Skip to main content
SpringerLink
Log in

Prognostic value of disseminated colorectal tumor cells in the liver: results of follow-up examinations

  • Original Article
  • Published:
International Journal of Colorectal Disease Aims and scope Submit manuscript

Abstract

Background and aims

Dissemination of tumor cells is an initial step in metastatic disease. Detection of disseminated tumor cells (DTC) in blood, bone marrow and lymph nodes has been associated with reduced disease-free survival, but to date there are no data for hepatic DTC. We investigated the prognostic relevance of hepatic DTC that are present in patients with colorectal cancer (CRC) at the time of surgery.

Patients and methods

In 121 patients with CRC clinically diagnosed for liver metastasis by ultrasound, CT, and exploration during surgery DNA from liver biopsy specimens obtained during surgery was examined by a PCR-RFLP assay for K-ras mutations as a marker for DTC. At the time of surgery 54 of the 121 were mutated in K-ras codons 12 or 13. After a median follow-up of 405 days all survivors were reevaluated by ultrasound/CT.

Results

Patients with a K-ras mutation in their primary tumor had a significantly lower probability of survival and higher risk of harboring a synchronous second colorectal carcinoma than patients with a K-ras wild-type tumor. Based on specimens taken intraoperatively DTC were found in the liver of 14 of 54 patients (26%). At follow-up only 10 of 40 patients (25%) with DTC-free liver had died of their disease but 9 of the 14 patients with hepatic DTC. Among the 14 patients with hepatic DTC 10 (71%) had developed new liver metastasis, compared to 12 of 40 (30%) in those without hepatic DTC.

Conclusion

Hepatic DTC in colorectal cancer patients is associated with reduced overall survival and increased risk of hepatic metastasis development. Further studies are necessary to corroborate our results since the number of patients studied is still limited.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. August DA, Ottow RT, Sugarbaker PH (1984) Clinical perspective of human colorectal cancer metastasis. Cancer Metastasis Rev 3:303–324

    CAS  PubMed  Google Scholar 

  2. Deans GT, Parks TG, Rowlands BJ, Spence RA (1992) Prognostic factors in colorectal cancer. Br J Surg 79:608–613

    CAS  PubMed  Google Scholar 

  3. Weiss L, Grundmann E, Torhorst J, Hartveit F, Moberg I, Eder M, Fenoglio-Preiser CM, Napier J, Horne CH, Lopez MJ (1986) Haematogenous metastatic patterns in colonic carcinoma: an analysis of 1541 necropsies. J Pathol 150:195–203

    CAS  PubMed  Google Scholar 

  4. Gilbert JM (1983) Distribution of metastases at necropsy in colorectal cancer. Clin Exp Metastasis 1:97–101

    CAS  PubMed  Google Scholar 

  5. Sanchez-Cespedes M, Esteller M, Hibi K, Cope FO, Westra WH, Piantadosi S, Herman JG, Jen J, Sidransky D (1999) Molecular detection of neoplastic cells in lymph nodes of metastatic colorectal cancer patients predicts recurrence. Clin Cancer Res 5:2450–2454

    CAS  Google Scholar 

  6. Greenson JK, Isenhart CE, Rice R, Mojzisik C, Houchens D, Martin EW (1994) Identification of occult micrometastases in pericolic lymph nodes of Duke’s B colorectal cancer patients using monoclonal antibodies against cytokeratin and CC49. Correlation with long-term survival. Cancer 73:563–569

    CAS  PubMed  Google Scholar 

  7. Miyake Y, Yamamoto H, Fujiwara Y, Ohue M, Sugita Y, Tomita N, Sekimoto M, Matsuura N, Shiozaki H, Monden M (2001) Extensive micrometastases to lymph nodes as a marker for rapid recurrence of colorectal cancer: a study of lymphatic mapping. Clin Cancer Res 7:1350–1357

    CAS  Google Scholar 

  8. Vogel I, Kalthoff H (2001) Disseminated tumour cells. Their detection and significance for prognosis of gastrointestinal and pancreatic carcinomas. Virchows Arch 439:109–117

    Article  CAS  PubMed  Google Scholar 

  9. Weitz J, Kienle P, Magener A, Koch M, Schrodel A, Willeke F, Autschbach F, Lacroix J, Lehnert T, Herfarth C, von Knebel-Doeberitz M (1999) Detection of disseminated colorectal cancer cells in lymph nodes, blood and bone marrow. Clin Cancer Res 5:1830–1836

