Abstract
Bone marrow (BM) is a prognostically relevant indicator organ of micrometastasis; however, the clinical importance of BM micrometastasis in gastric cancer patients is not yet known. In the present study, the BM of 267 consecutive patients with primary gastric cancer was examined for tumor cells using immunocytochemical techniques. Real-time quantitative RT-PCR was used to ensure that the tumor cells were detected properly. Among the 267 cases analyzed, 30 cases (11.2%) had cytokeratine-positive cells in the bone marrow. Positive findings were related to the tumor stage (P < 0.05) and to the prominent depth of invasion (P < 0.05). All patients with liver metastasis at operation had cytokeratine-positive cells in the BM. Recurrence of the disease was confirmed in 50 cases (18.7%); 4 of 30 (13.3%) in the cytokeratine-positive group and 46 of 237 (19.4%) in the cytokeratine-negative group. There were no significant differences in the 5-year survival rates between the cytokeratine-positive and cytokeratin-negative groups. Our study shows that BM micrometastasis increases according to tumor progression; however, only a subset of cancer cells may survive in the BM and finally evolve to a clinically apparent disease. Therefore it does not accurately predict the prognosis or recurrence of the disease.
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References
Champelovier P, Mongelard F, Seigneurin D (1999) CK20 gene expression: technical limits for the detection of circulating tumor cells. Anticancer Res 19:2073–2078
Choi HJ, Kim YK, Kim YH et al (2002) Occurrence and prognostic implications of micrometastases in lymph nodes from patients with submucosal gastric carcinoma. Ann Surg Oncol 9:13–19
de Manzoni G, Pelosi G, Pavanel F et al (2002) The presence of bone marrow cytokeratin-immunoreactive cells does not predict outcome in gastric cancer patients. Br J Cancer 86:1047–1051
Diel IJ, Kaufmann M, Goerner R et al (1992) Detection of tumor cells in bone marrow of patients with primary breast cancer: a prognostic factor for distant metastasis. J Clin Oncol 10:1534–1539
Gangnus R, Langer S, Breit E et al (2004) Genomic profiling of viable and proliferative micrometastatic cells from early-stage breast cancer patients. Clin Cancer Res 10:3457–3464
Gerhard M, Juhl H, Kalthoff H et al (1994) Specific detection of carcinoembryonic antigen-expressing tumor cells in bone marrow aspirates by polymerase chain reaction. J Clin Oncol 12:725–729
Heiss MM, Allgayer H, Gruetzner KU et al (1995) Individual development and uPA-receptor expression of disseminated tumour cells in bone marrow: a reference to early systemic disease in solid cancer. Nat Med 1:1035–1039
Ishigami S, Natsugoe S, Tokuda K et al (2003) Clinical impact of micrometastasis of the lymph node in gastric cancer. Am Surg 69:573–577
Ishii T, Fujiwara Y, Ohnaka S et al (2004) Rapid genetic diagnosis with the transcription-reverse transcription concerted reaction system for cancer micrometastasis. Ann Surg Oncol 11:778–785
Kakeji Y, Maehara Y, Shibahara K et al (1999) Clinical significance of micrometastasis in bone marrow of patients with gastric cancer and its relation to angiogenesis. Gastric Cancer 2:46–51
Klein CA, Blankenstein TJ, Schmidt-Kittler O et al (2002) Genetic heterogeneity of single disseminated tumour cells in minimal residual cancer. Lancet 360:683–689
Koch M, Kienle P, Hinz U et al (2005) Detection of hematogenous tumor cell dissemination predicts tumor relapse in patients undergoing surgical resection of colorectal liver metastases. Ann Surg 241:199–205
Lindemann F, Schlimok G, Dirschedl P et al (1992) Prognostic significance of micrometastatic tumour cells in bone marrow of colorectal cancer patients. Lancet 340:685–689
