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.
References
[1]
Forman, D.; Burley, V.J. Gastric cancer: Global pattern of the disease and an overview of environmental risk factors. Best Pract. Res. Clin. Gastroenterol. 2006, 20, 633–649.
[2]
Roviello, F.; Rossi, S.; Marrelli, D; Pedrazzani, C.; Corso, G.; Vindigni, C.; Morgagni, P.; Saragoni, L.; de Mansoni, G.; Tomezzoli, A. Number of LN metastases and its prognostic significance in early gastric cancer: A multicenter Italian study. J. Surg. Oncol. 2006, 94, 275–280. discussion 274.
[3]
Sasako, M.; Sano, T.; Yamamoto, S.; Kurokawa, Y.; Nashimoto, A.; Kurita, A.; Hiratsuka, M.; Tsujinaka, T.; Kinoshita, T.; Arai, K.; Yamamura, Y.; Okajima, K. D2 lymphadenectomy alone or with para-aortic nodal dissection for gastric cancer. N. Engl. J. Med. 2008, 359, 453–462.
[4]
Yasuda, K.; Adachi, Y.; Shiraishi, N.; Inomata, M.; Takeuchi, H.; Kitano, S. Prognostic effect of LN micrometastasis in patients with histologically node-negative gastric cancer. Ann. Surg. Oncol. 2002, 9, 771–774.
[5]
Siewert, J.R.; Kestlmeier, R.; Busch, R.; Bottcher, K.; Roder, J. D.; Muller, J.; Fellbaum, C.; Hofler, H. Benefits of D2 LN dissection for patients with gastric cancer and pN0 and pN1 LN metastases. Br. J. Surg. 1996, 83, 1144–1147.
[6]
Fukagawa, T.; Sasako, M.; Mann, G.B.; Sano, T.; Katai, H.; Maruyama, K.; Nakanishi, Y.; Shimoda, T. Immunohistochemically detected micrometastases of the lymph nodes in patients with gastric carcinoma. Cancer 2001, 92, 753–760.
[7]
Kikuchi, Y.; Tsuchiya, A.; Ando, Y.; Yoshida, T.; Takenosita, S. Immunohistochemical detection of LN microinvolvement in node-negative gastric cancer. Gastric Cancer 1999, 2, 173–178.
[8]
Nakajo, A.; Natsugoe, S.; Ishigami, S.; Matsumoto, M.; Nakashima, S.; Hokita, S.; Baba, M.; Takao, S.; Aikou, T. Detection and prediction of micrometastasis in the lymph nodes of patients with pN0 gastric cancer. Ann. Surg. Oncol. 2001, 8, 158–162.
[9]
Cai, J.; Ikeguchi, M.; Maeta, M.; Kaibara, N.; Sakatani, T. Clinicopathological value of immunohistochemical detection of occult involvement in pT3N0 gastric cancer. Gastric Cancer 1999, 2, 95–100.
[10]
Kitadai, Y.; Kodama, M.; Cho, S.; Kuroda, T.; Ochiumi, T.; Kimura, S.; Tanaka, S.; Matsumura, S.; Yasui, W.; Chayama, K. Quantitative analysis of lymphangiogenic markers for predicting metastasis of human gastric carcinoma to lymph nodes. Int. J. Cancer 2005, 115, 388–392.
[11]
Yonemura, Y.; Endo, Y.; Fujita, H.; Fushida, S.; Ninomiya, I.; Bandou, E.; Taniguchi, K.; Miwa, K.; Ohoyama, S.; Sugiyama, K.; Sasaki, T. Role of vascular endothelial growth factor C expression in the development of LN metastasis in gastric cancer. Clin. Cancer Res. 1999, 5, 1823–1829.
[12]
Amioka, T.; Kitadai, Y.; Tanaka, S.; Haruma, K.; Yoshihara, M.; Yasui, W.; Chayama, K. Vascular endothelial growth factor-C expression predicts LN metastasis of human gastric carcinomas invading the submucosa. Eur. J. Cancer 2002, 38, 1413–1419.
[13]
Murakami, T. Pathomorphological diagnosis. Definition and gross classification of early gastric cancer. Gann. Monogr. Cancer Res. 1971, 11, 53.
[14]
Seto, Y; Nagawa, H; Muto, T. Impact of LN metastasis on survival with early gastric cancer. World J. Surg. 1997, 21, 186–189. discussion 190.
