Korean J Gastroenterol.  2017 May;69(5):270-277. 10.4166/kjg.2017.69.5.270.

Micrometastasis in Gastric Cancer

Affiliations
  • 1Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea. jwchulkr@catholic.ac.kr

Abstract

Although the incidence and mortality rate of gastric cancer have been steadily declining, gastric cancer is still the fourth most common cancer in the world and more than 50% of cases occur in Eastern Asia. In Korea, gastric cancer is the second most common cancer and third cause of cancer related death. The standard surgical procedure for resectable advanced gastric cancer is D2 lymphadenectomy with radical gastrectomy. Even though R0 resection was completed, recurrence is relatively common, and contributes to the limited survival of the patients in gastric cancer. As a clinically relevant factor for detection of the recurrence, the presence of isolating tumor cells has been introduced and it is so called as "˜micrometastasis'. Numerous immunohistochemistry and molecular studies have shown that micrometastasis can be demonstrated not only in lymph nodes but also in such body compartments as the bone marrow, peritoneal cavity and blood. Herein, we review the current knowledge and evidence of the prognostic significance of micrometastasis in peritoneal, lymph node, bone marrow. Also, we discuss the current state of research on the circulating tumor cell in peripheral blood.

Keyword

Gastric cancer; Micrometastasis; Prognosis

MeSH Terms

Bone Marrow
Far East
Gastrectomy
Humans
Immunohistochemistry
Incidence
Korea
Lymph Node Excision
Lymph Nodes
Mortality
Neoplasm Micrometastasis*
Neoplastic Cells, Circulating
Peritoneal Cavity
Prognosis
Recurrence
Stomach Neoplasms*

