Clinical & Experimental Metastasis

, Volume 30, Issue 4, pp 457–470 | Cite as

The tumour biology of synchronous and metachronous colorectal liver metastases: a systematic review

  • A. A. P. Slesser
  • P. Georgiou
  • G. Brown
  • S. Mudan
  • R. GoldinEmail author
  • P. Tekkis
Research Paper


Forty to fifty percent of colorectal cancer (CRC) patients develop colorectal liver metastases (CLM) that are either synchronous or metachronous in presentation. Clarifying whether there is a biological difference between the two groups of liver metastases or their primaries could have important clinical implications. A systematic review was performed using the following resources: MEDLINE from PubMed (1950 to present), Embase, Cochrane and the Web of Knowledge. Thirty-one articles met the inclusion criteria. The review demonstrated that the majority of studies found differences in molecular marker expression between colorectal liver metastases and their respective primaries in both the synchronous and metachronous groups. Studies investigating genetic aberrations demonstrated that the majority of changes in the primary tumour were ‘maintained’ in the colorectal liver metastases. A limited number of studies compared the primary tumours of the synchronous and metachronous groups and generally demonstrated no differences in marker expression. Although there were conflicting results, the colorectal liver metastases in the synchronous and metachronous groups demonstrated some differences in keeping with a more aggressive tumour subtype in the synchronous group. This review suggests that biological differences may exist between the liver metastases of the synchronous and metachronous groups. Whether there are biological differences between the primaries of the synchronous and metachronous groups remains undetermined due to the limited number of studies available. Future research is required to determine whether differences exist between the two groups and should include comparisons of the primary tumours.


Colorectal cancer Colorectal liver metastases Molecular markers Biomarkers Synchronous colorectal liver metastases Metachronous colorectal liver metastases 



Colorectal liver metastases


Colorectal cancer


Synchronous colorectal liver metastases




Reverse transcription polymerase chain reaction


Two-dimensional difference gel electrophoresis


Fluorescence in situ hybridization


Oxford Centre for Evidence-Based Medicine Levels of Evidence



This review was based on work performed for a MD(Res) degree at Imperial College, London, Division of Surgery and Cancer.

Conflict of interest

The authors have no conflicts of interest to declare.


