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Cancers 2011, 3, 2141-2159; doi:10.

3390/cancers3022141
OPEN ACCESS

cancers
ISSN 2072-6694
www.mdpi.com/journal/cancers
Review

Lymph Node Metastasis of Gastric Cancer
Tomonori Akagi 1,*, Norio Shiraishi 2 and Seigo Kitano 1
1

2

Oita University Faculty of Medicine, Department of Gastroenterological Surgery, 1-1 Idaigaoka,
Hasama-machi, Oita 879-5593, Japan; E-Mail: geka1@oita-u.ac.jp
Surgical division, Center for community medicine, Oita University, 1-1 Idaigaoka, Hasama-machi,
Oita 879-5593, Japan; E-Mail: norioh@oita-u.ac.jp

* Author to whom correspondance should be addressed; E-Mail: tomakagi@med.oita-u.ac.jp;
Tel.: +81-97-586-5843, Fax: +81-97-549-6039.
Received: 9 February 2011; in revised form: 1 April 2011 / Accepted: 4 April 2011 /
Published: 26 April 2011

Abstract: Despite a decrease in incidence in recent decades, gastric cancer is still one of
the most common causes of cancer death worldwide [1]. In areas without screening for
gastric cancer, it is diagnosed late and has a high frequency of nodal involvement [1]. Even
in early gastric cancer (EGC), the incidence of lymph node (LN) metastasis exceeds 10%;
it was reported to be 14.1% overall and was 4.8 to 23.6% depending on cancer depth [2]. It
is important to evaluate LN status preoperatively for proper treatment strategy; however,
sufficient results are not being obtained using various modalities. Surgery is the only
effective intervention for cure or long-term survival. It is possible to cure local disease
without distant metastasis by gastrectomy and LN dissection. However, there is no survival
benefit from surgery for systemic disease with distant metastasis such as para-aortic lymph
node metastasis [3]. Therefore, whether the disease is local or systemic is an important
prognostic indicator for gastric cancer, and the debate continues over the importance of
extended lymphadenectomy for gastric cancer. The concept of micro-metastasis has been
described as a prognostic factor [4-9], and the biological mechanisms of LN metastasis are
currently under study [10-12]. In this article, we review the status of LN metastasis including
its molecular mechanisms and evaluate LN dissection for the treatment of gastric cancer.
Keywords: gastric cancer; lymph node metastasis; lymph node dissection

2. and histological type of the AGC. and the presence of lymphovascular invasion are important determinants of the likelihood of spread [2. but their diagnostic accuracy is limited. For example. A report from Japan suggested that >60% of untreated EGCs will progress to AGC within five years [21]. The overall incidence of LN metastases in T1 EGC is 10 to 20% [2.14-17]. Abdominal ultrasound (US) examination and computed tomography (CT) are usually used to examine the presence of invasion to other organs and metastatic lesions. EGC is defined as adenocarcinoma that is limited to the gastric mucosa or submucosa regardless of the involvement of regional lymph nodes (T1) [13]. As preoperative examinations. such as location. immunohistochemical staining.8% versus 23. endoscopy and barium meal examinations are routinely used to evaluate the cancerous lesion in the stomach. . Early Gastric Cancer (EGC) As proposed by the Japanese Society of Gastroenterological Endoscopy in 1962. study. In the Sano et al. However. affect the incidence and distribution of LN metastasis. Two issues are related to evaluation of the incidence of LN metastasis in AGC: First. 2. depth. Advanced Gastric Cancer The number of studies reviewing both the progression of LN metastasis from EGC to advanced gastric cancer (AGC) and the status of AGC is insufficient. 66. is necessary [23].6% for mucosal versus submucosal cancer. it is difficult to judge the presence and the extent of LN metastasis in AGC before operation. SE. Second. The Incidence of Lymph Node (LN) Metastasis in Gastric Cancer 1.7%) [19].2%. Nakajima et al. reported that the incidence of LN metastasis of gastric cancer with invasion to MP. and 82. the purpose of the preoperative evaluation is to initially stratify patients into two clinical groups: those with locoregional (stage I to III) disease and those with systemic (stage IV) involvement. respectively. The characteristics of the tumor such as the size. study evaluating 652 cases of resected EGC [2] showed that the incidence of LN metastasis to be 14. size. Many studies have clarified the status of LN metastasis in EGC.6%. the diagnosis of LN metastasis with resected specimens is affected by examination methods such as H and E staining. Therefore. and >4 cm in diameter. SI were 52. macroscopic type. Diagnosis of LN Metastasis in Gastric Cancer The accuracy rate of imaging examinations of LN metastasis in gastric cancer is not high. 2 to 4 cm. were associated with a low risk of LN metastases (1.1% overall: 4. histologic type. and nonulcerative type IIc T1 tumors of less than 1 cm in diameter.9%. 1. cancer depth. Smaller cancers were significantly less likely to be associated with positive nodes: 9% versus 20% and 30% for tumors <2 cm. respectively [22]. To predict the incidence and distribution of LN metastasis in detail before operation for AGC. many factors. 74. 3 2142 1.18-20].1. Such a volume of sufficient data has contributed to the development of indications for endoscopic treatment. and reverse polymerase chain reaction.Cancers 2011.4%. well-differentiated type I and IIa T1 tumors of less than 2 cm in diameter. SS. a special modality such as the computer information system developed by Maruyama et al. the Roviello et al.

reported that the detection rate of LN metastasis by transabdominal US was 5% [24]. EUS-guided fine needle aspiration of suspicious nodes and regional areas adds to the accuracy of nodal staging [51].44]. and distant nodal spread. It is good for widely evaluating metastatic disease.Cancers 2011.33]. false-positive findings may be attributed to inflammatory lymphadenopathy. Positron Emission Tomography (PET) The role of PET using 18-fluorodeoxyglucose (FDG) in the preoperative staging of gastric adenocarcinoma is evolving. 2. accuracy for nodal staging (65 to 90%) is only slightly greater with EUS as compared to CT [40. The classification of nodal status is usually based on LN size.43. however. From the standpoint of locoregional staging. Endoscopic Ultrasonography (EUS) In comparative studies. Due to problems with intraluminal gas. Furthermore.45-50]. Abdominal US There are few reports about the accuracy of preoperative LN status using abdominal ultrasonography. Another limitation of CT is its inability to accurately assess the depth of primary tumor invasion and the presence of LN involvement. abdominal US of the gastrointestinal tract is not commonly used and has not been developed. although newer CT techniques (such as three-dimensional multidetector-row CT) and magnetic resonance imaging may achieve similar results in terms of diagnostic accuracy in T staging [39. Rather than abdominal US. sensitivity and specificity rates for detection of regional nodal metastases ranged from 65 to 97% and 49 to 90%. and sensitivity of CT for detecting regional nodal metastases is limited for involved nodes that are smaller than 0.1. especially hepatic metastases. a number of studies of the effectiveness of endoscopic ultrasonography (EUS) have been reported (described in section 2. CT accurately assesses the T stage of the primary tumor in only about 50 to 70% of cases [28-34]. this usually does not impact the decision to proceed to surgery. 3 2143 2. however.8 cm [28. overstaging can also occur that is attributed to inflammation around the tumor or within the LNs [50]. Isozaki et al.2. intraperitoneal disease will be found at either staging laparoscopy or at open exploration [25-27].3. In several series of patients undergoing staging CT for gastric cancer or gastric plus esophageal cancer. Abdominal CT Dynamic CT scanning is usually performed early in the preoperative evaluation after a diagnosis of gastric cancer is made. EUS generally provides a more accurate prediction of T stage than does CT [40-42]. In 20 to 30% of patients with a negative CT.3). However. 2. Most errors in staging with EUS are due to understaging of nodal involvement and the depth of primary tumor invasion. a negative PET scan is not helpful because even large tumors with a diameter of several centimeters can be falsely negative if the . respectively [35-39]. In contrast. Furthermore. 2.4. ascites. EUS is not recommended for pretreatment evaluation of gastric cancer in the guidelines from the National Comprehensive Cancer Network (NCCN) [52]. CT is widely available and noninvasive. integrated PET/CT imaging can be useful to confirm malignant involvement of CT-detected lymphadenopathy [53].

