Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Liver metastases

Abstract

Liver metastases are commonly detected in a range of malignancies including colorectal cancer (CRC), pancreatic cancer, melanoma, lung cancer and breast cancer, although CRC is the most common primary cancer that metastasizes to the liver. Interactions between tumour cells and the tumour microenvironment play an important part in the engraftment, survival and progression of the metastases. Various cells including liver sinusoidal endothelial cells, Kupffer cells, hepatic stellate cells, parenchymal hepatocytes, dendritic cells, resident natural killer cells as well as other immune cells such as monocytes, macrophages and neutrophils are implicated in promoting and sustaining metastases in the liver. Four key phases (microvascular, pre-angiogenic, angiogenic and growth phases) have been identified in the process of liver metastasis. Imaging modalities such as ultrasonography, CT, MRI and PET scans are typically used for the diagnosis of liver metastases. Surgical resection remains the main potentially curative treatment among patients with resectable liver metastases. The role of liver transplantation in the management of liver metastasis remains controversial. Systemic therapies, newer biologic agents (for example, bevacizumab and cetuximab) and immunotherapeutic agents have revolutionized the treatment options for liver metastases. Moving forward, incorporation of genetic tests can provide more accurate information to guide clinical decision-making and predict prognosis among patients with liver metastases.

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Fig. 1: Metastatic invasion of tumour cells into the liver.
Fig. 2: Common primary cancers metastasizing to the liver.
Fig. 3: The phases of liver colonization by disseminated cancer cells.
Fig. 4: Reciprocal interactions between cancer cells and the various liver and immune cell types.
Fig. 5: Identification of colorectal liver metastasis with evidence of biliary dilatation on imaging studies.
Fig. 6: Imaging techniques to detect colorectal liver metastasis.

References

  1. Hess, K. R. et al. Metastatic patterns in adenocarcinoma. Cancer 106, 1624–1633 (2006). Registry analysis of the metastatic patterns for the main sites of primary adenocarcinoma.

    PubMed  Google Scholar 

  2. Paget, S. The distribution of secondary growths in cancer of the breast. 1889. Cancer Metastasis Rev. 8, 98–101 (1989).

    CAS  PubMed  Google Scholar 

  3. Brodt, P. Role of the microenvironment in liver metastasis: from pre- to prometastatic niches. Clin. Cancer Res. 22, 5971–5982 (2016).

    CAS  PubMed  Google Scholar 

  4. Peinado, H. et al. Pre-metastatic niches: organ-specific homes for metastases. Nat. Rev. Cancer 17, 302–317 (2017).

    CAS  PubMed  Google Scholar 

  5. Wagner, J. S., Adson, M. A., Van Heerden, J. A., Adson, M. H. & Ilstrup, D. M. The natural history of hepatic metastases from colorectal cancer. A comparison with resective treatment. Ann. Surg. 199, 502–508 (1984).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Anaya, D. A., Becker, N. S. & Abraham, N. S. Global graying, colorectal cancer and liver metastasis: new implications for surgical management. Crit. Rev. Oncol. Hematol. 77, 100–108 (2011).

    PubMed  Google Scholar 

  7. Edwards, B. K. et al. Annual Report to the Nation on the status of cancer, 1975–2010, featuring prevalence of comorbidity and impact on survival among persons with lung, colorectal, breast, or prostate cancer. Cancer 120, 1290–1314 (2014). Analysis over a period of 35 years on how cancer incidence changed for colorectal, breast, lung and prostate cancer.

    PubMed  Google Scholar 

  8. Horn, S. R. et al. Epidemiology of liver metastases. Cancer Epidemiol. 67, 101760 (2020). Recent publication with specific epidemiological information on liver metastasis and metastatic patterns of their primary tumours.

    PubMed  Google Scholar 

  9. de Ridder, J. et al. Incidence and origin of histologically confirmed liver metastases: an explorative case-study of 23,154 patients. Oncotarget 7, 55368–55376 (2016).

    PubMed  PubMed Central  Google Scholar 

  10. Golubnitschaja, O. & Sridhar, K. C. Liver metastatic disease: new concepts and biomarker panels to improve individual outcomes. Clin. Exp. Metastasis 33, 743–755 (2016).

    CAS  PubMed  Google Scholar 

  11. Torre, L. A. et al. Global cancer statistics, 2012. CA Cancer J. Clin. 65, 87–108 (2015).

    PubMed  Google Scholar 

  12. Hackl, C. et al. Treatment of colorectal liver metastases in Germany: a ten-year population-based analysis of 5772 cases of primary colorectal adenocarcinoma. BMC Cancer 14, 810 (2014).

    PubMed  PubMed Central  Google Scholar 

  13. Manfredi, S. et al. Epidemiology and management of liver metastases from colorectal cancer. Ann. Surg. 244, 254–259 (2006).

    PubMed  PubMed Central  Google Scholar 

  14. Slesser, A. A. et al. A meta-analysis comparing simultaneous versus delayed resections in patients with synchronous colorectal liver metastases. Surgical Oncol. 22, 36–47 (2013).

    CAS  Google Scholar 

  15. Siegel, R. L., Jakubowski, C. D., Fedewa, S. A., Davis, A. & Azad, N. S. Colorectal cancer in the young: epidemiology, prevention, management. Am. Soc. Clin. Oncol. Educ. Book. 40, 1–14 (2020).

    PubMed  Google Scholar 

  16. Siegel, R. L. et al. Colorectal cancer statistics, 2020. CA Cancer J. Clin. 70, 145–164 (2020).

    PubMed  Google Scholar 

  17. Nordlinger, B. et al. Perioperative FOLFOX4 chemotherapy and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC 40983): long-term results of a randomised, controlled, phase 3 trial. Lancet Oncol. 14, 1208–1215 (2013).

    CAS  PubMed  Google Scholar 

  18. Engstrand, J., Nilsson, H., Stromberg, C., Jonas, E. & Freedman, J. Colorectal cancer liver metastases - a population-based study on incidence, management and survival. BMC Cancer 18, 78 (2018).

    PubMed  PubMed Central  Google Scholar 

  19. Kobayashi, S. et al. Survival outcomes of resected BRAF V600E mutant colorectal liver metastases: a multicenter retrospective cohort study in Japan. Ann. Surg. Oncol. 27, 3307–3315 (2020).

    PubMed  Google Scholar 

  20. Bray, F. et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 68, 394–424 (2018).

    PubMed  Google Scholar 

  21. Rawla, P., Sunkara, T. & Gaduputi, V. Epidemiology of pancreatic cancer: global trends, etiology and risk factors. World J. Oncol. 10, 10–27 (2019).

    PubMed  PubMed Central  Google Scholar 

  22. Siegel, R. L., Miller, K. D. & Jemal, A. Cancer statistics, 2018. CA Cancer J. Clin. 68, 7–30 (2018).

    PubMed  Google Scholar 

  23. Conroy, T. et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N. Engl. J. Med. 364, 1817–1825 (2011).

    CAS  PubMed  Google Scholar 

  24. Ouyang, H. et al. Multimodality treatment of pancreatic cancer with liver metastases using chemotherapy, radiation therapy, and/or Chinese herbal medicine. Pancreas 40, 120–125 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Tas, F. Metastatic behavior in melanoma: timing, pattern, survival, and influencing factors. J. Oncol. 2012, 647684–647684 (2012).

    PubMed  PubMed Central  Google Scholar 

  26. Damsky, W. E., Rosenbaum, L. E. & Bosenberg, M. Decoding melanoma metastasis. Cancers 3, 126–163 (2010).

    PubMed  PubMed Central  Google Scholar 

  27. Damsky, W. E., Theodosakis, N. & Bosenberg, M. Melanoma metastasis: new concepts and evolving paradigms. Oncogene 33, 2413–2422 (2014).

    CAS  PubMed  Google Scholar 

  28. Lee, Y. T. Malignant melanoma: pattern of metastasis. CA Cancer J. Clin. 30, 137–142 (1980).

    CAS  PubMed  Google Scholar 

  29. Rose, D. M. et al. Surgical resection for metastatic melanoma to the liver: the John Wayne Cancer Institute and Sydney Melanoma Unit experience. Arch. Surg. 136, 950–955 (2001).

    CAS  PubMed  Google Scholar 

  30. Bustamante, P., Piquet, L., Landreville, S. & Burnier, J. V. Uveal melanoma pathobiology: metastasis to the liver. Semin. Cancer Biol. https://doi.org/10.1016/j.semcancer.2020.05.003 (2020).

    Article  PubMed  Google Scholar 

  31. Aronow, M. E., Topham, A. K. & Singh, A. D. Uveal melanoma: 5-year update on incidence, treatment, and survival (SEER 1973–2013). Ocul. Oncol. Pathol. 4, 145–151 (2018).

    PubMed  Google Scholar 

  32. Sisley, K. et al. Abnormalities of chromosomes 3 and 8 in posterior uveal melanoma correlate with prognosis. Genes Chromosomes Cancer 19, 22–28 (1997).

    CAS  PubMed  Google Scholar 

  33. Piperno-Neumann, S. et al. Prospective study of surveillance testing for metastasis in 100 high-risk uveal melanoma patients. J. Fr. Ophtalmol. 38, 526–534 (2015).

    CAS  PubMed  Google Scholar 

  34. Riihimäki, M. et al. Metastatic sites and survival in lung cancer. Lung Cancer 86, 78–84 (2014).

    PubMed  Google Scholar 

  35. Nakazawa, K. et al. Specific organ metastases and survival in small cell lung cancer. Oncol. Lett. 4, 617–620 (2012).