[15]
Folli, S.; Dente, M.; Dell'Amore, D.; Gaudio, M.; Nanni, O.; Saragoni, L.; Vio, A. Early gastric cancer: Prognostic factors in 223 patients. Br. J. Surg. 1995, 82, 952–956.
[16]
Nakamura, K.; Morisaki, T.; Sugitani, A.; Ogawa, T.; Uchiyama, A.; Kinukawa, N.; Tanaka, M. An early gastric carcinoma treatment strategy based on analysis of LN metastasis. Cancer 1999, 85, 1500–1505.
[17]
Gotoda, T.; Yanagisawa, A.; Sasako, M.; Ono, H.; Nakanishi, Y.; Shimoda, T.; Kato, Y. Incidence of LN metastasis from early gastric cancer: Estimation with a large number of cases at two large centers. Gastric Cancer 2000, 3, 219–225.
[18]
Nasu, J.; Nishina, T.; Hirasaki, S.; Moriwaki, T.; Hyodo, I.; Kurita, A.; Nishimura, R. Predictive factors of LN metastasis in patients with undifferentiated early gastric cancers. J. Clin. Gastroenterol. 2006, 40, 412–415.
[19]
Sano, T; Kobori, O; Muto, T. LN metastasis from early gastric cancer: Endoscopic resection of tumour. Br. J. Surg. 1992, 79, 241–244.
[20]
An, J.Y.; Baik, Y.H.; Choi, M.G.; Noh, J.H.; Sohn, T.S.; Kim, S. Predictive factors for LN metastasis in early gastric cancer with submucosal invasion: Analysis of a single institutional experience. Ann. Surg. 2007, 246, 749–753.
[21]
Tsukuma, H.; Oshima, A.; Narahara, H.; Morii, T. Natural history of early gastric cancer: A non-concurrent, long term, follow up study. Gut 2000, 47, 618–621.
[22]
Nakajima, T.; Ota, K.; Ishihara, S.; Oyama, S.; Nishi, M. Indication for the lymph node dissection of gastric cancer based on the pattern analysis small of lymphatic spread (in Japanese). Gan to Kagaku Ryoho 1994, 21, 1751–1755.
[23]
Maruyama, K.; Sasako, M.; Kinoshita, T.; Okabayashi, K. Reasonable LN dissection in radical gastrectomy for gastric cancer: Introduction of computer information system and lymphography technique by India-ink. Nippon Geka Gakkai Zasshi 1989, 90, 1318–1321.
[24]
Isozaki, H.; Okajima, K.; Nomura, E.; Fujii, K.; Sako, S.; Izumi, N.; Ohyama, T.; Komizo, Y.; Kitade, T. Preoperative diagnosis and surgical treatment for LN metastasis in gastric cancer (in Japanese). Gan To Kagaku Ryoho 1996, 23, 1275–1283.
[25]
Lowy, A.M.; Mansfield, P.F.; Leach, S.D.; Ajani, J. Laparoscopic staging for gastric cancer. Surgery 1996, 119, 611–614.
Power, D.G.; Schattner, M.A.; Gerdes, H.; Brenner, B.; Markowitz, A.J.; Capanu, M.; Coit, D.G.; Brennan, M.; Kelsen, D.P.; Shah, M.A. Endoscopic ultrasound can improve the selection for laparoscopy in patients with localized gastric cancer. J. Am. Coll. Surg. 2009, 208, 173–178.
[28]
Davies, J.; Chalmers, A.G.; Sue-Ling, H.M.; May, J.; Miller, G.V.; Martin, I.G.; Johnston, D. Spiral computed tomography and operative staging of gastric carcinoma: A comparison with histopathological staging. Gut 1997, 41, 314–319.
Abdalla, E.K.; Pisters, P.W. Staging and preoperative evaluation of upper gastrointestinal malignancies. Semin. Oncol. 2004, 31, 513–529.
[31]
Minami, M.; Kawauchi, N.; Itai, Y.; Niki, T.; Sasaki, Y. Gastric tumors: Radiologic-pathologic correlation and accuracy of T staging with dynamic CT. Radiology 1992, 185, 173–178.
[32]
Rossi, M.; Broglia, L.; Maccioni, F.; Bezzi, M.; Laghi, A.; Graziano, P.; Mingazzini, P.L.; Rossi, P. Hydro-CT in patients with gastric cancer: Preoperative radiologic staging. Eur. Radiol. 1997, 7, 659–664.