  1. 1.
    International Agency for Research on Cancer (IARC), 2012. Accessed 23 Jan 2012
  2. 2.
    Bruin SC, He Y et al (2011) Molecular alterations associated with liver metastases development in colorectal cancer patients. Br J Cancer 105(2):281–287PubMedCrossRefGoogle Scholar
  3. 3.
    Thomas P, Forse RA, Bajenova O (2011) Carcinoembryonic antigen (CEA) and its receptor hnRNP M are mediators of metastasis and the inflammatory response in the liver. Clin Exp Metastasis 28(8):923–932PubMedCrossRefGoogle Scholar
  4. 4.
    Bird NC, Mangnall D, Majeed AW (2006) Biology of colorectal liver metastases: a review. J Surg Oncol 94(1):68–80PubMedCrossRefGoogle Scholar
  5. 5.
    Tan EK, Ooi LL(2010) Colorectal cancer liver metastases–understanding the differences in the management of synchronous and metachronous disease. Ann Acad Med Singapore 39(9):719-33Google Scholar
  6. 6.
    Haddad AJ, Hani MB, Pawlik TM, Cunningham SC (2011) Colorectal liver metastases. Int. J. Surg. Oncol Article ID 285840. doi: 10.1155/2011/285840
  7. 7.
    Ghadjar P, Rubie C, Aebersold DM, Keilholz U (2009) The chemokine CCL20 and its receptor CCR6 in human malignancy with focus on colorectal cancer. Int J Cancer 125(4):741–745PubMedCrossRefGoogle Scholar
  8. 8.
    Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A (eds) (2010) AJCC cancer staging manual (7th ed). Springer, New YorkGoogle Scholar
  9. 9.
    Mekenkamp LJ, Koopman M, Teerenstra S, van Krieken JH, Mol L, Nagtegaal ID, Punt CJ (2010) Clinicopathological features and outcome in advanced colorectal cancer patients with synchronous vs metachronous metastases. Br J Cancer 103(2):159–164PubMedCrossRefGoogle Scholar
  10. 10.
    Dexiang Z, Li R, Ye W, Haifu W, Yunshi Z, Qinghai Y, Shenyong Z, Bo X, Li L, Xiangou P, Haohao L, Lechi Y, Tianshu L, Jia F, Xinyu Q, Jianmin X (2012) Outcome of patients with colorectal liver metastasis: analysis of 1,613 consecutive cases. Ann Surg Oncol 19(9):2860–2868PubMedCrossRefGoogle Scholar
  11. 11.
    Mantke R, Schmidt U, Wolff S, Kube R, Lippert H (2012) Incidence of synchronous liver metastases in patients with colorectal cancer in relationship to clinico-pathologic characteristics. Results of a German prospective multicentre observational study. Eur J Surg Oncol 38(3):259–265PubMedCrossRefGoogle Scholar
  12. 12.
    Moher D, Liberati A, Tetzlaff J, Altman DG (2010) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Int J Surg. doi: 10.1016/j.ijsu.2010.02.007 Google Scholar
  13. 13.
    Howick J, Chalmers I, Glasziou P, Greenhalgh T, Heneghan C, Liberati A, Moschetti I, Phillips B, Thornton H, Goddard O, Hodgkinson M. “The Oxford 2011 Levels of Evidence”. Oxford Centre for Evidence-Based Medicine. Accessed 23 Jan 2012
  14. 14.
    Swan PJ, Welsh FK, Chandrakumaran K, Rees M (2011) Long-term survival following delayed presentation and resection of colorectal liver metastases. Br J Surg 98(9):1309–1317. doi: 10.1002/bjs.7527. PubMedCrossRefGoogle Scholar
  15. 15.
    Wang SC, Lin JK, Wang HS, Yang SH, Li AF, Chang SC (2010) Nuclear expression of CXCR4 is associated with advanced colorectal cancer. Int J Colorectal Dis 25(10):1185–1191PubMedCrossRefGoogle Scholar
  16. 16.
    Rudmik LR, Magliocco AM (2005) Molecular mechanisms of hepatic metastasis in colorectal cancer. J Surg Oncol 92(4):347–359PubMedCrossRefGoogle Scholar
  17. 17.
    Li JQ, Miki H, Wu F, Saoo K, Nishioka M, Ohmori M, Imaida K (2002) Cyclin A correlates with carcinogenesis and metastasis, and p27(kip1) correlates with lymphatic invasion, in colorectal neoplasms. Hum Pathol 33(10):1006–1015PubMedCrossRefGoogle Scholar
  18. 18.
    Thomas GV, Szigeti K, Murphy M, Draetta G, Pagano M, Loda M (1998) Down-regulation of p27 is associated with development of colorectal adenocarcinoma metastases. Am J Pathol 153(3):681–687PubMedCrossRefGoogle Scholar
  19. 19.
