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Open Access 01-12-2023 | Hepatocellular Carcinoma | Original Article

Stiffness on shear wave elastography as a potential microenvironment biomarker for predicting tumor recurrence in HBV-related hepatocellular carcinoma

Authors: Xian Zhong, Haiyi Long, Lili Chen, Yuhua Xie, Yifan Shi, Jianyun Peng, Ruiying Zheng, Liya Su, Yu Duan, Xiaoyan Xie, Manxia Lin

Published in: Insights into Imaging | Issue 1/2023

Abstract

Background

To explore the pathologic basis and prognostic value of tumor and liver stiffness measured pre-operatively by two-dimensional shear wave elastography (2D-SWE) in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) patients who undergo hepatic resection.

Methods

A total of 191 HBV-infected patients with solitary resectable HCC were prospectively enrolled. The stiffness of intratumoral tissue, peritumoral tissue, adjacent liver tissue, and distant liver tissue was evaluated by 2D-SWE. The correlations between stiffness and pathological characteristics were analyzed in 114 patients. The predictive value of stiffness for recurrence-free survival (RFS) was evaluated, and Cutoff Finder was used for determining optimal cut-off stiffness values. Cox proportional hazards analysis was used to identify independent predictors of RFS.

Results

Pathologically, intratumoral stiffness was associated with stroma proportion and microvascular invasion (MVI) while peritumoral stiffness was associated with tumor size, capsule, and MVI. Adjacent liver stiffness was correlated with capsule and liver fibrosis stage while distant liver stiffness was correlated with liver fibrosis stage. Peritumoral stiffness, adjacent liver stiffness, and distant liver stiffness were all correlated to RFS (all p < 0.05). Higher peritumoral stiffness (> 49.4 kPa) (HR = 1.822, p = 0.023) and higher adjacent liver stiffness (> 24.1 kPa) (HR = 1.792, p = 0.048) were significant independent predictors of worse RFS, along with tumor size and MVI. The nomogram based on these variables showed a C-index of 0.77 for RFS prediction.

Conclusions

Stiffness measured by 2D-SWE could be a tumor microenvironment and tumor invasiveness biomarker. Peritumoral stiffness and adjacent liver stiffness showed important values in predicting tumor recurrence after curative resection in HBV-related HCC.

Clinical relevance statement

Tumor and liver stiffness measured by two-dimensional shear wave elastography serve as imaging biomarkers for predicting hepatocellular carcinoma recurrence, reflecting biological behavior and tumor microenvironment.

Key points

• Stiffness measured by two-dimensional shear wave elastography is a useful biomarker of tumor microenvironment and invasiveness.

• Higher stiffness indicated more aggressive behavior of hepatocellular carcinoma.

• The study showed the prognostic value of peritumoral stiffness and adjacent liver stiffness for recurrence-free survival.

• The nomogram integrating peritumoral stiffness, adjacent liver stiffness, tumor size, and microvascular invasion showed a C-index of 0.77.

Graphical Abstract

Available only for authorised users

Sung H, Ferlay J, Siegel RL et al (2021) Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 71:209–249CrossRefPubMed

Marrero JA, Kulik LM, Sirlin CB et al (2018) Diagnosis, staging, and management of hepatocellular carcinoma: 2018 practice guidance by the American Association for the study of liver diseases. Hepatology 68:723–750PubMed

Sükei T, Palma E, Urbani L (2021) Interplay between cellular and non-cellular components of the tumour microenvironment in hepatocellular carcinoma. Cancers (Basel) 13(21):5586PubMed

Schulze K, Nault JC, Villanueva A (2016) Genetic profiling of hepatocellular carcinoma using next-generation sequencing. J Hepatol 65:1031–1042PubMed

Schrader J, Gordon-Walker TT, Aucott RL et al (2011) Matrix stiffness modulates proliferation, chemotherapeutic response, and dormancy in hepatocellular carcinoma cells. Hepatology 53:1192–1205PubMed

Dong Y, Xie X, Wang Z et al (2014) Increasing matrix stiffness upregulates vascular endothelial growth factor expression in hepatocellular carcinoma cells mediated by integrin β1. Biochem Biophys Res Commun 444:427–432PubMed

You Y, Zheng Q, Dong Y et al (2016) Matrix stiffness-mediated effects on stemness characteristics occurring in HCC cells. Oncotarget 7:32221–32231PubMedPubMedCentral

Levental KR, Yu H, Kass L et al (2009) Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell 139:891–906PubMedPubMedCentral

Park SJ, Yoon JH, Lee DH, Lim WH, Lee JM (2021) Tumor stiffness measurements on MR elastography for single nodular hepatocellular carcinomas can predict tumor recurrence after hepatic resection. J Magn Reson Imaging 53:587–596PubMed

10.

