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Prognostic Value of Cytokeratin-Positive Bone Marrow Cells of Gastric Cancer Patients

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Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

Epithelial cells in the bone marrow of patients with gastric cancer suggest tumor dissemination; however, their prognostic implications are controversial. We prospectively evaluated the correlation of bone marrow findings, recurrence rate, and disease-free survival after long-term follow-up.

Methods

Bone marrow were aspirated from both iliac crests and stained with monoclonal cytokeratin (CK)-18 antibody in 209 patients before their initial operation. Patients were followed up for a median of 56 months.

Results

Overall, 39 (19%) of 209 patients and 15 (14%) of 109 R0-resected patients had CK-positive cells. CK-positive patients had more local, regional, and distant recurrence than CK-negative patients (P < .05). We found a significantly shorter disease-free survival (P < .05) in the patients with >2 CK-positive cells per 2 × 106 bone marrow cells (mean, 35 months) than in patients with ≤2 CK-positive cells per 2 × 106 bone marrow cells (mean, 70 months) or in patients with no CK-positive cells (mean, 86 months). Multivariate analysis confirmed that >2 CK-positive cells per 2 × 106 bone marrow cells was an independent prognostic factor for tumor-related death (P < .05).

Conclusions

Not only the mere presence of CK-positive epithelial cells in bone marrow, but also the cell number, correlates with prognosis. Our findings suggest that classifying CK-positive bone marrow cells in these patients will facilitate future studies.

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References

  1. Maruyama K, Okabayashi K, Kinoshita T. Progress in gastric cancer surgery in Japan and its limits of radicality. World J Surg 1987;11:418–25

    Article  PubMed  CAS  Google Scholar 

  2. Roder JD, Bottcher K, Siewert JR, Busch R, Hermanek P, Meyer HJ. Prognostic factors in gastric carcinoma. Results of the German Gastric Carcinoma Study 1992. Cancer 1993;72:2089–97

    Article  PubMed  CAS  Google Scholar 

  3. D’Angelica M, Gonen M, Brennan MF, Turnbull AD, Bains M, Karpeh MS. Patterns of initial recurrence in completely resected gastric adenocarcinoma. Ann Surg 2004;240:808–16

    Article  PubMed  Google Scholar 

  4. Sakar B, Karagol H, Gumus M, et al. Timing of death from tumor recurrence after curative gastrectomy for gastric cancer. Am J Clin Oncol 2004;27:205–9

    Article  PubMed  Google Scholar 

  5. Tajima Y, Yamazaki K, Nishino N, et al. Gastric and intestinal phenotypic marker expression in gastric carcinomas and recurrence pattern after surgery—immunohistochemical analysis of 213 lesions. Br J Cancer 2004;91:1342–8

    Article  PubMed  CAS  Google Scholar 

  6. 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;73:153–7

    Article  PubMed  CAS  Google Scholar 

  7. 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

    Article  PubMed  CAS  Google Scholar 

  8. Ishida K, Katsuyama T, Sugiyama A, Kawasaki S. Immunohistochemical evaluation of lymph node micrometastases from gastric carcinomas. Cancer 1997;79:1069–76

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  Google Scholar 

  10. Fukagawa T, Sasako M, Mann GB, et al. Immunohistochemically detected micrometastases of the lymph nodes in patients with gastric carcinoma. Cancer 2001;92:753–60

    Article  PubMed  CAS  Google Scholar 

  11. Schott A, Vogel I, Krueger U, et al. Isolated tumor cells are frequently detectable in the peritoneal cavity of gastric and colorectal cancer patients and serve as a new prognostic marker. Ann Surg 1998;227:372–9

    Article  PubMed  CAS  Google Scholar 

  12. Vogel P, Ruschoff J, Kummel S, et al. Prognostic value of microscopic peritoneal dissemination: comparison between colon and gastric cancer. Dis Colon Rectum 2000;43:92–100

    Article  PubMed  CAS  Google Scholar 

  13. Nakanishi H, Kodera Y, Yamamura Y, et al. Rapid quantitative detection of carcinoembryonic antigen-expressing free tumor cells in the peritoneal cavity of gastric-cancer patients with real-time RT-PCR on the lightcycler. Int J Cancer 2000;89:411–7

    Article  PubMed  CAS  Google Scholar 

  14. Yonemura Y, Fujimura T, Ninomiya I, et al. Prediction of peritoneal micrometastasis by peritoneal lavaged cytology and reverse transcriptase-polymerase chain reaction for matrix metalloproteinase-7 mRNA. Clin Cancer Res 2001;7:1647–53