They revealed that submucosally invasive gastric cancer (similar to mucosal cancers) and tumor size larger than 3 cm with lymphatic or vessel involvement are significantly correlated with an . NCCN guidelines for preoperative evaluation of gastric cancer suggest integrated PET/CT [52]. Gotoda and colleagues [17] were able to define the risk of LN metastasis.5. Most experience has therefore been gained with blue dye.1. PET is not an adequate replacement for staging laparoscopy. the accuracy was about 80% [66-68]. and the histological type. On the other hand. Many authors from Asia reported an accuracy of more than 98% [62-64]. 3 2144 tumor cells have fairly low metabolic activity. as in the other countries. most diffuse-type gastric cancers (signet ring carcinomas) are not FDG avid [54-58]. In Japan. with the false negative SLN rate ranging from 15% to 20% [66-68]. The choice of operative method for gastric cancer depends upon the location of the tumor in the stomach. endoscopic submucosal dissection (ESD) is indicated for a differentiated mucosal cancer smaller than 2 cm in diameter [75] because risk for LN metastasis is negligible [17]. the clinical stage. Thus. many issues are still to be resolved and further studies are recommended before this method can be introduced into daily practice. The results reported in the literature on SLN biopsy in gastric cancer are widely divergent. Furthermore. Regarding the utility of SLN navigation in an attempt to detect the nodal basin. gastrectomy with LN dissection is required in cases of possible node metastasis [72] because the presence of LN metastasis has a strong adverse influence on patient prognosis [73. in particular in early stages (T1-T2) [65].Cancers 2011. LN Dissection Complete surgical eradication of a gastric cancer with dissection of adjacent LNs represents the best chance for long-term survival. 3. Identification of the SLN by means of a radiolabeled colloid and perioperative detection with a gamma probe has the disadvantage of radioactive tracing not only from LNs but also from the adjacent injection site. The main reason for the poor accuracy could be the variability of the lymphatic routes in the gastric region. The main benefit of PET is that it is more sensitive than CT for the detection of distant metastases [42. 2. whereas other series from Western countries. resulting in a high rate of skip metastases. The major surgical considerations include the extent of luminal resection (total versus distal gastrectomy) and the extent of LN dissection. and is increasingly gaining acceptance as a therapy for EGC [70.74]. 3.71]. Sentinel Lymph Node (SLN) Biopsy The application of the SLN technique in gastric cancer began in the late 1990s. by using a large database involving more than 5000 patients who underwent gastrectomy with meticulous D2 level LN dissection. EGC Endoscopic resection is currently the standard treatment for EGC without the possibility of LN metastasis in Japan [69]. but blue dye flows through and travels to the next LNs in line. Intraoperative subserosal or preoperative endoscopic submucosal injections can be used for the administration of blue dye or radioactive tracer.58-60]. An important caveat is that the sensitivity of PET scanning for peritoneal carcinomatosis is only approximately 50% [61]. Recently.

3 2145 increased risk of LN metastasis. behind the pancreas. A consequence of more accurate staging is minimization of stage migration [84. When submucosal invasion of a tumor resected locally by ESD extends more than 300 mm. and along the aorta. The resulting improvement in stage-specific survival may explain. Further study of the optimal extent of LN dissection for early gastric cancer is expected. The draining LNs for the stomach can be divided into 16 stations: stations 1 to 6 are perigastric.  D3 dissection is a superextended LN dissection. suggested that optimal LN dissection levels are as follows: (1) local resection (D0) for lesions of <1 cm.2. left gastric. entailing removal of nodes along the hepatic. AGC 3. (2) limited LN dissection (D1) for 1. <30 mm was proposed by several reports [76. The extended indication including: (i) differentiated-type mucosal cancers without ulcerative findings. However. The term "extended lymphadenectomy" variably refers to either a D2 or D3 LN dissection. (iii) undifferentiated-type mucosal cancers without ulceration findings. and the remaining 10 are located adjacent to major vessels. Most Western surgeons (and the American Joint Committee on Cancer (AJCC)/International Union Against Cancer (UICC) TNM staging classification [81]) classify disease in these regions as distant metastases and do not routinely remove nodes in these areas during a potentially curative gastrectomy.1. and cancers penetrating deeply into the submucosal layer are most likely to be associated with LN metastasis.  D2 LN dissection is an extended LN dissection. additional gastrectomy and LN dissection are necessary [78].77].85]. patients with submucosal invasion are not necessary to undergo D2 lymph node dissection in the Japanese guideline. a practice that some suggest at least partially accounts for the better survival rates seen in Asia. celiac. the better results seen in Asian patients. whereas others use the term to denote a D2 LN dissection plus periaortic nodal dissection (PAND) alone [3]. regardless of tumour size. The term has been used by some to describe a D2 lymphadenectomy plus the removal of nodes within the porta hepatis and periaortic regions (stations 1-16). From analysis of data from 118 patients with submucosal invasion. Japanese surgeons routinely perform extended LN dissection. D3 was equivalent to D2+ which was described in the latest Japanese guideline in 2010 [80]. and splenic arteries as well as those in the splenic hilum (stations 1-11). <20 mm. which would adversely affect survival [82-84]. as compared to Western series [79].2. (ii) differentiated-type mucosal cancers with ulceration findings. In present article. Yasuda et al. and (iv) differentiated-type minute submucosal cancers (SM1) without ulceration findings. 3. The arguments in favor of extended lymphadenectomy (D2 or D3 versus D1) are that removing a larger number of nodes more accurately stages disease extent and that failure to remove these nodes leaves behind disease in as many as one-third of patients.Cancers 2011. <30 mm. Standard LN Dissection for AGC One of the most controversial areas in the surgical management of gastric cancer is the optimal extent of LN dissection. . in part.to 4-cm lesions. and (3) extended LN dissection (D2) for lesions >4 cm in diameter.  D1 l LN dissection refers to a limited dissection of only the perigastric lymph nodes.

. high incidence of insufficient nodal dissection (noncompliance). many Asian surgeons consider that both the Dutch and the MRC trials are flawed. This trial relied heavily upon input from a Japanese surgeon. Epidemiology and End Results (SEER) database between 1973 and 2000) [86]. 3 2146 The influence of total LN count on stage-specific survival was studied in a series of 3814 patients undergoing gastrectomy for T1-3 N0-1 (classified according to the 1997 AJCC gastric cancer staging system and reported to the Surveillance. Excess morbidity and mortality were clearly associated with the use of splenectomy and distal pancreatectomy to achieve complete node dissection.97].3. 5-year survival rates were no better for patients undergoing D2 compared to D1 dissection (33% versus 35%) [96]. T3N0. Moreover. Dutch trial: The largest randomized trial came from the Dutch Gastric Cancer Group and compared D1 with D2 LN dissection in 711 patients who were treated with curative intent [92. For every stage subgroup (T1/2N0. either in the initial report [92] or with longer follow-up [97. T3N1). Although cut-off point analysis revealed the greatest survival difference when 10 lymph nodes were examined. both postoperative morbidity (43% versus 25%) and mortality (10% versus 4%) were higher in the D2 group. as was operative mortality (13 versus 6%). Despite these efforts to maintain quality control of the surgical procedures. However. This was attributed to the detrimental impact of increased operative mortality in this group. multiple prospective randomized trials both in Asian and Western populations have failed to show a survival benefit with D2 versus D1 lymphadenectomy [90-92] or with D3 compared to D2 LN dissection [3. survival was significantly better as more nodes were examined. As was shown in the MRC trial. The findings of the three largest trials are as follows. who trained the Dutch surgeons in the technique of radical LN dissection and monitored the operative procedures. despite a significantly lower risk of recurrence. 3.93-95]. There are two main arguments against the routine use of extended LN dissection: the higher associated morbidity and mortality (particularly if splenectomy is performed to achieve extended LN dissection) and the lack of survival benefit for extended LN dissection in most large randomized trials. a statistically significant survival advantage in the radical dissection group was not observed. somewhat blurring the distinction between the groups. T1/2N1.Cancers 2011.1. Randomized Trials and Meta-analyses Although many retrospective studies and only one randomized controlled trial (RCT) by a single institution in Taiwan suggest that extended LN dissection improves survival [87-89].3. both underremoval and overremoval of required nodal stations occurred. The conclusion of the Dutch trial was that D2 LN dissection could not be routinely recommended. 3. unacceptably small hospital volume. These studies are heavily criticized for poor quality control of the surgery and the postoperative care.98]. Postoperative morbidity was significantly greater in the D2 group (46% versus 28%). D1 Versus D2 Dissection Medical Research Council (MRC) trial: The MRC trial randomly assigned 400 patients undergoing potentially curative resection to either a D1 or a D2 LN dissection [91]. always in favor of a greater number of nodes in the specimen. In a later follow-up. there were significant survival differences for cut-off points of up to 40 nodes examined.