    PubMed  PubMed Central  Google Scholar 

  36. Tamura, T. et al. Specific organ metastases and survival in metastatic non-small-cell lung cancer. Mol. Clin. Oncol. 3, 217–221 (2015).

    PubMed  Google Scholar 

  37. Funazo, T., Nomizo, T. & Kim, Y. H. Liver metastasis is associated with poor progression-free survival in patients with non-small cell lung cancer treated with nivolumab. J. Thorac. Oncol. 12, e140–e141 (2017).

    PubMed  Google Scholar 

  38. Elliott, J. A., Osterlind, K., Hirsch, F. R. & Hansen, H. H. Metastatic patterns in small-cell lung cancer: correlation of autopsy findings with clinical parameters in 537 patients. J. Clin. Oncol. 5, 246–254 (1987).

    CAS  PubMed  Google Scholar 

  39. Adam, R. et al. Is liver resection justified for patients with hepatic metastases from breast cancer? Ann. Surg. 244, 897–907; discussion 907–898 (2006).

    PubMed  PubMed Central  Google Scholar 

  40. Yao, J. C. et al. One hundred years after “carcinoid”: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J. Clin. Oncol. 26, 3063–3072 (2008).

    PubMed  Google Scholar 

  41. Modlin, I. M., Lye, K. D. & Kidd, M. A 5-decade analysis of 13,715 carcinoid tumors. Cancer 97, 934–959 (2003).

    PubMed  Google Scholar 

  42. Fairweather, M. et al. Management of neuroendocrine tumor liver metastases: long-term outcomes and prognostic factors from a large prospective database. Ann. Surg. Oncol. 24, 2319–2325 (2017).

    PubMed  Google Scholar 

  43. Soreide, K. et al. Global epidemiology of gastrointestinal stromal tumours (GIST): a systematic review of population-based cohort studies. Cancer Epidemiol. 40, 39–46 (2016).

    PubMed  Google Scholar 

  44. Corless, C. L., Fletcher, J. A. & Heinrich, M. C. Biology of gastrointestinal stromal tumors. J. Clin. Oncol. 22, 3813–3825 (2004).

    CAS  PubMed  Google Scholar 

  45. Seesing, M. F. et al. Resection of liver metastases in patients with gastrointestinal stromal tumors in the imatinib era: a nationwide retrospective study. Eur. J. Surg. Oncol. 42, 1407–1413 (2016).

    CAS  PubMed  Google Scholar 

  46. Bauer, S. et al. Long-term follow-up of patients with GIST undergoing metastasectomy in the era of imatinib – analysis of prognostic factors (EORTC-STBSG collaborative study). Eur. J. Surg. Oncol. 40, 412–419 (2014).

    CAS  PubMed  Google Scholar 

  47. Van den Eynden, G. G. et al. The multifaceted role of the microenvironment in liver metastasis: biology and clinical implications. Cancer Res. 73, 2031–2043 (2013).

    PubMed  Google Scholar 

  48. Vidal-Vanaclocha, F. in Liver Metastasis: Biology and Clinical Management (ed. Brodt, P.) 1 Online Resource (Springer Science+Business Media B.V. 2011).

  49. Wisse, E., De Zanger, R. B., Charels, K., Van Der Smissen, P. & McCuskey, R. S. The liver sieve: considerations concerning the structure and function of endothelial fenestrae, the sinusoidal wall and the space of Disse. Hepatology 5, 683–692 (1985).

    CAS  PubMed  Google Scholar 

  50. Wisse, E. & Knook, D. L. Kupffer cells and other liver sinusoidal cells: proceedings of the International Kupffer Cell Symposium held in Noordwijkerhout. 4-7 (Elsevier/North-Holland Biomedical Press 1977).

  51. Stanger, B. Z. Cellular homeostasis and repair in the mammalian liver. Annu. Rev. Physiol. 77, 179–200 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Malato, Y. et al. Fate tracing of mature hepatocytes in mouse liver homeostasis and regeneration. J. Clin. Invest. 121, 4850–4860 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Kolios, G., Valatas, V. & Kouroumalis, E. Role of Kupffer cells in the pathogenesis of liver disease. World J. Gastroententerol. 12, 7413–7420 (2006).

    CAS  Google Scholar 

  54. Keirsse, J. et al. The role of hepatic macrophages in liver metastasis. Cell Immunol. 330, 202–215 (2018).

    CAS  PubMed  Google Scholar 

  55. Kubes, P. & Jenne, C. Immune responses in the liver. Annu. Rev. Immunol. 36, 247–277 (2018).

    CAS  PubMed  Google Scholar 

  56. Crispe, I. N. The liver as a lymphoid organ. Annu. Rev. Immunol. 27, 147–163 (2009).

    CAS  PubMed  Google Scholar 

  57. Benlagha, K., Kyin, T., Beavis, A., Teyton, L. & Bendelac, A. A thymic precursor to the NK T cell lineage. Science 296, 553–555 (2002).

    CAS  PubMed  Google Scholar 

  58. Dashtsoodol, N. et al. Alternative pathway for the development of Vα14+ NKT cells directly from CD4CD8 thymocytes that bypasses the CD4+CD8+ stage. Nat. Immunol. 18, 274–282 (2017).

    CAS  PubMed  Google Scholar 

  59. Doherty, D. G. & O’Farrelly, C. Innate and adaptive lymphoid cells in the human liver. Immunol. Rev. 174, 5–20 (2000).

    CAS  PubMed  Google Scholar 

  60. Friedman, S. L. Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver. Physiol. Rev. 88, 125–172 (2008).

    CAS  PubMed  Google Scholar 

  61. Muhanna, N. et al. Activation of hepatic stellate cells after phagocytosis of lymphocytes: a novel pathway of fibrogenesis. Hepatology 48, 963–977 (2008).

    CAS  PubMed  Google Scholar 

  62. Crispe, I. N. Liver antigen-presenting cells. J. Hepatol. 54, 357–365 (2011).

    CAS  PubMed  Google Scholar 

  63. Doherty, D. G. Immunity, tolerance and autoimmunity in the liver: a comprehensive review. J. Autoimmun. 66, 60–75 (2016).

    CAS  PubMed  Google Scholar 

  64. Thery, C. & Amigorena, S. The cell biology of antigen presentation in dendritic cells. Curr. Opin. Immunol. 13, 45–51 (2001).

    CAS  PubMed  Google Scholar 

  65. Xia, S. et al. Hepatic microenvironment programs hematopoietic progenitor differentiation into regulatory dendritic cells, maintaining liver tolerance. Blood 112, 3175–3185 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Kim, J. & Bae, J. S. Tumor-associated macrophages and neutrophils in tumor microenvironment. Mediators Inflamm. 2016, 6058147 (2016).

    PubMed  PubMed Central  Google Scholar 

  67. Krenkel, O. & Tacke, F. Liver macrophages in tissue homeostasis and disease. Nat. Rev. Immunol. 17, 306–321 (2017).

    CAS  PubMed  Google Scholar 

  68. Grossman, J. G. et al. Recruitment of CCR2+ tumor associated macrophage to sites of liver metastasis confers a poor prognosis in human colorectal cancer. Oncoimmunology 7, e1470729 (2018).

    PubMed  PubMed Central  Google Scholar 

  69. Zhao, L. et al. Recruitment of a myeloid cell subset (CD11b/Gr1 mid) via CCL2/CCR2 promotes the development of colorectal cancer liver metastasis. Hepatology 57, 829–839 (2013).

    CAS  PubMed  Google Scholar 

  70. Aalto, K. et al. Siglec-9 is a novel leukocyte ligand for vascular adhesion protein-1 and can be used in PET imaging of inflammation and cancer. Blood 118, 3725–3733 (2011).

    CAS  PubMed  Google Scholar 

  71. Kivi, E. et al. Human siglec-10 can bind to vascular adhesion protein-1 and serves as its substrate. Blood 114, 5385–5392 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Paiva, A. E. et al. Pericytes in the premetastatic niche. Cancer Res. 78, 2779–2786 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Kruger, A. Premetastatic niche formation in the liver: emerging mechanisms and mouse models. J. Mol. Med. 93, 1193–1201 (2015).

    PubMed  Google Scholar 

  74. Matsumura, H. et al. Kupffer cells decrease metastasis of colon cancer cells to the liver in the early stage. Int. J. Oncol. 45, 2303–2310 (2014).

    PubMed  Google Scholar 

  75. Kimura, Y. et al. The innate immune receptor Dectin-2 mediates the phagocytosis of cancer cells by Kupffer cells for the suppression of liver metastasis. Proc. Natl Acad. Sci. USA 113, 14097–14102 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Braet, F. et al. The hepatic sinusoidal endothelial lining and colorectal liver metastases. World J. Gastroenterol. 13, 821–825 (2007).

    PubMed  PubMed Central  Google Scholar 

  77. Ramadori, G., Moriconi, F., Malik, I. & Dudas, J. Physiology and pathophysiology of liver inflammation, damage and repair. J. Physiol. Pharmacol. 59 (Suppl. 1), 107–117 (2008).

    PubMed  Google Scholar 

  78. Spicer, J., Ferri, L. & Brodt. P. in Liver Metastasis: Biology and Clinical Management Cancer Metastasis - Biology and Treatment (ed Brodt. P.) Ch. 6, 155-185 (Springer 2011).

  79. Ou, J. et al. Endothelial cell-derived fibronectin extra domain A promotes colorectal cancer metastasis via inducing epithelial-mesenchymal transition. Carcinogenesis 35, 1661–1670 (2014).

    CAS  PubMed  Google Scholar 

  80. Barbazan, J. et al. Liver metastasis is facilitated by the adherence of circulating tumor cells to vascular fibronectin deposits. Cancer Res. 77, 3431–3441 (2017).

