Gastric Cancer

, Volume 13, Issue 3, pp 191–196 | Cite as

The prognostic significance of isolated tumor cells in the lymph nodes of gastric cancer patients

  • Takeo Fukagawa
  • Mitsuru Sasako
  • Seiji Ito
  • Hayao Nakanishi
  • Hisae Iinuma
  • Shoji Natsugoe
  • Hitoshi Katai
  • Tadakazu Shimoda
Original Article



The clinical significance of isolated tumor cells (ITC) detected immunohistochemically in the lymph nodes of gastric cancer patients is controversial. The aim of this study was to examine the prognostic impact of ITC in patients with gastric cancer.


The data of a total of 402 patients with pathological T2N0 and T2N1 gastric cancer who underwent gastrectomy with D2 lymph node dissection between 1984 and 1990 at four participant hospitals were analyzed. All resected lymph nodes were reexamined by serial sectioning with hematoxylin & eosin (H&E) staining, and evaluated by immunohistochemistry using antibody against cytokeratin (AE1/3). The prevalence and prognostic significance of ITC were investigated.


ITC were detected in 187 of the 402 (47%) patients. A multivariate analysis identified the nodal status, histological type, and tumor size as significant factors predictive of the presence/absence of ITC. The 5-year and 10-year overall survival rates of patients with vs those without ITC were 84.4% (95% confidence interval [CI], 79.1–89.0) and 70.4% (95% CI, 64.1–76.7) vs 83.9% (95% CI, 78.6–89.2) and 72.0% (95% CI, 65.4–78.5), respectively. The hazard ratio for death in patients with ITC as compared with those without ITC was 0.90 (95% CI, 0.64–1.26; P = 0.53).


The presence of ITC in the lymph nodes does not affect the prognosis of patients with gastric cancer who have undergone gastrectomy with D2 lymph node dissection.

Key words

ITC Lymph node metastases Gastric cancer Immunohistochemistry Lymph node dissection 