pneumonia). a RCT comparing D1 versus D2 (including D3 in the first edition of the Japanese Classification of Gastric Carcinoma) showed for the first time superiority of D2 over D1 dissection in clinical trials [100]. In 2010 the 15-year follow up of the Dutch trial [101] was reported that D2 lymphadenectomy is associated with lower locoregional recurrence and gastric-cancer-related death rates than D1 surgery.2. The reasons for these counterintuitive results are unclear. the Chilean trial [104] and the Korean trial [105]. Para-aortic Lymph Node Dissection Japan Clinical Oncology Group (JCOG) trial 9501: The multicenter JCOG study 9501 randomly assigned 523 patients to D2 versus D3 (D2 + PAND) dissection. suggest that a D2 dissection can be performed safely with a perioperative mortality rate that is under 2%. These data underscore the marked differences in outcome between gastric cancers arising in Western and Asian populations. Five-year overall survival was 60% and 54% in the D2 and D1 groups. However.3.3. Further studies to clarify the survival benefit of extended LN dissection are necessary.9%). with their experience. The number of patients treated in an institute each year. although there were no differences in major complications (anastomotic leak. morbidity. abdominal abscess. showed clear negative correlation with hospital mortality. thus requiring the knowledge and experience of managing the associated complications [99]. A meta-analysis of the JCOG trial and two other smaller randomized trials of D2 versus D3 (with PAND) dissection [94. Thus. pancreatic fistula. 3. Thus. these issues are disputable. In the case of total gastrectomy. a certain incidence of morbidity is expected with this surgery.041). D2 dissection can be carried out with quite low hospital mortality (0%) and provides better survival than does D1 dissection.3. 3 2147 and adoption of the more aggressive option of D2 dissection by routine use of pancreaticosplenectomy. generalizability remains uncertain. Five-year recurrence-free survival rate (approximately 63% in both groups) and overall survival rate (70% versus 69%) were no better after extended LN dissection [3]. Nevertheless. One of the confounding issues with the JCOG trial is that in subgroup analysis.102]. termed hospital volume. respectively (P = 0. and reoperation rates. and perioperative mortality was very low (0.95] concluded that resection of the paraaortic nodes was inferior to a D2 dissection in terms of safety and was without any survival benefit [103]. Splenectomy for Dissection of LNs at the Splenic Hiatus There were two RCTs related to splenectomy for gastric cancer. The overall perioperative complication rate in the D3 group was significantly higher than that in the D2 group (28. This study is a single institutional study with three participating surgeons. thus.8%) in both groups [93]. despite the fact that D2 lymphandectomy was also associated with significantly higher postoperative mortality. patients who were node-positive fared significantly better with a D2 LN dissection than with more aggressive surgery. especially in low-volume hospitals.1% versus 20. paraaortic lymphadenectomy cannot be considered a routine practice for surgical treatment of gastric cancer.Cancers 2011. Both demonstrated no significant differences in postoperative mortality and 5-year . In 2006. patients with node-negative disease fared significantly better with the more aggressive operation than with D2 LN dissection. Conversely. the high survival rate in both groups is notable in view of the fact that over 60% of both groups had positive nodes. 3. Data from the JCOG trial. as well as those from other groups [93.

CA. However. France). 1% to 9%. In addition to the presence of LN micrometastasis. the significance of the N ratio has not been evaluated in patients with <15 examined LNs. and the results of this study are awaited.85. Marseilles. 4. There are specificities of several different antibodies. Therefore. postoperative morbidity. Xu et al. Some authors have pointed out the superiority of UICC/AJCC classification on the grounds of simplicity. a RCT to evaluate splenectomy for upper-third AGC is ongoing [106]. N ratio 1. Now. This trial includes the evaluation of long-term survival. the Japanese guideline has adopted the N categories based on numbers [80]. and stratification. This new classification reflects the degree of LN metastasis and reduces stage migration [84. the UICC/AJCC classification is used most widely for the staging of gastric cancer [107-109]. the Japanese Research Society for Gastric Carcinoma first proposed a classification based on the anatomical location of positive nodes. The Chilean trial. evaluated the prognostic value of the N ratio staging system compared with the N stage classification when <15 LNs were examined in gastric cancer patients.2. San Jose. Yasuda et al. the number and level of micrometastases in the LNs were strongly associated with the survival time of .108]. A new prognostic tool. showed higher postoperative morbidity. and the Korean trial showed significant differences in the incidence of operative complications. Micro-LN Metastasis Micrometastasis was defined as the presence of tumor cells—single or in small clusters—detected only by cytokeratin specific immunostaining that could not be detected by ordinary H and E staining.1. which was reviewed by the Japanese Gastric Cancer Association in 1998.Cancers 2011. such as stage migration [110-114]. reliability. Indianapolis. It can provide a more accurate estimation of prognosis than the classification based on anatomical lymphatic spread. N ration 2.115. In 1981. such AE1/AE3 (Boehringer Mannheim. 3 2148 survival. 0%. USA). demonstrated that LN micrometastasis is an independent prognostic indicator for patients with histologically node-negative gastric cancer invading the muscularis propria or deeper (T2 or T3) [4]. KL-1 (Immunotech. In 1997 and 2002. 4. The Role of LN Metastasis as a Prognostic Factor 4. and quality of life. N ration 3. IN. >25%. In 2010. these results did not support the use of prophylactic splenectomy to remove macroscopically negative LNs near the spleen in patients undergoing total gastrectomy for proximal gastric cancer. they have also mentioned some of the problems associated with it. the UICC and the AJCC proposed a new classification for N categories that was based on the number of metastatic LNs (N stage) [107. was proposed. They concluded that the positive N ratio is an independent prognostic factor. In Japan. Registration of about 500 patients has been completed.116]. Number and Location of LN Metastases The presence of LN metastasis (pN) is one of the most significant prognostic factors in patients with gastric cancer.2 (Becton Dickinson. N ratio categories were identified as follows: N ration 0. However the classification of LN metastasis in patients with gastric carcinoma is controversial. regardless of the number of LNs examined [117]. 10% to 25%. and CAM5. however. for the ratio between metastatic LNs and the total number of LNs examined (N ratio). USA). mortality.