    Lloyd RV, Erickson LA, Jin L, Kulig E, Qian X, Cheville JC, Scheithauer BW (1999) p27kip1: a multifunctional cyclin-dependent kinase inhibitor with prognostic significance in human cancers. Am J Pathol 154(2):313–323PubMedCrossRefGoogle Scholar
  20. 20.
    Li JQ, Miki H, Ohmori M, Wu F, Funamoto Y (2001) Expression of cyclin E and cyclin-dependent kinase 2 correlates with metastasis and prognosis in colorectal carcinoma. Hum Pathol 32(9):945–953PubMedCrossRefGoogle Scholar
  21. 21.
    Kobayashi H, Sugihara K, Uetake H, Higuchi T, Yasuno M, Enomoto M, Iida S, Azuma M, Mori R, Omori A, Lenz HJ, Danenberg KD, Danenberg PV (2008) Messenger RNA expression of TS and ERCC1 in colorectal cancer and matched liver metastasis. Int J Oncol 33(6):1257–1262PubMedGoogle Scholar
  22. 22.
    Inokuchi M, Uetake H, Shirota Y, Yamada H, Tajima M, Sugihara K (2004) Gene expression of 5-fluorouracil metabolic enzymes in primary colorectal cancer and corresponding liver metastasis. Cancer Chemother Pharmacol 53(5):391–396PubMedCrossRefGoogle Scholar
  23. 23.
    Ghadjar P, Coupland SE, Na IK, Noutsias M, Letsch A, Stroux A, Bauer S, Buhr HJ, Thiel E, Scheibenbogen C, Keilholz U (2006) Chemokine receptor CCR6 expression level and liver metastases in colorectal cancer. J Clin Oncol 24(12):1910–1916PubMedCrossRefGoogle Scholar
  24. 24.
    Kim J, Takeuchi H, Lam ST, Turner RR, Wang HJ, Kuo C, Foshag L, Bilchik AJ, Hoon DS (2005) Chemokine receptor CXCR4 expression in colorectal cancer patients increases the risk for recurrence and for poor survival. J Clin Oncol 23(12):2744–2753PubMedCrossRefGoogle Scholar
  25. 25.
    Ghadjar P, Rubie C, Aebersold DM, Keilholz U (2009) The chemokine CCL20 and its receptor CCR6 in human malignancy with focus on colorectal cancer. Int J Cancer 125(4):741–745PubMedCrossRefGoogle Scholar
  26. 26.
    Wu Y, Jin M, Xu H, Shimin Z, He S, Wang L, Zhang Y (2010) Clinicopathologic significance of HIF-1α, CXCR4, and VEGF expression in colon cancer. Clin Dev Immunol Epub 2010 Oct 7Google Scholar
  27. 27.
    Kim YW, Ko YT, Kim NK, Chung HC, Min BS, Lee KY, Park JP, Kim H (2010) A comparative study of protein expression in primary colorectal cancer and synchronous hepatic metastases: the significance of matrix metalloproteinase-1 expression as a predictor of liver metastasis. Scand J Gastroenterol 45(2):217–225PubMedCrossRefGoogle Scholar
  28. 28.
    Esposito DL, Aru F, Lattanzio R, Morgano A, Abbondanza M, Malekzadeh R, Bishehsari F, Valanzano R, Russo A, Piantelli M, Moschetta A, Lotti LV, Mariani-Costantini R (2012) The insulin receptor substrate 1 (IRS1) in intestinal epithelial differentiation and in colorectal cancer. PLoS One 7(4):e36190PubMedCrossRefGoogle Scholar
  29. 29.
    Bommer GT, Feng Y, Iura A, Giordano TJ, Kuick R, Kadikoy H, Sikorski D, Wu R, Cho KR (2010) Fearon ER.IRS1 regulation by Wnt/beta-catenin signaling and varied contribution of IRS1 to the neoplastic phenotype. J Biol Chem 285(3):1928–1938PubMedCrossRefGoogle Scholar
  30. 30.
    Ayaki M, Komatsu K, Mukai M, Murata K, Kameyama M, Ishiguro S, Miyoshi J, Tatsuta M, Nakamura H (2001) Reduced expression of focal adhesion kinase in liver metastases compared with matched primary human colorectal adenocarcinomas. Clin Cancer Res 7(10):3106–3112PubMedGoogle Scholar
  31. 31.
    Kuramochi H, Nakajima G, Kaneko Y, Nakamura A, Inoue Y, Yamamoto M, Hayashi K (2012) Amphiregulin and Epiregulin mRNA expression in primary colorectal cancer and corresponding liver metastases. BMC Cancer 13(12):88CrossRefGoogle Scholar
  32. 32.
    Carter SL, Eklund AC, Kohane IS, Harris LN, Szallasi ZA (2006) Signature of chromosomal instability inferred from gene expression profiles predicts clinical outcome in multiple human cancers. Nat Genet 38(9):1043–1048PubMedCrossRefGoogle Scholar
  33. 33.
    Yamauchi T, Watanabe M, Kubota T, Hasegawa H, Ishii Y, Endo T, Kabeshima Y, Yorozuya K, Yamamoto K, Mukai M, Kitajima M (2002) Cyclooxygenase-2 expression as a new marker for patients with colorectal cancer. Dis Colon Rectum 45(1):98–103PubMedCrossRefGoogle Scholar