Wang J, Shan Q, Liu Y et al (2019) 3D MR elastography of hepatocellular carcinomas as a potential biomarker for predicting tumor recurrence. J Magn Reson Imaging 49:719–730PubMed

11.

Zhang L, Chen J, Jiang H et al (2022) MR elastography as a biomarker for prediction of early and late recurrence in HBV-related hepatocellular carcinoma patients before hepatectomy. Eur J Radiol 152:110340PubMedPubMedCentral

12.

Dong Y, Zheng Q, Wang Z et al (2019) Higher matrix stiffness as an independent initiator triggers epithelial-mesenchymal transition and facilitates HCC metastasis. J Hematol Oncol 12:112PubMedPubMedCentral

13.

Cho HJ, Kim B, Kim HJ et al (2020) Liver stiffness measured by MR elastography is a predictor of early HCC recurrence after treatment. Eur Radiol 30:4182–4192PubMed

14.

Jung KS, Kim SU, Choi GH et al (2012) Prediction of recurrence after curative resection of hepatocellular carcinoma using liver stiffness measurement (FibroScan®). Ann Surg Oncol 19:4278–4286PubMed

15.

Lee PC, Chiou YY, Chiu NC et al (2020) Liver stiffness measured by acoustic radiation force impulse elastography predicted prognoses of hepatocellular carcinoma after radiofrequency ablation. Sci Rep 10:2006PubMedPubMedCentral

16.

Lee YR, Park SY, Kim SU et al (2017) Using transient elastography to predict hepatocellular carcinoma recurrence after radiofrequency ablation. J Gastroenterol Hepatol 32:1079–1086PubMed

17.

Jung KS, Kim JH, Kim SU et al (2014) Liver stiffness value-based risk estimation of late recurrence after curative resection of hepatocellular carcinoma: development and validation of a predictive model. PLoS One 9:e99167PubMedPubMedCentral

18.

Affo S, Yu LX, Schwabe RF (2017) The role of cancer-associated fibroblasts and fibrosis in liver cancer. Annu Rev Pathol 12:153–186PubMed

19.

Kim MN, Kim SU, Kim BK et al (2015) Increased risk of hepatocellular carcinoma in chronic hepatitis B patients with transient elastography-defined subclinical cirrhosis. Hepatology 61:1851–1859PubMed

20.

Akima T, Tamano M, Hiraishi H (2011) Liver stiffness measured by transient elastography is a predictor of hepatocellular carcinoma development in viral hepatitis. Hepatol Res 41:965–970PubMed

21.

Dietrich CF, Bamber J, Berzigotti A et al (2017) EFSUMB guidelines and recommendations on the clinical use of liver ultrasound elastography, update 2017 (Long Version). Ultraschall Med 38:e48

22.

Gao Y, Zheng J, Liang P et al (2018) Liver fibrosis with two-dimensional US shear-wave elastography in participants with chronic hepatitis B: a prospective multicenter study. Radiology 289:407–415PubMed

23.

Gu JH, Zhu L, Jiang TA (2021) Quantitative ultrasound elastography methods in focal liver lesions including hepatocellular carcinoma: from diagnosis to prognosis. Ultrasound Q 37:90–96PubMed

24.

Yao Z, Dong Y, Wu G et al (2018) Preoperative diagnosis and prediction of hepatocellular carcinoma: radiomics analysis based on multi-modal ultrasound images. BMC Cancer 18:1089PubMedPubMedCentral

25.

Praktiknjo M, Krabbe V, Pohlmann A et al (2018) Evolution of nodule stiffness might predict response to local ablative therapy: a series of patients with hepatocellular carcinoma. PLoS One 13:e0192897PubMedPubMedCentral

26.

Park HS, Kim YJ, Yu MH, Jung SI, Jeon HJ (2015) Shear wave elastography of focal liver lesion: intraobserver reproducibility and elasticity characterization. Ultrasound Q 31:262–271PubMed

27.

Zhong X, Chen L, Long H et al (2022) The “stiff rim” sign of hepatocellular carcinoma on shear wave elastography: correlation with pathological features and potential prognostic value. Abdom Radiol (NY). https://doi.org/10.1007/s00261-022-03628-9CrossRefPubMed

28.

Guibal A, Boularan C, Bruce M et al (2013) Evaluation of shearwave elastography for the characterisation of focal liver lesions on ultrasound. Eur Radiol 23:1138–1149PubMed

29.

Grgurevic I, Bokun T, Salkic NN et al (2018) Liver elastography malignancy prediction score for noninvasive characterization of focal liver lesions. Liver Int 38:1055–1063PubMed

30.

