ReviewDetection of micrometastases in sentinel node navigation surgery for 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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