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Cellular and Molecular Biology

Histopathological growth patterns of liver metastasis: updated consensus guidelines for pattern scoring, perspectives and recent mechanistic insights

Abstract

The first consensus guidelines for scoring the histopathological growth patterns (HGPs) of liver metastases were established in 2017. Since then, numerous studies have applied these guidelines, have further substantiated the potential clinical value of the HGPs in patients with liver metastases from various tumour types and are starting to shed light on the biology of the distinct HGPs. In the present guidelines, we give an overview of these studies, discuss novel strategies for predicting the HGPs of liver metastases, such as deep-learning algorithms for whole-slide histopathology images and medical imaging, and highlight liver metastasis animal models that exhibit features of the different HGPs. Based on a pooled analysis of large cohorts of patients with liver-metastatic colorectal cancer, we propose a new cut-off to categorise patients according to the HGPs. An up-to-date standard method for HGP assessment within liver metastases is also presented with the aim of incorporating HGPs into the decision-making processes surrounding the treatment of patients with liver-metastatic cancer. Finally, we propose hypotheses on the cellular and molecular mechanisms that drive the biology of the different HGPs, opening some exciting preclinical and clinical research perspectives.

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Fig. 1: The histopathological growth patterns of liver metastases (H&E images).
Fig. 2: Survival of patients with colorectal liver metastases according to different cut-off values for histopathological growth patterns.
Fig. 3: H&E image of the escape phenotype.
Fig. 4: Immunohistochemical staining as an aid to HGP scoring.
Fig. 5: Patient-derived xenograft (PDX) mice models for CRC liver metastases with a desmoplastic and a replacement HGP (H&E images).
Fig. 6: Images of melan-A immunostaining of melanoma liver metastases.
Fig. 7: New biological insights into growth patterns through immunohistochemical analyses.

Data availability

Not applicable.

References

  1. van Dam PJ, van der Stok EP, Teuwen LA, Van den Eynden GG, Illemann M, Frentzas S, et al. International consensus guidelines for scoring the histopathological growth patterns of liver metastasis. Br J Cancer. 2017;117:1427–41.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Stremitzer S, Vermeulen P, Graver S, Kockx M, Dirix L, Yang D, et al. Immune phenotype and histopathological growth pattern in patients with colorectal liver metastases. Br J Cancer. 2020;122:1518–24.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  3. Liang JY, Xi SY, Shao Q, Yuan YF, Li BK, Zheng Y, et al. Histopathological growth patterns correlate with the immunoscore in colorectal cancer liver metastasis patients after hepatectomy. Cancer Immunol Immunother. 2020;69:2623–34.

    CAS  Article  PubMed  Google Scholar 

  4. Hoppener DJ, Nierop PMH, Hof J, Sideras K, Zhou G, Visser L, et al. Enrichment of the tumour immune microenvironment in patients with desmoplastic colorectal liver metastasis. Br J Cancer. 2020;123:196–206.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Watanabe K, Mitsunaga S, Kojima M, Suzuki H, Irisawa A, Takahashi H, et al. The “histological replacement growth pattern” represents aggressive invasive behavior in liver metastasis from pancreatic cancer. Cancer Med. 2020;9:3130–41.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. Messaoudi N, Henault D, Stephen D, Cousineau I, Simoneau E, Rong Z, et al. Prognostic implications of adaptive immune features in MMR-proficient colorectal liver metastases classified by histopathological growth patterns. Br J Cancer. 2022;126:1329–38.

    CAS  Article  PubMed  Google Scholar 

  7. Gulia S, Khurana S, Shet T, Gupta S. Radiographically occult intrasinusoidal liver metastases leading to hepatic failure in a case of breast cancer. BMJ Case Rep. 2016;2016:bcr2015214120.

  8. Cheng J, Wei J, Tong T, Sheng W, Zhang Y, Han Y, et al. Prediction of histopathologic growth patterns of colorectal liver metastases with a noninvasive imaging method. Ann Surg Oncol. 2019;26:4587–98.

    Article  PubMed  Google Scholar 

  9. Han Y, Chai F, Wei J, Yue Y, Cheng J, Gu D, et al. Identification of predominant histopathological growth patterns of colorectal liver metastasis by multi-habitat and multi-sequence based radiomics analysis. Front Oncol. 2020;10:1363.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Starmans MPA, Buisman FE, Renckens M, Willemssen F, van der Voort SR, Groot Koerkamp B, et al. Distinguishing pure histopathological growth patterns of colorectal liver metastases on CT using deep learning and radiomics: a pilot study. Clin Exp Metastasis. 2021;38:483–94.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Alzubi MA, Sohal SS, Sriram M, Turner TH, Zot P, Idowu M, et al. Quantitative assessment of breast cancer liver metastasis expansion with patient-derived xenografts. Clin Exp Metastasis. 2019;36:257–69.