    CAS  PubMed  Google Scholar 

  81. Taylor, D. P., Clark, A., Wheeler, S. & Wells, A. Hepatic nonparenchymal cells drive metastatic breast cancer outgrowth and partial epithelial to mesenchymal transition. Breast Cancer Res. Treat. 144, 551–560 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Lucotti, S. et al. Aspirin blocks formation of metastatic intravascular niches by inhibiting platelet-derived COX-1/thromboxane A2. J. Clin. Invest. 129, 1845–1862 (2019).

    PubMed  PubMed Central  Google Scholar 

  83. Wen, S. W., Ager, E. I. & Christophi, C. Bimodal role of Kupffer cells during colorectal cancer liver metastasis. Cancer Biol. Ther. 14, 606–613 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Ciner, A. T., Jones, K., Muschel, R. J. & Brodt, P. The unique immune microenvironment of liver metastases: challenges and opportunities. Semin. Cancer Biol. https://doi.org/10.1016/j.semcancer.2020.06.003 (2020). Recent and comprehensive review of the liver immune microenvironment and its targeting.

    Article  PubMed  Google Scholar 

  85. Costa-Silva, B. et al. Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver. Nat. Cell Biol. 17, 816–826 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Yu, X. et al. Immune modulation of liver sinusoidal endothelial cells by melittin nanoparticles suppresses liver metastasis. Nat. Commun. 10, 574 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Shaul, M. E. & Fridlender, Z. G. Cancer-related circulating and tumor-associated neutrophils - subtypes, sources and function. FEBS J. 285, 4316–4342 (2018).

    CAS  PubMed  Google Scholar 

  88. Mizuno, R. et al. The role of tumor-associated neutrophils in colorectal cancer. Int. J. Mol. Sci. 20, 529 (2019).

    CAS  PubMed Central  Google Scholar 

  89. Spicer, J., Brodt, P. & Ferri, L. E. in Liver Metastasis: Biology and Clinical Management (ed Brodt, P.) 155-185 (Springer 2011).

  90. Cools-Lartigue, J. et al. Neutrophil extracellular traps sequester circulating tumor cells and promote metastasis. J. Clin. Invest. 123, 3446–3458 (2013).

    CAS  PubMed Central  Google Scholar 

  91. Albrengues, J. et al. Neutrophil extracellular traps produced during inflammation awaken dormant cancer cells in mice. Science 361, eaao4227 (2018).

    PubMed  PubMed Central  Google Scholar 

  92. Giese, M. A., Hind, L. E. & Huttenlocher, A. Neutrophil plasticity in the tumor microenvironment. Blood 133, 2159–2167 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Fridlender, Z. G. et al. Polarization of tumor-associated neutrophil phenotype by TGF-beta: “N1” versus “N2” TAN. Cancer Cell 16, 183–194 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Rayes, R. F. et al. Loss of neutrophil polarization in colon carcinoma liver metastases of mice with an inducible, liver-specific IGF-I deficiency. Oncotarget 9, 15691–15704 (2018).

    PubMed  PubMed Central  Google Scholar 

  95. Tabaries, S. et al. Granulocytic immune infiltrates are essential for the efficient formation of breast cancer liver metastases. Breast Cancer Res. 17, 45 (2015).

    PubMed  PubMed Central  Google Scholar 

  96. Gordon-Weeks, A. N. et al. Neutrophils promote hepatic metastasis growth through fibroblast growth factor 2-dependent angiogenesis in mice. Hepatology 65, 1920–1935 (2017).

    CAS  PubMed  Google Scholar 

  97. Coffelt, S. B., Wellenstein, M. D. & de Visser, K. E. Neutrophils in cancer: neutral no more. Nat. Rev. Cancer 16, 431–446 (2016).

    CAS  PubMed  Google Scholar 

  98. Qian, B. Z. Inflammation fires up cancer metastasis. Semin. Cancer Biol. 47, 170–176 (2017).

    CAS  PubMed  Google Scholar 

  99. Li, X. et al. Targeting of tumour-infiltrating macrophages via CCL2/CCR2 signalling as a therapeutic strategy against hepatocellular carcinoma. Gut 66, 157–167 (2017).

    CAS  PubMed  Google Scholar 

  100. Mills, C. D. Anatomy of a discovery: m1 and m2 macrophages. Front. Immunol. 6, 212 (2015).

    PubMed  PubMed Central  Google Scholar 

  101. Dey, A., Allen, J. & Hankey-Giblin, P. A. Ontogeny and polarization of macrophages in inflammation: blood monocytes versus tissue macrophages. Front. Immunol. 5, 683 (2014).

    PubMed  Google Scholar 

  102. Ehling, J. et al. CCL2-dependent infiltrating macrophages promote angiogenesis in progressive liver fibrosis. Gut 63, 1960–1971 (2014).

    CAS  PubMed  Google Scholar 

  103. Karlmark, K. R. et al. Hepatic recruitment of the inflammatory Gr1+ monocyte subset upon liver injury promotes hepatic fibrosis. Hepatology 50, 261–274 (2009).

    CAS  PubMed  Google Scholar 

  104. Milette, S., Sicklick, J. K., Lowy, A. M. & Brodt, P. Molecular pathways: targeting the microenvironment of liver metastases. Clin. Cancer Res. 23, 6390–6399 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Condamine, T. & Gabrilovich, D. I. Molecular mechanisms regulating myeloid-derived suppressor cell differentiation and function. Trends Immunol. 32, 19–25 (2011).

    CAS  PubMed  Google Scholar 

  106. Zhao, W. et al. Hepatic stellate cells promote tumor progression by enhancement of immunosuppressive cells in an orthotopic liver tumor mouse model. Lab. Invest. 94, 182–191 (2014).

    CAS  PubMed  Google Scholar 

  107. Gabrilovich, D. I. Myeloid-derived suppressor cells. Cancer Immunol. Res. 5, 3–8 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Gabrilovich, D. I., Ostrand-Rosenberg, S. & Bronte, V. Coordinated regulation of myeloid cells by tumours. Nat. Rev. Immunol. 12, 253–268 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Gabrilovich, D. I. & Nagaraj, S. Myeloid-derived suppressor cells as regulators of the immune system. Nat. Rev. Immunol. 9, 162–174 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Sade-Feldman, M. et al. Tumor necrosis factor-alpha blocks differentiation and enhances suppressive activity of immature myeloid cells during chronic inflammation. Immunity 38, 541–554 (2013).

    CAS  PubMed  Google Scholar 

  111. Svoronos, N. et al. Tumor cell-independent estrogen signaling drives disease progression through mobilization of myeloid-derived suppressor cells. Cancer Discov. 7, 72–85 (2017).

    CAS  PubMed  Google Scholar 

  112. Lin, Q. et al. The mechanism of the premetastatic niche facilitating colorectal cancer liver metastasis generated from myeloid-derived suppressor cells induced by the S1PR1-STAT3 signaling pathway. Cell Death Dis. 10, 693 (2019).

    PubMed  PubMed Central  Google Scholar 

  113. Milette, S. et al. Sexual dimorphism and the role of estrogen in the immune microenvironment of liver metastases. Nat. Commun. 10, 5745 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Nielsen, S. R. et al. Macrophage-secreted granulin supports pancreatic cancer metastasis by inducing liver fibrosis. Nat. Cell Biol. 18, 549–560 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Taura, K. et al. Hepatic stellate cells secrete angiopoietin 1 that induces angiogenesis in liver fibrosis. Gastroenterology 135, 1729–1738 (2008).

    CAS  PubMed  Google Scholar 

  116. Vinas, O. et al. Human hepatic stellate cells show features of antigen-presenting cells and stimulate lymphocyte proliferation. Hepatology 38, 919–929 (2003).

    CAS  PubMed  Google Scholar 

  117. Charles, R. et al. Human hepatic stellate cells inhibit T-cell response through B7-H1 pathway. Transplantation 96, 17–24 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Jiang, G. et al. Hepatic stellate cells preferentially expand allogeneic CD4+ CD25+ FoxP3+ regulatory T cells in an IL-2-dependent manner. Transplantation 86, 1492–1502 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Hochst, B. et al. Activated human hepatic stellate cells induce myeloid derived suppressor cells from peripheral blood monocytes in a CD44-dependent fashion. J. Hepatol. 59, 528–535 (2013).

    CAS  PubMed  Google Scholar 

  120. Shimizu, S. et al. Ultrastructure of early phase hepatic metastasis of human colon carcinoma cells with special reference to desmosomal junctions with hepatocytes. Pathol. Int. 50, 953–959 (2000).

    CAS  PubMed  Google Scholar 

  121. Mook, O. R. F. et al. Interactions between colon cancer cells and hepatocytes in rats in relation to metastasis. J. Cell. Mol. Med. 12, 2052–2061 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Huang, J., Pan, C., Hu, H., Zheng, S. & Ding, L. Osteopontin-enhanced hepatic metastasis of colorectal cancer cells. PLoS ONE 7, e47901 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Tabaries, S. et al. Claudin-2 promotes breast cancer liver metastasis by facilitating tumor cell interactions with hepatocytes. Mol. Cell Biol. 32, 2979–2991 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Georges, R. et al. Sequential biphasic changes in claudin1 and claudin4 expression are correlated to colorectal cancer progression and liver metastasis. J. Cell. Mol. Med. 16, 260–272 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Zvibel, I. et al. Transcriptional profiling identifies genes induced by hepatocyte-derived extracellular matrix in metastatic human colorectal cancer cell lines. Clin. Exp. Metastasis 30, 189–200 (2013).

    CAS  PubMed  Google Scholar 

  126. Li, H. et al. Human and mouse colon cancer utilizes CD95 signaling for local growth and metastatic spread to liver. Gastroenterology 137, 934–944.e934 (2009).