[33]
Dux, M.; Richter, G.M.; Hansmann, J.; Kuntz, C.; Kauffmann, G.W. Helical hydro-CT for diagnosis and staging of gastric carcinoma. J. Comput. Assist. Tomogr. 1999, 23, 913–922.
[34]
Lee, I.J.; Lee, J.M.; Kim, S.H.; Shin, C.I.; Lee, J.Y.; Kim, S.H.; Han, J.K.; Choi, B.I. Diagnostic performance of 64-channel multidetector CT in the evaluation of gastric cancer: Differentiation of mucosal cancer (T1a) from submucosal involvement (T1b and T2). Radiology 2010, 255, 805–814.
[35]
D'Elia, F.; Zingarelli, A.; Palli, D.; Grani, M. Hydro-dynamic CT preoperative staging of gastric cancer: Correlation with pathological findings. A prospective study of 107 cases. Eur. Radiol. 2000, 10, 1877–1885.
[36]
Sohn, K.M.; Lee, J.M.; Lee, S.Y.; Ahn, B.Y.; Park, S.M.; Kim, K.M. Comparing MR imaging and CT in the staging of gastric carcinoma. AJR Am. J. Roentgenol. 2000, 174, 1551–1557.
[37]
Kienle, P.; Buhl, K.; Kuntz, C.; Dux, M.; Hartmann, C.; Axel, B.; Herfarth, C.; Lehnert, T. Prospective comparison of endoscopy, endosonography and computed tomography for staging of tumours of the oesophagus and gastric cardia. Digestion 2002, 66, 230–236.
[38]
Wakelin, S.J.; Deans, C.; Crofts, T.J.; Allan, P.L.; Plevris, J.N.; Paterson-Brown, S. A comparison of computerised tomography, laparoscopic ultrasound and endoscopic ultrasound in the preoperative staging of oesophago-gastric carcinoma. Eur. J. Radiol. 2002, 41, 161–167.
[39]
Yan, C.; Zhu, Z.G.; Yan, M.; Zhang, H.; Pan, Z.L.; Chen, J.; Xiang, M.; Chen, M.M.; Liu, B.Y.; Yin, H.R.; et al. Value of multidetector-row computed tomography in the preoperative T and N staging of gastric carcinoma: A large-scale Chinese study. J. Surg. Oncol. 2009, 100, 205–214.
[40]
Willis, S.; Truong, S.; Gribnitz, S.; Fass, J.; Schumpelick, V. Endoscopic ultrasonography in the preoperative staging of gastric cancer: Accuracy and impact on surgical therapy. Surg. Endosc. 2000, 14, 951–954.
[41]
Meining, A.; Dittler, H.J.; Wolf, A.; Lorenz, R.; Schusdziarra, V.; Siewert, J. R.; Classen, M.; Hofler, H.; Rosch, T. You get what you expect? A critical appraisal of imaging methodology in endosonographic cancer staging. Gut 2002, 50, 599–603.
[42]
Yeung, HW; Macapinlac, H; Karpeh, M; Finn, RD; Larson, SM. Accuracy of FDG-PET in Gastric Cancer. Preliminary Experience. Clin. Positron Imaging 1998, 1, 213–221.
[43]
Bhandari, S.; Shim, C.S.; Kim, J.H.; Jung, I.S.; Cho, J.Y.; Lee, J.S.; Lee, M.S.; Kim, B.S. Usefulness of three-dimensional, multidetector row CT (virtual gastroscopy and multiplanar reconstruction) in the evaluation of gastric cancer: A comparison with conventional endoscopy, EUS, and histopathology. Gastrointest Endosc. 2004, 59, 619–626.
[44]
Kwee, R.M.; Kwee, T.C. Imaging in local staging of gastric cancer: A systematic review. J. Clin. Oncol. 2007, 25, 2107–2116.
Kelly, S.; Harris, K.M.; Berry, E.; Hutton, J.; Roderick, P.; Cullingworth, J.; Gathercole, L.; Smith, M.A. A systematic review of the staging performance of endoscopic ultrasound in gastro-oesophageal carcinoma. Gut 2001, 49, 534–539.
[47]
Botet, J.F.; Lightdale, C.J.; Zauber, A.G.; Gerdes, H.; Winawer, S.J.; Urmacher, C.; Brennan, M.F. Preoperative staging of gastric cancer: Comparison of endoscopic US and dynamic CT. Radiology 1991, 181, 426–432.