  1. 1.
    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.CrossRefPubMedGoogle Scholar
  2. 2.
    Hayashi N, Arakawa H, Nagase H, Yanagisawa A, Kato Y, Ohta H, et al. Genetic diagnosis identifies occult lymph node metastases undetectable by the histopathological method. Cancer Res 1994;54:3853–3856.PubMedGoogle Scholar
  3. 3.
    Izbicki JR, Hosch SB, Pichlmeier U, Rehders A, Busch C, Niendorf A, et al. Prognostic value of immunohistochemically identifiable tumor cells in lymph nodes of patients with completely resected esophageal cancer. N Engl J Med 1997;337:1188–1194.CrossRefPubMedGoogle Scholar
  4. 4.
    Mimori K, Fukagawa T, Kosaka Y, Kita Y, Ishikawa K, Etoh T, et al. Hematogenous metastasis in gastric cancer requires isolated tumor cells and expression of vascular endothelial growth factor receptor-1. Clin Cancer Res 2008;14:2609–2616.CrossRefPubMedGoogle Scholar
  5. 5.
    Wiedswang G, Borgen E, Karesen R, Kvalheim G, Nesland JM, Qvist H, et al. Detection of isolated tumor cells in bone marrow is an independent prognostic factor in breast cancer. J Clin Oncol 2003;21:3469–3478.CrossRefPubMedGoogle Scholar
  6. 6.
    O’sullivan GC, Collins JK, Kelly J, Morgan J, Madden M, Shanahan F. Micrometastases: marker of metastatic potential or evidence of residual disease? Gut 1997;40:512–515.PubMedGoogle Scholar
  7. 7.
    Braun S, Pantel K, Muller P, Janni W, Hepp F, Kentenich CR, 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.CrossRefPubMedGoogle Scholar
  8. 8.
    Hermanek P, Hutter RV, Sobin LH, Wittekind C. International Union against Cancer. Classification of isolated tumor cells and micrometastasis. Cancer 1999;86:2668–2673.CrossRefPubMedGoogle Scholar
  9. 9.
    Sobin LH. TNM, sixth edition: new developments in general concepts and rules. Semin Surg Oncol 2003;21:19–22.CrossRefPubMedGoogle Scholar
  10. 10.
    Bonenkamp JJ, Hermans J, Sasako M, van de Velde CJ, Welvaart K, Songun I, et al. Extended lymph-node dissection for gastric cancer. New Engl J Med 1999;340:908–914.CrossRefPubMedGoogle Scholar
  11. 11.
    Hamilton SR, Aaltonen LA. WHO classification of tumors: pathology and genetics of the digestive system. Lyon, France: IARC; 2000.Google Scholar
  12. 12.
    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.CrossRefPubMedGoogle Scholar
  13. 13.
    Kell MR, Winter DC, O’sullivan GC, Shanahan F, Redmond HP. Biological behaviour and clinical implications of micrometastases. Br J Surg 2000;87:1629–1639.CrossRefPubMedGoogle Scholar
  14. 14.
    Hara M, Hirai T, Nakanishi H, Kanemitsu Y, Komori K, Tatematsu M, et al. Isolated tumor cell in lateral lymph node has no influence on the prognosis of rectal cancer patients. Int J Colorectal Dis 2007;22:911–917.CrossRefPubMedGoogle Scholar
  15. 15.
    Lee MR, Hong CW, Yoon SN, Lim SB, Park KJ, Lee MJ, et al. Isolated tumor cells in lymph nodes are not a prognostic marker for patients with stage I and stage II colorectal cancer. J Surg Oncol 2006;93:13–18; discussion 18–9.CrossRefPubMedGoogle Scholar
  16. 16.
    Fournier K, Schiller A, Perry RR, Laronga C. Micrometastasis in the sentinel lymph node of breast cancer does not mandate completion axillary dissection. Ann Surg 2004;239:859–863; discussion 863–5.CrossRefPubMedGoogle Scholar
  17. 17.
    Scheri RP, Essner R, Turner RR, Ye X, Morton DL. Isolated tumor cells in the sentinel node affect long-term prognosis of patients with melanoma. Ann Surg Oncol 2007;14:2861–2866.CrossRefPubMedGoogle Scholar
  18. 18.
    Brennan MF. Lymph-node dissection for gastric cancer. New Engl J Med 1999;340:956–958.CrossRefPubMedGoogle Scholar
  19. 19.
    Doekhie FS, Mesker WE, van Krieken JH, Kok NF, Hartgrink HH, Kranenbarg EK, et al. Clinical relevance of occult tumor cells in lymph nodes from gastric cancer patients. Am J Surg Pathol 2005;29:1135–1144.CrossRefPubMedGoogle Scholar
  20. 20.
    Scheunemann P, Izbicki JR, Pantel K. Tumorigenic potential of apparently tumor-free lymph nodes. N Engl J Med 1999;340:1687.CrossRefPubMedGoogle Scholar
  21. 21.
    Natsugoe S, Nakashima S, Matsumoto M, Nakajo A, Miyazono F, Kijima F, et al. Paraaortic lymph node micrometastasis and tumor cell microinvolvement in advanced gastric carcinoma. Gastric Cancer 1999;2:179–185.CrossRefPubMedGoogle Scholar
  22. 22.
    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.CrossRefPubMedGoogle Scholar
  23. 23.
    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.CrossRefPubMedGoogle Scholar
  24. 24.
    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.CrossRefPubMedGoogle Scholar
  25. 25.
    Scheunemann P, Stoecklein NH, Hermann K, Rehders A, Eisenberger CF, Knoefel WT, et al. Occult disseminated tumor cells in lymph nodes of patients with gastric carcinoma. A critical appraisal of assessment and relevance. Langenbecks Arch Surg 2009;394:105–113.CrossRefPubMedGoogle Scholar
  26. 26.
    Horstmann O, Fuzesi L, Markus PM, Werner C, Becker H. Significance of isolated tumor cells in lymph nodes among gastric cancer patients. J Cancer Res Clin Oncol 2004;130:733–740.CrossRefPubMedGoogle Scholar
  27. 27.
    Fukagawa T, Sasako M, Shimoda T, Sano T, Katai H, Saka M, et al. The prognostic impact of isolated tumor cells in lymph nodes of T2N0 gastric cancer: comparison of American and Japanese gastric cancer patients. Ann Surg Oncol 2009;16:609–613.CrossRefPubMedGoogle Scholar
  28. 28.
    Noda N, Sasako M, Yamaguchi N, Nakanishi Y. Ignoring small lymph nodes can be a major cause of staging error in gastric cancer. Br J Surg 1998;85:831–834.CrossRefPubMedGoogle Scholar
  29. 29.
    Cserni G, Bianchi S, Boecker W, Decker T, Lacerda M, Rank F, et al. Improving the reproducibility of diagnosing micrometastases and isolated tumor cells. Cancer 2005;103:358–367.CrossRefPubMedGoogle Scholar
  30. 30.
    de Mascarel I, MacGrogan G, Debled M, Brouste V, Mauriac L. Distinction between isolated tumor cells and micrometastases in breast cancer: is it reliable and useful? Cancer 2008;112:1672–1678.CrossRefPubMedGoogle Scholar
  31. 31.
    Sakuramoto S, Sasako M, Yamaguchi T, Kinoshita T, Fujii M, Nashimoto A, et al. Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine. N Engl J Med 2007;357:1810–1820.CrossRefPubMedGoogle Scholar
  32. 32.
    Macdonald JS, Smalley SR, Benedetti J, Hundahl SA, Estes NC, Stemmermann GN, et al. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med 2001;345:725–730.CrossRefPubMedGoogle Scholar
  33. 33.
    Chambers AF, Groom AC, MacDonald IC. Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer 2002;2:563–572.CrossRefPubMedGoogle Scholar
  34. 34.
    Hosch S, Kraus J, Scheunemann P, Izbicki JR, Schneider C, Schumacher U, et al. Malignant potential and cytogenetic characteristics of occult disseminated tumor cells in esophageal cancer. Cancer Res 2000;60:6836–6840.PubMedGoogle Scholar
  35. 35.
    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.CrossRefPubMedGoogle Scholar

Copyright information

© The International Gastric Cancer Association and The Japanese Gastric Cancer Association 2010

Authors and Affiliations

  • Takeo Fukagawa
    • 1
  • Mitsuru Sasako
    • 2
  • Seiji Ito
    • 3
  • Hayao Nakanishi
    • 4
  • Hisae Iinuma
    • 5
  • Shoji Natsugoe
    • 6
  • Hitoshi Katai
    • 1
  • Tadakazu Shimoda
    • 7
  1. 1.Gastric Surgery DivisionNational Cancer Center HospitalTokyoJapan
  2. 2.Digestive SurgeryHyogo Medical CollegeHyogoJapan
  3. 3.Department of Gastrointestinal SurgeryAichi Cancer Center HospitalNagoyaJapan
  4. 4.Division of Oncological PathologyAichi Cancer Center Research InstituteNagoyaJapan
  5. 5.Department of SurgeryTeikyo UniversityTokyoJapan
  6. 6.Department of Surgical OncologyKagoshima UniversityKagoshimaJapan
  7. 7.Clinical Laboratory DivisionNational Cancer Center HospitalTokyoJapan

Personalised recommendations