    CAS  PubMed  Google Scholar 

  127. Yoshioka, T. et al. Significance of integrin αvβ5 and erbB3 in enhanced cell migration and liver metastasis of colon carcinomas stimulated by hepatocyte-derived heregulin. Cancer Sci. 101, 2011–2018 (2010).

    CAS  PubMed  Google Scholar 

  128. Dome, B., Hendrix, M. J., Paku, S., Tovari, J. & Timar, J. Alternative vascularization mechanisms in cancer: pathology and therapeutic implications. Am. J. Pathol. 170, 1–15 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Tiegs, G. & Lohse, A. W. Immune tolerance: what is unique about the liver. J. Autoimmun. 34, 1–6 (2010).

    CAS  PubMed  Google Scholar 

  130. Heymann, F. & Tacke, F. Immunology in the liver–from homeostasis to disease. Nat. Rev. Gastroenterol. Hepatol. 13, 88–110 (2016).

    CAS  PubMed  Google Scholar 

  131. Bilen, M. A. et al. Sites of metastasis and association with clinical outcome in advanced stage cancer patients treated with immunotherapy. BMC Cancer 19, 857 (2019).

    PubMed  PubMed Central  Google Scholar 

  132. Tumeh, P. C. et al. Liver metastasis and treatment outcome with anti-PD-1 monoclonal antibody in patients with melanoma and NSCLC. Cancer Immunol. Res. 5, 417–424 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Yu, J. et al. Liver metastasis restrains immunotherapy efficacy via macrophage-mediated T cell elimination. Nat. Med. 27, 152–164 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Burnier, J. V. et al. Type IV collagen-initiated signals provide survival and growth cues required for liver metastasis. Oncogene 30, 3766–3783 (2011).

    CAS  PubMed  Google Scholar 

  135. Qi, S., Perrino, S., Miao, X., Lamarche-Vane, N. & Brodt, P. The chemokine CCL7 regulates invadopodia maturation and MMP-9 mediated collagen degradation in liver-metastatic carcinoma cells. Cancer Lett. 483, 98–113 (2020).

    CAS  PubMed  Google Scholar 

  136. Vaniotis, G. et al. Collagen IV-conveyed signals can regulate chemokine production and promote liver metastasis. Oncogene 37, 3790–3805 (2018).

    CAS  PubMed  Google Scholar 

  137. Goddard, E. T. et al. The rodent liver undergoes weaning-induced involution and supports breast cancer metastasis. Cancer Discov. 7, 177–187 (2017).

    CAS  PubMed  Google Scholar 

  138. Salarian, M. et al. Precision detection of liver metastasis by collagen-targeted protein MRI contrast agent. Biomaterials 224, 119478 (2019).

    CAS  PubMed  Google Scholar 

  139. Nystrom, H., Tavelin, B., Bjorklund, M., Naredi, P. & Sund, M. Improved tumour marker sensitivity in detecting colorectal liver metastases by combined type IV collagen and CEA measurement. Tumour Biol. 36, 9839–9847 (2015).

    PubMed  Google Scholar 

  140. Steele, C. W. et al. CXCR2 inhibition profoundly suppresses metastases and augments immunotherapy in pancreatic ductal adenocarcinoma. Cancer Cell 29, 832–845 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Barnhill, R. et al. Replacement and desmoplastic histopathological growth patterns in cutaneous melanoma liver metastases: frequency, characteristics, and robust prognostic value. J. Pathol. Clin. Res. 6, 195–206 (2020).

    PubMed  PubMed Central  Google Scholar 

  142. Van den Eynden, G. G. et al. Tumor stromal phenotypes define VEGF sensitivity–letter. Clin. Cancer Res. 20, 5140 (2014).

    PubMed  Google Scholar 

  143. Stessels, F. et al. Breast adenocarcinoma liver metastases, in contrast to colorectal cancer liver metastases, display a non-angiogenic growth pattern that preserves the stroma and lacks hypoxia. Br. J. Cancer 90, 1429–1436 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Watanabe, K. et al. The “histological replacement growth pattern” represents aggressive invasive behavior in liver metastasis from pancreatic cancer. Cancer Med. 9, 3130–3141 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Frentzas, S. et al. Vessel co-option mediates resistance to anti-angiogenic therapy in liver metastases. Nat. Med. 22, 1294–1302 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. Kalluri, R. The biology and function of exosomes in cancer. J. Clin. Invest. 126, 1208–1215 (2016).

    PubMed  PubMed Central  Google Scholar 

  147. Wortzel, I., Dror, S., Kenific, C. M. & Lyden, D. Exosome-mediated metastasis: communication from a distance. Dev. Cell 49, 347–360 (2019).

    CAS  PubMed  Google Scholar 

  148. Zhang, H. et al. Exosome-delivered EGFR regulates liver microenvironment to promote gastric cancer liver metastasis. Nat. Commun. 8, 15016 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Desmond, B. J., Dennett, E. R. & Danielson, K. M. Circulating extracellular vesicle microRNA as diagnostic biomarkers in early colorectal cancer-a review. Cancers 12, 52 (2019).

    PubMed Central  Google Scholar 

  150. Shao, Y. et al. Colorectal cancer-derived small extracellular vesicles establish an inflammatory premetastatic niche in liver metastasis. Carcinogenesis 39, 1368–1379 (2018).

    CAS  PubMed  Google Scholar 

  151. Rahbari, N. N. et al. Anti-VEGF therapy induces ECM remodeling and mechanical barriers to therapy in colorectal cancer liver metastases. Sci. Transl. Med. 8, 360ra135 (2016).

    PubMed  PubMed Central  Google Scholar 

  152. Yang, Y. et al. Discontinuation of anti-VEGF cancer therapy promotes metastasis through a liver revascularization mechanism. Nat. Commun. 7, 12680 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Im, J. H. et al. G-CSF rescues tumor growth and neo-angiogenesis during liver metastasis under host angiopoietin-2 deficiency. Int. J. Cancer 132, 315–326 (2013).

    CAS  PubMed  Google Scholar 

  154. Sahani, D. V., Bajwa, M. A., Andrabi, Y., Bajpai, S. & Cusack, J. C. Current status of imaging and emerging techniques to evaluate liver metastases from colorectal carcinoma. Ann. Surg. 259, 861–872 (2014). Comprehensive review on the different imaging techniques to evaluate liver metastases from colorectal cancer.

    PubMed  Google Scholar 

  155. Minami, Y. & Kudo, M. Hepatic malignancies: correlation between sonographic findings and pathological features. World J. Radiol. 2, 249–256 (2010).

    PubMed  PubMed Central  Google Scholar 

  156. Estrella, J. S. et al. Intrabiliary growth of liver metastases: clinicopathologic features, prevalence, and outcome. Am. J. Surg. Pathol. 37, 1571–1579 (2013).

    PubMed  PubMed Central  Google Scholar 

  157. Niekel, M. C., Bipat, S. & Stoker, J. Diagnostic imaging of colorectal liver metastases with CT, MR imaging, FDG PET, and/or FDG PET/CT: a meta-analysis of prospective studies including patients who have not previously undergone treatment. Radiology 257, 674–684 (2010).

    PubMed  Google Scholar 

  158. Floriani, I. et al. Performance of imaging modalities in diagnosis of liver metastases from colorectal cancer: a systematic review and meta-analysis. J. Magn. Reson. Imaging 31, 19–31 (2010).

    PubMed  Google Scholar 

  159. Ito, T. et al. The diagnostic advantage of EOB-MR imaging over CT in the detection of liver metastasis in patients with potentially resectable pancreatic cancer. Pancreatology 17, 451–456 (2017).

    PubMed  Google Scholar 

  160. Bahri, H. et al. High prognostic value of 18F-FDG PET for metastatic gastroenteropancreatic neuroendocrine tumors: a long-term evaluation. J. Nucl. Med. 55, 1786–1790 (2014).

    CAS  PubMed  Google Scholar 

  161. Weber, W. A. Use of PET for monitoring cancer therapy and for predicting outcome. J. Nucl. Med. 46, 983–995 (2005).

    CAS  PubMed  Google Scholar 

  162. De Bruyne, S. et al. Value of DCE-MRI and FDG-PET/CT in the prediction of response to preoperative chemotherapy with bevacizumab for colorectal liver metastases. Br. J. Cancer 106, 1926–1933 (2012).

    PubMed  PubMed Central  Google Scholar 

  163. Tan, M. C., Linehan, D. C., Hawkins, W. G., Siegel, B. A. & Strasberg, S. M. Chemotherapy-induced normalization of FDG uptake by colorectal liver metastases does not usually indicate complete pathologic response. J. Gastrointest. Surg. 11, 1112–1119 (2007).

    PubMed  Google Scholar 

  164. Has Simsek, D. et al. Can complementary 68Ga-DOTATATE and 18F-FDG PET/CT establish the missing link between histopathology and therapeutic approach in gastroenteropancreatic neuroendocrine tumors? J. Nucl. Med. 55, 1811–1817 (2014).

    PubMed  Google Scholar 

  165. Hope, T. A. et al. Appropriate use criteria for somatostatin receptor PET imaging in neuroendocrine tumors. J. Nucl. Med. 59, 66–74 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. Balogova, S. et al. 18F-fluorodihydroxyphenylalanine vs other radiopharmaceuticals for imaging neuroendocrine tumours according to their type. Eur. J. Nucl. Med. Mol. Imaging 40, 943–966 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  167. Koopmans, K. P. et al. Improved staging of patients with carcinoid and islet cell tumors with 18F-dihydroxy-phenyl-alanine and 11C-5-hydroxy-tryptophan positron emission tomography. J. Clin. Oncol. 26, 1489–1495 (2008).