    CAS  Google Scholar 

  10. O’Sullivan GC, Collins JK, Kelly J, Morgan J, Madden M, Shanahan F (1997) Micrometastases: marker of metastatic potential or evidence of residual disease? Gut 40:512–515

    CAS  PubMed  Google Scholar 

  11. Soeth E, Roder C, Juhl H, Kruger U, Kremer B, Kalthoff H (1996) The detection of disseminated tumor cells in bone marrow from colorectal-cancer patients by a cytokeratin-20-specific nested reverse-transcriptase-polymerase-chain reaction is related to the stage of disease. Int J Cancer 69:278–282

    Article  CAS  PubMed  Google Scholar 

  12. Leinung S, Wurl P, Weiss CL, Roder I, Schonfelder M (2000) Cytokeratin-positive cells in bone marrow in comparison with other prognostic factors in colon carcinoma. Langenbecks Arch Surg 385:337–343

    Article  CAS  PubMed  Google Scholar 

  13. Leinung S, Wurl P, Schonfelder A, Weiss CL, Roder I, Schonfelder M (2000) Detection of cytokeratin-positive cells in bone marrow in breast cancer and colorectal carcinoma in comparison with other factors of prognosis. J Hematother Stem Cell Res 9:905–911

    Article  CAS  PubMed  Google Scholar 

  14. Hardingham JE, Kotasek D, Sage RE, Eaton MC, Pascoe VH, Dobrovic A (1995) Detection of circulating tumor cells in colorectal cancer by immunobead-PCR is a sensitive prognostic marker for relapse of disease. Mol Med 1:789–794

    CAS  PubMed  Google Scholar 

  15. Hardingham JE, Hewett PJ, Sage RE, Finch JL, Nuttall JD, Kotasek D, Dobrovic A (2000) Molecular detection of blood-borne epithelial cells in colorectal cancer patients and in patients with benign bowel disease. Int J Cancer 89:8–13

    Article  CAS  PubMed  Google Scholar 

  16. Taniguchi T, Makino M, Suzuki K, Kaibara N (2000) Prognostic significance of reverse transcriptase-polymerase chain reaction measurement of carcinoembryonic antigen mRNA levels in tumor drainage blood and peripheral blood of patients with colorectal carcinoma. Cancer 89:970–976

    Article  CAS  PubMed  Google Scholar 

  17. Soeth E, Vogel I, Roder C, Juhl H, Marxsen J, Kruger U, Henne-Bruns D, Kremer B, Kalthoff H (1997) Comparative analysis of bone marrow and venous blood isolates from gastrointestinal cancer patients for the detection of disseminated tumor cells using reverse transcription PCR Cancer Res 57:3106–3110

    CAS  Google Scholar 

  18. Schimanski CC, Sutter C, Linnemann U, Berger MR (1999) Sampling technique influences the detection of K-ras mutations in normal appearing mucosa of colorectal cancer patients. Int J Oncol 15:391–398

    CAS  PubMed  Google Scholar 

  19. Schimanski CC, Linnemann U, Arbogast R, Berger MR (2001) Extended staging results from the detection of isolated tumor cells in the liver of colorectal cancer patients. Oncol Rep 8:185–188

    CAS  PubMed  Google Scholar 

  20. Schimanski CC, Linnemann U, Berger MR (1999) Sensitive detection of K-ras mutations augments diagnosis of colorectal cancer metastases in the liver. Cancer Res 59:5169–5175

    CAS  PubMed  Google Scholar 

  21. Kalbfleisch LD, Prentice RL (eds) (1980) The statistical analysis of failure time data. Wiley, New York

  22. Andreyev HJ, Norman AR, Cunningham D, Oates JR, Clarke PA (1998) Kirsten ras mutations in patients with colorectal cancer: the multicenter “RASCAL” study. J Natl Cancer Inst 90:675–684

    Article  CAS  PubMed  Google Scholar 

  23. Andreyev H, Norman AR, Cunningham D, Oates J, Dix BR, Iacopetta BJ, Young J, Walsh T, Ward R, Hawkins N, Beranek M et al (2001) Kirsten ras mutations in patients with colorectal cancer: the ‘RASCAL II’ study. Br J Cancer 85:692–696

    Article  CAS  PubMed  Google Scholar 

  24. Schimanski CC, Linnemann U, Galle PR, Arbogast R, Berger MR (2003) Hepatic disseminated tumor cells in colorectal cancer UICC stage 4 patients: Prognostic implications. Int J Oncol 23:791–796

