J Gastric Cancer.  2015 Mar;15(1):1-9. 10.5230/jgc.2015.15.1.1.

Current Status and Scope of Lymph Node Micrometastasis in Gastric Cancer

• Lee CM
• Park SS
• Kim JH

• KMID: 2372365
• DOI: http://doi.org/10.5230/jgc.2015.15.1.1

Abstract

Recently, lymph node micrometastasis has been evaluated for its prognostic value in gastric cancer. Lymph node micrometastasis cannot be detected via a usual pathologic examination, but it can be detected by using some other techniques including immunohistochemistry and reverse transcription-polymerase chain reaction assay. With the development of such diagnostic techniques, the detection rate of lymph node micrometastasis is constantly increasing. Although the prognostic value of lymph node micrometastasis remains debatable, its clinical impact is apparently remarkable in both early and advanced gastric cancer. At present, studies on the prognostic value of lymph node micrometastasis are evolving to overcome its current limitations and extend the scope of its application.

Keyword

Lymph nodes; Micrometastasis; Stomach neoplasms

MeSH Terms

Immunohistochemistry
Lymph Nodes*
Neoplasm Micrometastasis*
Stomach Neoplasms*

Figure

• 

  Fig. 1 Microscopic view of micrometastatic foci (immunocytochemistry stain with antibody CAM 5.2, ×400). Micrometastatic foci were stained with brownish color by immunohistochemical staining.

Reference

1. Siewert JR, Böttcher K, Stein HJ, Roder JD. Relevant prognostic factors in gastric cancer: ten-year results of the German Gastric Cancer Study. Ann Surg. 1998; 228:449–461.

2. Nitti D, Marchet A, Olivieri M, Ambrosi A, Mencarelli R, Belluco C, et al. 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.

3. Kwon SJ, Kim GS. Prognostic significance of lymph node metastasis in advanced carcinoma of the stomach. Br J Surg. 1996; 83:1600–1603.

4. Maehara Y, Okuyama T, Moriguchi S, Orita H, Kusumoto H, Korenaga D, et al. Prophylactic lymph node dissection in patients with advanced gastric cancer promotes increased survival time. Cancer. 1992; 70:392–395.

5. Maehara Y, Oshiro T, Endo K, Baba H, Oda S, Ichiyoshi Y, et al. Clinical significance of occult micrometastasis lymph nodes from patients with early gastric cancer who died of recurrence. Surgery. 1996; 119:397–402.

6. Siewert JR, Kestlmeier R, Busch R, Böttcher K, Roder JD, Müller J, et al. Benefits of D2 lymph node dissection for patients with gastric cancer and pN0 and pN1 lymph node metastases. Br J Surg. 1996; 83:1144–1147.

7. Ishida K, Katsuyama T, Sugiyama A, Kawasaki S. Immunohistochemical evaluation of lymph node micrometastases from gastric carcinomas. Cancer. 1997; 79:1069–1076.

8. Deng J, Liang H, Sun D, Zhang R, Zhan H, Wang X. Prognosis of gastric cancer patients with node-negative metastasis following curative resection: outcomes of the survival and recurrence. Can J Gastroenterol. 2008; 22:835–839.

9. Saito H, Kuroda H, Matsunaga T, Fukuda K, Tatebe S, Tsujitani S, et al. Prognostic indicators in node-negative advanced gastric cancer patients. J Surg Oncol. 2010; 101:622–625.

10. Ru Y, Zhang L, Chen Q, Gao SG, Wang GP, Qu ZF, et al. Detection and clinical significance of lymph node micrometastasis in gastric cardia adenocarcinoma. J Int Med Res. 2012; 40:293–299.

11. Yonemura Y, Endo Y, Hayashi I, Kawamura T, Yun HY, Bandou E. Proliferative activity of micrometastases in the lymph nodes of patients with gastric cancer. Br J Surg. 2007; 94:731–736.