    Article  PubMed  Google Scholar 

  12. Piquet L, Dewit L, Schoonjans N, Millet M, Berube J, Gerges PRA. et al. Synergic interactions between hepatic stellate cells and uveal melanoma in metastatic growth. Cancers. 2019;11:1043.

  13. Vlachogiannis G, Hedayat S, Vatsiou A, Jamin Y, Fernandez-Mateos J, Khan K, et al. Patient-derived organoids model treatment response of metastatic gastrointestinal cancers. Science. 2018;359:920–6.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. Ibrahim NS, Lazaris A, Rada M, Petrillo SK, Huck L, Hussain S, et al. Angiopoietin1 deficiency in hepatocytes affects the growth of colorectal cancer liver metastases (CRCLM). Cancers. 2019;12:35.

  15. Masaki S, Hashimoto Y, Kunisho S, Kimoto A, Kitadai Y. Fatty change of the liver microenvironment influences the metastatic potential of colorectal cancer. Int J Exp Pathol. 2020;101:162–70.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. Tabaries S, Annis MG, Lazaris A, Petrillo SK, Huxham J, Abdellatif A, et al. Claudin-2 promotes colorectal cancer liver metastasis and is a biomarker of the replacement type growth pattern. Commun Biol. 2021;4:657.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. Bartlett AQ, Pennock ND, Klug A, Schedin P. Immune milieu established by postpartum liver involution promotes breast cancer liver metastasis. Cancers. 2021;13:1698.

  18. Galjart B, Nierop PMH, van der Stok EP, van den Braak R, Hoppener DJ, Daelemans S, et al. Angiogenic desmoplastic histopathological growth pattern as a prognostic marker of good outcome in patients with colorectal liver metastases. Angiogenesis. 2019;22:355–68.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Hoppener DJ, Galjart B, Nierop PMH, Buisman FE, van der Stok EP, Coebergh van den Braak RRJ, et al. Histopathological growth patterns and survival after resection of colorectal liver metastasis: an external validation study. JNCI Cancer Spectr. 2021;5:pkab026.

    Article  PubMed Central  Google Scholar 

  20. Zhaoyang X, Carlos Fernádez M, Danyil K, Béla B, Le D, Qianni Z. Tissue region growing for hispathology image segmentation. In: Proceedings of the 2018 3rd International Conference on Biomedical Imaging, Signal Processing. Bari, Italy: Association for Computing Machinery; 2018.

  21. Tellez D, Höppener D, Verhoef C, Grünhagen D, Nierop P, Drozdzal M, et al. Extending unsupervised neural image compression with supervised multitask learning. Proc Mach Learn Res. 2020;121:770–83.

    Google Scholar 

  22. Tellez D, Litjens G, van der Laak J, Ciompi F. Neural image compression for gigapixel histopathology image analysis. IEEE Trans Pattern Anal Mach Intell. 2021;43:567–78.

    Article  PubMed  Google Scholar 

  23. Nierop PMH, Galjart B, Hoppener DJ, van der Stok EP, Coebergh van den Braak RRJ, Vermeulen PB, et al. Salvage treatment for recurrences after first resection of colorectal liver metastases: the impact of histopathological growth patterns. Clin Exp Metastasis. 2019;36:109–18.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Nierop PMH, Hoppener DJ, van der Stok EP, Galjart B, Buisman FE, Balachandran VP, et al. Histopathological growth patterns and positive margins after resection of colorectal liver metastases. HPB. 2020;22:911–9.

    Article  PubMed  Google Scholar 

  25. Buisman FE, Van der Stok EP, Galjart B, Vermeulen PB, Balachandran VP, Coebergh van den Braak RRJ, et al. Histopathological growth patterns as biomarker for adjuvant systemic chemotherapy in patients with resected colorectal liver metastases. Clin Exp Metastasis. 2020;37:593–605.

  26. Masson P. Les tumeurs. Traité De Pathologie Et Thérapie Appliquées. 1923;27:572–4.

    Google Scholar 

  27. Hamperl H. Die morphologie der tumoren. Lehrb Der Allgemeinen Pathologie Und Der Pathologischen Anat. 1956;6:243–4.

    Google Scholar 

  28. Elias H, Bouldin RF. Reaction of the normal liver parenchyma to metastatic carcinoma. Acta Hepatosplenol. 1962;9:357–86.

    CAS  Google Scholar 

  29. Elias H, Bierring F, Grunnet I. Cellular changes in the vicinity of metastatic carcinoma, observed by light and electron microscopy. Oncologia. 1964;18:210–24.

    CAS  Article  PubMed  Google Scholar 

  30. Vermeulen PB, Colpaert C, Salgado R, Royers R, Hellemans H, Van Den Heuvel E, et al. Liver metastases from colorectal adenocarcinomas grow in three patterns with different angiogenesis and desmoplasia. J Pathol. 2001;195:336–42.

  31. Latacz E, Caspani E, Barnhill R, Lugassy C, Verhoef C, Grunhagen D, et al. Pathological features of vessel co-option versus sprouting angiogenesis. Angiogenesis. 2020;23:43–54.