    PubMed  CAS  Google Scholar 

  15. Thorban S, Rosenberg R, Busch R, Roder RJ. Epithelial cells in bone marrow of oesophageal cancer patients: a significant prognostic factor in multivariate analysis. Br J Cancer 2000;83:35–9

    Article  PubMed  CAS  Google Scholar 

  16. Schlimok G, Funke I, Pantel K, et al. Micrometastatic tumour cells in bone marrow of patients with gastric cancer: methodological aspects of detection and prognostic significance. Eur J Cancer 1991;27:1461–5

    Article  PubMed  CAS  Google Scholar 

  17. Juhl H, Stritzel M, Wroblewski A, et al. Immunocytological detection of micrometastatic cells: comparative evaluation of findings in the peritoneal cavity and the bone marrow of gastric, colorectal and pancreatic cancer patients. Int J Cancer 1994;57:330–5

    Article  PubMed  CAS  Google Scholar 

  18. Lindemann F, Schlimok G, Dirschedl P, Witte J, Riethmuller G. Prognostic significance of micrometastatic tumour cells in bone marrow of colorectal cancer patients. Lancet 1992;340:685–9

    Article  PubMed  CAS  Google Scholar 

  19. Neumaier M, Gerhard M, Wagener C. Diagnosis of micrometastases by the amplification of tissue-specific genes. Gene 1995;159:43–7

    Article  PubMed  CAS  Google Scholar 

  20. Sloane JP, Ormerod MG, Neville AM. Potential pathological application of immunocytochemical methods to the detection of micrometastases. Cancer Res 1980;40:3079–82

    PubMed  CAS  Google Scholar 

  21. Sobin LH, Fleming ID. TNM Classification of Malignant Tumors, fifth edition (1997). Union Internationale Contre le Cancer and the American Joint Committee on Cancer. Cancer 1997;80:1803–4

    Article  PubMed  CAS  Google Scholar 

  22. Wittekind C, Compton CC, Greene FL, Sobin LH. TNM residual tumor classification revisited. Cancer 2002;94:2511–6

    Article  PubMed  Google Scholar 

  23. Hermanek P, Hutter RV, Sobin LH, Wittekind C. International Union Against Cancer. Classification of isolated tumor cells and micrometastasis. Cancer 1999;86:2668–73

    Article  PubMed  CAS  Google Scholar 

  24. Cordell JL, Falini B, Erber WN, et al. Immunoenzymatic labeling of monoclonal antibodies using immune complexes of alkaline phosphatase and monoclonal anti-alkaline phosphatase (APAAP complexes). J Histochem Cytochem 1984;32:219–29

    PubMed  CAS  Google Scholar 

  25. Gerhartz HH, Schmetzer H. Detection of minimal residual disease in acute myeloid leukemia. Leukemia 1990;4:508–16

    PubMed  CAS  Google Scholar 

  26. Moll R, Franke WW. Intermediate filaments and their interaction with membranes. The desmosome-cytokeratin filament complex and epithelial differentiation. Pathol Res Pract 1982;175:146–61

    PubMed  CAS  Google Scholar 

  27. Soligo D, Lambertenghi-Deliliers G, Berti E, Polli N, Polli EE. Immunohistochemical evaluation of bone marrow involvement in hairy cell leukemia during interferon therapy. Blut 1987;55:121–6

    Article  PubMed  CAS  Google Scholar 

  28. Kaplan EL, Meier P. Nonparametric estimation from incomplete observation. J Am Stat Assoc 1958;53:457–81

    Article  Google Scholar 

  29. Cox CP. On estimating relative potency from quadratic log-dose response relationships. Biometrics 1972;28:875–81

    Article  PubMed  CAS  Google Scholar 

  30. Broll R, Lembcke K, Stock C, et al. Tumor cell dissemination in bone marrow and peritoneal cavity. An immunocytochemical study of patients with stomach or colorectal carcinoma (in German). Langenbecks Arch Chir 1996;381:51–8

    Article  PubMed  CAS  Google Scholar 

  31. Kakeji Y, Maehara Y, Shibahara K, et al. Clinical significance of micrometastasis in bone marrow of patients with gastric cancer and its relation to angiogenesis. Gastric Cancer 1999;2:46–51

    Article  PubMed  Google Scholar 

  32. Jauch KW, Heiss MM, Gruetzner U, et al. Prognostic significance of bone marrow micrometastases in patients with gastric cancer. J Clin Oncol 1996;14:1810–7

    PubMed  CAS  Google Scholar 

  33. 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;29:450–4

    Article  PubMed  Google Scholar 

  34. Maehara Y, Hasuda S, Abe T, et al. Tumor angiogenesis and micrometastasis in bone marrow of patients with early gastric cancer. Clin Cancer Res 1998;4:2129–34