12. Choi HJ, Kim YK, Kim YH, Kim SS, Hong SH. Occurrence and prognostic implications of micrometastases in lymph nodes from patients with submucosal gastric carcinoma. Ann Surg Oncol. 2002; 9:13–19.

13. Cai J, Ikeguchi M, Maeta M, Kaibara N. Micrometastasis in lymph nodes and microinvasion of the muscularis propria in primary lesions of submucosal gastric cancer. Surgery. 2000; 127:32–39.

14. Lee E, Chae Y, Kim I, Choi J, Yeom B, Leong AS. Prognostic relevance of immunohistochemically detected lymph node micrometastasis in patients with gastric carcinoma. Cancer. 2002; 94:2867–2873.

15. Yasuda K, Adachi Y, Shiraishi N, Inomata M, Takeuchi H, Kitano S. Prognostic effect of lymph node micrometastasis in patients with histologically node-negative gastric cancer. Ann Surg Oncol. 2002; 9:771–774.

16. Hata M, Machi J, Mamou J, Yanagihara ET, Saegusa-Beecroft E, Kobayashi GK, et al. Entire-volume serial histological examination for detection of micrometastases in lymph nodes of colorectal cancers. Pathol Oncol Res. 2011; 17:835–841.

17. Matsumoto M, Natsugoe S, Ishigami S, Nakashima S, Nakajo A, Miyazono F, et al. Lymph node micrometastasis and lymphatic mapping determined by reverse transcriptase-polymerase chain reaction in pN0 gastric carcinoma. Surgery. 2002; 131:630–635.

18. Sobin LH, Wittekind C. International Union against Cancer. TNM classification of malignant tumours. 6th ed. New York: Wiley-Liss;2002. p. xxiii. p. 239.

19. Sobin LH, Gospodarowicz MK, Wittekind C. International Union against Cancer. TNM classification of malignant tumours. 7th ed. Chichester, West Sussex, UK; Hoboken, NJ: Wiley-Blackwell;2010. p. xx. p. 309.

20. Arigami T, Uenosono Y, Yanagita S, Nakajo A, Ishigami S, Okumura H, et al. Clinical significance of lymph node micrometastasis in gastric cancer. Ann Surg Oncol. 2013; 20:515–521.

21. Kashimura H, Ajioka Y, Watanabe H, Nishikura K, Iiri T, Asakura H. Risk factors for nodal micrometastasis of submucosal gastric carcinoma: assessment of indications for endoscopic treatment. Gastric Cancer. 1999; 2:33–39.

22. Harrison LE, Choe JK, Goldstein M, Meridian A, Kim SH, Clarke K. Prognostic significance of immunohistochemical micrometastases in node negative gastric cancer patients. J Surg Oncol. 2000; 73:153–157.

23. Okada Y, Fujiwara Y, Yamamoto H, Sugita Y, Yasuda T, Doki Y, et al. Genetic detection of lymph node micrometastases in patients with gastric carcinoma by multiple-marker reverse transcriptase-polymerase chain reaction assay. Cancer. 2001; 92:2056–2064.

24. Nakajo A, Natsugoe S, Ishigami S, Matsumoto M, Nakashima S, Hokita S, et al. Detection and prediction of micrometastasis in the lymph nodes of patients with pN0 gastric cancer. Ann Surg Oncol. 2001; 8:158–162.

25. Morgagni P, Saragoni L, Scarpi E, Zattini PS, Zaccaroni A, Morgagni D, et al. Lymph node micrometastases in early gastric cancer and their impact on prognosis. World J Surg. 2003; 27:558–561.

26. Arigami T, Natsugoe S, Uenosono Y, Arima H, Mataki Y, Ehi K, et al. Lymphatic invasion using D2-40 monoclonal antibody and its relationship to lymph node micrometastasis in pN0 gastric cancer. Br J Cancer. 2005; 93:688–693.

27. Sonoda H, Yamamoto K, Kushima R, Yamamoto H, Naitoh H, Okabe H, et al. Detection of lymph node micrometastasis in pN0 early gastric cancer: efficacy of duplex RT-PCR with MUC2 and TFF1 in mucosal cancer. Oncol Rep. 2006; 16:411–416.