[48]
Fukuya, T.; Honda, H.; Hayashi, T.; Kaneko, K.; Tateshi, Y.; Ro, T.; Maehara, Y.; Tanaka, M.; Tsuneyoshi, M.; Masuda, K. Lymph-node metastases: Efficacy for detection with helical CT in patients with gastric cancer. Radiology 1995, 197, 705–711.
[49]
de Manzoni, G.; Pedrazzani, C.; Di Leo, A.; Bonfiglio, M.; Tedesco, P.; Tasselli, S.; Veraldi, G.F.; Cordiano, C. Experience of endoscopic ultrasound in staging adenocarcinoma of the cardia. Eur. J. Surg. Oncol. 1999, 25, 595–598.
[50]
Tsendsuren, T.; Jun, S.M.; Mian, X.H. Usefulness of endoscopic ultrasonography in preoperative TNM staging of gastric cancer. World J. Gastroenterol. 2006, 12, 43–47.
National Comprehensive Cancer Network (NCCN) guidelines. Available online: http://www.nccn.org/ (accessed on 13 December 2010).
[53]
Yun, M.; Lim, J.S.; Noh, S.H.; Hyung, W.J.; Cheong, J.H.; Bong, J.K.; Cho, A.; Lee, J.D. LN staging of gastric cancer using (18)F-FDG PET: A comparison study with CT. J. Nucl. Med. 2005, 46, 1582–1588.
[54]
De Potter, T.; Flamen, P.; Van Cutsem, E.; Penninckx, F.; Filez, L.; Bormans, G.; Maes, A.; Mortelmans, L. Whole-body PET with FDG for the diagnosis of recurrent gastric cancer. Eur. J. Nucl. Med. Mol. Imaging 2002, 29, 525–529.
[55]
Stahl, A.; Ott, K.; Weber, W.A.; Becker, K.; Link, T.; Siewert, J. R.; Schwaiger, M.; Fink, U. FDG PET imaging of locally advanced gastric carcinomas: Correlation with endoscopic and histopathological findings. Eur. J. Nucl. Med. Mol. Imaging 2003, 30, 288–295.
[56]
Kim, S.K.; Kang, K.W.; Lee, J.S.; Kim, H.K.; Chang, H.J.; Choi, J.Y.; Lee, J.H.; Ryu, K.W.; Kim, Y.W.; Bae, J.M. Assessment of LN metastases using 18F-FDG PET in patients with advanced gastric cancer. Eur. J. Nucl. Med. Mol. Imaging 2006, 33, 148–155.
[57]
Mukai, K.; Ishida, Y.; Okajima, K.; Isozaki, H.; Morimoto, T.; Nishiyama, S. Usefulness of preoperative FDG-PET for detection of gastric cancer. Gastric Cancer 2006, 9, 192–196.
[58]
Chen, J.; Cheong, J.H.; Yun, M.J.; Kim, J.; Lim, J.S.; Hyung, W.J.; Noh, S.H. Improvement in preoperative staging of gastric adenocarcinoma with positron emission tomography. Cancer 2005, 103, 2383–2390.
[59]
McAteer, D.; Wallis, F.; Couper, G.; Norton, M.; Welch, A.; Bruce, D.; Park, K.; Nicolson, M.; Gilbert, F.J.; Sharp, P. Evaluation of 18F-FDG positron emission tomography in gastric and oesophageal carcinoma. Br. J. Radiol. 1999, 72, 525–529.
[60]
Kinkel, K.; Lu, Y.; Both, M.; Warren, R.S.; Thoeni, R.F. Detection of hepatic metastases from cancers of the gastrointestinal tract by using noninvasive imaging methods (US, CT, MR imaging, PET): A meta-analysis. Radiology 2002, 224, 748–756.
[61]
Yoshioka, T.; Yamaguchi, K.; Kubota, K.; Saginoya, T.; Yamazaki, T.; Ido, T.; Yamaura, G.; Takahashi, H.; Fukuda, H.; Kanamaru, R. Evaluation of 18F-FDG PET in patients with advanced, metastatic, or recurrent gastric cancer. J. Nucl. Med. 2003, 44, 690–699.
[62]
Kitagawa, Y.; Fujii, H.; Mukai, M.; Kubota, T.; Otani, Y.; Kitajima, M. Radio-guided sentinel node detection for gastric cancer. Br. J. Surg. 2002, 89, 604–608.
[63]
Miwa, K.; Kinami, S.; Taniguchi, K.; Fushida, S.; Fujimura, T.; Nonomura, A. Mapping sentinel nodes in patients with early-stage gastric carcinoma. Br. J. Surg. 2003, 90, 178–182.
