AI Chat Paper
Discover the SciOpen Platform and Achieve Your Research Goals with Ease.
Macrotrabecular‐massive hepatocellular carcinoma (MTM‐HCC) is a subtype of HCC with a very poor prognosis and exhibits biological behaviors and clinical presentations that distinguish it from conventional HCC. Vessels encapsulating tumor clusters (VETC) is a unique pattern of vascular growth that is more common in patients with MTM‐HCC. This unique interaction between the angiogenic system and tumor cells is of general interest. Early diagnosis and appropriate treatment of HCC with MTM and VETC patterns help prevent early recurrence and improve prognosis. This review summarizes the existing findings for HCC with MTM and VETC patterns.
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424. https://doi.org/10.3322/caac.21492
Ferlay J, Colombet M, Soerjomataram I, Mathers C, Parkin D, Pineros M, et al. Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods. Int J Cancer. 2019;144(8):1941–53. https://doi.org/10.1002/ijc.31937
Llovet JM, Kelley RK, Villanueva A, Singal AG, Pikarsky E, Roayaie S, et al. Hepatocellular carcinoma. Nat Rev Dis Prim. 2021;7(1):6. https://doi.org/10.1038/s41572‐020‐00240‐3
Galle PR, Forner A, Llovet JM, Mazzaferro V, Piscaglia F, Raoul JL, et al. EASL clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol. 2018;69(1):182–236. https://doi.org/10.1016/j.jhep.2018.03.019
Calderaro J, Couchy G, Imbeaud S, Amaddeo G, Letouze E, Blanc JF, et al. Histological subtypes of hepatocellular carcinoma are related to gene mutations and molecular tumour classification. J Hepatol. 2017;67(4):727–38. https://doi.org/10.1016/j.jhep.2017.05.014
Ziol M, Poté N, Amaddeo G, Laurent A, Nault J, Oberti F, et al. Macrotrabecular‐massive hepatocellular carcinoma: a distinctive histological subtype with clinical relevance. Hepatology. 2018;68(1):103–12. https://doi.org/10.1002/hep.29762
Sun Y, Wu L, Zhong Y, Zhou K, Hou Y, Wang Z, et al. Single‐cell landscape of the ecosystem in early‐relapse hepatocellular carcinoma. Cell. 2021;184(2):404–21.e16. https://doi.org/10.1016/j.cell.2020.11.041
Dian MJ, Li J, Zhang XL, Li ZJ, Zhou Y, Zhou W, et al. MST4 negatively regulates the EMT, invasion and metastasis of HCC cells by inactivating PI3K/AKT/Snail1 axis. J Cancer. 2021;12(15):4463–77. https://doi.org/10.7150/jca.60008
Jin X, Yin J, Zhu H, Li W, Yu K, Liu M, et al. SMG9 serves as an oncogene to promote the tumor progression via EMT and Wnt/β‐catenin signaling pathway in hepatocellular carcinoma. Front Pharmacol. 2021;12:701454. https://doi.org/10.3389/fphar.2021.701454
Fang JH, Zhou HC, Zhang C, Shang L, Zhang L, Xu J, et al. A novel vascular pattern promotes metastasis of hepatocellular carcinoma in an epithelial‐mesenchymal transition‐independent manner. Hepatology. 2015;62(2):452–65. https://doi.org/10.1002/hep.27760
Yoneda N, Matsui O, Kobayashi S, Kitao A, Kozaka K, Inoue D, et al. Current status of imaging biomarkers predicting the biological nature of hepatocellular carcinoma. Jpn J Radiol. 2019;37(3):191–208. https://doi.org/10.1007/s11604‐019‐00817‐3