Reference

1. Piazuelo MB, Correa P. Gastric cancer: overview. Colomb Med (Cali). 2013; 44:192–201. eCollection 2013.
2. Shimada Y. JGCA (The Japan Gastric Cancer Association). Gastric cancer treatment guidelines. Jpn J Clin Oncol. 2004; 34:58.
3. Oh CM, Won YJ, Jung KW, et al. Cancer statistics in Korea: incidence, mortality, survival, and prevalence in 2013. Cancer Res Treat. 2016; 48:436–450.
4. Yashiro M, Matsuoka T. Sentinel node navigation surgery for gastric cancer: overview and perspective. World J Gastrointest Surg. 2015; 7:1–9.
5. Nashimoto A, Akazawa K, Isobe Y, et al. Gastric cancer treated in 2002 in Japan: 2009 annual report of the JGCA nationwide registry. Gastric Cancer. 2013; 16:1–27.
6. Yamada E, Miyaishi S, Nakazato H, et al. The surgical treatment of cancer of the stomach. Int Surg. 1980; 65:387–399.
7. Marano L, Polom K, Patriti A, et al. Surgical management of advanced gastric cancer: an evolving issue. Eur J Surg Oncol. 2016; 42:18–27.
8. Maehara Y, Oshiro T, Endo K, et al. Clinical significance of occult micrometastasis lymph nodes from patients with early gastric cancer who died of recurrence. Surgery. 1996; 119:397–402.
9. Ishida K, Katsuyama T, Sugiyama A, Kawasaki S. Immunohistochemical evaluation of lymph node micrometastases from gastric carcinomas. Cancer. 1997; 79:1069–1076.
10. Liefers GJ, Cleton-Jansen AM, van de Velde CJ, et al. Micrometastases and survival in stage II colorectal cancer. N Engl J Med. 1998; 339:223–228.
11. Pantel K, Cote RJ, Fodstad O. Detection and clinical importance of micrometastatic disease. J Natl Cancer Inst. 1999; 91:1113–1124.
12. Goeminne JC, Guillaume T, Symann M. Pitfalls in the detection of disseminated non-hematological tumor cells. Ann Oncol. 2000; 11:785–792.
13. Mezhir JJ, Shah MA, Jacks LM, Brennan MF, Coit DG, Strong VE. Positive peritoneal cytology in patients with gastric cancer: natural history and outcome of 291 patients. Indian J Surg Oncol. 2011; 2:16–23.
14. Badgwell B, Cormier JN, Krishnan S, et al. Does neoadjuvant treatment for gastric cancer patients with positive peritoneal cytology at staging laparoscopy improve survival? Ann Surg Oncol. 2008; 15:2684–2691.
15. Koga S, Kaibara N, Iitsuka Y, Kudo H, Kimura A, Hiraoka H. Prognostic significance of intraperitoneal free cancer cells in gastric cancer patients. J Cancer Res Clin Oncol. 1984; 108:236–238.
16. Bando E, Yonemura Y, Takeshita Y, et al. Intraoperative lavage for cytological examination in 1,297 patients with gastric carcinoma. Am J Surg. 1999; 178:256–262.
17. Bonenkamp JJ, Songun I, Hermans J, van de Velde CJ. Prognostic value of positive cytology findings from abdominal washings in patients with gastric cancer. Br J Surg. 1996; 83:672–674.
18. Ribeiro U Jr, Safatle-Ribeiro AV, Zilberstein B, et al. Does the intraoperative peritoneal lavage cytology add prognostic information in patients with potentially curative gastric resection? J Gastrointest Surg. 2006; 10:170–176. discussion 176-177.
19. Bentrem D, Wilton A, Mazumdar M, Brennan M, Coit D. The value of peritoneal cytology as a preoperative predictor in patients with gastric carcinoma undergoing a curative resection. Ann Surg Oncol. 2005; 12:347–353.
20. Japanese Gastric Cancer Association. Japanese classification of gastric carcinoma: 3rd English edition. Gastric Cancer. 2011; 14:101–112.
21. Washington K. 7th edition of the AJCC cancer staging manual: stomach. Ann Surg Oncol. 2010; 17:3077–3079.
22. La Torre M, Ferri M, Giovagnoli MR, et al. Peritoneal wash cytology in gastric carcinoma. Prognostic significance and therapeutic consequences. Eur J Surg Oncol. 2010; 36:982–986.
23. Yabusaki H, Nakagawa S, Nashimoto A. Clinical significance of washing cytology in patients with advanced gastric cancer. Gan To Kagaku Ryoho. 2005; 32:1643–1645.
24. Dalal KM, Woo Y, Kelly K, et al. Detection of micrometastases in peritoneal washings of gastric cancer patients by the reverse transcriptase polymerase chain reaction. Gastric Cancer. 2008; 11:206–213.
25. Noura S, Yamamoto H, Ohnishi T, et al. Comparative detection of lymph node micrometastases of stage II colorectal cancer by reverse transcriptase polymerase chain reaction and immunohistochemistry. J Clin Oncol. 2002; 20:4232–4241.
26. Sugita Y, Fujiwara Y, Taniguchi H, et al. Quantitative molecular diagnosis of peritoneal lavage fluid for prediction of peritoneal recurrence in gastric cancer. Int J Oncol. 2003; 23:1419–1423.