    PubMed  CAS  Google Scholar 

  35. O’Sullivan GC, Collins JK, O’Brien F, et al. Micrometastases in bone marrow of patients undergoing “curative” surgery for gastrointestinal cancer. Gastroenterology 1995;109:1535–40

    Article  PubMed  CAS  Google Scholar 

  36. Allgayer H, Heiss MM, Riesenberg R, Babic R, Jauch KW, Schildberg FW. Immunocytochemical phenotyping of disseminated tumor cells in bone marrow by uPA receptor and CK18: investigation of sensitivity and specificity of an immunogold/alkaline phosphatase double staining protocol. J Histochem Cytochem 1997;45:203–12

    PubMed  CAS  Google Scholar 

  37. Funke I, Fries S, Rolle M, et al. Comparative analyses of bone marrow micrometastases in breast and gastric cancer. Int J Cancer 1996;65:755–61

    Article  PubMed  CAS  Google Scholar 

  38. Heiss MM, Allgayer H, Gruetzner KU, Babic R, Jauch KW, Schildberg FW. Clinical value of extended biologic staging by bone marrow micrometastases and tumor-associated proteases in gastric cancer. Ann Surg 1997;226:736–44

    Article  PubMed  CAS  Google Scholar 

  39. Heiss MM, Simon EH, Beyer BC, et al. Minimal residual disease in gastric cancer: evidence of an independent prognostic relevance of urokinase receptor expression by disseminated tumor cells in the bone marrow. J Clin Oncol 2002;20:2005–16

    Article  PubMed  CAS  Google Scholar 

  40. 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;73:83–7

    PubMed  CAS  Google Scholar 

  41. Ryan P, McCarthy S, Kelly J, et al. Prevalence of bone marrow micrometastases in esophagogastric cancer patients with and without neoadjuvant chemoradiotherapy. J Surg Res 2004;117:121–6

    Article  PubMed  Google Scholar 

  42. O’Sullivan GC, Sheehan D, Clarke A, et al. Micrometastases in esophagogastric cancer: high detection rate in resected rib segments. Gastroenterology 1999;116:543–8

    Article  PubMed  CAS  Google Scholar 

  43. Bonavina L, Soligo D, Quirici N, et al. Bone marrow-disseminated tumor cells in patients with carcinoma of the esophagus or cardia. Surgery 2001;129:15–22

    Article  PubMed  CAS  Google Scholar 

  44. de Manzoni G, Pelosi G, Pavanel F, et al. The presence of bone marrow cytokeratin-immunoreactive cells does not predict outcome in gastric cancer patients. Br J Cancer 2002;86:1047–51

    Article  PubMed  Google Scholar 

  45. 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;10:171–5

    Article  PubMed  Google Scholar 

  46. Jonas S, Weinrich M, Tullius SG, et al. Microscopic tumor cell dissemination in gastric cancer. Surg Today 2004;34:101–6

    Article  PubMed  Google Scholar 

  47. Pantel K, Schlimok G, Kutter D, et al. Frequent down-regulation of major histocompatibility class I antigen expression on individual micrometastatic carcinoma cells. Cancer Res 1991;51:4712–5

    PubMed  CAS  Google Scholar 

  48. Andratschke M, Pauli C, Stein M, Chaubal S, Wollenberg B. MHC-class I antigen expression on micrometastases in bone marrow of patients with head and neck squamous cell cancer. Anticancer Res 2003;23:1467–71

    PubMed  CAS  Google Scholar 

  49. Hynes NE, Stern DF. The biology of erbB-2/neu/HER-2 and its role in cancer. Biochim Biophys Acta 1994;1198:165–84

    PubMed  Google Scholar 

  50. Maxwell-Armstrong CA, Durrant LG, Scholefield JH. Immunotherapy for colorectal cancer. Am J Surg 1999;177:344–8

    Article  PubMed  CAS  Google Scholar 

  51. Vermorken JB, Claessen AM, van Tinteren H, et al. Active specific immunotherapy for stage II and stage III human colon cancer: a randomised trial. Lancet 1999;353:345–50

    Article  PubMed  CAS  Google Scholar 

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Acknowledgment

The authors thank Markus Niederstrasser for his assistance in statistical analysis.

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Correspondence to Peter M. Schlag MD, PhD.

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Gretschel, S., Schick, C., Schneider, U. et al. Prognostic Value of Cytokeratin-Positive Bone Marrow Cells of Gastric Cancer Patients. Ann Surg Oncol 14, 373–380 (2007). https://doi.org/10.1245/s10434-006-9039-3

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