    CAS  Article  PubMed  Google Scholar 

  32. van Dam PJ, Daelemans S, Ross E, Waumans Y, Van Laere S, Latacz E, et al. Histopathological growth patterns as a candidate biomarker for immunomodulatory therapy. Semin Cancer Biol. 2018;52:86–93.

    Article  CAS  PubMed  Google Scholar 

  33. Lugassy C, Kleinman HK, Vermeulen PB, Barnhill RL. Angiotropism, pericytic mimicry and extravascular migratory metastasis: an embryogenesis-derived program of tumor spread. Angiogenesis. 2020;23:27–41.

    CAS  Article  PubMed  Google Scholar 

  34. Allison KH, Fligner CL, Parks WT. Radiographically occult, diffuse intrasinusoidal hepatic metastases from primary breast carcinomas: a clinicopathologic study of 3 autopsy cases. Arch Pathol Lab Med. 2004;128:1418–23.

    Article  PubMed  Google Scholar 

  35. Simone C, Murphy M, Shifrin R, Zuluaga Toro T, Reisman D. Rapid liver enlargement and hepatic failure secondary to radiographic occult tumor invasion: two case reports and review of the literature. J Med Case Rep. 2012;6:402.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Watson AJ. Diffuse intra-sinusoidal metastatic carcinoma of the liver. J Pathol Bacteriol. 1955;69:207–17.

    CAS  Article  PubMed  Google Scholar 

  37. Vaideeswar P, Munot S, Rojekar A, Deodhar K. Hepatic diffuse intra-sinusoidal metastases of pulmonary small-cell carcinoma. J Postgrad Med. 2012;58:230–1.

    CAS  Article  PubMed  Google Scholar 

  38. Stessels F, Van den Eynden G, Van der Auwera I, Salgado R, Van den Heuvel E, Harris AL, 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. 2004;90:1429–36.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  39. Hoppener DJ, Nierop PMH, Herpel E, Rahbari NN, Doukas M, Vermeulen PB, et al. Histopathological growth patterns of colorectal liver metastasis exhibit little heterogeneity and can be determined with a high diagnostic accuracy. Clin Exp Metastasis. 2019;36:311–9.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  40. Terayama N, Terada T, Nakanuma Y. Histologic growth patterns of metastatic carcinomas of the liver. Jpn J Clin Oncol. 1996;26:24–9.

    CAS  Article  PubMed  Google Scholar 

  41. Frentzas S, Simoneau E, Bridgeman VL, Vermeulen PB, Foo S, Kostaras E, et al. Vessel co-option mediates resistance to anti-angiogenic therapy in liver metastases. Nat Med. 2016;22:1294–302.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  42. Bohlok A, Vermeulen P, Leduc S, Latacz E, Botzenhart L, Richard F, et al. Association between the histopathological growth patterns of liver metastases and survival after hepatic surgery in breast cancer patients. NPJ Breast Cancer. 2020;6:64.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  43. Horn SR, Stoltzfus KC, Lehrer EJ, Dawson LA, Tchelebi L, Gusani NJ, et al. Epidemiology of liver metastases. Cancer Epidemiol. 2020;67:101760.

    Article  PubMed  Google Scholar 

  44. Barnhill R, Vermeulen P, Daelemans S, van Dam PJ, Roman-Roman S, Servois V, et al. Replacement and desmoplastic histopathological growth patterns: a pilot study of prediction of outcome in patients with uveal melanoma liver metastases. J Pathol Clin Res. 2018;4:227–40.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  45. Barnhill R, van Dam PJ, Vermeulen P, Champenois G, Nicolas A, Rawson RV, et al. Replacement and desmoplastic histopathological growth patterns in cutaneous melanoma liver metastases: frequency, characteristics, and robust prognostic value. J Pathol Clin Res. 2020;6:195–206.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Grossniklaus HE, Zhang Q, You S, McCarthy C, Heegaard S, Coupland SE. Metastatic ocular melanoma to the liver exhibits infiltrative and nodular growth patterns. Hum Pathol. 2016;57:165–75.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Grossniklaus HE. Progression of ocular melanoma metastasis to the liver: the 2012 Zimmerman lecture. JAMA Ophthalmol. 2013;131:462–9.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  48. Meyer Y, Bohlok A, Hoppener D, Galjart B, Doukas M, Grunhagen DJ, et al. Histopathological growth patterns of resected non-colorectal, non-neuroendocrine liver metastases: a retrospective multicenter studyss. Clin Exp Metastasis. 2022;39:433–42.

    CAS  Article  PubMed  Google Scholar 

  49. Fernandez Moro C, Bozoky B, Gerling M. Growth patterns of colorectal cancer liver metastases and their impact on prognosis: a systematic review. BMJ Open Gastroenterol. 2018;5:e000217.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Kwapisz D. Oligometastatic breast cancer. Breast Cancer. 2019;26:138–46.