    PubMed  Google Scholar 

  168. Fiebrich, H. B. et al. Total 18F-Dopa PET tumour uptake reflects metabolic endocrine tumour activity in patients with a carcinoid tumour. Eur. J. Nucl. Med. Mol. Imaging 38, 1854–1861 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  169. Heinemann, V. et al. Early tumour shrinkage (ETS) and depth of response (DpR) in the treatment of patients with metastatic colorectal cancer (mCRC). Eur. J. Cancer 51, 1927–1936 (2015).

    PubMed  Google Scholar 

  170. Chun, Y. S. et al. Association of computed tomography morphologic criteria with pathologic response and survival in patients treated with bevacizumab for colorectal liver metastases. JAMA 302, 2338–2344 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. Frankel, T. L., Gian, R. K. & Jarnagin, W. R. Preoperative imaging for hepatic resection of colorectal cancer metastasis. J. Gastrointest. Oncol. 3, 11–18 (2012).

    PubMed  PubMed Central  Google Scholar 

  172. Peloso, A. et al. Combined use of intraoperative ultrasound and indocyanine green fluorescence imaging to detect liver metastases from colorectal cancer. HPB 15, 928–934 (2013).

    PubMed  PubMed Central  Google Scholar 

  173. Tot, T. Cytokeratins 20 and 7 as biomarkers: usefulness in discriminating primary from metastatic adenocarcinoma. Eur. J. Cancer 38, 758–763 (2002).

    CAS  PubMed  Google Scholar 

  174. Shimonishi, T., Miyazaki, K. & Nakanuma, Y. Cytokeratin profile relates to histological subtypes and intrahepatic location of intrahepatic cholangiocarcinoma and primary sites of metastatic adenocarcinoma of liver. Histopathology 37, 55–63 (2000).

    CAS  PubMed  Google Scholar 

  175. Liu, H., Shi, J., Wilkerson, M. L. & Lin, F. Immunohistochemical evaluation of GATA3 expression in tumors and normal tissues: a useful immunomarker for breast and urothelial carcinomas. Am. J. Clin. Pathol. 138, 57–64 (2012).

    PubMed  Google Scholar 

  176. Chu, P. G., Schwarz, R. E., Lau, S. K., Yen, Y. & Weiss, L. M. Immunohistochemical staining in the diagnosis of pancreatobiliary and ampulla of Vater adenocarcinoma: application of CDX2, CK17, MUC1, and MUC2. Am. J. Surg. Pathol. 29, 359–367 (2005).

    PubMed  Google Scholar 

  177. Mukhopadhyay, S. & Katzenstein, A. L. Subclassification of non-small cell lung carcinomas lacking morphologic differentiation on biopsy specimens: utility of an immunohistochemical panel containing TTF-1, napsin A, p63, and CK5/6. Am. J. Surg. Pathol. 35, 15–25 (2011).

    PubMed  Google Scholar 

  178. Gould, V. E. et al. Synaptophysin expression in neuroendocrine neoplasms as determined by immunocytochemistry. Am. J. Pathol. 126, 243–257 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  179. Wiedenmann, B., Franke, W. W., Kuhn, C., Moll, R. & Gould, V. E. Synaptophysin: a marker protein for neuroendocrine cells and neoplasms. Proc. Natl Acad. Sci. USA 83, 3500–3504 (1986).

    CAS  PubMed  PubMed Central  Google Scholar 

  180. Wilson, B. S. & Lloyd, R. V. Detection of chromogranin in neuroendocrine cells with a monoclonal antibody. Am. J. Pathol. 115, 458–468 (1984).

    CAS  PubMed  PubMed Central  Google Scholar 

  181. Gown, A. M., Fulton, R. S. & Kandalaft, P. L. Markers of metastatic carcinoma of breast origin. Histopathology 68, 86–95 (2016).

    PubMed  Google Scholar 

  182. Truong, L. D. & Shen, S. S. Immunohistochemical diagnosis of renal neoplasms. Arch. Pathol. Lab. Med. 135, 92–109 (2011).

    PubMed  Google Scholar 

  183. Laury, A. R. et al. A comprehensive analysis of PAX8 expression in human epithelial tumors. Am. J. Surg. Pathol. 35, 816–826 (2011).

    PubMed  Google Scholar 

  184. Terada, T., Ohta, T., Sasaki, M., Nakanuma, Y. & Kim, Y. S. Expression of MUC apomucins in normal pancreas and pancreatic tumours. J. Pathol. 180, 160–165 (1996).

    CAS  PubMed  Google Scholar 

  185. Brimo, F. & Epstein, J. I. Immunohistochemical pitfalls in prostate pathology. Hum. Pathol. 43, 313–324 (2012).

    CAS  PubMed  Google Scholar 

  186. Sepulveda, A. R. et al. Molecular biomarkers for the evaluation of colorectal cancer: guideline from the American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and the American Society of Clinical Oncology. J. Clin. Oncol. 35, 1453–1486 (2017).

    CAS  PubMed  Google Scholar 

  187. Tsilimigras, D. I. et al. Clinical significance and prognostic relevance of KRAS, BRAF, PI3K and TP53 genetic mutation analysis for resectable and unresectable colorectal liver metastases: a systematic review of the current evidence. Surg. Oncol. 27, 280–288 (2018). Comprehensive systematic review on the significance of genetic mutations in resectable and unresectable colorectal liver metastases.

    PubMed  Google Scholar 

  188. Schwarz, R. E. et al. Systemic cytotoxic and biological therapies of colorectal liver metastases: expert consensus statement. HPB 15, 106–115 (2013).

    PubMed  Google Scholar 

  189. Margonis, G. A. et al. Association between specific mutations in KRAS codon 12 and colorectal liver metastasis. JAMA Surg. 150, 722–729 (2015).

    PubMed  PubMed Central  Google Scholar 

  190. Margonis, G. A. et al. KRAS mutation status dictates optimal surgical margin width in patients undergoing resection of colorectal liver metastases. Ann. Surg. Oncol. 24, 264–271 (2017).

    PubMed  Google Scholar 

  191. Margonis, G. A. et al. Codon 13 KRAS mutation predicts patterns of recurrence in patients undergoing hepatectomy for colorectal liver metastases. Cancer 122, 2698–2707 (2016).

    CAS  PubMed  Google Scholar 

  192. Wu, X. Z., Ma, F. & Wang, X. L. Serological diagnostic factors for liver metastasis in patients with colorectal cancer. World J. Gastroenterol. 16, 4084–4088 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  193. Locker, G. Y. et al. ASCO 2006 update of recommendations for the use of tumor markers in gastrointestinal cancer. J. Clin. Oncol. 24, 5313–5327 (2006).

    CAS  PubMed  Google Scholar 

  194. Fong, Y., Fortner, J., Sun, R. L., Brennan, M. F. & Blumgart, L. H. Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001 consecutive cases. Ann. Surg. 230, 309–318; discussion 318-321 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  195. Pantel, K. & Alix-Panabieres, C. Real-time liquid biopsy in cancer patients: fact or fiction? Cancer Res. 73, 6384–6388 (2013).

    CAS  PubMed  Google Scholar 

  196. Zhang, W. et al. Liquid biopsy for cancer: circulating tumor cells, circulating free DNA or exosomes? Cell Physiol. Biochem. 41, 755–768 (2017).

    CAS  PubMed  Google Scholar 

  197. Alix-Panabieres, C., Schwarzenbach, H. & Pantel, K. Circulating tumor cells and circulating tumor DNA. Annu. Rev. Med. 63, 199–215 (2012).

    CAS  PubMed  Google Scholar 

  198. Alix-Panabieres, C. & Pantel, K. Circulating tumor cells: liquid biopsy of cancer. Clin. Chem. 59, 110–118 (2013).

    CAS  PubMed  Google Scholar 

  199. Cohen, S. J. et al. Relationship of circulating tumor cells to tumor response, progression-free survival, and overall survival in patients with metastatic colorectal cancer. J. Clin. Oncol. 26, 3213–3221 (2008).

    PubMed  Google Scholar 

  200. Seeberg, L. T. et al. Circulating tumor cells in patients with colorectal liver metastasis predict impaired survival. Ann. Surg. 261, 164–171 (2015).

    PubMed  Google Scholar 

  201. Tien, Y. W. et al. A high circulating tumor cell count in portal vein predicts liver metastasis from periampullary or pancreatic cancer: a high portal venous CTC count predicts liver metastases. Medicine 95, e3407 (2016).

    PubMed  PubMed Central  Google Scholar 

  202. Crowley, E., Di Nicolantonio, F., Loupakis, F. & Bardelli, A. Liquid biopsy: monitoring cancer-genetics in the blood. Nat. Rev. Clin. Oncol. 10, 472–484 (2013).

    CAS  PubMed  Google Scholar 

  203. Siravegna, G., Marsoni, S., Siena, S. & Bardelli, A. Integrating liquid biopsies into the management of cancer. Nat. Rev. Clin. Oncol. 14, 531–548 (2017).

    CAS  PubMed  Google Scholar 

  204. Thierry, A. R. et al. Clinical validation of the detection of KRAS and BRAF mutations from circulating tumor DNA. Nat. Med. 20, 430–435 (2014).

    CAS  PubMed  Google Scholar 

  205. Misale, S. et al. Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer. Nature 486, 532–536 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  206. Heitzer, E. et al. Complex tumor genomes inferred from single circulating tumor cells by array-CGH and next-generation sequencing. Cancer Res. 73, 2965–2975 (2013).

