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Occult Tumour Cells in Lymph Nodes from Gastric Cancer Patients: Should Isolated Tumour Cells Also Be Considered?

  • Gastrointestinal Oncology
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Introduction

Regional lymph node metastasis is an important prognostic factor for patients with gastric cancer. Occult tumour cells (OTCs), including either micrometastases (MMs) or isolated tumour cells (ITCs), may be a key factor in the development of cancer recurrence in pN0 patients.

Aims

We aimed to determine the frequency and prognostic significance for disease recurrence of OTCs.

Materials and Methods

This retrospective cohort study included all consecutive patients with pN0 gastric adenocarcinoma between January 2000 and December 2011 (n = 73). Immunohistochemistry using the pan-cytokeratin antibody AE1/AE3 was used to detect OTCs in 1257 isolated lymph nodes.

Results

OTCs were identified in 30 patients (41%), including 20 cases with MMs (27%) and 10 cases with ITCs (14%). Disease recurrence and cancer-related death were observed in 24 (33%) and 20 patients (27%), respectively, and both were significantly associated with the detection of OTCs. A significant difference was also observed for the mean survival time between patients with OTCs and those without OTCs [100 vs 158 months (p = 0.015)]. The presence of OTCs was statistically significantly associated with the Lauren classification, tumour size and lymphatic permeation. Multivariate analyses revealed that only age, T stage and the presence of ITCs in lymph nodes were independent factors for recurrence. The presence of ITCs increased the risk for recurrence by 11.1-fold.

Conclusions

In a significant proportion of patients diagnosed as stage pN0, OTCs may be identified in lymph nodes if carefully searched for, which can negatively affect their prognosis. The presence of ITCs was found to be an independent factor for recurrence and after proper validation should be considered during lymph node assessment for prognosis definition.

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References

  1. Sonoda H, Tani T. Clinical significance of molecular diagnosis for gastric cancer lymph node micrometastasis. World J Gastroenterol. 2014;20(38):13728–33.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Zhao BHX, Zhang J, Luo R, Lu H, Xu H, Huang B. Clinicopathologic factors associated with recurrence and long-term survival in node-negative advanced gastric cancer patients. Rev Esp Enferm Dig. 2019;111(2):111–20.

    PubMed  Google Scholar 

  3. Liu YF, Guo S, Zhao R, Chen YG, Wang XQ, Xu KS. Correlation of vascular endothelial growth factor expression with tumor recurrence and poor prognosis in patients with pN0 gastric cancer. World J Surg. 2012;36(1):109–17.

    Article  PubMed  Google Scholar 

  4. Lee CM, Park SS, Kim JH. Current status and scope of lymph node micrometastasis in gastric cancer. J Gastric Cancer. 2015;15(1):1–9.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Jeuck TL, Wittekind C. Gastric carcinoma: stage migration by immunohistochemically detected lymph node micrometastases. Gastric Cancer. 2015;18(1):100–8.

    Article  CAS  PubMed  Google Scholar 

  6. Edge SB, Compton CC. The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol. 2010;17(6):1471–4.

  7. Tavares A, Monteiro-Soares M, Viveiros F, Maciel Barbosa J, Dinis-Ribeiro M. Occult tumor cells in lymph nodes of patients with gastric cancer: a systematic review on their prevalence and predictive role. Oncology. 2015;89(5):245–54.

    Article  CAS  PubMed  Google Scholar 

  8. Isozaki H, Okajima K, Fujii K. Histological evaluation of lymph node metastasis on serial sectioning in gastric cancer with radical lymphadenectomy. Hepatogastroenterology. 1997;44(16):1133–6.

    CAS  PubMed  Google Scholar 

  9. 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(6):1589–95.

    PubMed  Google Scholar 

  10. 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(2):158–62.

    Article  CAS  PubMed  Google Scholar 

  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(6):731–6.

    Article  CAS  PubMed  Google Scholar 

  12. 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(11):2867–73.

    Article  PubMed  Google Scholar 

  13. 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(4):753–60.

    Article  CAS  PubMed  Google Scholar 

  14. Higashi H, Natsugoe S, Ishigami S, Uenosono Y, Matsumoto M, Nakajo A, et al. Distribution of lymph node metastasis including micrometastasis in gastric cancer with submucosal invasion. World J Surg. 2003;27(4):455–9.