    Article  PubMed  Google Scholar 

  51. Tran CG, Sherman SK, Chandrasekharan C, Howe JR. Surgical management of neuroendocrine tumor liver metastases. Surg Oncol Clin N. Am. 2021;30:39–55.

    Article  PubMed  Google Scholar 

  52. Teng S, Li YE, Yang M, Qi R, Huang Y, Wang Q, et al. Tissue-specific transcription reprogramming promotes liver metastasis of colorectal cancer. Cell Res. 2020;30:34–49.

    CAS  Article  PubMed  Google Scholar 

  53. Nielsen K, Rolff HC, Eefsen RL, Vainer B. The morphological growth patterns of colorectal liver metastases are prognostic for overall survival. Mod Pathol. 2014;27:1641–8.

    CAS  Article  PubMed  Google Scholar 

  54. Eefsen RL, Vermeulen PB, Christensen IJ, Laerum OD, Mogensen MB, Rolff HC, et al. Growth pattern of colorectal liver metastasis as a marker of recurrence risk. Clin Exp Metastasis. 2015;32:369–81.

    CAS  Article  PubMed  Google Scholar 

  55. Kuczynski EA, Yin M, Bar-Zion A, Lee CR, Butz H, Man S, et al. Co-option of liver vessels and not sprouting angiogenesis drives acquired sorafenib resistance in hepatocellular carcinoma. J Natl Cancer Inst. 2016;108:djw030.

    Article  CAS  PubMed Central  Google Scholar 

  56. Bridgeman VL, Vermeulen PB, Foo S, Bilecz A, Daley F, Kostaras E, et al. Vessel co-option is common in human lung metastases and mediates resistance to anti-angiogenic therapy in preclinical lung metastasis models. J Pathol. 2017;241:362–74.

    CAS  Article  PubMed  Google Scholar 

  57. Leenders WP, Kusters B, Verrijp K, Maass C, Wesseling P, Heerschap A, et al. Antiangiogenic therapy of cerebral melanoma metastases results in sustained tumor progression via vessel co-option. Clin Cancer Res. 2004;10:6222–30.

    CAS  Article  PubMed  Google Scholar 

  58. Martens T, Laabs Y, Gunther HS, Kemming D, Zhu Z, Witte L, et al. Inhibition of glioblastoma growth in a highly invasive nude mouse model can be achieved by targeting epidermal growth factor receptor but not vascular endothelial growth factor receptor-2. Clin Cancer Res. 2008;14:5447–58.

    CAS  Article  PubMed  Google Scholar 

  59. Mentha G, Terraz S, Morel P, Andres A, Giostra E, Roth A, et al. Dangerous halo after neoadjuvant chemotherapy and two-step hepatectomy for colorectal liver metastases. Br J Surg. 2009;96:95–103.

    CAS  Article  PubMed  Google Scholar 

  60. Rubbia-Brandt L, Giostra E, Brezault C, Roth AD, Andres A, Audard V, et al. Importance of histological tumor response assessment in predicting the outcome in patients with colorectal liver metastases treated with neo-adjuvant chemotherapy followed by liver surgery. Ann Oncol. 2007;18:299–304.

    CAS  Article  PubMed  Google Scholar 

  61. Nierop PM, Hoppener DJ, Buisman FE, van der Stok EP, Galjart B, Balachandran VP, et al. Preoperative systemic chemotherapy alters the histopathological growth patterns of colorectal liver metastases. J Pathol Clin Res. 2022;8:48–64.

    Article  CAS  PubMed  Google Scholar 

  62. Gomez Dorronsoro ML, Vera R, Ortega L, Plaza C, Miquel R, Garcia M, et al. Recommendations of a group of experts for the pathological assessment of tumour regression of liver metastases of colorectal cancer and damage of non-tumour liver tissue after neoadjuvant therapy. Clin Transl Oncol. 2014;16:234–42.

    CAS  Article  PubMed  Google Scholar 

  63. Powley IR, Patel M, Miles G, Pringle H, Howells L, Thomas A, et al. Patient-derived explants (PDEs) as a powerful preclinical platform for anti-cancer drug and biomarker discovery. Br J Cancer. 2020;122:735–44.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Voabil P, de Bruijn M, Roelofsen LM, Hendriks SH, Brokamp S, van den Braber M, et al. An ex vivo tumor fragment platform to dissect response to PD-1 blockade in cancer. Nat Med. 2021;27:1250–61.

    CAS  Article  PubMed  Google Scholar 

  65. Fornabaio G, Barnhill RL, Lugassy C, Bentolila LA, Cassoux N, Roman-Roman S, et al. Angiotropism and extravascular migratory metastasis in cutaneous and uveal melanoma progression in a zebrafish model. Sci Rep. 2018;8:10448.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Latacz E, van Dam PJ, Vanhove C, Llado L, Descamps B, Ruiz N, et al. Can medical imaging identify the histopathological growth patterns of liver metastases? Semin Cancer Biol. 2021;71:33–41.