    CAS  PubMed  Google Scholar 

  207. Li, G., Tang, W. & Yang, F. Cancer liquid biopsy using integrated microfluidic exosome analysis platforms. Biotechnol. J. 15, e1900225 (2020).

    PubMed  Google Scholar 

  208. Merker, J. D. et al. Circulating tumor DNA analysis in patients with cancer: american society of clinical oncology and college of american pathologists joint review. J. Clin. Oncol. 36, 1631–1641 (2018).

    CAS  PubMed  Google Scholar 

  209. Huang, S. et al. microRNA biomarkers in colorectal cancer liver metastasis. J. Cancer 9, 3867–3873 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  210. Wang, L. G. & Gu, J. Serum microRNA-29a is a promising novel marker for early detection of colorectal liver metastasis. Cancer Epidemiol. 36, e61–e67 (2012).

    CAS  PubMed  Google Scholar 

  211. Kingham, T. P. et al. MicroRNA-203 predicts human survival after resection of colorectal liver metastasis. Oncotarget 8, 18821–18831 (2017).

    PubMed  Google Scholar 

  212. Geng, L. et al. MicroRNA-192 suppresses liver metastasis of colon cancer. Oncogene 33, 5332–5340 (2014).

    CAS  PubMed  Google Scholar 

  213. Costas-Chavarri, A. et al. Treatment of patients with early-stage colorectal cancer: ASCO resource-stratified guideline. J. Glob. Oncol. 5, 1–19 (2019).

    PubMed  Google Scholar 

  214. Pawlik, T. M. & Choti, M. A. Surgical therapy for colorectal metastases to the liver. J. Gastrointest. Surg. 11, 1057–1077 (2007).

    PubMed  Google Scholar 

  215. Altendorf-Hofmann, A. & Scheele, J. A critical review of the major indicators of prognosis after resection of hepatic metastases from colorectal carcinoma. Surg. Oncol. Clin. N. Am. 12, 165–192 (2003).

    PubMed  Google Scholar 

  216. Pulitano, C. et al. Liver resection for colorectal metastases in presence of extrahepatic disease: results from an international multi-institutional analysis. Ann. Surg. Oncol. 18, 1380–1388 (2011).

    PubMed  Google Scholar 

  217. Cloyd, J. M., Wiseman, J. T. & Pawlik, T. M. Surgical management of pancreatic neuroendocrine liver metastases. J. Gastrointest. Oncol. 11, 590–600 (2020).

    PubMed  PubMed Central  Google Scholar 

  218. Kunz, P. L. et al. Consensus guidelines for the management and treatment of neuroendocrine tumors. Pancreas 42, 557–577 (2013).

    PubMed  PubMed Central  Google Scholar 

  219. Pavel, M. et al. ENETS consensus guidelines for the management of patients with liver and other distant metastases from neuroendocrine neoplasms of foregut, midgut, hindgut, and unknown primary. Neuroendocrinology 95, 157–176 (2012).

    CAS  PubMed  Google Scholar 

  220. Jin, K. et al. Surgical management for non-functional pancreatic neuroendocrine neoplasms with synchronous liver metastasis: a consensus from the Chinese Study Group for Neuroendocrine Tumors (CSNET). Int. J. Oncol. 49, 1991–2000 (2016).

    PubMed  Google Scholar 

  221. Singh, S. et al. Consensus recommendations for the diagnosis and management of pancreatic neuroendocrine tumors: guidelines from a Canadian National Expert Group. Ann. Surg. Oncol. 22, 2685–2699 (2015).

    PubMed  Google Scholar 

  222. Saxena, A., Chua, T. C., Perera, M., Chu, F. & Morris, D. L. Surgical resection of hepatic metastases from neuroendocrine neoplasms: a systematic review. Surgical Oncol. 21, e131–e141 (2012).

    Google Scholar 

  223. Mayo, S. C. et al. Surgery versus intra-arterial therapy for neuroendocrine liver metastasis: a multicenter international analysis. Ann. Surg. Oncol. 18, 3657–3665 (2011).

    PubMed  Google Scholar 

  224. Scott, A. T. et al. Effective cytoreduction can be achieved in patients with numerous neuroendocrine tumor liver metastases (NETLMs). Surgery 165, 166–175 (2019).

    PubMed  Google Scholar 

  225. Ejaz, A. et al. Cytoreductive debulking surgery among patients with neuroendocrine liver metastasis: a multi-institutional analysis. HPB 20, 277–284 (2018).

    PubMed  Google Scholar 

  226. Adam, R. et al. Hepatic resection for noncolorectal nonendocrine liver metastases: analysis of 1,452 patients and development of a prognostic model. Ann. Surg. 244, 524–535 (2006).

    PubMed  PubMed Central  Google Scholar 

  227. Groeschl, R. T. et al. Hepatectomy for noncolorectal non-neuroendocrine metastatic cancer: a multi-institutional analysis. J. Am. Coll. Surg. 214, 769–777 (2012).

    PubMed  Google Scholar 

  228. Gaujoux, S. et al. Resection of adrenocortical carcinoma liver metastasis: is it justified? Ann. Surg. Oncol. 19, 2643–2651 (2012).

    PubMed  Google Scholar 

  229. Gleisner, A. L. et al. Is resection of periampullary or pancreatic adenocarcinoma with synchronous hepatic metastasis justified? Cancer 110, 2484–2492 (2007).

    PubMed  Google Scholar 

  230. Pawlik, T. M. et al. Hepatic resection for metastatic melanoma: distinct patterns of recurrence and prognosis for ocular versus cutaneous disease. Ann. Surg. Oncol. 13, 712–720 (2006).

    PubMed  Google Scholar 

  231. Muhlbacher, F. et al. Is orthotopic liver transplantation a feasible treatment for secondary cancer of the liver? Transpl. Proc. 23, 1567–1568 (1991).

    CAS  Google Scholar 

  232. Hagness, M. et al. Liver transplantation for nonresectable liver metastases from colorectal cancer. Ann. Surg. 257, 800–806 (2013).

    PubMed  Google Scholar 

  233. Dueland, S. et al. Survival following liver transplantation for patients with nonresectable liver-only colorectal metastases. Ann. Surg. 271, 212–218 (2020).

    PubMed  Google Scholar 

  234. Moris, D. et al. Liver transplantation for unresectable colorectal liver metastases: a systematic review. J. Surg. Oncol. 116, 288–297 (2017).

    PubMed  Google Scholar 

  235. Le Treut, Y. P. et al. Liver transplantation for neuroendocrine tumors in Europe — results and trends in patient selection: a 213-case European liver transplant registry study. Ann. Surg. 257, 807–815 (2013).

    PubMed  Google Scholar 

  236. Moris, D. et al. Liver transplantation in patients with liver metastases from neuroendocrine tumors: a systematic review. Surgery 162, 525–536 (2017).

    PubMed  Google Scholar 

  237. Crocetti, L., de Baere, T., Pereira, P. L. & Tarantino, F. P. CIRSE standards of practice on thermal ablation of liver tumours. Cardiovasc. Intervent. Radiol. 43, 951–962 (2020).

    PubMed  Google Scholar 

  238. Ruers, T. et al. Radiofrequency ablation combined with systemic treatment versus systemic treatment alone in patients with non-resectable colorectal liver metastases: a randomized EORTC Intergroup phase II study (EORTC 40004). Ann. Oncol. 23, 2619–2626 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  239. Ruers, T. et al. Local treatment of unresectable colorectal liver metastases: results of a randomized phase II trial. J. Natl Cancer Inst. 109, djx015 (2017).

    PubMed Central  Google Scholar 

  240. Otto, G. et al. Radiofrequency ablation as first-line treatment in patients with early colorectal liver metastases amenable to surgery. Ann. Surg. 251, 796–803 (2010).

    PubMed  Google Scholar 

  241. Lubner, M. G., Brace, C. L., Ziemlewicz, T. J., Hinshaw, J. L. & Lee, F. T. Jr. Microwave ablation of hepatic malignancy. Semin. Intervent. Radiol. 30, 56–66 (2013).

    PubMed  PubMed Central  Google Scholar 

  242. Correa-Gallego, C. et al. A retrospective comparison of microwave ablation vs. radiofrequency ablation for colorectal cancer hepatic metastases. Ann. Surg. Oncol. 21, 4278–4283 (2014).

    PubMed  PubMed Central  Google Scholar 

  243. Meijerink, M. R. et al. Radiofrequency and microwave ablation compared to systemic chemotherapy and to partial hepatectomy in the treatment of colorectal liver metastases: a systematic review and meta-analysis. Cardiovasc. Intervent. Radiol. 41, 1189–1204 (2018).

    PubMed  PubMed Central  Google Scholar 

  244. Shibata, T., Niinobu, T., Ogata, N. & Takami, M. Microwave coagulation therapy for multiple hepatic metastases from colorectal carcinoma. Cancer 89, 276–284 (2000).

    CAS  PubMed  Google Scholar 

  245. Meijerink, M. R., Puijk, R. S. & van den Tol, P. M. P. COLLISION trial seeks to answer time-honored question: “Thermal ablation or surgery for colorectal liver metastases?” Cardiovasc. Intervent. Radiol. 42, 1059–1061 (2019).

    PubMed  Google Scholar 

  246. Gurusamy, K. et al. Liver resection surgery versus thermal ablation for colorectal LiVer MetAstases (LAVA): study protocol for a randomised controlled trial. Trials 19, 105 (2018).

    PubMed  PubMed Central  Google Scholar 

  247. Ruarus, A. H. et al. Conductivity rise during irreversible electroporation: true permeabilization or heat? Cardiovasc. Intervent. Radiol. 41, 1257–1266 (2018).