    PubMed  Google Scholar 

  25. Weitz J, Kienle P, Lacroix J, Willeke F, Benner A, Lehnert T, Herfarth C, von Knebel-Doeberitz M (1998) Dissemination of tumor cells in patients undergoing surgery for colorectal cancer. Clin Cancer Res 4:343–348

    CAS  PubMed  Google Scholar 

  26. Weitz J, Koch M, Kienle P, Schrodel A, Willeke F, Benner A, Lehnert T, Herfarth C, von Knebel-Doeberitz M (2000) Detection of hematogenic tumor cell dissemination in patients undergoing resection of liver metastases of colorectal cancer. Ann Surg 232:66–72

    CAS  PubMed  Google Scholar 

  27. Wharton RQ, Jonas SK, Glover C, Khan ZA, Klokouzas A, Quinn H, Henry M, Allen Mersh TG (1999) Increased detection of circulating tumor cells in the blood of colorectal carcinoma patients using two reverse transcription-PCR assays and multiple blood samples. Clin Cancer Res 5:4158–4163

    CAS  Google Scholar 

  28. Schirmacher P, Dienes HP, Moll R (1998) De novo expression of nonhepatocellular cytokeratins in Mallory body formation. Virchows Arch 432:143–152

    Article  CAS  PubMed  Google Scholar 

  29. Weiss L (1996) Metastatic inefficiency: intravascular and intraperitoneal implantation of cancer cells. Cancer Treat Res 82:1–11

    CAS  PubMed  Google Scholar 

  30. Riethmüller G, Schneider Gadicke E, Schlimok G, Schmiegel W, Raab R, Hoffken K, Gruber R, Pichlmaier H, Hirche H, Pichlmayr R et al (1994) Randomised trial of monoclonal antibody for adjuvant therapy of resected Dukes’ C colorectal carcinoma. German Cancer Aid 17-1A Study Group. Lancet 343:1177–1183

    PubMed  Google Scholar 

  31. Riethmüller G, Holz E, Schlimok G, Schmiegel W, Raab R, Hoffken K, Gruber R, Funke I, Pichlmaier H, Hirche H, Buggisch P, Witte J, Pichlmayr R (1998) Monoclonal antibody therapy for resected Dukes’ C colorectal cancer: seven-year outcome of a multicenter randomized trial. J Clin Oncol 16:1788–1794

    CAS  PubMed  Google Scholar 

  32. Juweid ME, Stadtmauer E, Hajjar G, Sharkey RM, Suleiman S, Luger S, Swayne LC, Alavi A, Goldenberg DM (1999) Pharmacokinetics, dosimetry, and initial therapeutic results with131I- and (111) In-90Y-labeled humanized LL2 anti-CD22 monoclonal antibody in patients with relapsed, refractory non-Hodgkin’s lymphoma. Clin Cancer Res 5 [Suppl]:3292s–3303s

Download references

Acknowledgements

The authors gratefully acknowledge the support given by the Else Kröner-Fresenius-Stiftung and are indebted to Dr. Robert Owen for stylistic improvements in the manuscript. This article is dedicated to Dr. med. Karl Schimanski, on the occasion of his 70th birthday.

Author information

Authors and Affiliations

  1. Department of Surgery, Municipal Hospital Nürnberg Nord, Nuremberg, Germany

    Ulrich Linnemann & Christoph Gebhardt

  2. Toxicology and Chemotherapy Unit, German Cancer Research Center, Im Neuenheimer Feld 280, 69120, Heidelberg, Germany

    Christoph C. Schimanski & Martin R. Berger

  3. First Medical Department, University Hospital Mainz, Mainz, Germany

    Christoph C. Schimanski

Authors
  1. Ulrich Linnemann
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Christoph C. Schimanski
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Christoph Gebhardt
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Martin R. Berger
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Martin R. Berger.

Additional information

U. Linnemann and C.C. Schimanski contributed equally to this work

Rights and permissions

Reprints and permissions

About this article

Cite this article

Linnemann, U., Schimanski, C.C., Gebhardt, C. et al. Prognostic value of disseminated colorectal tumor cells in the liver: results of follow-up examinations. Int J Colorectal Dis 19, 380–386 (2004). https://doi.org/10.1007/s00384-003-0555-3

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00384-003-0555-3

Keywords

Search

Navigation