reported that LN micrometastasis correlated with a significantly worse survival rate in patients with T1 or T2 tumors [8]. VEGF-C and VEGF-D are ligands for VEGFR-3 (Flt-4). According to the UICC. comprising cancer cells in soft tissue discontinuous with the primary lesion. is found during routine examination of about 10–28% of resected gastric carcinoma specimens [118]. on the basis of the status of extranodal spread. . Nakajo et al. but should otherwise be regarded as part of the primary tumor [107]. 4. this type of tumor spread should be regarded as LN metastasis if the nodule has the form and smooth contour of a LN. These results indicate that quantitative analysis of lymphangiogenic markers in gastric cancer may be useful in predicting metastasis of gastric cancer to regional LNs. Etoh et al. showed that the presence of LN micrometastasis did not affect survival in a large number of patients with T2 gastric cancer [6].Cancers 2011. have been identified [124-126]. It is controversial whether LN micrometastasis detected by immunohistochemistry predicts the clinical outcome of patients with histologically node-negative gastric cancer [5-9]. Molecular Biological Findings of LN Metastasis Although the phenomenon of lymphatic spread of tumor has been well recognized for over a century. However. Fukagawa et al. also found a significant relation between LN micrometastasis and poor prognosis in patients with T3 gastric cancer [9]. Some studies have. These reports support the notion that extranodal metastasis should be included in the clinical classification of gastric cancer. 3 2149 patients. Lymphangiogenesis.122]. Moreover. Cai et al. Although there is a large amount of data regarding angiogenesis. the growth of new lymphatic vessels. 5. was important [120]. this parameter may be helpful for deciding treatment strategies for adjuvant chemotherapy. and the correlation between lymphatic vessel density and metastasis to LNs is controversial. Extra-LN Metastasis Extranodal metastasis. suggested that such tumor extension represents peritoneal seeding from either the primary tumor or metastatic LNs. Nevertheless.3. A number of lymphatic-specific proteins. the mechanisms by which cancer cells enter into and proliferate within the lymphatic system remain unclear [121. and prox-1. a tyrosine kinase receptor that is expressed predominantly in lymphatic endothelial cells [127]. although immunohistochemical detection of micrometastasis has not spread worldwide because of the complexity of the immunohistochemical technique used in Japan. is believed to underlie LN metastasis [123]. described that classification of patients into a capsule rupture group or no capsule rupture group. Recent reports have shown that overexpression of VEGF-C or VEGF-D induces tumor lymphangiogenesis and promotes lymphatic metastasis in mouse tumor models [128-130]. Several studies have shown that expression of VEGF-C and VEGF-D by tumor cells correlates well with LN metastasis of gastric carcinoma [10-12]. Nakamura et al. however. reported that extranodal metastasis was closely related to a poor prognosis [119]. there are few reports on lymphangiogenesis. LYVE-1. such as podoplanin.

Saragoni.. Aikou.. Mann. Kitano. 275-280. T. A. basic research to clarify molecular biological mechanism of LN metastasis is necessary to obtain more favorable survival in patients with gastric cancer. Yamamoto. Morgagni. Kikuchi. Takenosita. Detection and prediction of micrometastasis in the lymph nodes of patients with pN0 gastric cancer. A. M.. K.. Yoshida.. Maruyama. 2006. Cancer 2001. Kurita. R. K... Clinicopathological value of immunohistochemical detection of occult involvement in pT3N0 gastric cancer. Baba. 2006. S. J. 158-162. Pedrazzani. C. To improve locoregional control of gastric cancer. 6. T. M.. Adachi. Y.. T. 2. Ann. 83. 1996. Forman... 2. Rossi.. Kurokawa. K. Nakajo. Kinoshita. Oncol. Roder. Y. 3. J. S.. Surg.. S. Conclusions There is no doubt that gastrectomy with regional LN dissection is the most useful modality for the treatment of AGC. Shimoda.. M. 7. Nashimoto.. H. P.Cancers 2011. Natsugoe. G.. Fellbaum. J. Fukagawa. Number of LN metastases and its prognostic significance in early gastric cancer: A multicenter Italian study. 94. 2001.. Additionally.... Benefits of D2 LN dissection for patients with gastric cancer and pN0 and pN1 LN metastases. Hiratsuka.. Siewert. 8. Hofler. Busch. Roviello.. K. H.. S.. 771-774. de Mansoni. Hokita. Matsumoto. D.. Sano. several studies have shown that more extended resection than D2 surgery has no impact on survival.. D.. 5.. Immunohistochemically detected micrometastases of the lymph nodes in patients with gastric carcinoma. Y. Surg.. 4. Sasako. 9. Tsuchiya. A. J. 2002. Shiraishi.. T.. K. gastrectomy with D2 lymphadenectomy is the gold standard of treatment for this cancer. Arai. C. Tomezzoli. Best Pract.. M. Med.. Prognostic effect of LN micrometastasis in patients with histologically node-negative gastric cancer. N.. 95-100. Clin. Res.. However. Yasuda. G.. Y. M.. Oncol. Ikeguchi. N. M. Gastric cancer: Global pattern of the disease and an overview of environmental risk factors. Sano. Gastroenterol. S. V. S. M. R. Ann. B. M. 2.. D. S.. J. C. 173-178. Surg. A.. Gastric Cancer 1999. discussion 274. G.. Cai.. Corso. L. 359. 2008. .. Marrelli. Immunohistochemical detection of LN microinvolvement in node-negative gastric cancer. R. Takao. Br. 3 2150 6. Sakatani.. T. Okajima. Gastric Cancer 1999. 9.J. H. 453-462. Ishigami.. J. 633-649. Yamamura... 20. 1144-1147. F.. N. D2 lymphadenectomy alone or with para-aortic nodal dissection for gastric cancer. T. Maeta. Katai. 8. the development of modalities for accurate preoperative determination of the status of LN metastasis and the establishment of multimodal treatment involving chemotherapy or radiotherapy in addition to surgery is expected. Sasako. T. S. J.. In Japan and Korea. Burley. Takeuchi. References 1. Surg. S. 753-760.. Y. Nakashima. Inomata. Muller. Bottcher. 92. Y.. Vindigni. Engl.. T. Ando.. Oncol. Nakanishi. Tsujinaka. A. T. Kestlmeier. Kaibara.

11. 388-392. 47. Seto Y... K. 1318-1321. E. 13. K.. H. Fujita. Preoperative diagnosis and surgical treatment for LN metastasis in gastric cancer (in Japanese). K. Morisaki. 618-621. Br.. Miwa. L. Oyama. Sasaki. Kurita. Cancer 1999... 21. Okabayashi. S. Tanaka. K. Murakami. Y. Endo. M. 23. 16.. 21. 15. Tanaka. I. Komizo.. R. 412-415. K.. long term. N. Izumi.. 1500-1505. M. Sasako. Quantitative analysis of lymphangiogenic markers for predicting metastasis of human gastric carcinoma to lymph nodes. Saragoni.. .. Yonemura. D. 3 10. Surg. J. T. Y. T.. T. J. E. Nanni.. Cancer Res. 1275-1283. H. Matsumura. 11. Gastric Cancer 2000.. K. Nishi... Tanaka. Pathomorphological diagnosis. Gut 2000. Amioka. K. Ogawa. Muto T.... 38. Nomura. Kimura. Bandou... Fujii. J. Kobori O. S. J. K..S. Nakajima. 20.. Fushida. Br. A. W. Natural history of early gastric cancer: A non-concurrent. S. J. 82. Chayama. Reasonable LN dissection in radical gastrectomy for gastric cancer: Introduction of computer information system and lymphography technique by India-ink. Nakanishi. Eur. A. 1413-1419. discussion 190. Nishina... World J. Y Incidence of LN metastasis from early gastric cancer: Estimation with a large number of cases at two large centers.. 85. Dell'Amore. Nasu. K.. 1751-1755.H. T. Clin. Ota. Role of vascular endothelial growth factor C expression in the development of LN metastasis in gastric cancer. Y. 2151 Kitadai. Kitade.. Nakamura. 2007.. Gan To Kagaku Ryoho 1996. J. M. M. K.. 22. Morii. S. Surg.. Hyodo. Gann. A. Yasui. Early gastric cancer: Prognostic factors in 223 patients. Ninomiya. Vio... S. Uchiyama.. T. Indication for the lymph node dissection of gastric cancer based on the pattern analysis small of lymphatic spread (in Japanese). Ochiumi. 115. Surg. M. Cancer Res. 1992. 21.. I. Dente. 1971.. H. Nippon Geka Gakkai Zasshi 1989...H. 40. 24... Ohoyama. T.. Oshima. T. follow up study. Sasako. 12.. Yanagisawa. 53. Sako... Tsukuma. Kitadai. Kuroda.. H. Predictive factors for LN metastasis in early gastric cancer with submucosal invasion: Analysis of a single institutional experience. An early gastric carcinoma treatment strategy based on analysis of LN metastasis. Okajima. A. Noh. Y. S... S. 219-225. Cho. Kodama.. T. Ishihara.Cancers 2011. J.. Impact of LN metastasis on survival with early gastric cancer. Maruyama. S.. A. Sohn. N. 246. Surg. Y.. LN metastasis from early gastric cancer: Endoscopic resection of tumour.. 3. Nagawa H. S.. T. 1997. Int. 749-753.. T. 18. A. Kinukawa. Cancer 2002. 1823-1829. Sugitani. Kim. T. 186-189... 241-244.. W. Gan to Kagaku Ryoho 1994. Sano T. Yoshihara. H.. 79. Yasui. M. K. Choi.. 1999. S. Y. Vascular endothelial growth factor-C expression predicts LN metastasis of human gastric carcinomas invading the submucosa. Definition and gross classification of early gastric cancer. Y. Folli. O.. T. Baik. 14... Moriwaki. Gotoda.. Sugiyama. Nishimura. 1995. T. Chayama. Ohyama. M. 5. M. Hirasaki.. Monogr. 17. 2006. 90. Ann. An. Gaudio. Narahara. S.. Cancer 2005. T. T. S.. Muto T.. Haruma. Taniguchi. Ono. 23. 19.. Kato.Y. Kinoshita. J.G. K. Gastroenterol. M. Isozaki. 952-956.. T. Shimoda.. Predictive factors of LN metastasis in patients with undifferentiated early gastric cancers. T. Clin.. S.