    PubMed  PubMed Central  Google Scholar 

  248. Hosein, P. J. et al. Percutaneous irreversible electroporation for the treatment of colorectal cancer liver metastases with a proposal for a new response evaluation system. J. Vasc. Interv. Radiol. 25, 1233–1239 e1232 (2014).

    PubMed  Google Scholar 

  249. Kelly, C. & Cassidy, J. Chemotherapy in metastatic colorectal cancer. Surgical Oncol. 16, 65–70 (2007).

    Google Scholar 

  250. Giacchetti, S. et al. Phase III multicenter randomized trial of oxaliplatin added to chronomodulated fluorouracil-leucovorin as first-line treatment of metastatic colorectal cancer. J. Clin. Oncol. 18, 136–147 (2000).

    CAS  PubMed  Google Scholar 

  251. Tol, J. et al. Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. N. Engl. J. Med. 360, 563–572 (2009).

    CAS  PubMed  Google Scholar 

  252. Saltz, L. B. et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin. Oncol. 26, 2013–2019 (2008).

    CAS  PubMed  Google Scholar 

  253. Gordon, M. S. et al. Phase I safety and pharmacokinetic study of recombinant human anti-vascular endothelial growth factor in patients with advanced cancer. J. Clin. Oncol. 19, 843–850 (2001).

    CAS  PubMed  Google Scholar 

  254. El Zouhairi, M., Charabaty, A. & Pishvaian, M. J. Molecularly targeted therapy for metastatic colon cancer: proven treatments and promising new agents. Gastrointest. Cancer Res. 4, 15–21 (2011).

    PubMed  PubMed Central  Google Scholar 

  255. Hurwitz, H. et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N. Engl. J. Med. 350, 2335–2342 (2004).

    CAS  PubMed  Google Scholar 

  256. Ohhara, Y. et al. Comparison between three oxaliplatin-based regimens with bevacizumab in patients with metastatic colorectal cancer. Onco Targets Ther. 8, 529–537 (2015).

    PubMed  PubMed Central  Google Scholar 

  257. Kim, S. A. et al. Conversion surgery after cetuximab or bevacizumab plus FOLFIRI chemotherapy in colorectal cancer patients with liver- and/or lung-limited metastases. J. Cancer Res. Clin. Oncol. 146, 2399–2410 (2020).

    CAS  PubMed  Google Scholar 

  258. Sobrero, A. F. et al. EPIC: phase III trial of cetuximab plus irinotecan after fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer. J. Clin. Oncol. 26, 2311–2319 (2008).

    CAS  PubMed  Google Scholar 

  259. Schwartzberg, L. S. et al. PEAK: a randomized, multicenter phase II study of panitumumab plus modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or bevacizumab plus mFOLFOX6 in patients with previously untreated, unresectable, wild-type KRAS exon 2 metastatic colorectal cancer. J Clin Oncol 32, 2240–2247 (2014).

    CAS  PubMed  Google Scholar 

  260. Amado, R. G. et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J. Clin. Oncol. 26, 1626–1634 (2008).

    CAS  PubMed  Google Scholar 

  261. Bolhuis, K., Kos, M., van Oijen, M. G. H., Swijnenburg, R. J. & Punt, C. J. A. Conversion strategies with chemotherapy plus targeted agents for colorectal cancer liver-only metastases: a systematic review. Eur. J. Cancer 141, 225–238 (2020).

    PubMed  Google Scholar 

  262. Van Cutsem, E. et al. ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann. Oncol. 27, 1386–1422 (2016). Guidelines on the management of patients with metastatic colorectal cancer.

    PubMed  Google Scholar 

  263. Adam, R. & Kitano, Y. Multidisciplinary approach of liver metastases from colorectal cancer. Ann. Gastroenterol. Surg. 3, 50–56 (2019).

    PubMed  PubMed Central  Google Scholar 

  264. Yao, J. C. et al. Everolimus for advanced pancreatic neuroendocrine tumors. N. Engl. J. Med. 364, 514–523 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  265. Raymond, E. et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N. Engl. J. Med. 364, 501–513 (2011).

    CAS  PubMed  Google Scholar 

  266. Yao, J. C. et al. Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study. Lancet 387, 968–977 (2016).

    CAS  PubMed  Google Scholar 

  267. Cloyd, J. M., Konda, B., Shah, M. H. & Pawlik, T. M. The emerging role of targeted therapies for advanced well-differentiated gastroenteropancreatic neuroendocrine tumors. Expert Rev. Clin. Pharmacol. 12, 101–108 (2019).

    CAS  PubMed  Google Scholar 

  268. Moertel, C. G., Hanley, J. A. & Johnson, L. A. Streptozocin alone compared with streptozocin plus fluorouracil in the treatment of advanced islet-cell carcinoma. N. Engl. J. Med. 303, 1189–1194 (1980).

    CAS  PubMed  Google Scholar 

  269. Kunz, P. L. et al. A randomized study of temozolomide or temozolomide and capecitabine in patients with advanced pancreatic neuroendocrine tumors: a trial of the ECOG-ACRIN Cancer Research Group (E2211). J. Clin. Oncol. 36, 4004–4004 (2018).

    Google Scholar 

  270. Strosberg, J. et al. Phase 3 trial of 177Lu-Dotatate for midgut neuroendocrine tumors. N. Engl. J. Med. 376, 125–135 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  271. Zhu, J., Yang, Y., Zhou, L., Jiang, M. & Hou, M. A long-term follow-up of the imatinib mesylate treatment for the patients with recurrent gastrointestinal stromal tumor (GIST): the liver metastasis and the outcome. BMC Cancer 10, 199 (2010).

    PubMed  PubMed Central  Google Scholar 

  272. Kim, E. J. & Zalupski, M. M. Systemic therapy for advanced gastrointestinal stromal tumors: beyond imatinib. J. Surg. Oncol. 104, 901–906 (2011).

    CAS  PubMed  Google Scholar 

  273. Vokes, E. E. et al. Nivolumab versus docetaxel in previously treated advanced non-small-cell lung cancer (CheckMate 017 and CheckMate 057): 3-year update and outcomes in patients with liver metastases. Ann. Oncol. 29, 959–965 (2018).

    CAS  PubMed  Google Scholar 

  274. Peters, S. et al. Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer. N. Engl. J. Med. 377, 829–838 (2017).

    CAS  PubMed  Google Scholar 

  275. Asahara, T. et al. Studies of postoperative transarterial infusion chemotherapy for liver metastasis of colorectal carcinoma after hepatectomy. Hepatogastroenterology 45, 805–811 (1998).

    CAS  PubMed  Google Scholar 

  276. Lorenz, M. et al. Randomized trial of surgery versus surgery followed by adjuvant hepatic arterial infusion with 5-fluorouracil and folinic acid for liver metastases of colorectal cancer. German Cooperative on Liver Metastases (Arbeitsgruppe Lebermetastasen). Ann. Surg. 228, 756–762 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  277. Kemeny, N. et al. Hepatic arterial infusion of chemotherapy after resection of hepatic metastases from colorectal cancer. N. Engl. J. Med. 341, 2039–2048 (1999).

    CAS  PubMed  Google Scholar 

  278. Kemeny, N. E. & Gonen, M. Hepatic arterial infusion after liver resection. N. Engl. J. Med. 352, 734–735 (2005).

    CAS  PubMed  Google Scholar 

  279. Bolton, J. S. et al. Hepatic arterial infusion and systemic chemotherapy after multiple metastasectomy in patients with colorectal carcinoma metastatic to the liver: a North Central Cancer Treatment Group (NCCTG) phase II study, 92-46-52. Clin. Colorectal Cancer 11, 31–37 (2012).

    CAS  PubMed  Google Scholar 

  280. Boileve, A. et al. Hepatic arterial infusion of oxaliplatin plus systemic chemotherapy and targeted therapy for unresectable colorectal liver metastases. Eur. J. Cancer 138, 89–98 (2020).

    CAS  PubMed  Google Scholar 

  281. D’Angelica, M. I. et al. Phase II trial of hepatic artery infusional and systemic chemotherapy for patients with unresectable hepatic metastases from colorectal cancer: conversion to resection and long-term outcomes. Ann. Surg. 261, 353–360 (2015).

    PubMed  Google Scholar 

  282. Massmann, A. et al. Transarterial chemoembolization (TACE) for colorectal liver metastases — current status and critical review. Langenbecks Arch. Surg. 400, 641–659 (2015).

    PubMed  Google Scholar 

  283. Richardson, A. J., Laurence, J. M. & Lam, V. W. Transarterial chemoembolization with irinotecan beads in the treatment of colorectal liver metastases: systematic review. J. Vasc. Interv. Radiol. 24, 1209–1217 (2013).

    PubMed  Google Scholar 

  284. Fiorentini, G. et al. Intra-arterial infusion of irinotecan-loaded drug-eluting beads (DEBIRI) versus intravenous therapy (FOLFIRI) for hepatic metastases from colorectal cancer: final results of a phase III study. Anticancer Res. 32, 1387–1395 (2012).

    CAS  PubMed  Google Scholar 

  285. Lau, W. Y. et al. Selective internal radiation therapy for nonresectable hepatocellular carcinoma with intraarterial infusion of 90yttrium microspheres. Int. J. Radiat. Oncol. Biol. Phys. 40, 583–592 (1998).

    CAS  PubMed  Google Scholar 

  286. Yan, Z. P., Lin, G., Zhao, H. Y. & Dong, Y. H. An experimental study and clinical pilot trials on yttrium-90 glass microspheres through the hepatic artery for treatment of primary liver cancer. Cancer 72, 3210–3215 (1993).