    Article  PubMed  Google Scholar 

  15. Miyake K, Seshimo A, Kameoka S. Assessment of lymph node micrometastasis in early gastric cancer in relation to sentinel nodes. Gastric Cancer. 2006;9(3):197–202.

    Article  PubMed  Google Scholar 

  16. Yanagita S, Natsugoe S, Uenosono Y, Arima H, Kozono T, Ehi K, et al. Morphological distribution of metastatic foci in sentinel lymph nodes with gastric cancer. Ann Surg Oncol. 2008;15(3):770–6.

    Article  PubMed  Google Scholar 

  17. Yanagita S, Natsugoe S, Uenosono Y, Arigami T, Arima H, Kozono T, et al. Detection of micrometastases in sentinel node navigation surgery for gastric cancer. Surg Oncol. 2008;17(3):203–10.

    Article  PubMed  Google Scholar 

  18. Morita D, Tsuda H, Ichikura T, Kimura M, Aida S, Kosuda S, et al. Analysis of sentinel node involvement in gastric cancer. Clin Gastroenterol Hepatol. 2007;5(9):1046–52.

    Article  PubMed  Google Scholar 

  19. Ishigami S, Natsugoe S, Tokuda K, Nakajo A, Higashi H, Watanabe T, et al. Clinical impact of micrometastasis of the lymph node in gastric cancer. Am Surg. 2003;69(7):573–7.

    PubMed  Google Scholar 

  20. 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(2):125–30.

    Article  PubMed  Google Scholar 

  21. 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(9):1135–44.

    Article  PubMed  Google Scholar 

  22. 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(1):32–9.

    Article  CAS  PubMed  Google Scholar 

  23. 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(2):95–100.

    Article  PubMed  Google Scholar 

  24. Cai J, Ikeguchi M, Tsujitani S, Maeta M, Liu J, Kaibara N. Significant correlation between micrometastasis in the lymph nodes and reduced expression of E-cadherin in early gastric cancer. Gastric Cancer. 2001;4(2):66–74.

    Article  CAS  PubMed  Google Scholar 

  25. Cai J, Ikeguchi M, Tsujitani S, Maeta M, Kaibara N. Micrometastasis in lymph nodes of mucosal gastric cancer. Gastric Cancer. 2000;3(2):91–6.

    Article  PubMed  Google Scholar 

  26. 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(8):771–4.

    Article  PubMed  Google Scholar 

  27. Japanese Gastric Cancer A. Japanese classification of gastric carcinoma: 3rd English edition. Gastric Cancer. 2011;14(2):101–12.

  28. Lauren P. The two histological main types of gastric carcinoma: diffuse and so-called intestinal-type carcinoma. An attempt at a histo-clinical classification. Acta Pathol Microbiol Scand. 1965;64:31–49.

  29. Marano L, D’Ignazio A, Cammillini F, Angotti R, Messina M, Marrelli D, et al. Comparison between 7th and 8th edition of AJCC TNM staging system for gastric cancer: old problems and new perspectives. Transl Gastroenterol Hepatol. 2019;4:22.

  30. Buskens CJ, Ten Kate FJ, Obertop H, Izbicki JR, van Lanschot JJ. Analysis of micrometastatic disease in histologically negative lymph nodes of patients with adenocarcinoma of the distal esophagus or gastric cardia. Dis Esophagus. 2008;21(6):488–95.

    Article  CAS  PubMed  Google Scholar 

  31. Wang GY, Wang SJ, Li Y, Wang LL, Wang XL, Song ZC, et al. Multi-antibody combined determination of lymph node micrometastasis in patients with gastric cancer. Ai Zheng. 2004;23(5):559–63.

    CAS  PubMed  Google Scholar 

  32. 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(12):733–40.

    Article  PubMed  Google Scholar 

  33. Zhou Y, Zhang GJ, Wang J, Zheng KY, Fu W. Current status of lymph node micrometastasis in gastric cancer. Oncotarget. 2017;8(31):51963–9.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Yun HY, Bandou E, Kawamura T, Kojima N, Itoh I, Kameya T, et al. Influence of micrometastasis on N stage in gastric cancer and clinical application. J Exp Clin Cancer Res. 2005;24(4):531–9.

    CAS  PubMed  Google Scholar 

  35. 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(1):33–9.

    Article  PubMed  Google Scholar 

  36. 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(3):173–8.

    Article  PubMed  Google Scholar 

  37. 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(4):409–14.