J.. 513-529. 34... Johnston. Lee.. Kuntz. 66... Wakelin.. K. Feussner. Hansmann..... C. 1997...M. 31. Deans.K.I..R. A. P.M. Itai. Coit... Sohn.J. Liu. Saeed. M.G. C. 37. I. Herfarth. D'Elia. Chen. Shin.J. P. J. Yan. Lee. S... Lehnert. Brennan. 35.D. A prospective study of 107 cases. G. 805-814. 173-178. D. Lee. Comparing MR imaging and CT in the staging of gastric carcinoma.. 1877-1885. 119. Siewert. 2152 Lowy.. 2002. K.L. Endoscopic ultrasound can improve the selection for laparoscopy in patients with localized gastric cancer. A. P.M. 208. Axel. et al. Lee.Cancers 2011. Park....G. Hydro-CT in patients with gastric cancer: Preoperative radiologic staging. Buhl.. M. J.... Gut 1997. L. 255. I. Y. Kauffmann. Illescas. A. Schattner. 26..A. 30...J. P.. J. A. 2000. Leach.. Am. . F.. Ahn.. 1551-1557 Kienle. M.H. T. M... Gerdes. C.P. 167. S. endosonography and computed tomography for staging of tumours of the oesophagus and gastric cardia. C. 29. Eur. M. Coll.G. P. G.I.. Grani. Chalmers.M. 2004.Y. 36.F. 10. Lee. Radiol.. D. S. 27. A. Broglia.H. C. Graziano.W. Comput. Abdalla. Zingarelli. Ajani. Walker.. Eur.N.H. J. 100. Sasaki.. J. Halvorsen. H. J. 31. R. F.... 38. 659-664. Digestion 2002. Pretherapeutic laparoscopic staging in advanced gastric carcinoma.... Fink. E. 41. Markowitz. S. Zhang. S. Radiol. 174. 161-167. P. Assist. M. 2009. Rossi.C. L. Mingazzini... Gastric tumors: Radiologic-pathologic correlation and accuracy of T staging with dynamic CT. Y. Crofts.M..L.. Sue-Ling.M. B.. Chen... Sussman.V. Meyers. J. Spiral computed tomography and operative staging of gastric carcinoma: A comparison with histopathological staging.. Radiology 1988. H. Martin. 41. S. Niki. A comparison of computerised tomography. 230-236. Yin. J. Radiology 1992.Y. laparoscopic ultrasound and endoscopic ultrasound in the preoperative staging of oesophago-gastric carcinoma. Richter. Choi. Eur. Omote.G.K.W. Surg. 205-214.. S. S.M. Semin. T. Value of multidetector-row computed tomography in the preoperative T and N staging of gastric carcinoma: A large-scale Chinese study... 335-340. 314-319. 39. 2009. B. D. Zhu. P. Oncol.. B. B. 913-922.. Rossi.Y. Kawauchi. 31..... M. Dux. 28. C. S.K.F.. Kim. Plevris. J.. J. B. 1999..M. Laparoscopic staging for gastric cancer. Staging and preoperative evaluation of upper gastrointestinal malignancies. Roentgenol. Oncol. D. Pan. M. R. Z.J.. 23. 3 25. Minami. F.. Hydro-dynamic CT preoperative staging of gastric cancer: Correlation with pathological findings.. Prospective comparison of endoscopy. Tomogr. Brenner. C. J. P. 611-614. J. H.. Bezzi. W. M. K. 173-178. Radiol.. Cohan. Maccioni. Kelsen.. Pisters. G.R.M. K. M. Radiology 2010. H.A. D. Paterson-Brown. M. Endoscopy 1999. Allan. N. T. J... Hartmann. W.M.A.. Surgery 1996. M.. Davies. J. 32.G. M. 185. 33.. Thompson. Gastric adenocarcinoma: CT versus surgical staging.. Han.. Yan. Shah.. Laghi. Power. Kuntz. Miller. Xiang.. Mansfield. Jr. Capanu. Dux. J. Silverman.M. Palli. U. Kim. 2000. Diagnostic performance of 64-channel multidetector CT in the evaluation of gastric cancer: Differentiation of mucosal cancer (T1a) from submucosal involvement (T1b and T2). J. 7.. Kim. M. H. AJR Am. Surg. 342-347.Y. Helical hydro-CT for diagnosis and staging of gastric carcinoma. Z. May..