[64]
Kim, M.C.; Kim, H.H.; Jung, G.J.; Lee, J.H.; Choi, S.R.; Kang, D.Y.; Roh, M.S.; Jeong, J.S. Lymphatic mapping and sentinel node biopsy using 99mTc tin colloid in gastric cancer. Ann. Surg. 2004, 239, 383–387.
[65]
Uenosono, Y.; Natsugoe, S.; Ehi, K.; Arigami, T.; Hokita, S.; Aikou, T. Detection of sentinel nodes and micrometastases using radioisotope navigation and immunohistochemistry in patients with gastric cancer. Br. J. Surg. 2005, 92, 886–889.
[66]
Rabin, I.; Chikman, B.; Halpern, Z.; Wassermann, I.; Lavy, R.; Gold-Deutch, R.; Sandbank, J.; Halevy, A. Sentinel node mapping for gastric cancer. Isr. Med. Assoc. J. 2006, 8, 40–43.
Sano, T.; Sasako, M.; Kinoshita, T.; Maruyama, K. Recurrence of early gastric cancer. Follow-up of 1475 patients and review of the Japanese literature. Cancer 1993, 72, 3174–3178.
[73]
Itoh, H.; Oohata, Y.; Nakamura, K.; Nagata, T.; Mibu, R.; Nakayama, F. Complete ten-year postgastrectomy follow-up of early gastric cancer. Am. J. Surg. 1989, 158, 14–16.
[74]
Ohta, H.; Noguchi, Y.; Takagi, K.; Nishi, M.; Kajitani, T.; Kato, Y. Early gastric carcinoma with special reference to macroscopic classification. Cancer 1987, 60, 1099–1106.
[75]
Ono, H.; Kondo, H.; Gotoda, T.; Shirao, K.; Yamaguchi, H.; Saito, D.; Hosokawa, K.; Shimoda, T.; Yoshida, S. Endoscopic mucosal resection for treatment of early gastric cancer. Gut 2001, 48, 225–229.
[76]
Gotoda, T.; Yanagisawa, A.; Sasako, M.; Ono, H.; Nakanishi, Y.; Shimoda, T.; Kato, Y. Incidence of lymph node metastasis from early gastric cancer: Estimation with a large number of cases at two large centers. Gastric Cancer 2000, 3, 219–225.
[77]
Hirasawa, T.; Gotoda, T.; Miyata, S.; Kato, Y.; Shimoda, T.; Taniguchi, H.; Fujisaki, J.; Sano, T.; Yamaguchi, T. Incidence of lymph node metastasis and the feasibility of endoscopic resection for undifferentiated-type early gastric cancer. Gastric Cancer 2009, 12, 148–152.
[78]
Yasuda, K.; Adachi, Y.; Shiraishi, N.; Inomata, M.; Takeuchi, H.; Kitano, S. Rate of detection of LN metastasis is correlated with the depth of submucosal invasion in early stage gastric carcinoma. Cancer 1999, 85, 2119–2123.
[79]
Noguchi, Y.; Yoshikawa, T.; Tsuburaya, A.; Motohashi, H.; Karpeh, M.S.; Brennan, M. F. Is gastric carcinoma different between Japan and the United States? Cancer 2000, 89, 2237–2246.
[80]
Japanese Gastric Cancer Association. Gastric Cancer Treatment Guidelines 2010; Kanehara-shuppan: Tokyo, Japan, 2010.
[81]
AJCC (American Joint Committee on Cancer). Cancer Staging Manual, 7th edition; Edge, S.B., Byrd, D.R., Compton, C.C., Eds.; Springer: New York, NY, USA, 2010; p. 117.
[82]
Wagner, P.K.; Ramaswamy, A.; Ruschoff, J.; Schmitz-Moormann, P.; Rothmund, M. LN counts in the upper abdomen: Anatomical basis for lymphadenectomy in gastric cancer. Br. J. Surg. 1991, 78, 825–827.
[83]
Roukos, DH; Kappas, AM. Targeting the optimal extent of LN dissection for gastric cancer. J. Surg. Oncol. 2002, 81, 59–62. discussion 62.
[84]
Bunt, A.M.; Hermans, J.; Smit, V.T.; van de Velde, C.J.; Fleuren, G.J.; Bruijn, J.A. Surgical/pathologic-stage migration confounds comparisons of gastric cancer survival rates between Japan and Western countries. J. Clin. Oncol. 1995, 13, 19–25.
