Elsevier

Surgical Oncology

Volume 17, Issue 3, September 2008, Pages 203-210
Surgical Oncology

Review
Detection of micrometastases in sentinel node navigation surgery for gastric cancer

https://doi.org/10.1016/j.suronc.2008.04.008Get rights and content

Abstract

Although lymph node metastasis is one of the important prognostic factors for patients with gastric cancer, the clinical significance of micrometastasis remains controversial. In the 6th edition of the TMN classification, micrometastases were classified as micrometastasis (MM) and isolated tumor cells (ITC) according to its greatest dimension. The accurate diagnosis of micrometastases is required when considering less invasive surgery, especially in early stage of gastric cancer. Since generating useful information about micrometastases by conventional RT-PCR is time-consuming, this procedure is not useful for rapid diagnosis during surgery. Recently some new methods of genetic diagnosis have reduced the amount of time required to obtain information about micrometastases in lymph nodes to 30–40 min. Such methodology can be clinically applied during less invasive surgery. The sentinel node (SN) concept has recently been applied to gastric cancer and SN navigation surgery (SNNS) is ideal for reduction of lymphadenectomy in patients with early gastric cancer. However, we should think about some conditions to establish SN concept for gastric cancer: the particle size of radioisotope, relationship between metastatic area and RI uptake, and the diagnosis of micrometastases by various method such as histological examination, immunostaining and RT-PCR. Here, we described the current status of MM and ITC in the lymph nodes and the SN concept in gastric cancer.

Section snippets

Clinical significance of micrometastasis in gastric cancer

The advocated concept of “so-called micrometastasis” based on morphological or methodological findings is also referred to as micrometastasis, microcarcinosis, occult metastasis, latent metastasis, microinvolvement, microenvironment and isolated tumor cells (ITC). The term “ITC” has recently been introduced into the TNM classification [1]. These are individual tumor cells or small cell clusters that do not exceed 0.2 mm in the greatest dimension, which are usually detected by

Sentinel node concept in gastric cancer

According to the sentinel node (SN) concept, SN is the first lymph node to receive lymphatic flow from the primary tumor and metastasis initially occurs at this site [17]. Thus, micrometastases are probably located in SNs as the first step of lymph node metastasis. SN navigation surgery (SNNS) has been clinically introduced for patients with breast cancer and malignant melanoma and it can also assess lymph node dissection areas [18], [19], [20], [21]. The SN concept has recently been applied to

Selection of tracer for sentinel node detection

Several authors have described SN mapping in gastric cancer. However, the SNs were detected by radioisotope (RI)-labeled colloid guided, dye-guided and both RI and dye guided methods. The most popular RI tracer is 99mTechnetium (99mTc) in forms such as 99mTc-tin colloid, 99mTc-sulfur colloid, 99mTc-serum albumin and 99mTc-phytate [31], [32], [33], [34]. The accuracy rate of dye method in SN mapping using patent blue is 98% [29]. Indocyanine green (ICG) can also detect SN [35], [36] and infrared

Ratios of metastatic areas and radioisotope uptake in sentinel nodes

SNs are identified by RI or dye uptake during surgery. However, even if macroscopically overt nodal metastases are found during operation, RI or dye is not always contained in such nodes. Miwa et al. reported that false negative results were found in 4 of 211 patients with early-stage gastric cancer using the dye method. All four patients with a false negative finding had a large clinical node [29]. Martin et al. reported that the highest RI count (in SNs) was not predictive of nodal metastasis

SN mapping in patients with clinical T1 and N0 gastric cancer

SN mapping by the RI method has been performed in patients with clinical T1 and N0 gastric cancer since 2000. Lymph node metastases are examined by conventional HE and IHC using cytokeratin antibody as described [26], [28], [43]. At the present time we have enrolled 139 patients with clinical T1 and N0 gastric cancer in our institute. On the day prior to surgery, about 3 mCi of 99mTc-tin colloid was injected endoscopically into the submucosa at four sites around the tumor using a 23-G needle.

Diagnosis of lymph node metastases including micrometastases

In SNNS, there is a problem regarding the diagnosis of lymph node metastases including micrometastases. As mentioned above, not all metastases are detected by routine histological examination. As lymph node metastasis is one of the most important prognostic factors in gastric cancer [9], [44], accurate diagnosis of lymph node metastasis before and during surgery is indispensable for SNNS. Although lymph nodes are three-dimensional structures, histological and IHC investigations are usually

Selection of markers in genetic diagnosis using RT-PCR

Several RT-PCR markers can detect micrometastases (Table 2), and carcinoembryonic antigen (CEA) is very popular. However, Honda et al. reported that 21.7% of differentiated tumors, 34.7% of undifferentiated tumors with a tubular component and 69.7% of pure undifferentiated tumors all express high levels of CEA [49]. Since gastric cancer comprises various histological types, markers other than CEA might be required to detect micrometastases by RT-PCR. Cytokeratin-19 (CK19) is a candidate for

Establishing marker cut-off values

Metastatic and benign nodes without cancer cells should be compared to establish cut-off values of markers. Kubota et al. compared cut-off values assessed as CEA and CK20 expression between histologically proven nodal metastasis and benign nodes obtained from patients without cancer. Their results indicated that duplex quantitative real-time RT-PCR using CEA and CK20 primers is the most sensitive method of detecting micrometastases and useful for evaluating the prognostic significance of lymph

Clinical application of the diagnosis of micrometastases

The presence of micrometastases in lymph nodes of gastric cancer has been confirmed by various methods. The concept of micrometastases should be applied not only to the prediction of prognosis and adjustment of staging migration but also to actual clinical practice. Intraoperative detection of micrometastases in lymph nodes is useful for determining the extent of lymphadenectomy. Conventional RT-PCR requires several steps and thus can generate information after 2–3 h. Thus, a more rapid

Conclusion and outlook

The presence of micrometastases in lymph nodes might be related to recurrence and prognosis in patients with gastric cancer. The clinical significance of micrometastases should be surveyed in a large patient population with the same disease stage who undergo the same types of surgery. Recent progress in RT-PCR technology means that about 30–40 min is required to determine micrometastases status. Since this is a relatively short time in which to reach an intraoperative diagnosis of

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