28. Wu ZY, Li JH, Zhan WH, He YL, Wan J. Effect of lymph node micrometastases on prognosis of gastric carcinoma. World J Gastroenterol. 2007; 13:4122–4125.

29. Ishii K, Kinami S, Funaki K, Fujita H, Ninomiya I, Fushida S, et al. Detection of sentinel and non-sentinel lymph node micrometastases by complete serial sectioning and immunohistochemical analysis for gastric cancer. J Exp Clin Cancer Res. 2008; 27:7.

30. Cao L, Hu X, Zhang Y, Huang G. Adverse prognosis of clustered-cell versus single-cell micrometastases in pN0 early gastric cancer. J Surg Oncol. 2011; 103:53–56.

31. Moll R, Franke WW, Schiller DL, Geiger B, Krepler R. The catalog of human cytokeratins: patterns of expression in normal epithelia, tumors and cultured cells. Cell. 1982; 31:11–24.

32. Yamamoto N, Kato Y, Yanagisawa A, Ohta H, Takahashi T, Kitagawa T. Predictive value of genetic diagnosis for cancer micrometastasis: histologic and experimental appraisal. Cancer. 1997; 80:1393–1398.

33. Shiraishi N, Sato K, Yasuda K, Inomata M, Kitano S. Multivariate prognostic study on large gastric cancer. J Surg Oncol. 2007; 96:14–18.

34. Al-Moundhri MS, Al-Bahrani B, Burney IA, Nirmala V, Al-Madhani A, Al-Mawaly K, et al. The prognostic determinants of gastric cancer treatment outcome in Omani Arab patients. Oncology. 2006; 70:90–96.

35. Dicken BJ, Saunders LD, Jhangri GS, de Gara C, Cass C, Andrews S, et al. Gastric cancer: establishing predictors of biologic behavior with use of population-based data. Ann Surg Oncol. 2004; 11:629–635.

36. Isozaki H, Okajima K, Fujii K. Histological evaluation of lymph node metastasis on serial sectioning in gastric cancer with radical lymphadenectomy. Hepatogastroenterology. 1997; 44:1133–1136.

37. Kikuchi Y, Tsuchiya A, Ando Y, Yoshida T, Takenosita S. Immunohistochemical detection of lymph node microinvolvement in node-negative gastric cancer. Gastric Cancer. 1999; 2:173–178.

38. Kim JJ, Song KY, Hur H, Hur JI, Park SM, Park CH. Lymph node micrometastasis in node negative early gastric cancer. Eur J Surg Oncol. 2009; 35:409–414.

39. Bostick PJ, Morton DL, Turner RR, Huynh KT, Wang HJ, Elashoff R, et al. Prognostic significance of occult metastases detected by sentinel lymphadenectomy and reverse transcriptase-polymerase chain reaction in early-stage melanoma patients. J Clin Oncol. 1999; 17:3238–3244.

40. Bostick PJ, Huynh KT, Sarantou T, Turner RR, Qi K, Giuliano AE, et al. Detection of metastases in sentinel lymph nodes of breast cancer patients by multiple-marker RT-PCR. Int J Cancer. 1998; 79:645–651.

41. Hoon DS, Bostick P, Kuo C, Okamoto T, Wang HJ, Elashoff R, et al. Molecular markers in blood as surrogate prognostic indicators of melanoma recurrence. Cancer Res. 2000; 60:2253–2257.

42. Gerhard M, Juhl H, Kalthoff H, Schreiber HW, Wagener C, Neumaier M. Specific detection of carcinoembryonic antigen-expressing tumor cells in bone marrow aspirates by polymerase chain reaction. J Clin Oncol. 1994; 12:725–729.

43. Kubota K, Nakanishi H, Hiki N, Shimizu N, Tsuji E, Yamaguchi H, et al. Quantitative detection of micrometastases in the lymph nodes of gastric cancer patients with real-time RT-PCR: a comparative study with immunohistochemistry. Int J Cancer. 2003; 105:136–143.