H.. 48. Tsendsuren. 595-598. T. G.D. A. Di Leo. Classen. 951-954. multidetector row CT (virtual gastroscopy and multiplanar reconstruction) in the evaluation of gastric cancer: A comparison with conventional endoscopy. 40.J. Pedrazzani. National Comprehensive Cancer Network (NCCN) guidelines. Noh. Bormans. 59. Truong.. J. T. Lee. Kaneko.. Nucl. P. Cullingworth. L.D. Finn RD. Yun. Roderick. Mol. Oncol. H. 41. Preliminary Experience. Gribnitz.J. Radiology 1991. Surg.. 1994. Schusdziarra.. Whole-body PET with FDG for the diagnosis of recurrent gastric cancer. Gut 2002. 705-711. A. 44.S. Honda. Karpeh M... Shim. Tateshi.. 54. 181. J..M. Chang.. 336-346. 29. de Manzoni.F.E. Tsuneyoshi. 25. 694-699. M.. B. W.. S. Berry. Jr....... A systematic review of the staging performance of endoscopic ultrasound in gastro-oesophageal carcinoma.. Tasselli.. Lee.. Endoscopic ultrasound-guided fine-needle aspiration. 1. 50... 1996. H.. Flamen. Kwee. J. Siewert. Larson SM. 2000. Eur.. 50.. Hofler. A. P. C. 25. M. Lin.. EUS. Med. Bonfiglio. 2153 Willis.. Botet.. A. Yeung HW. Imaging in local staging of gastric cancer: A systematic review. C. Erickson. Macapinlac H. J. Eur. C. Maes. S. Kelly. Endosc. G. T. K. T.. I. J. 1999...S.. Cho. Cheong. 2005.. F. T. Hutton.. Sivak.M.S. Pollack. Jung. 49.J. 534-539.. P. F. A. M. 52.. 3 40. B. A. You get what you expect? A critical appraisal of imaging methodology in endosonographic cancer staging.. Veraldi. Lorenz. Butler. C. J. J.. Katz. Van Cutsem. V. S. Lymph-node metastases: Efficacy for detection with helical CT in patients with gastric cancer. Bhandari. G. J.. Brennan. Nucl.. 213-221.B. E. J.G. J. Mortelmans.. 2107-2116. Bong. Zauber. Fass. S.A.K. J. M. Radiology 1995. M. J. 1582-1588. 43.A. 197. and histopathology. Penninckx. S. 46. Gathercole. Usefulness of three-dimensional. Kim. Positron Imaging 1998.. Smith. M. Fukuya. Lee. Accuracy of FDG-PET in Gastric Cancer.V. Endoscopic ultrasonography in the preoperative staging of gastric cancer: Accuracy and impact on surgical therapy. 599-603. .. 53. R. K...S. J. Wuerker.H.F. J.M.. 2007. R.. Urmacher. S. Masuda.S. C. V. M.Cancers 2011.. J.. Preoperative staging of gastric cancer: Comparison of endoscopic US and dynamic CT. Dittler.. J. E.. Tedesco.. 47. Gastrointest Endosc...H. Semin Oncol. T. Imaging 2002. M.. K. Cordiano.. 619-626. J. Wolf.J. X. Lightdale. 12.J. 2004. Gastrointest Endosc.H.. 42. 23. Clin.. S. K.. De Potter. LN staging of gastric cancer using (18)F-FDG PET: A comparison study with CT.. Kwee. 14.org/ (accessed on 13 December 2010). Kim. Med. Hyung... Gerdes. Oncol. Surg. Clin. Ro. S.A. R. F. J. 2006. Rosch. Harris. 426-432.. Jun. Meining. Endoscopic ultrasonography.H.C. H. L. Cho. Winawer. 51. Available online: http://www. Lim. T. World J. Filez. Experience of endoscopic ultrasound in staging adenocarcinoma of the cardia. Usefulness of endoscopic ultrasonography in preoperative TNM staging of gastric cancer. Y.. M. 525-529. R.. Maehara. Schumpelick. Gastroenterol.. 45. Y. Tanaka... Hayashi. Gut 2001. 43-47.. T. L. S.. 46.. Chak.Y.. 49. Durbin. K.nccn. R. Mian.. A.S.

.P.. 70.. H. M. Miwa. Isozaki.. 690-699.J. 58. Sentinel node mapping during laparoscopic distal gastrectomy for gastric cancer.S... T. Levine. K. J.. Axon..S. Kinkel. A. 288-295.J.K... F. Evaluation of 18F-FDG PET in patients with advanced. J. McAteer. J. A. S. A. Kitajima... Radiol. T.. Kim.. 2009.... Kang.. 8... 2004. H. Med. R. Noh. Bae. L. Okajima. Fukuda. 56. Lee. Choi. M.. Park.M.H. Imaging 2006. 709-718. Med.H. M... 62. M. Opin. Z.. 63. Ott. Br. Couper. Becker. 2003. Natsugoe. Med. Lee. T. Stewart. Fink. 33. Lu. S. 22. S. Aikou. 2154 Stahl. Rembacken. K. G. G.T. Y. Saginoya. M. 561-569. Kubota. P. Endoscopic resection of early gastric cancer: The Japanese perspective. Morimoto. Radio-guided sentinel node detection for gastric cancer. F... Roh. E. K. Weber.. Nonomura. Yamaguchi. 710-714. Kim.J. Gotoda. Evaluation of 18F-FDG positron emission tomography in gastric and oesophageal carcinoma. K. J. 525-529. Warren. P. Surg. Nishiyama.. Halevy. 69. Siewert. K. Gastroenterol. T. T. S. M. R. M.. 65. Ido. Curr.H. Detection of hepatic metastases from cancers of the gastrointestinal tract by using noninvasive imaging methods (US. E.J. Endoscopy 2001. Jung.. S. 60. B.. Masci. Y. Assessment of LN metastases using 18F-FDG PET in patients with advanced gastric cancer. 90. Nicolson. R. Mol.. Surg. R. 2383-2390.R. I.... Bruce.. C.W. S.Cancers 2011. Shen. 40-43. V. 9. J.. H. J. Gastric Cancer 2006. Link. K.F. J. 75. T. J.. Surg. U. Yun. J. T. H. 178-182. 1999. A. 22.. Cancer 2005. Gold-Deutch.R. Hokita. Mukai. J... Kang.. M. Thoeni... J. S. Taniguchi. Mapping sentinel nodes in patients with early-stage gastric carcinoma. 604-608.. Usefulness of preoperative FDG-PET for detection of gastric cancer.. J.. Fushida..K. K. D. T. J. Yamaura. Wassermann. Nucl. 2008. Kim. W.H. Tomajer. A. Kubota. 2006. Mukai. 239. Surg. Becher. 2002. G. Med. metastatic. Wallis.. Br. Doglioni. Chikman. 33. or recurrent gastric cancer. Ishida. Viale. 67. R. Am. Y. Yoshioka.. T. J. C.. 30. Albarello.. Kanamaru. Lim. Schwaiger. 89. PET): A meta-analysis.. M. Eur. Endosc.. CT. Ehi. Arigami. Mol. R. Eur. Kim. L. Y. T.. Di Palo. Chang..S. Choi. 59. Y. J. Kim..C. Cheong.S. 748-756. 2003.... McCarthy. FDG PET imaging of locally advanced gastric carcinomas: Correlation with endoscopic and histopathological findings. D.. Lavy... Fujimura. Radiology 2002.. J.. 68. Norton. 192-196. K. Takahashi. Imaging 2003.A. Br.H. 66. R. Rabin. 44. Uenosono. Sentinel lymph node mapping for gastric adenocarcinoma. Gilbert.S..... Endoscopic mucosal resection. Surg.. H. Improvement in preoperative staging of gastric adenocarcinoma with positron emission tomography. Halpern.H.. J. Staudacher... Fujii. Gotoda. Welch.. 886-889.. E. 92. Orsenigo. K. J. K. H.. 2005. 118-121. Both.. Jeong. Isr.. K. H. A. B. T. K.Y. Lymphatic mapping and sentinel node biopsy using 99mTc tin colloid in gastric cancer.. K. Detection of sentinel nodes and micrometastases using radioisotope navigation and immunohistochemistry in patients with gastric cancer.D. Ann. K... 61... 224.. S.. Kim. 64. S. Chen. 2006.Y.. Sandbank. E. D. Surg. 3 55. 57. Y. Fujii. Ryu. Kitagawa. T. Assoc.. J. 103.. Nucl. 383-387. J. Br..J.J. .. 148-155. J. Nucl.. MR imaging. Kinami. Otani. W. Hyung. Lee.W.. T. Sentinel node mapping for gastric cancer. 72.W. Sharp.. Geisinger. I. Yamazaki.