    Article  PubMed  Google Scholar 

  67. Wei S, Han Y, Zeng H, Ye S, Cheng J, Chai F, et al. Radiomics diagnosed histopathological growth pattern in prediction of response and 1-year progression free survival for colorectal liver metastases patients treated with bevacizumab containing chemotherapy. Eur J Radiol. 2021;142:109863.

    Article  PubMed  Google Scholar 

  68. Er EE, Valiente M, Ganesh K, Zou Y, Agrawal S, Hu J, et al. Pericyte-like spreading by disseminated cancer cells activates YAP and MRTF for metastatic colonization. Nat Cell Biol. 2018;20:966–78.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  69. Suzuki K, Tanaka M, Watanabe N, Saito S, Nonaka H, Miyajima A. p75 Neurotrophin receptor is a marker for precursors of stellate cells and portal fibroblasts in mouse fetal liver. Gastroenterology. 2008;135:270–81 e3.

    CAS  Article  PubMed  Google Scholar 

  70. Wells RG. The portal fibroblast: not just a poor man’s stellate cell. Gastroenterology. 2014;147:41–7.

    CAS  Article  PubMed  Google Scholar 

  71. Trim N, Morgan S, Evans M, Issa R, Fine D, Afford S, et al. Hepatic stellate cells express the low affinity nerve growth factor receptor p75 and undergo apoptosis in response to nerve growth factor stimulation. Am J Pathol. 2000;156:1235–43.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  72. Passino MA, Adams RA, Sikorski SL, Akassoglou K. Regulation of hepatic stellate cell differentiation by the neurotrophin receptor p75NTR. Science. 2007;315:1853–6.

    CAS  Article  PubMed  Google Scholar 

  73. Kendall TJ, Hennedige S, Aucott RL, Hartland SN, Vernon MA, Benyon RC, et al. p75 Neurotrophin receptor signaling regulates hepatic myofibroblast proliferation and apoptosis in recovery from rodent liver fibrosis. Hepatology. 2009;49:901–10.

    CAS  Article  PubMed  Google Scholar 

  74. Aimaiti Y, Jin X, Shao Y, Wang W, Li D. Hepatic stellate cells regulate hepatic progenitor cells differentiation via the TGF-beta1/Jagged1 signaling axis. J Cell Physiol. 2019;234:9283–96.

    CAS  Article  PubMed  Google Scholar 

  75. Cassiman D, Denef C, Desmet VJ, Roskams T. Human and rat hepatic stellate cells express neurotrophins and neurotrophin receptors. Hepatology. 2001;33:148–58.

    CAS  Article  PubMed  Google Scholar 

  76. Vidal-Vanaclocha F, Crende O, Garcia de Durango C, Herreros-Pomares A, Lopez-Domenech S, Gonzalez A, et al. Liver prometastatic reaction: Stimulating factors and responsive cancer phenotypes. Semin Cancer Biol. 2021;71:122–33.

    CAS  Article  PubMed  Google Scholar 

  77. Ciner AT, Jones K, Muschel RJ, Brodt P. The unique immune microenvironment of liver metastases: Challenges and opportunities. Semin Cancer Biol. 2021;71:143–56.

    CAS  Article  PubMed  Google Scholar 

  78. Kurebayashi Y, Kubota N, Sakamoto M. Immune microenvironment of hepatocellular carcinoma, intrahepatic cholangiocarcinoma and liver metastasis of colorectal adenocarcinoma: relationship with histopathological and molecular classifications. Hepatol Res. 2021;51:5–18.

    Article  PubMed  Google Scholar 

  79. Bohlok A, Duran Derijckere I, Azema H, Lucidi V, Vankerckhove S, Hendlisz A, et al. Clinico-metabolic characterization improves the prognostic value of histological growth patterns in patients undergoing surgery for colorectal liver metastases. J Surg Oncol. 2021;123:1773–83.

    Article  PubMed  PubMed Central  Google Scholar 

  80. Matsumoto K, Yoshitomi H, Rossant J, Zaret KS. Liver organogenesis promoted by endothelial cells prior to vascular function. Science. 2001;294:559–63.

    CAS  Article  PubMed  Google Scholar 

  81. Crivellato E, Nico B, Ribatti D. Contribution of endothelial cells to organogenesis: a modern reappraisal of an old Aristotelian concept. J Anat. 2007;211:415–27.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Ding BS, Cao Z, Lis R, Nolan DJ, Guo P, Simons M, et al. Divergent angiocrine signals from vascular niche balance liver regeneration and fibrosis. Nature. 2014;505:97–102.

    Article  CAS  PubMed  Google Scholar 

  83. Daniel E, Cleaver O. Vascularizing organogenesis: lessons from developmental biology and implications for regenerative medicine. Curr Top Dev Biol. 2019;132:177–220.