Tian WS, Lin MX, Zhou LY et al (2016) Maximum value measured by 2-D shear wave elastography helps in differentiating malignancy from benign focal liver lesions. Ultrasound Med Biol 42:2156–2166PubMed

31.

Lee S, Jung Y, Bae Y (2016) Clinical application of a color map pattern on shear-wave elastography for invasive breast cancer. Surg Oncol 25:44–48PubMed

32.

Evans A, Whelehan P, Thomson K et al (2012) Invasive breast cancer: relationship between shear-wave elastographic findings and histologic prognostic factors. Radiology 263:673–677PubMed

33.

Cong WM, Bu H, Chen J et al (2016) Practice guidelines for the pathological diagnosis of primary liver cancer: 2015 update. World J Gastroenterol 22:9279–9287PubMedPubMedCentral

34.

Desmet VJ, Gerber M, Hoofnagle JH, Manns M, Scheuer PJ (1994) Classification of chronic hepatitis: diagnosis, grading and staging. Hepatology 19:1513–1520PubMed

35.

Budczies J, Klauschen F, Sinn BV et al (2012) Cutoff Finder: a comprehensive and straightforward web application enabling rapid biomarker cutoff optimization. PLoS One 7:e51862PubMedPubMedCentral

36.

Riegler J, Labyed Y, Rosenzweig S et al (2018) Tumor elastography and its association with collagen and the tumor microenvironment. Clin Cancer Res 24:4455–4467PubMed

37.

Mohammadi H, Sahai E (2018) Mechanisms and impact of altered tumour mechanics. Nat Cell Biol 20:766–774PubMed

38.

Piersma B, Hayward MK, Weaver VM (2020) Fibrosis and cancer: a strained relationship. Biochim Biophys Acta Rev Cancer 1873:188356PubMedPubMedCentral

39.

Zhong X, Peng J, Xie Y et al (2022) A nomogram based on multi-modal ultrasound for prediction of microvascular invasion and recurrence of hepatocellular carcinoma. Eur J Radiol 151:110281PubMed

40.

Li M, Yin Z, Hu B et al (2022) MR elastography-based shear strain mapping for assessment of microvascular invasion in hepatocellular carcinoma. Eur Radiol 32:5024–5032PubMedPubMedCentral

41.

Kubo N, Araki K, Kuwano H, Shirabe K (2016) Cancer-associated fibroblasts in hepatocellular carcinoma. World J Gastroenterol 22:6841–6850PubMedCentral

42.

Hoshida Y, Villanueva A, Kobayashi M et al (2008) Gene expression in fixed tissues and outcome in hepatocellular carcinoma. N Engl J Med 359:1995–2004PubMedPubMedCentral

43.

O’Rourke JM, Sagar VM, Shah T, Shetty S (2018) Carcinogenesis on the background of liver fibrosis: implications for the management of hepatocellular cancer. World J Gastroenterol 24:4436–4447PubMedCentral

44.

Feng JC, Li J, Wu XW, Peng XY (2016) Diagnostic accuracy of supersonic shear imaging for staging of liver fibrosis: a meta-analysis. J Ultrasound Med 35:329–339PubMed

45.

Ju MJ, Qiu SJ, Fan J et al (2009) Peritumoral activated hepatic stellate cells predict poor clinical outcome in hepatocellular carcinoma after curative resection. Am J Clin Pathol 131:498–510PubMed

46.

Wallace MC, Friedman SL (2014) Hepatic fibrosis and the microenvironment: fertile soil for hepatocellular carcinoma development. Gene Expr 16:77–84PubMedPubMedCentral

47.

Ferraioli G, Tinelli C, Zicchetti M et al (2012) Reproducibility of real-time shear wave elastography in the evaluation of liver elasticity. Eur J Radiol 81:3102–3106PubMed

Title: Stiffness on shear wave elastography as a potential microenvironment biomarker for predicting tumor recurrence in HBV-related hepatocellular carcinoma
Authors: Xian Zhong
Haiyi Long
Lili Chen
Yuhua Xie
Yifan Shi
Jianyun Peng
Ruiying Zheng
Liya Su
Yu Duan
Xiaoyan Xie
Manxia Lin
Publication date: 01-12-2023
Publisher: Springer Vienna
Keywords: Hepatocellular Carcinoma
Hepatocellular Carcinoma
Published in: Insights into Imaging / Issue 1/2023
Electronic ISSN: 1869-4101
DOI: https://doi.org/10.1186/s13244-023-01505-7

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Stiffness on shear wave elastography as a potential microenvironment biomarker for predicting tumor recurrence in HBV-related hepatocellular carcinoma

Abstract

Background

Methods

Results

Conclusions

Clinical relevance statement

Key points

Graphical Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Clinical relevance statement

Key points

Graphical Abstract

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