Jou J, Diehl AM. Epithelial‐mesenchymal transitions and hepatocarcinogenesis. J Clin Invest. 2010;120(4):1031–4. https://doi.org/10.1172/jci42615
Wan L, Pantel K, Kang Y. Tumor metastasis: moving new biological insights into the clinic. Nat Med. 2013;19(11):1450–64. https://doi.org/10.1038/nm.3391
Renne SL, Woo HY, Allegra S, Rudini N, Yano H, Donadon M, et al. Vessels encapsulating tumor clusters (VETC) is a powerful predictor of aggressive hepatocellular carcinoma. Hepatology. 2020;71(1):183–95. https://doi.org/10.1002/hep.30814
Zhou HC, Fang JH, Shang LR, Zhang ZJ, Sang Y, Xu L, et al. MicroRNAs miR‐125b and miR‐100 suppress metastasis of hepatocellular carcinoma by disrupting the formation of vessels that encapsulate tumour clusters. J Pathol. 2016;240(4):450–60. https://doi.org/10.1002/path.4804
Jeon Y, Benedict M, Taddei T, Jain D, Zhang X. Macrotrabecular hepatocellular carcinoma: an aggressive subtype of hepatocellular carcinoma. Am J Surg Pathol. 2019;43(7):943–8. https://doi.org/10.1097/pas.0000000000001289
Fang JH, Xu L, Shang LR, Pan C, Ding J, Tang Y, et al. Vessels that encapsulate tumor clusters (VETC) pattern is a predictor of Sorafenib benefit in patients with hepatocellular carcinoma. Hepatology. 2019;70(3):824–39. https://doi.org/10.1002/hep.30366
Villa E, Critelli R, Lei B, Marzocchi G, Camma C, Giannelli G, et al. Neoangiogenesis‐related genes are hallmarks of fast‐growing hepatocellular carcinomas and worst survival. Results from a prospective study. Gut. 2016;65(5):861–9. https://doi.org/10.1136/gutjnl‐2014‐308483
Akiba J, Nakayama M, Sadashima E, Kusano H, Kondo R, Mihara Y, et al. Prognostic impact of vessels encapsulating tumor clusters and macrotrabecular patterns in hepatocellular carcinoma. Pathol Res Pract. 2022;238:154084. https://doi.org/10.1016/j.prp.2022.154084
Kawasaki J, Toshima T, Yoshizumi T, Itoh S, Mano Y, Wang H, et al. Prognostic impact of vessels that encapsulate tumor cluster (VETC) in patients who underwent liver transplantation for hepatocellular carcinoma. Ann Surg Oncol. 2021;28(13):8186–95. https://doi.org/10.1245/s10434‐021‐10209‐5
Yamashita YI, Baba H. Vessels encapsulating tumor clusters in hepatocellular carcinoma: a unique and valuable pathological imaging. Hepatobiliary Surg Nutr. 2020;9(4):484–7. https://doi.org/10.21037/hbsn.2019.11.16
Calderaro J, Ziol M, Paradis V, Zucman‐Rossi J. Molecular and histological correlations in liver cancer. J Hepatol. 2019;71(3):616–30. https://doi.org/10.1016/j.jhep.2019.06.001
Gerald D, Chintharlapalli S, Augustin HG, Benjamin LE. Angiopoietin‐2: an attractive target for improved antiangiogenic tumor therapy. Cancer Res. 2013;73(6):1649–57. https://doi.org/10.1158/0008‐5472.can‐12‐4697
Leong A, Kim M. The angiopoietin‐2 and TIE pathway as a therapeutic target for enhancing antiangiogenic therapy and immunotherapy in patients with advanced cancer. Int J Mol Sci. 2020;21(22):8689. https://doi.org/10.3390/ijms21228689
Vanderborght B, Lefere S, Vlierberghe HV, Devisscher L. The angiopoietin/Tie2 pathway in hepatocellular carcinoma. Cells. 2020;9(11):2382. https://doi.org/10.3390/cells9112382
Hoshida Y, Nijman SM, Kobayashi M, Chan JA, Brunet JP, Chiang DY, et al. Integrative transcriptome analysis reveals common molecular subclasses of human hepatocellular carcinoma. Cancer Res. 2009;69(18):7385–92. https://doi.org/10.1158/0008‐5472.can‐09‐1089
Tan PS, Nakagawa S, Goossens N, Venkatesh A, Huang T, Ward SC, et al. Clinicopathological indices to predict hepatocellular carcinoma molecular classification. Liver Int. 2016;36(1):108–18. https://doi.org/10.1111/liv.12889
Fu Y, Liu S, Zeng S, Shen H. From bench to bed: the tumor immune microenvironment and current immunotherapeutic strategies for hepatocellular carcinoma. J Exp Clin Cancer Res. 2019;38(1):396. https://doi.org/10.1186/s13046‐019‐1396‐4
Calderaro J, Meunier L, Nguyen CT, Boubaya M, Caruso S, Luciani A, et al. ESM1 as a marker of macrotrabecular‐massive hepatocellular carcinoma. Clin Cancer Res. 2019;25(19):5859–65. https://doi.org/10.1158/1078‐0432.ccr‐19‐0859
Zhou HC, Liu CX, Pan WD, Shang LR, Zheng JL, Huang BY, et al. Dual and opposing roles of the androgen receptor in VETC‐dependent and invasion‐dependent metastasis of hepatocellular carcinoma. J Hepatol. 2021;75(4):900–11. https://doi.org/10.1016/j.jhep.2021.04.053
Woo HY, Rhee H, Yoo JE, Kim SH, Choi GH, Kim DY, et al. Lung and lymph node metastases from hepatocellular carcinoma: comparison of pathological aspects. Liver Int. 2022;42(1):199–209. https://doi.org/10.1111/liv.15051
Kurebayashi Y, Matsuda K, Ueno A, Tsujikawa H, Yamazaki K, Masugi Y, et al. Immunovascular classification of HCC reflects reciprocal interaction between immune and angiogenic tumor microenvironments. Hepatology. 2022;75(5):1139–53. https://doi.org/10.1002/hep.32201
Zhang P, Ono A, Fujii Y, Hayes CN, Tamura Y, Miura R, et al. The presence of vessels encapsulating tumor clusters is associated with an immunosuppressive tumor microenvironment in hepatocellular carcinoma. Int J Cancer. 2022;151(12):2278–90.
Luo M, Liu X, Yong J, Ou B, Xu X, Zhao X, et al. Preoperative prediction of macrotrabecular‐massive hepatocellular carcinoma based on B‐Mode US and CEUS. Eur Radiol. 2022. https://doi.org/10.1007/s00330‐022‐09322‐0
Feng Z, Li H, Zhao H, Jiang Y, Liu Q, Chen Q, et al. Preoperative CT for characterization of aggressive macrotrabecular‐massive subtype and vessels that encapsulate tumor clusters pattern in hepatocellular carcinoma. Radiology. 2021;300(1):219–29. https://doi.org/10.1148/radiol.2021203614
Feng Z, Li H, Liu Q, Duan J, Zhou W, Yu X, et al. CT radiomics to predict macrotrabecular‐massive subtype and immune status in hepatocellular carcinoma. Radiology. 2022:221291. https://doi.org/10.1148/radiol.221291
Cannella R, Dioguardi Burgio M, Beaufrère A, Trapani L, Paradis V, Hobeika C, et al. Imaging features of histological subtypes of hepatocellular carcinoma: implication for LI‐RADS. JHEP Rep. 2021;3(6):100380. https://doi.org/10.1016/j.jhepr.2021.100380
Lewin M, Laurent‐Bellue A, Desterke C, Radu A, Feghali JA, Farah J, et al. Evaluation of perfusion CT and dual‐energy CT for predicting microvascular invasion of hepatocellular carcinoma. Abdom Radiol (NY). 2022;47(6):2115–27. https://doi.org/10.1007/s00261‐022‐03511‐7
Goh V, Sarker D, Osmany S, Cook GJR. Functional imaging techniques in hepatocellular carcinoma. Eur J Nucl Med Mol Imag. 2012;39(6):1070–9. https://doi.org/10.1007/s00259‐012‐2096‐x
Hu S, Kang Y, Xie Y, Yang T, Yang Y, Jiao J, et al. (18)F‐FDG PET/CT‐based radiomics nomogram for preoperative prediction of macrotrabecular‐massive hepatocellular carcinoma: a two‐center study. Abdom Radiol (NY). 2022;48(2):532–42. https://doi.org/10.1007/s00261‐022‐03722‐y
Hu S, Xie Y, Yang T, Yang Y, Zou Q, Jiao J, et al. Tumor metabolism derived from (18)F‐FDG PET/CT in predicting the macrotrabecular‐massive subtype of hepatocellular carcinoma. Quant Imag Med Surg. 2023;13(1):309–19. https://doi.org/10.21037/qims‐22‐523
Mulé S, Galletto Pregliasco A, Tenenhaus A, Kharrat R, Amaddeo G, Baranes L, et al. Multiphase liver MRI for identifying the macrotrabecular‐massive subtype of hepatocellular carcinoma. Radiology. 2020;295(3):562–71. https://doi.org/10.1148/radiol.2020192230
Katabathina VS, Khanna L, Surabhi VR, Minervini M, Shanbhogue K, Dasyam AK, et al. Morphomolecular classification update on hepatocellular adenoma, hepatocellular carcinoma, and intrahepatic cholangiocarcinoma. Radiographics. 2022;42(5):1338–57. https://doi.org/10.1148/rg.210206
Rhee H, Cho ES, Nahm JH, Jang M, Chung YE, Baek SE, et al. Gadoxetic acid‐enhanced MRI of macrotrabecular‐massive hepatocellular carcinoma and its prognostic implications. J Hepatol. 2021;74(1):109–21. https://doi.org/10.1016/j.jhep.2020.08.013
Zhu Y, Weng S, Li Y, Yan C, Ye R, Wen L, et al. A radiomics nomogram based on contrast‐enhanced MRI for preoperative prediction of macrotrabecular‐massive hepatocellular carcinoma. Abdom Radiol (NY). 2021;46(7):3139–48. https://doi.org/10.1007/s00261‐021‐02989‐x
Lan CY, Ling B, Guo WW, Yin W, Zhong XG, Han YM, et al. The relationship between vimentin protein expression in endothelial cells and contrast‐enhanced ultrasound characters in VETC (+) hepatocellular carcinoma. Zhonghua Zhong Liu Za Zhi. 2018;40(2):105–9.
Itoh S, Yoshizumi T, Kitamura Y, Yugawa K, Iseda N, Shimagaki T, et al. Impact of metabolic activity in hepatocellular carcinoma: association with immune status and vascular formation. Hepatol Commun. 2021;5(7):1278–89. https://doi.org/10.1002/hep4.1715
Yu Y, Fan Y, Wang X, Zhu M, Hu M, Shi C, et al. Gd‐EOB‐DTPA‐enhanced MRI radiomics to predict vessels encapsulating tumor clusters (VETC) and patient prognosis in hepatocellular carcinoma. Eur Radiol. 2022;32(2):959–70. https://doi.org/10.1007/s00330‐021‐08250‐9
Fan Y, Yu Y, Wang X, Hu M, Du M, Guo L, et al. Texture analysis based on Gd‐EOB‐DTPA‐enhanced MRI for identifying vessels encapsulating tumor clusters (VETC)‐positive hepatocellular carcinoma. J Hepatocell Carcinoma. 2021;8:349–59. https://doi.org/10.2147/jhc.s293755
Fan Y, Yu Y, Hu M, Wang X, Du M, Guo L, et al. Imaging features based on Gd‐EOB‐DTPA‐enhanced MRI for predicting vessels encapsulating tumor clusters (VETC) in patients with hepatocellular carcinoma. Br J Radiol. 2021;94(1119):20200950. https://doi.org/10.1259/bjr.20200950
Chen FM, Du M, Qi X, Bian L, Wu D, Zhang SL, et al. Nomogram estimating vessels encapsulating tumor clusters in hepatocellular carcinoma from preoperative gadoxetate disodium‐enhanced MRI. J Magn Reson Imag. 2022. https://doi.org/10.1002/jmri.28488
Kang TW, Lim HK, Lee MW, Kim Y, Rhim H, Lee WJ, et al. Aggressive intrasegmental recurrence of hepatocellular carcinoma after radiofrequency ablation: risk factors and clinical significance. Radiology. 2015;276(1):274–85. https://doi.org/10.1148/radiol.15141215
Gigante E, Haddad Y, Nault JC, Sutter O, Abou Ali E, Bonnet B, et al. Imaging and histological features of tumor biopsy sample predict aggressive intrasegmental recurrence of hepatocellular carcinoma after radiofrequency ablation. Sci Rep. 2022;12(1):18712. https://doi.org/10.1038/s41598‐022‐23315‐5
Schmittnaegel M, Rigamonti N, Kadioglu E, Cassara A, Wyser Rmili C, Kiialainen A, et al. Dual angiopoietin‐2 and VEGFA inhibition elicits antitumor immunity that is enhanced by PD‐1 checkpoint blockade. Sci Transl Med. 2017;9(385). https://doi.org/10.1126/scitranslmed.aak9670
Kuang DM, Zhao Q, Peng C, Xu J, Zhang JP, Wu C, et al. Activated monocytes in peritumoral stroma of hepatocellular carcinoma foster immune privilege and disease progression through PD‐L1. J Exp Med. 2009;206(6):1327–37. https://doi.org/10.1084/jem.20082173
Liu LL, Zhang SW, Chao X, Wang CH, Yang X, Zhang XK, et al. Coexpression of CMTM6 and PD‐L1 as a predictor of poor prognosis in macrotrabecular‐massive hepatocellular carcinoma. Cancer Immunol Immunother. 2021;70(2):417–29. https://doi.org/10.1007/s00262‐020‐02691‐9
Pinter M, Scheiner B, Peck‐Radosavljevic M. Immunotherapy for advanced hepatocellular carcinoma: a focus on special subgroups. Gut. 2021;70(1):204–14. https://doi.org/10.1136/gutjnl‐2020‐321702
Huang C, Zhu HX, Yao Y, Bian ZH, Zheng YJ, Li L, et al. Immune checkpoint molecules. Possible future therapeutic implications in autoimmune diseases. J Autoimmun. 2019;104:102333. https://doi.org/10.1016/j.jaut.2019.102333
Trinchet JC, Bourcier V, Chaffaut C, Ait Ahmed M, Allam S, Marcellin P, et al. Complications and competing risks of death in compensated viral cirrhosis (ANRS CO12 CirVir prospective cohort). Hepatology. 2015;62(3):737–50. https://doi.org/10.1002/hep.27743
Rim CH, Cheng J, Huang WY, Kimura T, Lee V, Zeng ZC, et al. An evaluation of hepatocellular carcinoma practice guidelines from a radiation oncology perspective. Radiother Oncol. 2020;148:73–81. https://doi.org/10.1016/j.radonc.2020.03.027
Islami F, Ward EM, Sung H, Cronin KA, Tangka FKL, Sherman RL, et al. Annual report to the nation on the status of cancer, Part 1: national cancer statistics. J Natl Cancer Inst. 2021;113(12):1648–69. https://doi.org/10.1093/jnci/djab131
Guo J, Wang S, Han Y, Jia Z, Wang R. Effects of transarterial chemoembolization on the immunological function of patients with hepatocellular carcinoma. Oncol Lett. 2021;22(1):554. https://doi.org/10.3892/ol.2021.12815
Zeng Q, Klein C, Caruso S, Maille P, Laleh NG, Sommacale D, et al. Artificial intelligence predicts immune and inflammatory gene signatures directly from hepatocellular carcinoma histology. J Hepatol. 2022;77(1):116–27. https://doi.org/10.1016/j.jhep.2022.01.018
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