  34. 34.
    Watanabe T, Kobunai T, Yamamoto Y, Kanazawa T, Konishi T, Tanaka T, Matsuda K, Ishihara S, Nozawa K, Eshima K, Muto T, Nagawa H (2010) Prediction of liver metastasis after colorectal cancer using reverse transcription-polymerase chain reaction analysis of 10 genes. Eur J Cancer 46(11):2119–2126PubMedCrossRefGoogle Scholar
  35. 35.
    Nakamoto RH, Uetake H, Iida S, Kolev YV, Soumaoro LT, Takagi Y, Yasuno M, Sugihara K (2007) Correlations between cyclooxygenase-2 expression and angiogenic factors in primary tumors and liver metastases in colorectal cancer. Jpn J Clin Oncol 37(9):679–685PubMedCrossRefGoogle Scholar
  36. 36.
    Pantaleo MA, Astolfi A, Nannini M, Paterini P, Piazzi G, Ercolani G, Brandi G, Martinelli G, Pession A, Pinna AD, Biasco G (2008) Gene expression profiling of liver metastases from colorectal cancer as potential basis for treatment choice. Br J Cancer 99(10):1729–1734PubMedCrossRefGoogle Scholar
  37. 37.
    Prabhudesai SG, Rekhraj S, Roberts G, Darzi AW, Ziprin P (2007) Apoptosis and chemo-resistance in colorectal cancer. J Surg Oncol 96(1):77–88 ReviewPubMedCrossRefGoogle Scholar
  38. 38.
    Yarom N, Jonker DJ (2011) The role of the epidermal growth factor receptor in the mechanism and treatment of colorectal cancer. Discov Med 11(57):95–105PubMedGoogle Scholar
  39. 39.
    De Jong KP, Stellema R, Karrenbeld A, Koudstaal J, Gouw AS, Sluiter WJ, Peeters PM, Slooff MJ, De Vries EG (1998) Clinical relevance of transforming growth factor alpha, epidermal growth factor receptor, p53, and Ki67 in colorectal liver metastases and corresponding primary tumors. Hepatology 28(4):971–979PubMedCrossRefGoogle Scholar
  40. 40.
    Kito A, Tanaka K, Fujimaki H, Nakazawa M, Togo S, Minami M, Shimada H (2007) Tumor doubling time and local immune response hepatic metastases from colorectal cancer. J Surg Oncol 96(6):525–533PubMedCrossRefGoogle Scholar
  41. 41.
    Miyagawa S, Soeda J, Takagi S, Miwa S, Ichikawa E, Noike T (2004) Prognostic significance of mature dendritic cells and factors associated with their accumulation in metastatic liver tumors from colorectal cancer. Hum Pathol 35(11):1392–1396PubMedCrossRefGoogle Scholar
  42. 42.
    van der Wal GE, Gouw AS, Kamps JA, Moorlag HE, Bulthuis ML, Molema G, de Jong KP (2012) Angiogenesis in synchronous and metachronous colorectal liver metastases: the liver as a permissive soil. Ann Surg 255(1):86–94PubMedCrossRefGoogle Scholar
  43. 43.
    Shirota Y, Ichikawa W, Uetake H, Yamada H, Nihei Z, Sugihara K (2002) Intratumoral dihydropyrimidine dehydrogenase messenger RNA level reflects tumor progression in human colorectal cancer. Ann Surg Oncol 9(6):599–603PubMedCrossRefGoogle Scholar
  44. 44.
    Shi H, Hood KA, Hayes MT, Stubbs RS (2011) Proteomic analysis of advanced colorectal cancer by laser capture microdissection and two-dimensional difference gel electrophoresis. J Proteomics 75(2):339–351PubMedCrossRefGoogle Scholar
  45. 45.
    D’Arrigo A, Belluco C, Ambrosi A, Digito M, Esposito G, Bertola A, Fabris M, Nofrate V, Mammano E, Leon A, Nitti D, Lise M (2005) Metastatic transcriptional pattern revealed by gene expression profiling in primary colorectal carcinoma. Int J Cancer 115(2):256–262PubMedCrossRefGoogle Scholar
  46. 46.
    Goldstein NS, Armin M (2001) Epidermal growth factor receptor immunohistochemical reactivity in patients with American Joint Committee on Cancer Stage IV colon adenocarcinoma: implications for a standardized scoring system. Cancer 92(5):1331–1346PubMedCrossRefGoogle Scholar
  47. 47.
    Al-Mulla F, Keith WN, Pickford IR, Going JJ, Birnie GD (1999) Comparative genomic hybridization analysis of primary colorectal carcinomas and their synchronous metastases. Genes Chromosomes Cancer 24(4):306–314PubMedCrossRefGoogle Scholar
  48. 48.