[85]
de Manzoni, G.; Verlato, G.; Roviello, F.; Morgagni, P.; Di Leo, A.; Saragoni, L.; Marrelli, D.; Kurihara, H.; Pasini, F. The new TNM classification of LN metastasis minimises stage migration problems in gastric cancer patients. Br. J. Cancer 2002, 87, 171–174.
[86]
Smith, D.D.; Schwarz, R.R.; Schwarz, R.E. Impact of total LN count on staging and survival after gastrectomy for gastric cancer: Data from a large US-population database. J. Clin. Oncol. 2005, 23, 7114–7124.
[87]
Noguchi, Y.; Imada, T.; Matsumoto, A.; Coit, D.G.; Brennan, M.F. Radical surgery for gastric cancer. A review of the Japanese experience. Cancer 1989, 64, 2053–2062.
[88]
Maruyama, K.; Okabayashi, K.; Kinoshita, T. Progress in gastric cancer surgery in Japan and its limits of radicality. World J. Surg. 1987, 11, 418–425.
[89]
Roder, J.D.; Bottcher, K.; Siewert, J.R.; Busch, R.; Hermanek, P.; Meyer, H.J. Prognostic factors in gastric carcinoma. Results of the German Gastric Carcinoma Study 1992. Cancer 1993, 72, 2089–2097.
[90]
Dent, D.M.; Madden, M.V.; Price, S.K. Randomized comparison of R1 and R2 gastrectomy for gastric carcinoma. Br. J. Surg. 1988, 75, 110–112.
[91]
Cuschieri, A.; Fayers, P.; Fielding, J.; Craven, J.; Bancewicz, J.; Joypaul, V.; Cook, P. Postoperative morbidity and mortality after D1 and D2 resections for gastric cancer: Preliminary results of the MRC randomised controlled surgical trial. The Surgical Cooperative Group. Lancet 1996, 347, 995–999.
[92]
Bonenkamp, J.J.; Hermans, J.; Sasako, M.; van de Velde, C.J.; Welvaart, K.; Songun, I.; Meyer, S.; Plukker, J.T.; Van Elk, P.; Obertop, H. Extended lymph-node dissection for gastric cancer. N. Engl. J. Med. 1999, 340, 908–914.
[93]
Sano, T.; Sasako, M.; Yamamoto, S.; Nashimoto, A.; Kurita, A.; Hiratsuka, M.; Tsujinaka, T.; Kinoshita, T.; Arai, K.; Yamamura, Y; et al. 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. J. Clin. Oncol. 2004, 22, 2767–2773.
[94]
Kulig, J.; Popiela, T.; Kolodziejczyk, P.; Sierzega, M.; Szczepanik, A. Standard D2 versus extended D2 (D2+) lymphadenectomy for gastric cancer: An interim safety analysis of a multicenter, randomized, clinical trial. Am. J. Surg. 2007, 193, 10–15.
[95]
Yonemura, Y.; Wu, C.C.; Fukushima, N.; Honda, I.; Bandou, E.; Kawamura, T.; Kamata, T.; Kim, B.S.; Matsuki, N.; Sawa, T; et al. Randomized clinical trial of D2 and extended paraaortic lymphadenectomy in patients with gastric cancer. Int. J. Clin. Oncol. 2008, 13, 132–137.
[96]
Cuschieri, A.; Weeden, S.; Fielding, J.; Bancewicz, J.; Craven, J.; Joypaul, V.; Sydes, M.; Fayers, P. Patient survival after D1 and D2 resections for gastric cancer: Long-term results of the MRC randomized surgical trial. Surgical Co-operative Group. Br. J. Cancer 1999, 79, 1522–1530.
[97]
Hartgrink, H.H.; van de Velde, C.J.; Putter, H.; Bonenkamp, J.J.; Klein Kranenbarg, E.; Songun, I.; Welvaart, K.; van Krieken, J.H.; Meijer, S.; Plukker, J.T.; et al. Extended LN dissection for gastric cancer: Who may benefit? Final results of the randomized Dutch gastric cancer group trial. J. Clin. Oncol. 2004, 22, 2069–2077.
[98]
Songun, I.; Putter, H.; Kranenbarg, E.M.; Sasako, M.; van de Velde, C.J. Surgical treatment of gastric cancer: 15-Year follow-up results of the randomised nationwide Dutch D1D2 trial. Lancet Oncol. 2010, 11, 439–449.