44. Ruud P, Fodstad O, Hovig E. Identification of a novel cytokeratin 19 pseudogene that may interfere with reverse transcriptase-polymerase chain reaction assays used to detect micrometastatic tumor cells. Int J Cancer. 1999; 80:119–125.

45. Kuo CT, Hoon DS, Takeuchi H, Turner R, Wang HJ, Morton DL, et al. Prediction of disease outcome in melanoma patients by molecular analysis of paraffin-embedded sentinel lymph nodes. J Clin Oncol. 2003; 21:3566–3572.

46. Yaguchi Y, Sugasawa H, Tsujimoto H, Takata H, Nakabayashi K, Ichikura T, et al. One-step nucleic acid amplification (OSNA) for the application of sentinel node concept in gastric cancer. Ann Surg Oncol. 2011; 18:2289–2296.

47. Tsujimoto M, Nakabayashi K, Yoshidome K, Kaneko T, Iwase T, Akiyama F, et al. One-step nucleic acid amplification for intraoperative detection of lymph node metastasis in breast cancer patients. Clin Cancer Res. 2007; 13:4807–4816.

48. Yanagita S, Natsugoe S, Uenosono Y, Arigami T, Funasako Y, Hirata M, et al. The utility of rapid diagnosis of lymph node metastasis in gastric cancer using a multiplex real-time reverse transcription polymerase chain reaction assay. Oncology. 2009; 77:205–211.

49. Fukagawa T, Sasako M, Mann GB, Sano T, Katai H, Maruyama K, et al. Immunohistochemically detected micrometastases of the lymph nodes in patients with gastric carcinoma. Cancer. 2001; 92:753–760.

50. Wang J, Yu JC, Kang WM, Wang WZ, Liu YQ, Gu P. The predictive effect of cadherin-17 on lymph node micrometastasis in pN0 gastric cancer. Ann Surg Oncol. 2012; 19:1529–1534.

51. Kim JH, Park JM, Jung CW, Park SS, Kim SJ, Mok YJ, et al. The significances of lymph node micrometastasis and its correlation with E-cadherin expression in pT1-T3N0 gastric adenocarcinoma. J Surg Oncol. 2008; 97:125–130.

52. Morgagni P, Saragoni L, Folli S, Gaudio M, Scarpi E, Bazzocchi F, et al. Lymph node micrometastases in patients with early gastric cancer: experience with 139 patients. Ann Surg Oncol. 2001; 8:170–174.

53. Ono H, Kondo H, Gotoda T, Shirao K, Yamaguchi H, Saito D, et al. Endoscopic mucosal resection for treatment of early gastric cancer. Gut. 2001; 48:225–229.

54. Hotta K, Oyama T, Akamatsu T, Tomori A, Hasebe O, Nakamura N, et al. A comparison of outcomes of endoscopic submucosal dissection (ESD) For early gastric neoplasms between high-volume and low-volume centers: multi-center retrospective questionnaire study conducted by the Nagano ESD Study Group. Intern Med. 2010; 49:253–259.

55. Jee YS, Hwang SH, Rao J, Park DJ, Kim HH, Lee HJ, et al. Safety of extended endoscopic mucosal resection and endoscopic submucosal dissection following the Japanese Gastric Cancer Association treatment guidelines. Br J Surg. 2009; 96:1157–1161.

56. Yamaguchi N, Isomoto H, Fukuda E, Ikeda K, Nishiyama H, Akiyama M, et al. Clinical outcomes of endoscopic submucosal dissection for early gastric cancer by indication criteria. Digestion. 2009; 80:173–181.

57. Rösch T. Endosonographic staging of gastric cancer: a review of literature results. Gastrointest Endosc Clin N Am. 1995; 5:549–557.

58. Polkowski M, Palucki J, Wronska E, Szawlowski A, Nasierowska-Guttmejer A, Butruk E. Endosonography versus helical computed tomography for locoregional staging of gastric cancer. Endoscopy. 2004; 36:617–623.