    Takahashi Y, Ishii Y, Nishida Y, Ikarashi M, Nagata T, Nakamura T, Yamamori S, Asai S (2006) Detection of aberrations of ubiquitin-conjugating enzyme E2C gene (UBE2C) in advanced colon cancer with liver metastases by DNA microarray and two-color FISH. Cancer Genet Cytogenet 168(1):30–35PubMedCrossRefGoogle Scholar
  49. 49.
    Kuramochi H, Hayashi K, Uchida K, Miyakura S, Shimizu D, Vallböhmer D, Park S, Danenberg KD, Takasaki K, Danenberg PV (2006) Vascular endothelial growth factor messenger RNA expression level is preserved in liver metastases compared with corresponding primary colorectal cancer. Clin Cancer Res 12(1):29–33PubMedCrossRefGoogle Scholar
  50. 50.
    Ono M, Sakamoto M, Ino Y, Moriya Y, Sugihara K, Muto T, Hirohashi S (1996) Cancer cell morphology at the invasive front and expression of cell adhesion-related carbohydrate in the primary lesion of patients with colorectal carcinoma with liver metastasis. Cancer 78(6):1179–1186PubMedCrossRefGoogle Scholar
  51. 51.
    Nanashima A, Yamaguchi H, Yasutake T, Sawai T, Kusano H, Tagawa Y, Nakagoe T, Ayabe H (1997) Gain of chromosome 20 is a frequent aberration in liver metastasis of colorectal cancers. Dig Dis Sci 42(7):1388–1393PubMedCrossRefGoogle Scholar
  52. 52.
    Kitabatake T, Kojima K, Fukasawa M, Beppu T, Futagawa S (2002) Correlation of thymidine phosphorylase staining and the Ki-67 labeling index to clinicopathologic factors and hepatic metastasis in patients with colorectal cancer. Surg Today 32(4):322–328PubMedCrossRefGoogle Scholar
  53. 53.
    Konishi K, Watanabe Y, Shen L, Guo Y, Castoro RJ, Kondo K, Chung W, Ahmed S, Jelinek J, Boumber YA, Estecio MR, Maegawa S, Kondo Y, Itoh F, Imawari M, Hamilton SR, Issa JP (2011) DNA methylation profiles of primary colorectal carcinoma and matched liver metastasis. PLoS One 6(11):e27889PubMedCrossRefGoogle Scholar
  54. 54.
    Petrowsky H, Sturm I, Graubitz O, Kooby DA, Staib-Sebler E, Gog C, Köhne CH, Hillebrand T, Daniel PT, Fong Y, Lorenz M (2001) Relevance of Ki-67 antigen expression and K-ras mutation in colorectal liver metastases. Eur J Surg Oncol 27(1):80–87PubMedCrossRefGoogle Scholar
  55. 55.
    Chen J, Li Q, Wang C, Wu J, Zhao G (2010) Prognostic significance of c-erbB-2 and vascular endothelial growth factor in colorectal liver metastases. Ann Surg Oncol 17(6):1555–1563PubMedCrossRefGoogle Scholar
  56. 56.
    Kochhar R, Halling KC, McDonnell S, Schaid DJ, French AJ, O’Connell MJ, Nagorney DM, Thibodeau SN (1997) Allelic imbalance and microsatellite instability in resected Duke’s D colorectal cancer. Diagn Mol Pathol 6(2):78–84PubMedCrossRefGoogle Scholar
  57. 57.
    Nanashima A, Shibata K, Nakayama T, Tobinaga S, Araki M, Kunizaki M, Takeshita H, Hidaka S, Sawai T, Nagayasu T, Yasutake T (2009) Clinical significance of microvessel count in patients with metastatic liver cancer originating from colorectal carcinoma. Ann Surg Oncol 16(8):2130–2137PubMedCrossRefGoogle Scholar
  58. 58.
    Kahlert C, Lahes S, Radhakrishnan P, Dutta S, Mogler C, Herpel E, Brand K, Steinert G, Schneider M, Mollenhauer M, Reissfelder C, Klupp F, Fritzmann J, Wunder C, Benner A, Kloor M, Huth C, Contin P, Ulrich A, Koch M, Weitz J (2011) Overexpression of ZEB2 at the invasion front of colorectal cancer is an independent prognostic marker and regulates tumor invasion in vitro. Clin Cancer Res 17(24):7654–7663PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2012

Authors and Affiliations

  • A. A. P. Slesser
    • 1
  • P. Georgiou
    • 1
    • 2
  • G. Brown
    • 3
  • S. Mudan
    • 2
    • 4
  • R. Goldin
    • 5
    Email author
  • P. Tekkis
    • 1
    • 2
  1. 1.Department of Colorectal SurgeryThe Royal Marsden HospitalLondonUK
  2. 2.Division of SurgeryImperial College, Chelsea and Westminster CampusLondonUK
  3. 3.Department of RadiologyRoyal Marsden HospitalSuttonUK
  4. 4.Department of Hepatobiliary SurgeryRoyal Marsden HospitalLondonUK
  5. 5.Centre for Pathology, Imperial College at St Mary’s HospitalLondonUK

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