Maehara Y, Baba H, Ohno S, Sugimachi K (1995) Cytokeratin staining reveals micrometastasis in lymph nodes of early gastric cancer. Surgery 117:480
Maehara Y, Oshiro T, Endo K et al (1996a) Clinical significance of occult micrometastasis lymph nodes from patients with early gastric cancer who died of recurrence. Surgery 119:397–402
Maehara Y, Yamamoto M, Oda S et al (1996b) Cytokeratin-positive cells in bone marrow for identifying distant micrometastasis of gastric cancer. Br J Cancer 73:83–87
Maehara Y, Hasuda S, Abe T et al (1998) Tumor angiogenesis and micrometastasis in bone marrow of patients with early gastric cancer. Clin Cancer Res 4:2129–2134
Macadam R, Sarela A, Wilson J et al (2003) Bone marrow micrometastases predict early post-operative recurrence following surgical resection of oesophageal and gastric carcinoma. Eur J Surg Oncol 29:450–454
Matsunami K, Nakamura T, Oguma H et al (2003) Detection of bone marrow micrometastasis in gastric cancer patients by immunomagnetic separation. Ann Surg Oncol 10:171–175
Morgagni P, Saragoni L, Scarpi E et al (2003) Lymph node micrometastases in early gastric cancer and their impact on prognosis. World J Surg 27:558–561
Mori M, Mimori K, Ueo H et al (1996) Molecular detection of circulating solid carcinoma cells in the peripheral blood: the concept of early systemic disease. Int J Cancer 68:739–743
Oki E, Maehara Y, Tokunaga E et al (2002) Detection of disseminated cancer cells in bone marrow of gastric cancer using real time quantitative reverse transcriptase polymerase chain reaction. Cancer Lett 188:191–198
Pantel K, Dickmanns A, Zippelius A et al (1995) Establishment of micrometastatic carcinoma cell lines: a novel source of tumor cell vaccines. J Natl Cancer Inst 87:1162–1168
Putz E, Witter K, Offner S et al (1999) 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 micrometastasis. Cancer Res 59:241–248
Slade MJ, Smith BM, Sinnett HD et al (1999) Quantitative polymerase chain reaction for the detection of micrometastases in patients with breast cancer. J Clin Oncol 17:870–879
Solakoglu O, Maierhofer C, Lahr G et al (2002) Heterogeneous proliferative potential of occult metastatic cells in bone marrow of patients with solid epithelial tumors. Proc Natl Acad Sci USA 99:2246–2251
Thorban S, Roder JD, Nekarda H et al (1996a) Immunocytochemical detection of disseminated tumor cells in the bone marrow of patients with esophageal carcinoma. J Natl Cancer Inst 88:1222–1227
Thorban S, Roder JD, Pantel K, Siewert JR (1996b) Immunocytochemical detection of isolated epithelial tumor cells in bone marrow of patients with pancreatic carcinoma. Am J Surg 172:297–298
Tokunaga E, Maehara Y, Oki E et al (2000) Application of quantitative RT-PCR using “TaqMan” technology to evaluate the expression of CK 18 mRNA in various cell lines. J Exp Clin Cancer Res 19:375–381
Yasuda K, Adachi Y, Shiraishi N et al (2002) Prognostic effect of lymph node micrometastasis in patients with histologically node-negative gastric cancer. Ann Surg Oncol 9:771–774
Weitz J, Kienle P, Magener A et al (1999) Detection of disseminated colorectal cancer cells in lymph nodes, blood and bone marrow. Clin Cancer Res 5:1830–1836
Woelfle U, Sauter G, Santjer S et al (2004) Down-regulated expression of cytokeratin 18 promotes progression of human breast cancer. Clin Cancer Res 10:2670–2674
Acknowledgments
We are grateful to J. Tsuchihashi and K. Miyamoto for technical assistance. This study was supported by grants from the Ministry of Education, Science, Sports and Culture of Japan.
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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 133, 995–1000 (2007). https://doi.org/10.1007/s00432-007-0258-1
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DOI: https://doi.org/10.1007/s00432-007-0258-1