[99]
Sasako, M.; Saka, M.; Fukagawa, T.; Katai, H.; Sano, T. Surgical treatment of advanced gastric cancer: Japanese perspective. Dig. Surg. 2007, 24, 101–107.
[100]
Wu, C.W.; Hsiung, C.A.; Lo, S.S.; Hsieh, M.C.; Chen, J.H.; Li, A.F.; Lui, W.Y.; Whang-Peng, J. Nodal dissection for patients with gastric cancer: A randomized controlled trial. Lancet Oncol. 2006, 7, 309–315.
[101]
Songun, I.; Putter, H.; Kranenbarg, E.M.; Sasako, M.; van de Velde, C.J. Surgical treatment of gastric cancer: 15-Year follow-up results of the randomised nationwide Dutch D1D2 trial. Lancet Oncol. 2010, 11, 439–449.
[102]
Smith, J.W.; Shiu, M.H.; Kelsey, L.; Brennan, M.F. Morbidity of radical lymphadenectomy in the curative resection of gastric carcinoma. Arch. Surg. 1991, 126, 1469–1473.
[103]
Chen, X.Z.; Hu, J.K.; Zhou, Z.G.; Rui, Y.Y.; Yang, K.; Wang, L.; Zhang, B.; Chen, Z.X.; Chen, J.P. Meta-analysis of effectiveness and safety of D2 plus para-aortic lymphadenectomy for resectable gastric cancer. J. Am. Coll. Surg. 2010, 210, 100–105.
[104]
Csendes, A.; Burdiles, P.; Rojas, J.; Braghetto, I.; Diaz, J.C.; Maluenda, F. A prospective randomized study comparing D2 total gastrectomy versus D2 total gastrectomy plus splenectomy in 187 patients with gastric carcinoma. Surgery 2002, 131, 401–407.
[105]
Yu, W.; Choi, G.S.; Chung, H.Y. Randomized clinical trial of splenectomy versus splenic preservation in patients with proximal gastric cancer. Br. J. Surg. 2006, 93, 559–563.
[106]
Sano, T.; Yamamoto, S.; Sasako, M. Randomized controlled trial to evaluate splenectomy in total gastrectomy for proximal gastric carcinoma: Japan clinical oncology group study JCOG 0110-MF. Jpn. J. Clin. Oncol. 2002, 32, 363–364.
[107]
Sobin, L.H.; Fleming, I.D. TNM Classification of Malignant Tumors, fifth edition (1997). Union Internationale Contre le Cancer and the American Joint Committee on Cancer. Cancer 1997, 80, 1803–1804.
[108]
Sobin, L.H.; Wittenkind, C.H. International Union against Cancer. TNM Classification of Malignant Tumors, 6th ed. ed.; John Wiley-Liss: New York, NY, USA, 2002.
[109]
Klein Kranenbarg, E.; Hermansm, J.; van Krieken, J.H.; van de Velde, C.J. Evaluation of the 5th edition of the TNM classification for gastric cancer: Improved prognostic value. Br. J. Cancer 2001, 84, 64–71.
[110]
Celen, O.; Yildirim, E.; Gulben, K.; Berberoglu, U. 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. Eur. J. Surg. Suppl. 2003, 588, 33–39.
[111]
Aurello, P.; D'Angelo, F.; Rossi, S.; Bellagamba, R.; Cicchini, C.; Nigri, G.; Ercolani, G.; De Angelis, R.; Ramacciato, G. Classification of LN metastases from gastric cancer: Comparison between N-site and N-number systems. Our experience and review of the literature. Am. Surg. 2007, 73, 359–366.
[112]
Ichikawa, D.; Kurioka, H.; Ueshima, Y.; Shirono, K.; Kan, K.; Shioaki, Y.; Lee, C.J.; Hamashima, T.; Deguchi, E.; Ikeda, E; et al. Prognostic value of LN staging in gastric cancer. Hepatogastroenterology 2003, 50, 301–304.
[113]
Coburn, N.G.; Swallow, C.J.; Kiss, A.; Law, C. Significant regional variation in adequacy of LN assessment and survival in gastric cancer. Cancer 2006, 107, 2143–2151.
[114]
Feinstein, A.R.; Sosin, D.M.; Wells, C.K. The Will Rogers phenomenon. Stage migration and new diagnostic techniques as a source of misleading statistics for survival in cancer. N. Engl. J. Med. 1985, 312, 1604–1608.