    Article  CAS  PubMed  Google Scholar 

  38. Del Rio P, Viani L, Bertocchi E, Iapichino G, Luzietti E, Dell’Abate P, et al. The prognostic role of tumor size in patients with gastric cancer. Ann Ital Chir. 2017;88:478–84.

    PubMed  Google Scholar 

  39. Nicholl MB, Elashoff D, Takeuchi H, Morton DL, Hoon DS. Molecular upstaging based on paraffin-embedded sentinel lymph nodes: ten-year follow-up confirms prognostic utility in melanoma patients. Ann Surg. 2011;253(1):116–22.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Jafferbhoy S, McWilliams B. Clinical significance and management of sentinel node micrometastasis in invasive breast cancer. Clin Breast Cancer. 2012;12(5):308–12.

    Article  PubMed  Google Scholar 

  41. 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(4):397–402.

    Article  CAS  PubMed  Google Scholar 

  42. 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(3):153–7.

    Article  CAS  PubMed  Google Scholar 

  43. 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(10):2861–6.

    Article  PubMed  Google Scholar 

  44. Lutken CD, Fiehn AK, Federspiel B, Achiam MP. Impact of isolated tumor cells in regional lymph nodes in adeno-and squamous cell carcinoma of the esophagus and the esophagogastric junction—a systematic review. Pathol Res Pract. 2019;215(5):849–54.

    Article  PubMed  Google Scholar 

  45. Thompson SK, Ruszkiewicz AR, Jamieson GG, Sullivan TR, Devitt PG. Isolated tumor cells in esophageal cancer: implications for the surgeon and the pathologist. Ann Surg. 2010;252(2):299–306.

    Article  PubMed  Google Scholar 

  46. Yang X, Hu T, Gu C, Yang S, Jiang D, Deng X, et al. The prognostic significance of isolated tumor cells detected within lateral lymph nodes in rectal cancer patients after laparoscopic lateral lymph node dissection. J Laparoendosc Adv Surg Tech A. 2019;29(11):1462–8.

    Article  PubMed  Google Scholar 

  47. Weixler B, Warschkow R, Guller U, Zettl A, von Holzen U, Schmied BM, et al. Isolated tumor cells in stage I & II colon cancer patients are associated with significantly worse disease-free and overall survival. BMC Cancer. 2016;16:106.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Akagi Y, Kinugasa T, Adachi Y, Shirouzu K. Prognostic significance of isolated tumor cells in patients with colorectal cancer in recent 10-year studies. Mol Clin Oncol. 2013;1(4):582–92.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Mescoli C, Albertoni L, Pucciarelli S, Giacomelli L, Russo VM, Fassan M, et al. Isolated tumor cells in regional lymph nodes as relapse predictors in stage I and II colorectal cancer. J Clin Oncol. 2012;30(9):965–71.

    Article  PubMed  Google Scholar 

  50. Faerden AE, Sjo OH, Bukholm IR, Andersen SN, Svindland A, Nesbakken A, et al. Lymph node micrometastases and isolated tumor cells influence survival in stage I and II colon cancer. Dis Colon Rectum. 2011;54(2):200–6.

    Article  PubMed  Google Scholar 

  51. Delomenie M, Bonsang-Kitzis H, Bats AS, Ngo C, Balaya V, Xuan HTN, et al. The clinical implication of lymph nodes micrometastases and isolated tumor cells in patients with cervical cancer: a systematic review. Eur J Obstet Gynecol Reprod Biol. 2019;241:71–6.

    Article  CAS  PubMed  Google Scholar 

  52. Wong SM, Almana N, Choi J, Hu J, Gagnon H, Natsuhara K, et al. Prognostic significance of residual axillary nodal micrometastases and isolated tumor cells after neoadjuvant chemotherapy for breast cancer. Ann Surg Oncol. 2019;26(11):3502–9.

    Article  PubMed  Google Scholar 

  53. Tsuda H. Histological examination of sentinel lymph nodes: significance of macrometastasis, micrometastasis, and isolated tumor cells. Breast Cancer. 2015;22(3):221–9.

    Article  PubMed  Google Scholar 

  54. Madsen EV, Elias SG, van Dalen T, van Oort PM, van Gorp J, Gobardhan PD, et al. Predictive factors of isolated tumor cells and micrometastases in axillary lymph nodes in breast cancer. Breast. 2013;22(5):748–52.