Clin.C. T. 2003. H.R. Targeting the optimal extent of LN dissection for gastric cancer. Surgical/pathologic-stage migration confounds comparisons of gastric cancer survival rates between Japan and Western countries. 82. F.. K. 74. T. T. Pasini. 81. 59-62. Cancer 1999. Miyata.. 1991.. 2119-2123.. Fleuren. 19-25. S. M. NY. Nakanishi. Yoshida. D.. S. Follow-up of 1475 patients and review of the Japanese literature. Br. Byrd. Cancer 1993. Kitano. Y.. p. Soehendra. K. Takeuchi. Rate of detection of LN metastasis is correlated with the depth of submucosal invasion in early stage gastric carcinoma. Oohata. 89. Cancer Staging Manual. 83. 73. Surg. Ruschoff.. 2010. Sano. Bunt. V.. R. Japanese Gastric Cancer Association. Y. 77. Oncol. T. D. Endoscopic mucosal resection.Cancers 2011. Recurrence of early gastric cancer.M. Kurihara. F. 2237-2246. D. Nagata. Oncol. T. de Manzoni. Surg. Gut 2001. Gastrointest Endosc.. K.... 7114-7124. 1995. 2053-2062. USA. S. J. Gastric Cancer 2000. T. Nakayama. 57. Y. Shirao.. Yamaguchi. Fujisaki. Noguchi. Smith. Japan. Edge. 2002. van de Velde.. Nakamura. Schmitz-Moormann.. 80.. 2010. M. 825-827.. Radical surgery for gastric cancer. J. 158. Rothmund.... Y. discussion 62... Endoscopic mucosal resection for treatment of early gastric cancer.... 79.T. Shimoda. T.. A.. D. T. Brennan. 76. A. 1099-1106. A. Saito.. Imada. Karpeh.. Complete ten-year postgastrectomy follow-up of early gastric cancer. Motohashi. Smit.D. S.. Tsuburaya. J.E. J. 72. M.. Roukos DH. M.. H. Y... Gastric Cancer Treatment Guidelines 2010. R. M. 3174-3178. D. N. Maruyama. The new TNM classification of LN metastasis minimises stage migration problems in gastric cancer patients. J... G. 48. Schwarz. Yanagisawa... K. R. T.. 567-579... Mibu... Shimoda. 117. Springer: New York.. 14-16.. H.A. Is gastric carcinoma different between Japan and the United States? Cancer 2000. L. 85. Gotoda. R. Matsumoto. 3 71. Kato. Marrelli..G. 64. Bruijn.. Cancer 2002. H.. 7th edition. H. 81. F. Impact of total LN count on staging and survival after gastrectomy for gastric cancer: Data from a large US-population database. 23. Y. Surg.. 219-225.. LN counts in the upper abdomen: Anatomical basis for lymphadenectomy in gastric cancer. Nakanishi. Noguchi. Kato. Y.. Y. Sasako. 86. H.J. Ono. A.. Hermans. Ramaswamy. M.. G. Taniguchi.. 84. Sano. Noguchi. Roviello. Verlato.. Adachi. Kajitani. J. Yasuda. Wagner. Takagi. Kanehara-shuppan: Tokyo. Hosokawa. 78. Shimoda. T. Kinoshita. J. A review of the Japanese experience.. K. 13. 78. . Inomata. Gotoda. Cancer 1989.. 12. C. T. Ohta.. Di Leo. 2005. Oncol. 85. Kondo. 2155 Soetikno. Coit. H. K. P. Compton. P. N.. Morgagni. Cancer 1987...F. Gotoda..R.. Gotoda. 87. M. 60. Clin. A. S. J. Kappas AM.. Eds. H. T. T. J. 148-152. Am. Br. H. Schwarz. T.M.. M. 87. Yamaguchi. 3.. 75. Hirasawa. T. Yoshikawa. Incidence of lymph node metastasis and the feasibility of endoscopic resection for undifferentiated-type early gastric cancer. Brennan.. P. Sasako.. G.. Y. 1989.. Itoh.. 225-229. Nishi. Saragoni.. Shiraishi. Early gastric carcinoma with special reference to macroscopic classification. Gastric Cancer 2009. 171-174. Y. T. C.. Incidence of lymph node metastasis from early gastric cancer: Estimation with a large number of cases at two large centers. F. J.B. Ono.K.J. A.. 72.. Kato. AJCC (American Joint Committee on Cancer). H.

W.. Plukker... T. 2008. T... Kolodziejczyk. T.. Lui.Cancers 2011. Katai..J. M. T. Cuschieri. V. Kurita. et al. 995-999. 2069-2077.. 1522-1530. 98. Postoperative morbidity and mortality after D1 and D2 resections for gastric cancer: Preliminary results of the MRC randomised controlled surgical trial.. 2767-2773. Sasako... Clin.. Meyer.. Patient survival after D1 and D2 resections for gastric cancer: Long-term results of the MRC randomized surgical trial. Sasako. Madden. Clin. Joypaul..H.. I.. 1987. 193. I. Cook. K. C... J. Arai. Oncol. Craven. Okabayashi.. Int. J. Bandou. Nodal dissection for patients with gastric cancer: A randomized controlled trial.T. Am.. Br. V. Joypaul. Weeden.V. P. Popiela. Surg. 91.. Chen.. 110-112.W.... J. A. 2007. R. J. Br. J. N. Hermanek. 100. P. 22.. 1999. A... I.. 2007. Li. Putter.. J. et al. J. Bonenkamp.J.K. S.T. Price. 2004. J. M. 2004. van Krieken.F. S. J. P. 2089-2097. T. . Sano. J. E. Engl. T. J. Sano. Standard D2 versus extended D2 (D2+) lymphadenectomy for gastric cancer: An interim safety analysis of a multicenter. Cuschieri. Fielding. Kranenbarg. M. Yamamura.. K. T... 72. Hartgrink. J. Surg.D. 95. J.... K. The Surgical Cooperative Group. Results of the German Gastric Carcinoma Study 1992. M. 89. 11. S. J. 99. randomized. Hsieh.C.. Yonemura. P. Hsiung. World J. P. Sawa. Fukagawa. Songun. 97. Extended LN dissection for gastric cancer: Who may benefit? Final results of the randomized Dutch gastric cancer group trial... et al. Yamamoto. 908-914. M. C. Songun. Cancer 1993.. Sydes. Prognostic factors in gastric carcinoma. Matsuki. 309-315. Lo.. Sierzega. K. S. Lancet 1996.A. Nashimoto. M. Fayers.. H. Extended lymph-node dissection for gastric cancer.J. I.M. T.... N. Dig... 2006. Randomized comparison of R1 and R2 gastrectomy for gastric carcinoma. Wu. Surgical treatment of gastric cancer: 15-Year follow-up results of the randomised nationwide Dutch D1D2 trial. H. J.. Meijer.H.. 418-425. Honda. et al. D. Sasako. Klein Kranenbarg. Tsujinaka. Saka. C. Whang-Peng.J. 2010.M.. Med. A. H..S. Putter. 13.C. 11. 96. H. 75. J. E. Van Elk. Plukker. 1988.. Cancer 1999. Gastric cancer surgery: Morbidity and mortality results from a prospective randomized controlled trial comparing D2 and extended para-aortic lymphadenectomy--Japan Clinical Oncology Group study 9501. Oncol. Wu. van de Velde. Obertop. Surg... M.. N. 3 88. 22. J. Meyer. S. Kamata.. Clin.. A. Surgical treatment of advanced gastric cancer: Japanese perspective. C. 347. Dent. C. J.. M. 92.R. M.. 101–107..J.. T. Roder. Y.. 24. S.. K... M. Siewert. H. Fayers. 7. Kawamura. Busch. J. 93. Randomized clinical trial of D2 and extended paraaortic lymphadenectomy in patients with gastric cancer. Fielding. clinical trial. Kinoshita. Hermans... Progress in gastric cancer surgery in Japan and its limits of radicality.. J.. Bottcher. J. T. 132-137. Kulig. K. 439-449. C. Hiratsuka. van de Velde.Y. A. S.. Kinoshita. H. J..J.. J. 94. Lancet Oncol. Fukushima. Sasako. 340. Songun. Surg.. J.H.. 10-15.. 90. Szczepanik. B.. A. Welvaart. 79. 2156 Maruyama. Kim.. Bancewicz. Craven. P. Bonenkamp. Oncol. Lancet Oncol. Surgical Co-operative Group. van de Velde.. Welvaart. Y. E. Bancewicz.