[115]
Nitti, D.; Marchet, A.; Olivieri, M.; Ambrosi, A.; Mencarelli, R.; Belluco, C.; Lise, M. 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. Ann. Surg. Oncol. 2003, 10, 1077–1085.
[116]
Inoue, K.; Nakane, Y.; Iiyama, H.; Sato, M.; Kanbara, T.; Nakai, K.; Okumura, S.; Yamamichi, K.; Hioki, K. The superiority of ratio-based LN staging in gastric carcinoma. Ann. Surg. Oncol. 2002, 9, 27–34.
[117]
Xu, D.Z.; Geng, Q.R.; Long, Z.J.; Zhan, Y.Q.; Li, W.; Zhou, Z.W.; Chen, Y.B.; Sun, X.W.; Chen, G.; Liu, Q. Positive LN ratio is an independent prognostic factor in gastric cancer after d2 resection regardless of the examined number of lymph nodes. Ann. Surg. Oncol. 2009, 16, 319–326.
[118]
Tanaka, T.; Kumagai, K.; Shimizu, K.; Masuo, K.; Yamagata, K. Peritoneal metastasis in gastric cancer with particular reference to lymphatic advancement; extranodal invasion is a significant risk factor for peritoneal metastasis. J. Surg. Oncol. 2000, 75, 165–171.
[119]
Etoh, T.; Sasako, M.; Ishikawa, K.; Katai, H.; Sano, T.; Shimoda, T. Extranodal metastasis is an indicator of poor prognosis in patients with gastric carcinoma. Br. J. Surg. 2006, 93, 369–373.
[120]
Nakamura, K.; Okamoto, Y.; Matsui, H.; Makuuchi, H.; Ogoshi, K. Impact of difference in the definition of extranodal spread on the outcome of node-positive patients with gastric cancer. Langenbecks Arch. Surg. 2010, 395, 211–216.
[121]
Pepper, M.S. Lymphangiogenesis and tumor metastasis: Myth or reality? Clin. Cancer Res. 2001, 7, 462–468.
[122]
McCarter, M.D.; Clarke, J.H.; Harken, A.H. Lymphangiogenesis is pivotal to the trials of a successful cancer metastasis. Surgery 2004, 135, 121–124.
[123]
Stacker, S.A.; Achen, M.G.; Jussila, L.; Baldwin, M.E.; Alitalo, K. Lymphangiogenesis and cancer metastasis. Nat. Rev. Cancer 2002, 2, 573–583.
[124]
Breiteneder-Geleff, S.; Soleiman, A.; Kowalski, H.; Horvat, R.; Amann, G.; Kriehuber, E.; Diem, K.; Weninger, W.; Tschachler, E.; Alitalo, K.; et al. Angiosarcomas express mixed endothelial phenotypes of blood and lymphatic capillaries: Podoplanin as a specific marker for lymphatic endothelium. Am. J. Pathol. 1999, 154, 385–394.
[125]
Banerji, S.; Ni, J.; Wang, S.X.; Clasper, S.; Su, J.; Tammi, R.; Jones, M.; Jackson, D.G. LYVE-1, a new homologue of the CD44 glycoprotein, is a lymph-specific receptor for hyaluronan. J. Cell Biol. 1999, 144, 789–801.
[126]
Wigle, J.T.; Oliver, G. Prox1 function is required for the development of the murine lymphatic system. Cell 1999, 98, 769–778.
[127]
Kaipainen, A.; Korhonen, J.; Mustonen, T.; van Hinsbergh, V.W.; Fang, G.H.; Dumont, D.; Breitman, M.; Alitalo, K. Expression of the fms-like tyrosine kinase 4 gene becomes restricted to lymphatic endothelium during development. Proc. Natl. Acad. Sci. USA 1995, 92, 3566–3570.
[128]
Skobe, M.; Hawighorst, T.; Jackson, D.G.; Prevo, R.; Janes, L.; Velasco, P.; Riccardi, L.; Alitalo, K.; Claffey, K.; Detmar, M. Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis. Nat. Med. 2001, 7, 192–198.
[129]
Karpanen, T.; Egeblad, M.; Karkkainen, M.J.; Kubo, H.; Yla-Herttuala, S.; Jaattela, M.; Alitalo, K. Vascular endothelial growth factor C promotes tumor lymphangiogenesis and intralymphatic tumor growth. Cancer Res. 2001, 61, 1786–1790.