    CAS  Article  PubMed  Google Scholar 

  84. Muthuswamy SK. Self-organization in cancer: Implications for histopathology, cancer cell biology, and metastasis. Cancer Cell. 2021;39:443–6.

    CAS  Article  PubMed  Google Scholar 

  85. Pezzella F, Di Bacco A, Andreola S, Nicholson AG, Pastorino U, Harris AL. Angiogenesis in primary lung cancer and lung secondaries. Eur J Cancer. 1996;32A:2494–500.

    CAS  Article  PubMed  Google Scholar 

  86. Evidence for novel non-angiogenic pathway in breast-cancer metastasis. Breast cancer progression working party. Lancet. 2000;355:1787–8.

    Article  Google Scholar 

  87. Teuwen LA, De Rooij L, Cuypers A, Rohlenova K, Dumas SJ, Garcia-Caballero M, et al. Tumor vessel co-option probed by single-cell analysis. Cell Rep. 2021;35:109253.

    CAS  Article  PubMed  Google Scholar 

  88. Chen YW, Rini BI. Approaches to first-line therapy for metastatic clear cell renal cell carcinoma. Curr Oncol Rep. 2022:24:695–702.

    CAS  Article  PubMed  Google Scholar 

  89. Sangro B, Sarobe P, Hervás-Stubbs S, Melero I. Advances in immunotherapy for hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol. 2021;18:525–43.

    Article  PubMed  PubMed Central  Google Scholar 

  90. Lee JC, Green MD, Huppert LA, Chow C, Pierce RH, Daud AI. The liver-immunity nexus and cancer immunotherapy. Clin Cancer Res. 2022;28:5–12.

    CAS  Article  PubMed  Google Scholar 

  91. Garcia-Vicién G, Mezheyeuski A, Micke P, Ruiz N, Ruffinelli JC, Mils K, et al. Spatial immunology in liver metastases from colorectal carcinoma according to the histologic growth pattern. Cancers. 2022;14:689.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Szczepanski JM, Mendiratta-Lala M, Fang JM, Choi WT, Karamchandani DM, Westerhoff M. Sinusoidal growth pattern of hepatic melanoma metastasis: implications for histopathologic diagnosis. Am J Surg Pathol. 2021;46:832–9.

    Article  PubMed  Google Scholar 

  93. Li WH, Wang S, Liu Y, Wang XF, Wang YF, Chai RM. Differentiation of histopathological growth patterns of colorectal liver metastases by MRI features. Quant Imaging Med Surg. 2022;12:608–17.

    Article  PubMed  PubMed Central  Google Scholar 

  94. de Ridder JA, Knijn N, Wiering B, de Wilt JH, Nagtegaal ID. Lymphatic invasion is an independent adverse prognostic factor in patients with colorectal liver metastasis. Ann Surg Oncol. 2015;22:S638–45.

    Article  PubMed  Google Scholar 

  95. Serrablo A, Paliogiannis P, Pulighe F, Moro SS, Borrego-Estella V, Attene F, et al. Impact of novel histopathological factors on the outcomes of liver surgery for colorectal cancer metastases. Eur J Surg Oncol. 2016;42:1268–77.

    CAS  Article  PubMed  Google Scholar 

  96. Fonseca GM, de Mello ES, Faraj SF, Kruger JAP, Coelho FF, Jeismann VB, et al. Prognostic significance of poorly differentiated clusters and tumor budding in colorectal liver metastases. J Surg Oncol. 2018;117:1364–75.

    CAS  Article  PubMed  Google Scholar 

  97. Cremolini C, Milione M, Marmorino F, Morano F, Zucchelli G, Mennitto A, et al. Differential histopathologic parameters in colorectal cancer liver metastases resected after triplets plus bevacizumab or cetuximab: a pooled analysis of five prospective trials. Br J Cancer. 2018;118:955–65.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  98. Falcao D, Alexandrino H, Caetano Oliveira R, Martins J, Ferreira L, Martins R, et al. Histopathologic patterns as markers of prognosis in patients undergoing hepatectomy for colorectal cancer liver metastases—pushing growth as an independent risk factor for decreased survival. Eur J Surg Oncol. 2018;44:1212–9.

    Article  PubMed  Google Scholar 

  99. Ao T, Kajiwara Y, Yonemura K, Shinto E, Mochizuki S, Okamoto K, et al. Prognostic significance of histological categorization of desmoplastic reaction in colorectal liver metastases. Virchows Arch. 2019;475:341–8.

    Article  PubMed  Google Scholar 

  100. Zhang Y, Luo X, Lin J, Fu S, Feng P, Su H, et al. Gelsolin promotes cancer progression by regulating epithelial-mesenchymal transition in hepatocellular carcinoma and correlates with a poor prognosis. J Oncol. 2020;2020:1980368.