27. Katsuragi K, Yashiro M, Sawada T, Osaka H, Ohira M, Hirakawa K. Prognostic impact of PCR-based identification of isolated tumour cells in the peritoneal lavage fluid of gastric cancer patients who underwent a curative R0 resection. Br J Cancer. 2007; 97:550–556.
28. Kodera Y, Nakanishi H, Ito S, et al. Prognostic significance of intraperitoneal cancer cells in gastric carcinoma: detection of cytokeratin 20 mRNA in peritoneal washes, in addition to detection of carcinoembryonic antigen. Gastric Cancer. 2005; 8:142–148.
29. Takata A, Kurokawa Y, Fujiwara Y, et al. Prognostic value of CEA and CK20 mRNA in the peritoneal lavage fluid of patients undergoing curative surgery for gastric cancer. World J Surg. 2014; 38:1107–1111.
30. Mori K, Aoyagi K, Ueda T, et al. Highly specific marker genes for detecting minimal gastric cancer cells in cytology negative peritoneal washings. Biochem Biophys Res Commun. 2004; 313:931–937.
31. Li Z, Zhang D, Zhang H, et al. Prediction of peritoneal recurrence by the mRNA level of CEA and MMP-7 in peritoneal lavage of gastric cancer patients. Tumour Biol. 2014; 35:3463–3470.
32. Ajani JA, Bentrem DJ, Besh S, et al. Gastric cancer, version 2.2013: featured updates to the NCCN guidelines. J Natl Compr Canc Netw. 2013; 11:531–546.
33. D'Ugo DM, Pende V, Persiani R, Rausei S, Picciocchi A. Laparoscopic staging of gastric cancer: an overview. J Am Coll Surg. 2003; 196:965–974.
34. Ajani JA, Mansfield PF, Lynch PM, et al. Enhanced staging and all chemotherapy preoperatively in patients with potentially resectable gastric carcinoma. J Clin Oncol. 1999; 17:2403–2411.
35. Tourani SS, Cabalag C, Link E, Chan ST, Duong CP. Laparoscopy and peritoneal cytology: important prognostic tools to guide treatment selection in gastric adenocarcinoma. ANZ J Surg. 2015; 85:69–73.
36. Brar SS, Mahar AL, Helyer LK, et al. Processes of care in the multidisciplinary treatment of gastric cancer: results of a RAND/UCLA expert panel. JAMA Surg. 2014; 149:18–25.
37. Kwon SJ, Kim GS. Prognostic significance of lymph node metastasis in advanced carcinoma of the stomach. Br J Surg. 1996; 83:1600–1603.
38. Nitti D, Marchet A, Olivieri M, 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.
39. 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.
40. Morgagni P, Saragoni L, Folli S, et al. Lymph node micrometastases in patients with early gastric cancer: experience with 139 patients. Ann Surg Oncol. 2001; 8:170–174.
41. Morgagni P, Saragoni L, Scarpi E, et al. Lymph node micrometastases in early gastric cancer and their impact on prognosis. World J Surg. 2003; 27:558–561.
42. Kim JH, Park JM, Jung CW, 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.
43. Matsumoto M, Natsugoe S, Ishigami S, et al. Lymph node micrometastasis and lymphatic mapping determined by reverse transcriptase-polymerase chain reaction in pN0 gastric carcinoma. Surgery. 2002; 131:630–635.
44. Okada Y, Fujiwara Y, Yamamoto H, 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.
45. 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.
46. Arigami T, Natsugoe S, Uenosono Y, 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.
47. Davids V, Kidson SH, Hanekom GS. Melanoma patient staging: histopathological versus molecular evaluation of the sentinel node. Melanoma Res. 2003; 13:313–324.
48. 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; 8:9 Suppl. 90S–93S.
49. 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.
50. 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.
51. Miyake K, Seshimo A, Kameoka S. Assessment of lymph node micrometastasis in early gastric cancer in relation to sentinel nodes. Gastric Cancer. 2006; 9:197–202.
52. Sonoda H, Yamamoto K, Kushima R, 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.
53. 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.
54. 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.
55. Cai J, Ikeguchi M, Tsujitani S, Maeta M, Kaibara N. Micrometastasis in lymph nodes of mucosal gastric cancer. Gastric Cancer. 2000; 3:91–96.
56. Japanese Gastric Cancer Association. Japanese gastric cancer treatment guidelines 2010 (ver. 3). Gastric Cancer. 2011; 14:113–123.
57. Ono H, Yao K, Fujishiro M, et al. Guidelines for endoscopic submucosal dissection and endoscopic mucosal resection for early gastric cancer. Dig Endosc. 2016; 28:3–15.
58. Pimentel-Nunes P, Dinis-Ribeiro M, Ponchon T, et al. Endoscopic submucosal dissection: European Society of Gastrointestinal Endoscopy (ESGE) guideline. Endoscopy. 2015; 47:829–854.