. Chen. C. Aurello. C. 359-366. C. 108. G. A. H.H.. 3 2157 101 Songun. 113. Feinstein.J.. 64-71. L. et al. 2002. T. Bellagamba. 106. Ikeda. P.. M. 109. Z.H.J.. G. 439-449. N. USA. 105..S.. 73. Wang.. Swallow. Cancer 2001. J. 2143-2151. 301-304. Am. Surg. Ueshima. Wells. Br. 363-364.R.. The Will Rogers phenomenon.. M.. M. Burdiles. 100-105. K.G. 588. Nigri. Law. 110... Surg. Rojas.. Randomized controlled trial to evaluate splenectomy in total gastrectomy for proximal gastric carcinoma: Japan clinical oncology group study JCOG 0110-MF. Cicchini. 33-39..Y. 114.. 210. I..G. Significant regional variation in adequacy of LN assessment and survival in gastric cancer. Choi. K. 111. Sano.M. Yildirim. I. .F. Ramacciato.. L. 2007. Yamamoto. Chen. Classification of LN metastases from gastric cancer: Comparison between N-site and N-number systems... Surg. Randomized clinical trial of splenectomy versus splenic preservation in patients with proximal gastric cancer. Zhou.. Arch. Meta-analysis of effectiveness and safety of D2 plus para-aortic lymphadenectomy for resectable gastric cancer. E. Hermansm. A.K.D. Ercolani. Chung.. Smith.H. J. Kranenbarg. 2003..Z.. 112. N. 11. Diaz. TNM Classification of Malignant Tumors. J. Union Internationale Contre le Cancer and the American Joint Committee on Cancer. E. L. 84. Ichikawa. Putter. C. Suppl. J.W. Kiss. Lancet Oncol. A. A prospective randomized study comparing D2 total gastrectomy versus D2 total gastrectomy plus splenectomy in 187 patients with gastric carcinoma. International Union against Cancer. Rui. 107. G. Surgical treatment of gastric cancer: 15-Year follow-up results of the randomised nationwide Dutch D1D2 trial. 93. J. 1803-1804. Br. Our experience and review of the literature.. C. 559-563. Shirono. 401-407... Hu. C. NY.P. J.. Surgery 2002. 2002. 6th ed.Y. E.. Hepatogastroenterology 2003. van de Velde.. O. J. Y. Engl. Klein Kranenbarg. 32. P. U. Sasako.J. Sobin. 103. 2010.. Kurioka. C. Deguchi.M. Braghetto. Clin. Sobin. E.X. Yu. Cancer 2006.. Kan. J. F. Evaluation of the 5th edition of the TNM classification for gastric cancer: Improved prognostic value. John Wiley-Liss: New York. Sosin. S. Chen.. J... TNM Classification of Malignant Tumors. 104. R. X.. Fleming.H. Cancer 1997. Maluenda...C. van Krieken. Prognostic value of LN staging in gastric cancer... Kelsey... K. fifth edition (1997). Stage migration and new diagnostic techniques as a source of misleading statistics for survival in cancer..... Lee. 107. W. Oncol. Jpn. Y. J. D'Angelo. Celen. Coburn. G. B.H. J. Berberoglu. Hamashima.. 126. C.. F. 80... M. van de Velde. I.Cancers 2011. H.. Sasako. 1469-1473. L. 2010. Am. R. 2006.J. 50. D.. Morbidity of radical lymphadenectomy in the curative resection of gastric carcinoma. Eur. De Angelis. Yang. Rossi. J. T. 312. Csendes. Zhang. Wittenkind. Coll. 131. 1985.. Shiu. Surg. Med. K. Y. E. 1604-1608. Prediction of survival in gastric carcinoma related to LN grading by the new American Joint Committee on Cancer/Union International Contre le Cancer System or the Japanese system. Gulben. H. Z.K.. Surg. S. Brennan. J. Shioaki. 1991. 102.. D.

H. Detmar. Banerji. Dumont... K.. J. K. Jackson. a new homologue of the CD44 glycoprotein.. M. Jones. 1999. Nat... S. Positive LN ratio is an independent prognostic factor in gastric cancer after d2 resection regardless of the examined number of lymph nodes. T. 118. 16. 128.. 9. Alitalo. K. Makuuchi. 27-34... C. 2010. 124. 2001.. Z..W. Y.. Sato. Lymphangiogenesis is pivotal to the trials of a successful cancer metastasis.A. 211-216. A.D. Oliver.. Ni. K. J. 120. Surgery 2004. A. 135. McCarter. Alitalo. 165-171. Etoh. G. Surg.G. Cell 1999. Masuo. Liu. 7. Breitman. Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis. 10. extranodal invasion is a significant risk factor for peritoneal metastasis. Surg.. A. M. T.. Chen. G. Clarke.. 98. 75. K. Pathol. Chen. Q.. 116.. M.H. Achen. D.. Oncol. J. Tammi... 121-124. V. 319-326.. Surg. M. Natl. Wigle... The superiority of ratio-based LN staging in gastric carcinoma. T.X. Sun. 769-778.. Cancer 2002.. Ann. Su. Yamamichi. R. Clasper. Janes. Claffey.. Tanaka. 92..B.W. D. M. M. W. 2009.. Kriehuber. Ishikawa.. Expression of the fms-like tyrosine kinase 4 gene becomes restricted to lymphatic endothelium during development... 2.. Lymphangiogenesis and cancer metastasis. Acad. K. Ambrosi. Marchet. K. 127. M. Breiteneder-Geleff... R. Extranodal metastasis is an indicator of poor prognosis in patients with gastric carcinoma.. W. T. 192-198.. Prevo. Amann.. S. K. et al.. 2000. Shimoda.T. Riccardi.. M.. Jussila. 119. Nitti. Sci.. Y. H. X.. K. 573-583. H. J.. P. 123. Ann. J. 122. Ann. L. Alitalo.. Hawighorst. J. K. 144. Mustonen. E.G. LYVE-1. K. A. Soleiman.Cancers 2011. T.R. Li. K. Peritoneal metastasis in gastric cancer with particular reference to lymphatic advancement. Lymphangiogenesis and tumor metastasis: Myth or reality? Clin. D.... Long.. Xu.. S. Matsui.. Katai. 2006. Langenbecks Arch. Velasco. 462-468.. 126. Okumura. Kumagai.... Skobe. Ogoshi.. Nakane. J.. A. 3 2158 115. L.S. 93.G. T. Sano.. Oncol. Zhan. H. K. 3566-3570.. D. Alitalo. Horvat. Y. Am. 125. Geng. 1999. Shimizu. Oncol. is a lymph-specific receptor for hyaluronan. M.Q. Oncol. 7. Zhou. Cell Biol. Surg. Y. Belluco. Baldwin. Fang.W.. G. Mencarelli. Okamoto. L.. D. 2003. Cancer Res.. H. Impact of difference in the definition of extranodal spread on the outcome of node-positive patients with gastric cancer. M. 117. S. Lise.. J. 121. Jackson. Wang. 789-801... Weninger.H. 1077-1085.. M. R.. .. Yamagata. Sasako. Q.. J. K. 2002. Rev. Prox1 function is required for the development of the murine lymphatic system. Tschachler.J. K.E. Harken. 2001.H.. 385-394. R. Ratio between metastatic and examined lymph nodes is an independent prognostic factor after D2 resection for gastric cancer: Analysis of a large European monoinstitutional experience. Pepper. Olivieri... Inoue. Hioki. Nat. Iiyama. T. van Hinsbergh. Diem. Korhonen. E.. S. Proc.. Surg. 395. Nakamura. K. Nakai. Z. USA 1995. 369-373.. Br. 154. K.Z. Kaipainen. Kowalski.. S. G. M. Med. Surg. Kanbara. Angiosarcomas express mixed endothelial phenotypes of blood and lymphatic capillaries: Podoplanin as a specific marker for lymphatic endothelium. Stacker.

D. 672-682. R. licensee MDPI. Karkkainen.. H. Huarte. 61. M. et al.. Jussila. 20. Yla-Herttuala. S.. Switzerland.. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons. M..... Banerji.J.. Jackson. Mandriota.org/licenses/by/3. R. T. © 2011 by the authors.. Karpanen. Cancer Res. Alitalo. Montesano..0/). J. 3 2159 129. Egeblad. Prevo.G. 1786-1790. M. K.J. Vascular endothelial growth factor C promotes tumor lymphangiogenesis and intralymphatic tumor growth. Jaattela. Basel. L. Vascular endothelial growth factor-C-mediated lymphangiogenesis promotes tumour metastasis. A.. S... Jeltsch.Cancers 2011. S. . 2001. Kubo.. 130. Baetens.. M. Compagni. EMBO J. 2001. D.