    PubMed  PubMed Central  Google Scholar 

  101. Baldin P, Van den Eynde M, Mlecnik B, Bindea G, Beniuga G, Carrasco J, et al. Prognostic assessment of resected colorectal liver metastases integrating pathological features, RAS mutation and Immunoscore. J Pathol Clin Res. 2021;7:27–41.

    Article  PubMed  Google Scholar 

  102. Temido MJ, Caetano Oliveira R, Martins R, Serodio M, Costa B, Carvalho C, et al. Prognostic factors after hepatectomy for gastric adenocarcinoma liver metastases: desmoplastic growth pattern as the key to improved overall survival. Cancer Manag Res. 2020;12:11689–99.

    Article  PubMed  PubMed Central  Google Scholar 

  103. Jayme VR, Fonseca GM, Amaral IMA, Coelho FF, Kruger JAP, Jeismann VB, et al. Infiltrative tumor borders in colorectal liver metastasis: should we enlarge margin size? Ann Surg Oncol. 2021;28:7636–46.

    Article  PubMed  Google Scholar 

  104. Zhang YL, He HJ, Cheng J, Shen DH. [Value of histopathological growth pattern in predicting 3-year progression free survival after operation in patients with liver metastasis of colorectal cancer]. Zhonghua Bing Li Xue Za Zhi. 2021;50:26–31.

    CAS  PubMed  Google Scholar 

  105. Meyer YM, Beumer BR, Hoppener DJ, Nierop PMH, Doukas M, de Wilde RF, et al. Histopathological growth patterns modify the prognostic impact of microvascular invasion in non-cirrhotic hepatocellular carcinoma. HPB. 2021;24:507–15.

    Article  PubMed  Google Scholar 

  106. Vles MD, Hoppener DJ, Galjart B, Moelker A, Vermeulen PB, Grunhagen DJ, et al. Local tumour control after radiofrequency or microwave ablation for colorectal liver metastases in relation to histopathological growth patterns. HPB. 2022. online ahead of print.

  107. Ceausu AR, Ciolofan A, Cimpean AM, Magheti A, Mederle O, Raica M. The mesenchymal-epithelial and epithelial-mesenchymal cellular plasticity of liver metastases with digestive origin. Anticancer Res. 2018;38:811–6.

    CAS  PubMed  Google Scholar 

  108. Lazaris A, Amri A, Petrillo SK, Zoroquiain P, Ibrahim N, Salman A, et al. Vascularization of colorectal carcinoma liver metastasis: insight into stratification of patients for anti-angiogenic therapies. J Pathol Clin Res. 2018;4:184–92.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  109. Wu JB, Sarmiento AL, Fiset PO, Lazaris A, Metrakos P, Petrillo S, et al. Histologic features and genomic alterations of primary colorectal adenocarcinoma predict growth patterns of liver metastasis. World J Gastroenterol. 2019;25:3408–25.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  110. Blank A, Schenker C, Dawson H, Beldi G, Zlobec I, Lugli A. Evaluation of tumor budding in primary colorectal cancer and corresponding liver metastases based on H&E and pancytokeratin staining. Front Med. 2019;6:247.

    Article  Google Scholar 

  111. Palmieri V, Lazaris A, Mayer TZ, Petrillo SK, Alamri H, Rada M, et al. Neutrophils expressing lysyl oxidase-like 4 protein are present in colorectal cancer liver metastases resistant to anti-angiogenic therapy. J Pathol. 2020;251:213–23.

    CAS  Article  PubMed  Google Scholar 

  112. Ao T, Kajiwara Y, Yonemura K, Shinto E, Mochizuki S, Okamoto K, et al. Morphological consistency of desmoplastic reactions between the primary colorectal cancer lesion and associated metastatic lesions. Virchows Arch. 2020;477:47–55.

    CAS  Article  PubMed  Google Scholar 

  113. Rada M, Kapelanski-Lamoureux A, Petrillo S, Tabaries S, Siegel P, Reynolds AR, et al. Runt related transcription factor-1 plays a central role in vessel co-option of colorectal cancer liver metastases. Commun Biol. 2021;4:950.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  114. Burren S, Reche K, Blank A, Galvan JA, Dawson H, Berger MD, et al. RHAMM in liver metastases of stage IV colorectal cancer with mismatch-repair proficient status correlates with tumor budding, cytotoxic T-cells and PD-1/PD-L1. Pathol Res Pr. 2021;223:153486.

    CAS  Article  Google Scholar 

  115. Donnem T, Reynolds AR, Kuczynski EA, Gatter K, Vermeulen PB, Kerbel RS, et al. Non-angiogenic tumours and their influence on cancer biology. Nat Rev Cancer. 2018;18:323–36.

    CAS  Article  PubMed  Google Scholar 

  116. Baldin P, Van den Eynde M, Hubert C, Jouret-Mourin A, Komuta M. The role of the pathologist and clinical implications in colorectal liver metastasis. Acta Gastroenterol Belg. 2018;81:419–26.