59. Weidner N. New paradigm for vessel intravasation by tumor cells. Am J Pathol. 2002; 160:1937–1939.
60. Langheinrich MC, Schellerer V, Perrakis A, et al. Molecular mechanisms of lymphatic metastasis in solid tumors of the gastrointestinal tract. Int J Clin Exp Pathol. 2012; 5:614–623.
61. Dicken BJ, Graham K, Hamilton SM, et al. Lymphovascular invasion is associated with poor survival in gastric cancer: an application of gene-expression and tissue array techniques. Ann Surg. 2006; 243:64–73.
62. del Casar JM, Corte MD, Alvarez A, et al. Lymphatic and/or blood vessel invasion in gastric cancer: relationship with clinicopathological parameters, biological factors and prognostic significance. J Cancer Res Clin Oncol. 2008; 134:153–161.
63. Kim JH, Park SS, Park SH, et al. Clinical significance of immunohistochemically-identified lymphatic and/or blood vessel tumor invasion in gastric cancer. J Surg Res. 2010; 162:177–183.
64. Kim H, Kim JH, Park JC, Lee YC, Noh SH, Kim H. Lymphovascular invasion is an important predictor of lymph node metastasis in endoscopically resected early gastric cancers. Oncol Rep. 2011; 25:1589–1595.
65. Du CY, Chen JG, Zhou Y, et al. Impact of lymphatic and/or blood vessel invasion in stage II gastric cancer. World J Gastroenterol. 2012; 18:3610–3616.
66. Li P, He HQ, Zhu CM, et al. The prognostic significance of lymphovascular invasion in patients with resectable gastric cancer: a large retrospective study from Southern China. BMC Cancer. 2015; 15:370.
67. Skobe M, Hawighorst T, Jackson DG, et al. Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis. Nat Med. 2001; 7:192–198.
68. Parr C, Jiang WG. Quantitative analysis of lymphangiogenic markers in human colorectal cancer. Int J Oncol. 2003; 23:533–539.
69. Arigami T, Natsugoe S, Uenosono Y, 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.
70. Gresta LT, Rodrigues-Júnior IA, de Castro LP, Cassali GD, Cabral MM. Assessment of vascular invasion in gastric cancer: a comparative study. World J Gastroenterol. 2013; 19:3761–3769.
71. Veronesi U, Paganelli G, Viale G, et al. A randomized comparison of sentinel-node biopsy with routine axillary dissection in breast cancer. N Engl J Med. 2003; 349:546–553.
72. Morton DL, Thompson JF, Essner R, et al. Validation of the accuracy of intraoperative lymphatic mapping and sentinel lymphadenectomy for early-stage melanoma: a multicenter trial. Multicenter Selective Lymphadenectomy Trial Group. Ann Surg. 1999; 230:453–463. discussion 463-455.
73. Kitagawa Y, Fujii H, Mukai M, et al. The role of the sentinel lymph node in gastrointestinal cancer. Surg Clin North Am. 2000; 80:1799–1809.
74. Hiratsuka M, Miyashiro I, Ishikawa O, et al. Application of sentinel node biopsy to gastric cancer surgery. Surgery. 2001; 129:335–340.
75. Saikawa Y, Otani Y, Kitagawa Y, 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.
76. Takeuchi H, Oyama T, Kamiya S, et al. Laparoscopy-assisted proximal gastrectomy with sentinel node mapping for early gastric cancer. World J Surg. 2011; 35:2463–2471.
77. Shimizu Y, Takeuchi H, Sakakura Y, et al. Molecular detection of sentinel node micrometastases in patients with clinical N0 gastric carcinoma with real-time multiplex reverse transcription-polymerase chain reaction assay. Ann Surg Oncol. 2012; 19:469–477.
78. Yaguchi Y, Sugasawa H, Tsujimoto H, 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.
79. Ryu KW, Eom BW, Nam BH, et al. Is the sentinel node biopsy clinically applicable for limited lymphadenectomy and modified gastric resection in gastric cancer? A meta-analysis of feasibility studies. J Surg Oncol. 2011; 104:578–584.
80. Kitagawa Y, Fujii H, Kumai K, et al. Recent advances in sentinel node navigation for gastric cancer: a paradigm shift of surgical management. J Surg Oncol. 2005; 90:147–151. discussion 151-152.
81. Braun S, Pantel K, Müller P, et al. Cytokeratin-positive cells in the bone marrow and survival of patients with stage I, II, or III breast cancer. N Engl J Med. 2000; 342:525–533.
82. Lindemann F, Schlimok G, Dirschedl P, Witte J, Riethmüller G. Prognostic significance of micrometastatic tumour cells in bone marrow of colorectal cancer patients. Lancet. 1992; 340:685–689.
83. Diel IJ, Kaufmann M, Goerner R, Costa SD, Kaul S, Bastert G. Detection of tumor cells in bone marrow of patients with primary breast cancer: a prognostic factor for distant metastasis. J Clin Oncol. 1992; 10:1534–1539.