    Article  PubMed  Google Scholar 

  55. Vestjens JH, de Boer M, van Diest PJ, van Deurzen CH, van Dijck JA, Borm GF, et al. Prognostic impact of isolated tumor cells in breast cancer axillary nodes: single tumor cell(s) versus tumor cell cluster(s) and microanatomic location. Breast Cancer Res Treat. 2012;131(2):645–51.

    Article  PubMed  Google Scholar 

  56. de Boer M, van Dijck JA, Bult P, Borm GF, Tjan-Heijnen VC. Breast cancer prognosis and occult lymph node metastases, isolated tumor cells, and micrometastases. J Natl Cancer Inst. 2010;102(6):410–25.

    Article  PubMed  Google Scholar 

  57. van Diest PJ, de Boer M, van Deurzen CH, Tjan-Heijnen VC. Micrometastases and isolated tumor cells in breast cancer are indeed associated with poorer outcome. J Clin Oncol. 2010;28(9):e140; author reply e1–2.

  58. Tjan-Heijnen VC, Pepels MJ, de Boer M. Prognostic impact of isolated tumor cells and micrometastases in axillary lymph nodes of breast cancer patients. Breast Dis. 2010;31(2):107–13.

    Article  PubMed  Google Scholar 

  59. Leidenius MH, Vironen JH, Heikkila PS, Joensuu H. Influence of isolated tumor cells in sentinel nodes on outcome in small, node-negative (pT1N0M0) breast cancer. Ann Surg Oncol. 2010;17(1):254–62.

    Article  PubMed  Google Scholar 

  60. de Boer M, van Deurzen CH, van Dijck JA, Borm GF, van Diest PJ, Adang EM, et al. Micrometastases or isolated tumor cells and the outcome of breast cancer. N Engl J Med. 2009;361(7):653–63.

    Article  PubMed  Google Scholar 

  61. 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(5):558–61.

    Article  PubMed  Google Scholar 

  62. 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(1):13–9.

    Article  PubMed  Google Scholar 

  63. Shimizu Y, Takeuchi H, Sakakura Y, Saikawa Y, Nakahara T, Mukai M, 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(2):469–77.

    Article  PubMed  Google Scholar 

  64. Kinami S, Fujimura T, Ojima E, Fushida S, Ojima T, Funaki H, et al. PTD classification: proposal for a new classification of gastric cancer location based on physiological lymphatic flow. Int J Clin Oncol. 2008;13(4):320–9.

    Article  PubMed  Google Scholar 

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Acknowledgement

The authors would like to thank the entire anatomy-pathological service for support. Amélia Tavares’ contribution was sponsored by the “Fundação para a Ciência e Tecnologia (FCT)”, Portugal, Grant Number SFRH/SINTD/60026/2009.

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Authors and Affiliations

  1. Department of General Surgery, Centro Hospitalar de Vila Nova de Gaia/Espinho, Porto, Portugal

    A. Tavares MD & J. Maciel PhD

  2. Faculty of Medicine, University of Porto, Porto, Portugal

    A. Tavares MD

  3. Institute of Molecular Pathology and Immunology, University of Porto (Ipatimup), Porto, Portugal

    X. Wen MD & F. Carneiro PhD

  4. Institute for Research Innovation in Health (i3S), University of Porto, Porto, Portugal

    X. Wen MD & F. Carneiro PhD

  5. Department of Pathology, Centro Hospitalar Vila Nova de Gaia/Espinho, Porto, Portugal

    X. Wen MD

  6. Faculty of Health Sciences, Universidade Fernando Pessoa, Porto, Portugal

    J. Maciel PhD

  7. Department of Pathology, Centro Hospitalar Universitário São João (CHUSJ), Porto, Portugal

    F. Carneiro PhD

  8. Department of Pathology, Faculty of Medicine, University of Porto (FMUP), Porto, Portugal

    F. Carneiro PhD

  9. Department of Gastroenterology, Oncology Portuguese Institute of Porto, Porto, Portugal

    M. Dinis-Ribeiro PhD

  10. MEDCIDS/CINTESIS Faculty of Medicine, University of Porto, Porto, Portugal

    M. Dinis-Ribeiro PhD

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Correspondence to A. Tavares MD.

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Tavares, A., Wen, X., Maciel, J. et al. Occult Tumour Cells in Lymph Nodes from Gastric Cancer Patients: Should Isolated Tumour Cells Also Be Considered?. Ann Surg Oncol 27, 4204–4215 (2020). https://doi.org/10.1245/s10434-020-08524-4

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