfur colloid (particle size <200 nm) or 99m Tc colloidal albumin, are widely used in the United States and Europe. But these colloids are not commercially available in Japan. Because favorable results have been reported in breast and gastrointestinal cancers with the use of large-particle radiotracers, 99m Tc-tin colloid was used in the Hayashi study.

In the Hayashi study data indicate a significant difference in distributions between HNs and BNs. Roughly half of the HNs were stained blue and half of the BNs were radioactive, but half of the SNs identified using each technique were non-SNs by the other identification technique. This discrepancy may be explained as follows: Each tracer may not have been administered in the same exact location because the two tracers were not administered at the same time; mild inflammation of the gastric mucosa was occasionally observed after injection of the tin colloid, and it may have modified the lymphatic flow from the primary lesion; and similar discrepancies were observed even when the two tracers were administered at the same time in other organs.So this may reflect differences in the accumulation mechanism of these tracers to lymph nodes ( 1, 7 ).
In addition, data indicated there might have been a false-negative result if the dye-guided technique was applied alone, and two results were possibly false negatives when the gamma probe-guided technique was applied alone. There were no technical failures described when tracers were administered for each possible false-negative case; eg, leakage of tracers into the abdominal cavity or gastric lumen. No accompanying diseases were revealed before or during operation, such as adhesions of other tissues or scar formation around the primary lesion.These data suggest that the dual-mapping technique using dye and gamma probe guidance would be suitable for the detection of SNs for gastric carcinoma ( 1 ).

Micrometastases in regional lymph nodes that are not detectable by single sectioning and hematoxylin and eosin staining are gaining importance in prognosis and potentially survival in breast, melanoma, and other cancers. In the field of gastric cancer, a considerable proportion of N0 patients have been upgraded to N (+) by multistep sectioning and immunohistochemical staining of regional lymph nodes. Further analysis, including such micrometastasis-detecting techniques, would be required to verify the SN concept in gastric cancer ( 1 ).

In the Arai study fifty-four patients with early gastric cancer who had only one lymph node metastasis were regarded retrospectively as patients with a possible sentinel node metastasis, and the morphological features of these nodes were assessed. The level I nodes in seven patients with a possible skip metastasis at routine haematoxylin and eosin staining were re-examined using cytokeratin (CK) immunostaining.
The shape of the gastric cancer lesion could be examined in 53 of the patients; more than one-third (20 of 53 ) were microfocal type. Concerning the intranodal cancer foci, the marginal sinus type was found in 32 affected nodes, medullary sinus type in 14 and mixed type in seven. Forty-three per cent of suspected sentinel nodes were the largest in size among all nodes from the station. CK immunostaining of seven non-metastatic nodes with haematoxylin and eosin revealed that three were CK positive.
These findings suggest that possible sentinel nodes detected by conventional means may not always be primary portions of any metastasis. Adoption of sentinel node biopsy in gastric cancer must await the development of improved procedures for diagnosis during surgery ( 9 ).

Kitagawa et al stress the concept that accurate and sensitive intraoperative evaluation of harvested SNs is critical to accurate decision making at the time of surgery because a false negative study may affect the ultimate prognosis for the patient. Establishment of a system with intraoperative quantitative real-time RT-PCR for use of a multiple markers will be required for any future study.
Technical errors using the single-mapping agent approach are reduced by adding a different approach for lymphatic mapping. The radioguided method lets us confirm the complete harvest of SNs with multidirectional and widespread distribution with the use of the gamma probe, and the dye procedure lets us perform real-time observation of the visualized lymphatic vessels. Preoperative lymphoscintigraphy is not essential for gastric cancer in which of SNs in unexpected sites distant from primary lesion is relatively low in comparison with esophageal cancer.
Although there are several issues to be resolved, this novel procedure has the potential for great benefit to improve quality control in the treatment of upper GI Cancer. Well-designed clinical trials of lymphatic mapping for upper GI cancer will be essential to determine whether this technique is widely applicable in the management of these tumors.
Laparoscopic detection of SNs in gastric cancer is feasible and useful to extend the indications for novel, minimally invasive surgery, such as laparoscopic wedge resection of the stomach ( 12 ).


1) Hideki Hayashi et al. Sentinel Lymph Node Mapping for Gastric Cancer Using a Dual Procedure with Dye- and Gamma Probe-Guided Techniques. J Am Coll Surg 2003;196:68-74. Pub Med

2) Aikou T, Higashi H, Natsugoe S, et al. Can sentinel node navigation surgery reduce the extent of lymph node dissection in gastric cancer? Ann Surg Oncol 2001;8[Suppl 9]:90S-93S. Pub Med

3) Hiratsuka M, Miyashiro I, Ishikawa O, et al. Application of sentinel node biopsy to gastric cancer surgery. Surgery 2001;129:335-340. Pub Med

4) Kitagawa Y, Fujii H, Mukai M, et al. The role of the sentinel lymph node in gastrointestinal cancer. Surg Clin North Am 2000;80:1799-1809. Pub Med

5) Nakamura T, Fujii H, Kitagawa Y, et al. Preparation of 99mTc-colloid with particle size as you like for sentinel node detection.J Nucl Med 2001;42[Suppl 5]:20P.

6) 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;42:460-466. Pub Med

7) Merrie AE, van Ri AM, Phillips LV, et al. Diagnostic use of the sentinel node in colon cancer. Dis Colon Rectum 2001;44:410-417. Pub Med

8) Yasuda S, Shimada H, Ogoshi K, et al. Preliminary study for sentinel lymph node identification with Tc-99m tin colloid in patients with esophageal or gastric cancer. Tokai J Exp Clin Med 2001;26:15-18.

9) K. Arai, Y. Iwasaki and T. Takahashi. Clinicopathological analysis of early gastric cancer with solitary lymph node metastasis. British Journal of Surgery 2002, 89, 1435-1437. Pub Med

10) 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: 149-57. Pub Med

11) Nakamura K, Morisaki T, Noshiro H, Torata N, Kinukawa N, Tanaka M. Morphometric analysis of regional lymph nodes with and without metastasis from early gastric carcinoma. Cancer 2000; 88: 2438-42. Pub Med

12) Y Kitagawa et al. Intraoperative lymphatic mapping and sentinel lymph node sampling in esophageal and gastric cancer. Surg Oncol Clin N Am ( 2002 ) 293-304. Pub Med

13) Sano T et al. Gastric lymphadenectomy and detection of sentinel nodes. Recent Results Cancer Res 2000; 157: 253-8.

14) Miwa K. Sentinel node concept and its application for cancer surgery. Nippon Geka Gakkai Zasshi 2000; 101: 307-10. Pub Med

15) Kitagawa Y, Kitajima M. Gastrointestinal cancer and sentinel node navigation surgery. J Surg Oncol 2002; 79: 188-93. Pub Med

16) ) Kitagawa Y et al. Sentinel node navigation for esophageal, gastric and colorectal cancer. Proceedings of American Society of Clinical Oncology. S Francisco, CA: 2001. p 2280.

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