84. Thorban S, Roder JD, Pantel K, Siewert JR. Immunocytochemical detection of isolated epithelial tumor cells in bone marrow of patients with pancreatic carcinoma. Am J Surg. 1996; 172:297–298.
85. Pantel K, Dickmanns A, Zippelius A, et al. Establishment of micrometastatic carcinoma cell lines: a novel source of tumor cell vaccines. J Natl Cancer Inst. 1995; 87:1162–1168.
86. Putz E, Witter K, Offner S, et al. Phenotypic characteristics of cell lines derived from disseminated cancer cells in bone marrow of patients with solid epithelial tumors: establishment of working models for human micrometastases. Cancer Res. 1999; 59:241–248.
87. Borgen E, Beiske K, Trachsel S, et al. Immunocytochemical detection of isolated epithelial cells in bone marrow: non-specific staining and contribution by plasma cells directly reactive to alkaline phosphatase. J Pathol. 1998; 185:427–434.
88. Valladares-Ayerbes M, Blanco M, Haz M, et al. Prognostic impact of disseminated tumor cells and microRNA-17-92 cluster deregulation in gastrointestinal cancer. Int J Oncol. 2011; 39:1253–1264.
89. Oki E, Maehara Y, Tokunaga E, et al. Detection of disseminated cancer cells in bone marrow of gastric cancer using real time quantitative reverse transcriptase polymerase chain reaction. Cancer Lett. 2002; 188:191–198.
90. Dardaei L, Shahsavani R, Ghavamzadeh A, et al. The detection of disseminated tumor cells in bone marrow and peripheral blood of gastric cancer patients by multimarker (CEA, CK20, TFF1 and MUC2) quantitative real-time PCR. Clin Biochem. 2011; 44:325–330.
91. Maehara Y, Yamamoto M, Oda S, et al. Cytokeratin-positive cells in bone marrow for identifying distant micrometastasis of gastric cancer. Br J Cancer. 1996; 73:83–87.
92. Matsunami K, Nakamura T, Oguma H, Kitamura Y, Takasaki K. Detection of bone marrow micrometastasis in gastric cancer patients by immunomagnetic separation. Ann Surg Oncol. 2003; 10:171–175.
93. Macadam R, Sarela A, Wilson J, MacLennan K, Guillou P. Bone marrow micrometastases predict early post-operative recurrence following surgical resection of oesophageal and gastric carcinoma. Eur J Surg Oncol. 2003; 29:450–454.
94. Jauch KW, Heiss MM, Gruetzner U, et al. Prognostic significance of bone marrow micrometastases in patients with gastric cancer. J Clin Oncol. 1996; 14:1810–1817.
95. Oki E, Kakeji Y, Baba H, et al. Clinical significance of cytokeratin positive cells in bone marrow of gastric cancer patients. J Cancer Res Clin Oncol. 2007; 133:995–1000.
96. Racila E, Euhus D, Weiss AJ, et al. Detection and characterization of carcinoma cells in the blood. Proc Natl Acad Sci U S A. 1998; 95:4589–4594.
97. Ghossein RA, Bhattacharya S, Rosai J. Molecular detection of micrometastases and circulating tumor cells in solid tumors. Clin Cancer Res. 1999; 5:1950–1960.
98. Gaforio JJ, Serrano MJ, Sanchez-Rovira P, et al. Detection of breast cancer cells in the peripheral blood is positively correlated with estrogen-receptor status and predicts for poor prognosis. Int J Cancer. 2003; 107:984–990.
99. Shariat SF, Roudier MP, Wilcox GE, et al. Comparison of immunohistochemistry with reverse transcription-PCR for the detection of micrometastatic prostate cancer in lymph nodes. Cancer Res. 2003; 63:4662–4670.
100. Straub B, Müller M, Krause H, Schrader M, Miller K. Quantitative real-time rt-PCR for detection of circulating prostate-specific antigen mRNA using sequence-specific oligonucleotide hybridization probes in prostate cancer patients. Oncology. 2003; 65:Suppl 1. 12–17.
101. Moreno JG, O'Hara SM, Gross S, et al. Changes in circulating carcinoma cells in patients with metastatic prostate cancer correlate with disease status. Urology. 2001; 58:386–392.
102. Kolostova K, Matkowski R, Gurlich R, et al. Detection and cultivation of circulating tumor cells in gastric cancer. Cytotechnology. 2016; 68:1095–1102.
103. Allard WJ, Matera J, Miller MC, et al. Tumor cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects or patients with nonmalignant diseases. Clin Cancer Res. 2004; 10:6897–6904.
104. Farace F, Massard C, Vimond N, et al. A direct comparison of CellSearch and ISET for circulating tumour-cell detection in patients with metastatic carcinomas. Br J Cancer. 2011; 105:847–853.
105. Cristofanilli M, Budd GT, Ellis MJ, et al. Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med. 2004; 351:781–791.
106. Okabe H, Tsunoda S, Hosogi H, et al. Circulating tumor cells as an independent predictor of survival in advanced gastric cancer. Ann Surg Oncol. 2015; 22:3954–3961.
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