59. Sano T, Hollowood A. Early gastric cancer: diagnosis and less invasive treatments. Scand J Surg. 2006; 95:249–255.

60. Aikou T, Higashi H, Natsugoe S, Hokita S, Baba M, Tako S. Can sentinel node navigation surgery reduce the extent of lymph node dissection in gastric cancer? Ann Surg Oncol. 2001; 8:90S–93S.

61. 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.

62. Arigami T, Natsugoe S, Uenosono Y, Mataki Y, Ehi K, Higashi H, et al. Evaluation of sentinel node concept in gastric cancer based on lymph node micrometastasis determined by reverse transcription-polymerase chain reaction. Ann Surg. 2006; 243:341–347.

63. Tajima Y, Yamazaki K, Masuda Y, Kato M, Yasuda D, Aoki T, et al. Sentinel node mapping guided by indocyanine green fluorescence imaging in gastric cancer. Ann Surg. 2009; 249:58–62.

64. Chao C, Wong SL, Ackermann D, Simpson D, Carter MB, Brown CM, et al. Utility of intraoperative frozen section analysis of sentinel lymph nodes in breast cancer. Am J Surg. 2001; 182:609–615.

65. Tanis PJ, Boom RP, Koops HS, Faneyte IF, Peterse JL, Nieweg OE, et al. Frozen section investigation of the sentinel node in malignant melanoma and breast cancer. Ann Surg Oncol. 2001; 8:222–226.

66. Lee HS, Lee HE, Park do J, Park YS, Kim HH. Precise pathologic examination decreases the false-negative rate of sentinel lymph node biopsy in gastric cancer. Ann Surg Oncol. 2012; 19:772–778.

67. Saikawa Y, Otani Y, Kitagawa Y, Yoshida M, Wada N, Kubota T, et al. Interim results of sentinel node biopsy during laparoscopic gastrectomy: possible role in function-preserving surgery for early cancer. World J Surg. 2006; 30:1962–1968.

68. Takeuchi H, Kitagawa Y. New sentinel node mapping technologies for early gastric cancer. Ann Surg Oncol. 2013; 20:522–532.

69. Takeuchi H, Oyama T, Kamiya S, Nakamura R, Takahashi T, Wada N, et al. Laparoscopy-assisted proximal gastrectomy with sentinel node mapping for early gastric cancer. World J Surg. 2011; 35:2463–2471.

70. Bok GH, Kim YJ, Jin SY, Chun CG, Lee TH, Kim HG, et al. Endoscopic submucosal dissection with sentinel node navigation surgery for early gastric cancer. Endoscopy. 2012; 44:953–956.

71. Takeuchi H, Kitagawa Y. Sentinel node navigation surgery in patients with early gastric cancer. Dig Surg. 2013; 30:104–111.

72. Washington K. 7th edition of the AJCC cancer staging manual: stomach. Ann Surg Oncol. 2010; 17:3077–3079.

73. Hirata K, Horikoshi N, Aiba K, Okazaki M, Denno R, Sasaki K, et al. Pharmacokinetic study of S-1, a novel oral fluorouracil antitumor drug. Clin Cancer Res. 1999; 5:2000–2005.

74. Ohtsu A. Current status and future prospects of chemotherapy for metastatic gastric cancer: a review. Gastric Cancer. 2005; 8:95–102.

75. Koizumi W, Narahara H, Hara T, Takagane A, Akiya T, Takagi M, et al. S-1 plus cisplatin versus S-1 alone for first-line treatment of advanced gastric cancer (SPIRITS trial): a phase III trial. Lancet Oncol. 2008; 9:215–221.

76. Lee CM, Cho JM, Jang YJ, Park SS, Park SH, Kim SJ, et al. Should lymph node micrometastasis be considered in node staging for gastric cancer?: the significance of lymph node micrometastasis in gastric cancer. Ann Surg Oncol. 2014; [Epub].