It is more than 10 years since the sentinel node (SN) concept for gastric cancer surgery was first discussed.(1,2) However, SN for gastric cancer is not yet clinically used universally, although less invasive modified surgical approaches based on the SN concept have already been put into practice for malignant melanoma and breast cancer.

What is the problem in the clinical application of SN in gastric cancer surgery? As a member of the first group to use SN biopsy with indocyanine green (ICG) in gastric cancer surgery,(2) I review here the current status of SN for gastric cancer surgery and discuss these problems.

Gastrectomy with regional lymphadenectomy is indicated for patients with gastric cancer and clinically suspicious lymph node (LN) metastases. The procedure is associated with a satisfactory long-term outcome. This "standard procedure" is usually conducted even when the primary tumor is small. However, there is controversy regarding the application of this procedure for patients with T1 gastric cancer because most of these patients are free of nodal metastases. In terms of the results, it appears that lymphadenectomy is being conducted at far higher rate than necessary in these patients. Thus, we need a reliable indicator that confirms the absence of LN metastases with high accuracy, in order to exclude lymphadenectomy from the surgical procedure used for patients with T1 gastric cancer and preserve a larger volume of the stomach without jeopardizing long-term outcome.

The SN is defined as a LN that directly drains a specific cancer. The concept of SN is based on the notion that non-SNs are unlikely to contain cancer cells if the SN is cancer cell-free. In 1992, Morton et al.(3) demonstrated the concept of SN in a clinical study involving patients with malignant melanoma. Since then, the SN technique has been applied to the surgical management of a variety of cancers to avoid unnecessary lymphadenectomy.(4,5)

With regard to gastric cancer, two Japanese studies were reported around the outset of the 21st century. Hiratsuka et al.(2) reported that SN biopsy using ICG can be performed with a high success rate, and that the SN status can predict the LN status with a high degree of accuracy. Kitagawa et al.(1) reported their preliminary data using intraoperative radiation technique and a gamma probe.

After the above two pioneering works in this area, several single institutional studies supported the validity of the SN concept for gastric cancer. In most of these studies, patients had T1 gastric cancer, and thus only a small number of patients reported in those studies had LN metastases. Moreover, the SN biopsy protocol varies according to the surgeon. Therefore, not only single institutional studies with small number in different ways, but also studies with large number in a unified way have been conducted to evaluate the feasibility and clinical application of this technique. Under these circumstances, two multi-institutional prospective clinical trials; the Japan Clinical Oncology Group trial (JCOG0302) and the Japanese Society for Sentinel Node Navigation Surgery (SNNS) trial, were conducted in Japan. The design and results of the two studies showed some rather large differences, as summarized in Table 1.

The multicenter clinical trial, JCOG0302 (GCSSG-SNB, UMIN-CTR ID: C000000059), was designed to evaluate the feasibility and accuracy of diagnosis using SN biopsy in T1 gastric cancer (Fig. 1). In other words, the feasibility of excluding lymphadenectomy during surgery for T1 gastric cancer was evaluated in patients with green nodes, representing SNs detected by ICG, which were considered cancer cell-free, by using intraoperative histopathological examination of frozen sections with hematoxylin-eosin (H&E) staining. The primary endpoint was the false negative rate (number of patients with an intraoperative negative SN biopsy/number of patients confirmed later to have LN metastases). Patients with only intraoperative SN-positive biopsy were defined as "false positive" in the JCOG0302 trial. Caution should be exercised because patients with intraoperative SN-negative biopsy but SN-positive histopathological examination of paraffin sections were defined as false negative in the trial although such SN biopsy was considered feasible based on the SN concept. The trial started in 2004, however recruitment of patients was terminated midway before the goal because of the unexpected high false negative rate. Our pilot study adopted multi-planes for detection of metastases,(2) however, in the multicenter trial setting, only one plane of largest dimension of frozen section was adopted in the trial for convenience. The planned learning period of 5 patients in each institution is probably an underestimation because the true number is considered to be 30 patients at present, as determined by the Japanese Society for SNNS. That is to say, the JCOG0302 was a trial to evaluate the feasibility of the current clinical setting, including several issues on the SN concept as well as intraoperative histopathological examination using frozen sections and learning period. Detailed analysis of the false negative cases indicated that these issues adversely affected the outcome than expected (unpublished data).

Another multicenter clinical trial was conducted by the Japanese Society for SNNS to evaluate the diagnostic accuracy of SNNS based on radio-guided method for LN metastases. The primary endpoint was the sensitivity of detection of metastases (number of patients with confirmed diagnosis of positive SN biopsy/number of patients with confirmed diagnosis of LN metastases). The SNNS trial differed from the JCOG0302 trial in that the entry criteria included both T1 and T2 gastric cancer, SN biopsy was performed by the dual tracer method (radioactivity was a mandatory requirement), SNs could be harvested in both surgical field and background table after gastrectomy, histopathological examination was performed on both frozen and paraffin sections, and only 12 well-experienced hospitals with more than 30 patients for learning period were included. The aim of the trial was to evaluate the SN concept in gastric cancer surgery based on the premise of substantial experience. The trial setting placed less emphasis on the accuracy of intraoperative histopathological examination of frozen sections and learning period, than the JCOG0302 trial. However, further steps are theoretically required for clinical application because detection of SN was unregulated before gastrectomy with lymphadenectomy.

There are several matters of debate in performing the actual procedures, such as the type of tracer, the site of injection, how to detect and harvest, and how to detect metastatic SNs. These issues have to be addressed further to establish the best procedure.

Now that we know what the problems are and how to avoid them, we can continue pursuing our goal.