    CAS  PubMed  Google Scholar 

  117. Kuczynski EA, Vermeulen PB, Pezzella F, Kerbel RS, Reynolds AR. Vessel co-option in cancer. Nat Rev Clin Oncol. 2019;16:469–93.

    CAS  Article  PubMed  Google Scholar 

  118. Oliveira RC, Alexandrino H, Cipriano MA, Tralhao JG. Liver metastases and histological growth patterns: biological behavior and potential clinical implications-another path to individualized medicine? J Oncol. 2019;2019:6280347.

    Article  PubMed  PubMed Central  Google Scholar 

  119. Kuczynski EA, Reynolds AR. Vessel co-option and resistance to anti-angiogenic therapy. Angiogenesis. 2020;23:55–74.

    CAS  Article  PubMed  Google Scholar 

  120. Oliveira RC, Alexandrino H, Cipriano MA, Alves FC, Tralhao JG. Predicting liver metastases growth patterns: Current status and future possibilities. Semin Cancer Biol. 2021;71:42–51.

    Article  PubMed  Google Scholar 

  121. Rigamonti A, Feuerhake F, Donadon M, Locati M, Marchesi F. Histopathological and immune prognostic factors in colorectal liver metastases. Cancers. 2021;13:1075.

  122. Garcia-Vicien G, Mezheyeuski A, Banuls M, Ruiz-Roig N, Mollevi DG. The tumor microenvironment in liver metastases from colorectal carcinoma in the context of the histologic growth patterns. Int J Mol Sci. 2021;22:1544.

  123. Haas G, Fan S, Ghadimi M, De Oliveira T, Conradi LC. Different forms of tumor vascularization and their clinical implications focusing on vessel co-option in colorectal cancer liver metastases. Front Cell Dev Biol. 2021;9:612774.

    Article  PubMed  PubMed Central  Google Scholar 

  124. Rompianesi G, Pegoraro F, Ceresa CD, Montalti R, Troisi RI. Artificial intelligence in the diagnosis and management of colorectal cancer liver metastases. World J Gastroenterol. 2022;28:108–22.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  125. Paku S, Lapis K. Morphological aspects of angiogenesis in experimental liver metastases. Am J Pathol. 1993;143:926–36.

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Vidal-Vanaclocha F. The prometastatic microenvironment of the liver. Cancer Microenviron. 2008;1:113–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Barsky SH, Doberneck SA, Sternlicht MD, Grossman DA, Love SM. ‘Revertant’ DCIS in human axillary breast carcinoma metastases. J Pathol. 1997;183:188–94.

    CAS  Article  PubMed  Google Scholar 

  128. Schuppan D, Kim YO. Evolving therapies for liver fibrosis. J Clin Invest. 2013;123:1887–901.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  129. Dezso K, Papp V, Bugyik E, Hegyesi H, Safrany G, Bodor C, et al. Structural analysis of oval-cell-mediated liver regeneration in rats. Hepatology. 2012;56:1457–67.

    CAS  Article  PubMed  Google Scholar 

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Acknowledgements

The current guidelines are the result of numerous discussions at the annual meetings of the international Liver Metastasis Research Network.

Funding

The work by CD, PV, GF, VD, LD and DL on breast cancer liver metastasis is supported by the Foundation against Cancer (Stichting tegen Kanker, Grant C/2020/1441). PV and LD are supported by the Koning Boudewijnstichting. GF is a recipient of a post-doctoral mandate sponsored by the KOOR from the University Hospitals Leuven. PS is a William Dawson Scholar of McGill University and acknowledges funding from the Canadian Institutes of Health Research (CIHR: MOP-136907; PJT-175088). HN is supported by the Swedish Research Council, Wallenberg Foundations/Knut and Alice Wallenberg Foundation, Region Västerbotten, the Swedish Cancer Society, the Cancer Research Foundation in Northern Sweden and Umeå University. MG is supported by The Swedish Research Foundation (2018–02023) and The Swedish Association for Medical Research. QZ is supported by Engineering and Physical Sciences Research Council (project EP/N034708/1). DGM is supported by the Fondo de Investigaciones Sanitarias of the Spanish Government, Fondo Europeo de Desarrollo Regional (FEDER) “Una manera de hacer Europa”/“A way of shaping Europe” (grant PI18/1140) and by AGAUR Department of Health of the Generalitat de Catalunya (grant SGR771). WRJ is supported by grant U01 CA238444–02 from the National Cancer Institute.

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All authors were involved in writing and reviewing the manuscript. DH, CFM, NG, MG, YM, DJG, WRJ, MIDA, MD and CF generated and analysed data.

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Correspondence to Peter B. Vermeulen.

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Latacz, E., Höppener, D., Bohlok, A. et al. Histopathological growth patterns of liver metastasis: updated consensus guidelines for pattern scoring, perspectives and recent mechanistic insights. Br J Cancer 127, 988–1013 (2022). https://doi.org/10.1038/s41416-022-01859-7

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