    CAS  PubMed  Google Scholar 

  287. Kucuk, O. N., Soydal, C., Lacin, S., Ozkan, E. & Bilgic, S. Selective intraarterial radionuclide therapy with yttrium-90 (Y-90) microspheres for unresectable primary and metastatic liver tumors. World J. Surg. Oncol. 9, 86 (2011).

    PubMed  PubMed Central  Google Scholar 

  288. Bienert, M. et al. 90Y microsphere treatment of unresectable liver metastases: changes in 18F-FDG uptake and tumour size on PET/CT. Eur. J. Nucl. Med. Mol. Imaging 32, 778–787 (2005).

    CAS  PubMed  Google Scholar 

  289. Wasan, H. S. et al. First-line selective internal radiotherapy plus chemotherapy versus chemotherapy alone in patients with liver metastases from colorectal cancer (FOXFIRE, SIRFLOX, and FOXFIRE-Global): a combined analysis of three multicentre, randomised, phase 3 trials. Lancet Oncol. 18, 1159–1171 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  290. Kang, J. I. et al. A phase I trial of proton stereotactic body radiation therapy for liver metastases. J. Gastrointest. Oncol. 10, 112–117 (2019).

    PubMed  PubMed Central  Google Scholar 

  291. Hong, T. S. et al. Phase II study of proton-based stereotactic body radiation therapy for liver metastases: importance of tumor genotype. J. Natl Cancer Inst. 109, djx031 (2017).

    Google Scholar 

  292. Mahadevan, A. et al. Stereotactic body radiotherapy (SBRT) for liver metastasis - clinical outcomes from the international multi-institutional RSSearch(R) Patient Registry. Radiat. Oncol. 13, 26 (2018).

    PubMed  PubMed Central  Google Scholar 

  293. Mogrovejo, E., Manickam, P., Amin, M. & Cappell, M. S. Characterization of the syndrome of acute liver failure caused by metastases from breast carcinoma. Dig. Dis. Sci. 59, 724–736 (2014).

    PubMed  Google Scholar 

  294. Rahnemai-Azar, A. A. et al. Update on liver failure following hepatic resection: strategies for prediction and avoidance of post-operative liver insufficiency. J. Clin. Transl. Hepatol. 6, 97–104 (2018).

    PubMed  Google Scholar 

  295. Sangro, B. et al. Liver disease induced by radioembolization of liver tumors: description and possible risk factors. Cancer 112, 1538–1546 (2008).

    PubMed  Google Scholar 

  296. Ito, K. et al. Biliary sclerosis after hepatic arterial infusion pump chemotherapy for patients with colorectal cancer liver metastasis: incidence, clinical features, and risk factors. Ann. Surg. Oncol. 19, 1609–1617 (2012).

    PubMed  Google Scholar 

  297. King, P. D. & Perry, M. C. Hepatotoxicity of chemotherapy. Oncologist 6, 162–176 (2001).

    CAS  PubMed  Google Scholar 

  298. Blazeby, J. M. et al. Validation of the European Organization for Research and Treatment of Cancer QLQ-LMC21 questionnaire for assessment of patient-reported outcomes during treatment of colorectal liver metastases. Br. J. Surg. 96, 291–298 (2009).

    CAS  PubMed  Google Scholar 

  299. Adamowicz, K., Saad, E. D. & Jassem, J. Health-related quality of life assessment in contemporary phase III trials in advanced colorectal cancer. Cancer Treat. Rev. 50, 194–199 (2016).

    PubMed  Google Scholar 

  300. Gong, J. et al. Moving beyond conventional clinical trial end points in treatment-refractory metastatic colorectal cancer: a composite quality-of-life and symptom control end point. Clin. Ther. 39, 2135–2145 (2017).

    PubMed  Google Scholar 

  301. Rees, J. R. et al. The prognostic value of patient-reported outcome data in patients with colorectal hepatic metastases who underwent surgery. Clin. Colorectal Cancer 15, 74–81 e71 (2016).

    PubMed  Google Scholar 

  302. Wolstenholme, J. et al. Quality of life in the FOXFIRE, SIRFLOX and FOXFIRE-global randomised trials of selective internal radiotherapy for metastatic colorectal cancer. Int. J. Cancer 147, 1078–1085 (2020).

    CAS  PubMed  Google Scholar 

  303. Helou, J. et al. Quality of life changes after stereotactic ablative radiotherapy for liver metastases: a prospective cohort analysis. Radiother. Oncol. 129, 435–440 (2018).

    PubMed  Google Scholar 

  304. Kemeny, N. E. et al. Hepatic arterial infusion versus systemic therapy for hepatic metastases from colorectal cancer: a randomized trial of efficacy, quality of life, and molecular markers (CALGB 9481). J. Clin. Oncol. 24, 1395–1403 (2006).

    CAS  PubMed  Google Scholar 

  305. Soveri, L. M. et al. Long-term neuropathy and quality of life in colorectal cancer patients treated with oxaliplatin containing adjuvant chemotherapy. Acta Oncol. 58, 398–406 (2019).

    CAS  PubMed  Google Scholar 

  306. Lin, X., Hong, S., Chen, J., Chen, W. & Wu, Z. The potential targets for metastases: a study on altered circular RNA profile in breast cancer liver metastases. Epigenomics 11, 1237–1250 (2019).

    CAS  PubMed  Google Scholar 

  307. Ejaz, A. et al. Associations between patient perceptions of communication, cure, and other patient-related factors regarding patient-reported quality of care following surgical resection of lung and colorectal cancer. J. Gastrointest. Surg. 20, 812–826 (2016).

    PubMed  Google Scholar 

  308. Fretland, Å. A. et al. Laparoscopic versus open resection for colorectal liver metastases: the OSLO-COMET randomized controlled trial. Ann. Surg. 267, 199–207 (2018).

    PubMed  Google Scholar 

  309. Rubenstein, J. H., Enns, R., Heidelbaugh, J., Barkun, A. & Clinical Guidelines Committee. American gastroenterological association institute guideline on the diagnosis and management of Lynch syndrome. Gastroenterology 149, 777–782; quiz e716-777 (2015).

    PubMed  Google Scholar 

  310. Geiersbach, K. B. & Samowitz, W. S. Microsatellite instability and colorectal cancer. Arch. Pathol. Lab. Med. 135, 1269–1277 (2011).

    CAS  PubMed  Google Scholar 

  311. Achrol, A. S., Rennert, R. C., Anders, C. et al. Brain metastases. Nat. Rev. Dis. Prim. 5, 5 (2019).

Download references

Author information

Authors and Affiliations

Authors

Contributions

Introduction (T.M.P. and D.I.T.); Epidemiology (D.I.T and P.-A.C.); Mechanisms/pathophysiology (P.B. and R.J.M.); Diagnosis, screening and prevention (I.E., E.d.S. and D.I.T.); Management (R.W.P., T.M.P. and D.I.T.); Quality of life (M.I.D.); Outlook (R.J.M. and M.D.); Overview of Primer (T.M.P.).

Corresponding author

Correspondence to Timothy M. Pawlik.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information

Nature Reviews Disease Primers thanks H. Baba, M. Ducreux, P. Galle, G. Poston, M. Schmid and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

Left-sided tumours

Tumours that originate from the left descending colon.

Right-sided tumours

Tumours that originate from the first part of the colon corresponding to the ascending colon.

Conversion treatment

The use of cytotoxic drugs and/or chemotherapy that shrink the tumour to a level considered amenable to resection.

Stage M1c melanoma

The cancer has spread to any other location that does not involve the central nervous system.

Monosomy

The state of having a single copy of a chromosome pair in contrast to the usual two copies found in diploid cells.

Intravasation

Invasion of cancer cells through the basement membrane into a blood or lymphatic vessel.

Kupffer cells

Macrophages that are phagocytic and reside in sinusoids of the liver in proximity to the endothelial cells.

Sinusoidal vessels

Low-pressure vascular channels that receive blood from terminal branches of the hepatic artery and portal vein at the periphery of lobules and deliver it into central veins.

Space of Disse

The perisinusoidal space in the liver between a hepatocyte and a sinusoid.

Myelopoiesis

Process in which innate immune cells, such as neutrophils, dendritic cells and monocytes, develop from a myeloid progenitor cell.

Desmosomes

Specialized adhesive protein complexes that localize to intercellular junctions and are responsible for maintaining the mechanical integrity of tissues.

Ring enhancement

Characteristic feature in CT, which represents a zonal area of viable tumour cells.

Cytoreduction

Approach to cancer treatment that aims to reduce the number of cancer cells via resection of the primary tumour or metastatic deposits.

Future liver remnant

Volume of functional liver after resection

Cytokeratin

Type of structural protein that is expressed by the epithelial cells.

Microsatellite instability

The condition of genetic hypermutability (predisposition to mutation) that results from impaired DNA mismatch repair.

Hilar lymphadenopathy

Enlargement of lymph nodes at the hepatic hilum.

Disease-free interval

Interval from the treatment of the primary tumour to the detection of metastases.

Metachronous metastasis

Metastasis developed after a period of time from diagnosis of the primary tumour.

Hepatic hilum

Anatomical region where bile ducts, hepatic arterial branches, portal vein branches, lymphatics and nerves enter or leave the liver.

Heat-sink phenomenon

Phenomenon that limits ablation effectiveness when the target lesion is close (<1 cm) to a large blood vessel (≥3 mm diameter); the flowing blood causes a cooling effect, thereby reducing the ablation volume.

Local control rate

Rate of controlling cancer growth at the local site of origin.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Tsilimigras, D.I., Brodt, P., Clavien, PA. et al. Liver metastases. Nat Rev Dis Primers 7, 27 (2021). https://doi.org/10.1038/s41572-021-00261-6

Download citation

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41572-021-00261-6

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing