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01-08-2021 | Hepatocellular Carcinoma | S.I. : HCC Treatment

HCC: role of pre- and post-treatment tumor biology in driving adverse outcomes and rare responses to therapy

Authors: Sandeep Arora, Roberta Catania, Amir Borhani, Natally Horvat, Kathryn Fowler, Carla Harmath

Published in: Abdominal Radiology | Issue 8/2021

Abstract

Liver cancer is the fastest-growing cause of cancer deaths in the United States and is a complex disease. The response of hepatocellular carcinoma (HCC) to treatment can be variable. Predicting response to determine the most effective therapy is an active area of research. Our understanding of underlying factors which drive response to therapy is continually increasing. As more therapies for the treatment of this disease evolve, it is crucial to identify and match the ideal therapy for a particular tumor and patient. The potential predicative imaging features of tumor behavior, while of research interest, have not been validated for clinical use and do not currently inform treatment planning. If further validated though, prognostic features may be used in the future to personalize treatment plans according to individual patients and tumors. Unexpected post-treatment responses such as potential tumor biology changes and abscopal effect which are important to be aware of. This review is intended for radiologists who routinely interpret post treatment HCC imaging and is designed to increase their cognizance about how HCC tumor biology drives response to therapy and explore rare responses to therapy.

Kim, H., Jang, M. & Park, Y. N. Histopathological Variants of Hepatocellular Carcinomas: an Update According to the 5th Edition of the WHO Classification of Digestive System Tumors. J Liver Cancer 20, 17–24, doi:https://doi.org/10.17998/jlc.20.1.17 (2020).

Torbenson MS, N. I., Park YN, Roncalli M, Sakamoto M. Hepatocellular carcinoma. WHO Classification of Tumours, 5th Edition, “Digestive System Tumours”. Geneva, Switzerland: WHO Press, 229–239 (2019).

Mule, S. et al. Multiphase Liver MRI for Identifying the Macrotrabecular-Massive Subtype of Hepatocellular Carcinoma. Radiology 295, 562-571, doi:https://doi.org/10.1148/radiol.2020192230 (2020).CrossRefPubMed

Kim, J. H., Joo, I. & Lee, J. M. Atypical Appearance of Hepatocellular Carcinoma and Its Mimickers: How to Solve Challenging Cases Using Gadoxetic Acid-Enhanced Liver Magnetic Resonance Imaging. Korean J Radiol 20, 1019-1041, doi:https://doi.org/10.3348/kjr.2018.0636 (2019).CrossRefPubMedPubMedCentral

Köhler, B. C. et al. Liver cancers with stem/progenitor-cell features - a rare chemotherapy-sensitive malignancy. Oncotarget 8, 59991-59998, doi:https://doi.org/10.18632/oncotarget.19000 (2017).CrossRefPubMedPubMedCentral

Roayaie, S. et al. A system of classifying microvascular invasion to predict outcome after resection in patients with hepatocellular carcinoma. Gastroenterology 137, 850-855, doi:https://doi.org/10.1053/j.gastro.2009.06.003 (2009).CrossRefPubMed

Banerjee, S. et al. A computed tomography radiogenomic biomarker predicts microvascular invasion and clinical outcomes in hepatocellular carcinoma. Hepatology (Baltimore, Md.) 62, 792–800, doi:https://doi.org/10.1002/hep.27877 (2015).

Katabathina, V. S. et al. Decoding Genes: Current Update on Radiogenomics of Select Abdominal Malignancies. Radiographics 40, 1600-1626, doi:https://doi.org/10.1148/rg.2020200042 (2020).CrossRefPubMed

Wang, W. T. et al. Assessment of Microvascular Invasion of Hepatocellular Carcinoma with Diffusion Kurtosis Imaging. Radiology 286, 571-580, doi:https://doi.org/10.1148/radiol.2017170515 (2018).CrossRefPubMed

10.

Renzulli, M. et al. Can Current Preoperative Imaging Be Used to Detect Microvascular Invasion of Hepatocellular Carcinoma? Radiology 279, 432-442, doi:https://doi.org/10.1148/radiol.2015150998 (2016).CrossRefPubMed

11.

Rhee, H. et al. Hepatocellular Carcinoma with Irregular Rim-Like Arterial Phase Hyperenhancement: More Aggressive Pathologic Features. Liver Cancer 8, 24-40, doi:https://doi.org/10.1159/000488540 (2019).CrossRefPubMed

12.

Min, J. H. et al. Interobserver Variability and Diagnostic Performance of Gadoxetic Acid-enhanced MRI for Predicting Microvascular Invasion in Hepatocellular Carcinoma. Radiology 297, 573-581, doi:https://doi.org/10.1148/radiol.2020201940 (2020).CrossRefPubMed

13.

Unal, E., Idilman, I. S., Akata, D., Ozmen, M. N. & Karcaaltincaba, M. Microvascular invasion in hepatocellular carcinoma. Diagn Interv Radiol 22, 125-132, doi:https://doi.org/10.5152/dir.2015.15125 (2016).CrossRefPubMedPubMedCentral

14.

Hu, H. et al. A non-smooth tumor margin on preoperative imaging assesses microvascular invasion of hepatocellular carcinoma: A systematic review and meta-analysis. Sci Rep 7, 15375, doi:https://doi.org/10.1038/s41598-017-15491-6 (2017).CrossRefPubMedPubMedCentral

15.

Huang, M. et al. Prediction of Microvascular Invasion in Hepatocellular Carcinoma: Preoperative Gd-EOB-DTPA-Dynamic Enhanced MRI and Histopathological Correlation. Contrast Media Mol Imaging 2018, 9674565, doi:https://doi.org/10.1155/2018/9674565 (2018).CrossRefPubMedPubMedCentral

16.

Xu, X. et al. Radiomic analysis of contrast-enhanced CT predicts microvascular invasion and outcome in hepatocellular carcinoma. J Hepatol 70, 1133-1144, doi:https://doi.org/10.1016/j.jhep.2019.02.023 (2019).CrossRefPubMed

17.

Ji, G. W. et al. Radiomic Features at Contrast-enhanced CT Predict Recurrence in Early Stage Hepatocellular Carcinoma: A Multi-Institutional Study. Radiology 294, 568-579, doi:https://doi.org/10.1148/radiol.2020191470 (2020).CrossRefPubMed

18.

Choi, S. Y. et al. Imaging Features of Gadoxetic Acid-enhanced and Diffusion-weighted MR Imaging for Identifying Cytokeratin 19-positive Hepatocellular Carcinoma: A Retrospective Observational Study. Radiology 286, 897-908, doi:https://doi.org/10.1148/radiol.2017162846 (2018).CrossRefPubMed

19.

Morio, K. et al. Preoperative PET-CT is useful for predicting recurrent extrahepatic metastasis of hepatocellular carcinoma after resection. Eur J Radiol 124, 108828, doi:https://doi.org/10.1016/j.ejrad.2020.108828 (2020).CrossRefPubMed

20.

Fowler, K. J., Potretzke, T. A., Hope, T. A., Costa, E. A. & Wilson, S. R. LI-RADS M (LR-M): definite or probable malignancy, not specific for hepatocellular carcinoma. Abdom Radiol (NY) 43, 149-157, doi:https://doi.org/10.1007/s00261-017-1196-2 (2018).CrossRef

21.

van der Pol, C. B. et al. Accuracy of the Liver Imaging Reporting and Data System in Computed Tomography and Magnetic Resonance Image Analysis of Hepatocellular Carcinoma or Overall Malignancy-A Systematic Review. Gastroenterology 156, 976-986, doi:https://doi.org/10.1053/j.gastro.2018.11.020 (2019).CrossRefPubMed

22.

Cha, D. I. et al. Preoperative Prediction for Early Recurrence Can Be as Accurate as Postoperative Assessment in Single Hepatocellular Carcinoma Patients. Korean J Radiol 21, 402-412, doi:https://doi.org/10.3348/kjr.2019.0538 (2020).CrossRefPubMedPubMedCentral

23.

Lee, S. et al. Gadoxetic acid-enhanced MRI as a predictor of recurrence of HCC after liver transplantation. Eur Radiol 30, 987-995, doi:https://doi.org/10.1007/s00330-019-06424-0 (2020).CrossRefPubMed

24.

Kitao, A. et al. Gadoxetic acid-enhanced MR imaging for hepatocellular carcinoma: molecular and genetic background. Eur Radiol 30, 3438-3447, doi:https://doi.org/10.1007/s00330-020-06687-y (2020).CrossRefPubMed

25.

Kobayashi, S., Kozaka, K., Gabata, T., Matsui, O. & Minami, T. Intraarterial and intravenous contrast enhanced CT and MR imaging of multi-step hepatocarcinogenesis defining the early stage of hepatocellular carcinoma development. Hepatoma Research 6, 36, doi:https://doi.org/10.20517/2394-5079.2020.24 (2020).CrossRef

26.

Joo, I. et al. Radiologic-Pathologic Correlation of Hepatobiliary Phase Hypointense Nodules without Arterial Phase Hyperenhancement at Gadoxetic Acid-enhanced MRI: A Multicenter Study. Radiology 296, 335-345, doi:https://doi.org/10.1148/radiol.2020192275 (2020).CrossRefPubMed

27.

Tefera, J. et al. Fibronodular hepatocellular carcinoma-a new variant of liver cancer: clinical, pathological and radiological correlation. J Clin Pathol 74, 31-35, doi:https://doi.org/10.1136/jclinpath-2020-206574 (2021).CrossRefPubMed

28.

Lin, D. & Wu, J. Hypoxia inducible factor in hepatocellular carcinoma: A therapeutic target. World J Gastroenterol 21, 12171-12178, doi:https://doi.org/10.3748/wjg.v21.i42.12171 (2015).CrossRefPubMedPubMedCentral

29.

Guo, Y. et al. Hypoxiainducible factors in hepatocellular carcinoma (Review). Oncol Rep 43, 3-15, doi:https://doi.org/10.3892/or.2019.7397 (2020).CrossRefPubMed

30.

Wang, B. et al. Increased expression of vascular endothelial growth factor in hepatocellular carcinoma after transcatheter arterial chemoembolization. Acta Radiol 49, 523-529, doi:https://doi.org/10.1080/02841850801958890 (2008).CrossRefPubMed

31.

Sergio, A. et al. Transcatheter arterial chemoembolization (TACE) in hepatocellular carcinoma (HCC): the role of angiogenesis and invasiveness. Am J Gastroenterol 103, 914-921, doi:https://doi.org/10.1111/j.1572-0241.2007.01712.x (2008).CrossRefPubMed

32.

Liu, K. et al. The Changes of HIF-1alpha and VEGF Expression After TACE in Patients With Hepatocellular Carcinoma. J Clin Med Res 8, 297-302, doi:https://doi.org/10.14740/jocmr2496w (2016).CrossRefPubMedPubMedCentral

33.

Schicho, A. et al. Impact of Different Embolic Agents for Transarterial Chemoembolization (TACE) Procedures on Systemic Vascular Endothelial Growth Factor (VEGF) Levels. J Clin Transl Hepatol 4, 288-292, doi:https://doi.org/10.14218/JCTH.2016.00058 (2016).CrossRefPubMedPubMedCentral

34.

Petrillo, M. et al. Hypoxia and tumor angiogenesis in the era of hepatocellular carcinoma transarterial loco-regional treatments. Future Oncol 14, 2957-2967, doi:https://doi.org/10.2217/fon-2017-0739 (2018).CrossRefPubMed

35.

Ziv, E. et al. NRF2 Dysregulation in Hepatocellular Carcinoma and Ischemia: A Cohort Study and Laboratory Investigation. Radiology 297, 225-234, doi:https://doi.org/10.1148/radiol.2020200201 (2020).CrossRefPubMed

36.

Huang, M. et al. Regulation of COX-2 expression and epithelial-to-mesenchymal transition by hypoxia-inducible factor-1alpha is associated with poor prognosis in hepatocellular carcinoma patients post TACE surgery. Int J Oncol 48, 2144-2154, doi:https://doi.org/10.3892/ijo.2016.3421 (2016).CrossRefPubMedPubMedCentral

37.

Savic, L. J. et al. Molecular MRI of the Immuno-Metabolic Interplay in a Rabbit Liver Tumor Model: A Biomarker for Resistance Mechanisms in Tumor-targeted Therapy? Radiology 296, 575-583, doi:https://doi.org/10.1148/radiol.2020200373 (2020).CrossRefPubMed

38.

Xu, M. et al. Neoadjuvant Locoregional Therapy and Recurrent Hepatocellular Carcinoma after Liver Transplantation. J Am Coll Surg 225, 28-40, doi:https://doi.org/10.1016/j.jamcollsurg.2017.03.015 (2017).CrossRefPubMedPubMedCentral

39.

Peng, Z. et al. Microvascular Invasion as a Predictor of Response to Treatment with Sorafenib and Transarterial Chemoembolization for Recurrent Intermediate-Stage Hepatocellular Carcinoma. Radiology 292, 237-247, doi:https://doi.org/10.1148/radiol.2019181818 (2019).CrossRefPubMed

40.

Murali, N., Laage-Gaupp, F. M., Chapiro, J. & Geschwind, J. F. Science to Practice: Decrypting the Enigma of Ablation-induced Off-Target Effects-Is Network Pathway Analysis the Final Piece of the Puzzle? Radiology 286, 405-408, doi:https://doi.org/10.1148/radiol.2017171779 (2018).CrossRefPubMed

41.

Kumar, G. et al. Targeting STAT3 to Suppress Systemic Pro-Oncogenic Effects from Hepatic Radiofrequency Ablation. Radiology 286, 524-536, doi:https://doi.org/10.1148/radiol.2017162943 (2018).CrossRefPubMed

42.

Liao, H. et al. Thermal Ablation Induces Transitory Metastatic Growth by Means of the STAT3/c-Met Molecular Pathway in an Intrahepatic Colorectal Cancer Mouse Model. Radiology 294, 464-472, doi:https://doi.org/10.1148/radiol.2019191023 (2020).CrossRefPubMed

43.

Zhang, R. et al. Activated hepatic stellate cells promote progression of post-heat residual hepatocellular carcinoma from autophagic survival to proliferation. Int J Hyperthermia 36, 253-263, doi:https://doi.org/10.1080/02656736.2018.1558459 (2019).CrossRefPubMed

44.

Jondal, D. E. et al. Single-Dose Neoadjuvant AKT Pathway Inhibitor Reduces Growth of Hepatocellular Carcinoma after Laser Thermal Ablation in Small-Animal Model. Radiology 292, 752-759, doi:https://doi.org/10.1148/radiol.2019190115 (2019).CrossRefPubMed

45.

Salem, R., Mazzaferro, V. & Sangro, B. Yttrium 90 radioembolization for the treatment of hepatocellular carcinoma: biological lessons, current challenges, and clinical perspectives. Hepatology 58, 2188-2197, doi:https://doi.org/10.1002/hep.26382 (2013).CrossRefPubMed

46.

Carpizo, D. R. et al. Pilot study of angiogenic response to yttrium-90 radioembolization with resin microspheres. J Vasc Interv Radiol 25, 297–306 e291, doi:https://doi.org/10.1016/j.jvir.2013.10.030 (2014).

47.

Gordon, A. C. et al. Yttrium-90 Radioembolization and Tumor Hypoxia: Gas-challenge BOLD Imaging in the VX2 Rabbit Model of Hepatocellular Carcinoma. Academic Radiology, doi:https://doi.org/https://doi.org/10.1016/j.acra.2020.04.012 (2020).CrossRefPubMed

48.

de Jesús KA & X, X. Mechanisms of radioresistance in hepatocellular carcinoma. Oncology and Translational Medicine 3, 165–170, doi:https://doi.org/10.1007/s10330-017-0223-3 (2017).

49.

Guo, J. et al. Mechanisms of resistance to chemotherapy and radiotherapy in hepatocellular carcinoma. Translational Cancer Research 7, 765-781 (2018).CrossRef

50.

Imamura, H. et al. Risk factors contributing to early and late phase intrahepatic recurrence of hepatocellular carcinoma after hepatectomy. J Hepatol 38, 200-207, doi:https://doi.org/10.1016/s0168-8278(02)00360-4 (2003).CrossRefPubMed

51.

Tung-Ping Poon, R., Fan, S. T. & Wong, J. Risk factors, prevention, and management of postoperative recurrence after resection of hepatocellular carcinoma. Ann Surg 232, 10–24, doi:https://doi.org/10.1097/00000658-200007000-00003 (2000).

52.

de'Angelis, N., Landi, F., Carra, M. C. & Azoulay, D. Managements of recurrent hepatocellular carcinoma after liver transplantation: A systematic review. World J Gastroenterol 21, 11185–11198, doi:https://doi.org/10.3748/wjg.v21.i39.11185 (2015).

53.

Maccali, C. et al. Recurrence of hepatocellular carcinoma after liver transplantation: Prognostic and predictive factors of survival in a Latin American cohort. Liver Int, doi:https://doi.org/10.1111/liv.14736 (2020).CrossRefPubMed

54.

Hollebecque, A. et al. Natural history and therapeutic management of recurrent hepatocellular carcinoma after liver transplantation. Gastroenterol Clin Biol 33, 361-369, doi:https://doi.org/10.1016/j.gcb.2009.02.036 (2009).CrossRefPubMed

55.

Boteon, Y., Flores Carvalho, M. A., Panconesi, R., Muiesan, P. & Schlegel, A. Preventing Tumour Recurrence after Liver Transplantation: The Role of Machine Perfusion. International Journal of Molecular Sciences 21, 5791 (2020).CrossRef

56.

Tasdogan, B. E., Ma, M., Simsek, C., Saberi, B. & Gurakar, A. Update on Immunosuppression in Liver Transplantation. Euroasian J Hepatogastroenterol 9, 96-101, doi:https://doi.org/10.5005/jp-journals-10018-1301 (2019).CrossRefPubMedPubMedCentral

57.

VanHuis, A. & Loy, V. Myth: Liver Transplant Provides a Cure for Liver Disease. Clin Liver Dis (Hoboken) 13, 154-157, doi:https://doi.org/10.1002/cld.770 (2019).CrossRef

58.

Borhani, A. A., Hosseinzadeh, K., Almusa, O., Furlan, A. & Nalesnik, M. Imaging of posttransplantation lymphoproliferative disorder after solid organ transplantation. Radiographics 29, 981–1000; discussion 1000–1002, doi:https://doi.org/10.1148/rg.294095020 (2009).

59.

Poovorawan, K., Linlawan, S., Wisedopas, N. & Komolmit, P. Post liver transplantation lymphoproliferative disorder mimics recurrence of hepatocellular carcinoma. BMJ Case Rep 2013, doi:https://doi.org/10.1136/bcr-2013-200837 (2013).

60.

Nishihara, Y. et al. Biliary phenotype of hepatocellular carcinoma after preoperative transcatheter arterial chemoembolization. J Gastroenterol Hepatol 23, 1860-1868, doi:https://doi.org/10.1111/j.1440-1746.2008.05601.x (2008).CrossRefPubMed

61.

Takamatsu S, N. H., Otsukasa S, Kawachi Y, Maruyama H. Combined Hepatocellular-Cholangiocarcinoma Associated With Radiofrequency Ablation for Hepatocellular Carcinoma. . Journal of Medical Cases, North America, (2015).

62.

Wiles, C., Jutric, Z., Shen, J. & Newell, P. Sarcomatous transformation of hepatocellular carcinoma following treatment with Y-90 radioembolization. HPB 20, S138-S139, doi:https://doi.org/https://doi.org/10.1016/j.hpb.2018.02.550 (2018).CrossRef

63.

Huz, J. I., Melis, M. & Sarpel, U. Spontaneous regression of hepatocellular carcinoma is most often associated with tumour hypoxia or a systemic inflammatory response. HPB (Oxford) 14, 500-505, doi:https://doi.org/10.1111/j.1477-2574.2012.00478.x (2012).CrossRef

64.

Demaria, S. & Formenti, S. C. The abscopal effect 67 years later: from a side story to center stage. Br J Radiol 93, 20200042, doi:https://doi.org/10.1259/bjr.20200042 (2020).CrossRefPubMedPubMedCentral

65.

Duffy, A. G. et al. Tremelimumab in combination with ablation in patients with advanced hepatocellular carcinoma. J Hepatol 66, 545-551, doi:https://doi.org/10.1016/j.jhep.2016.10.029 (2017).CrossRefPubMed

66.

Xu, H. et al. Immune abscopal effect of microwave ablation for lung metastases of endometrial carcinoma. J Cancer Res Ther 16, 1718-1721, doi:https://doi.org/10.4103/jcrt.JCRT_1399_20 (2020).CrossRefPubMed

Title: HCC: role of pre- and post-treatment tumor biology in driving adverse outcomes and rare responses to therapy
Authors: Sandeep Arora
Roberta Catania
Amir Borhani
Natally Horvat
Kathryn Fowler
Carla Harmath
Publication date: 01-08-2021
Publisher: Springer US
Keywords: Hepatocellular Carcinoma
Hepatocellular Carcinoma
Published in: Abdominal Radiology / Issue 8/2021
Print ISSN: 2366-004X
Electronic ISSN: 2366-0058
DOI: https://doi.org/10.1007/s00261-021-03192-8

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