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Gadoxetic acid‑enhanced MRI for evaluation of vessels encapsulating tumor clusters and microvascular invasion in hepatocellular carcinoma

Qi Qu¹, Tao Zhang¹, Xueqin Zhang¹, Mengtian Lu¹, Zixin Liu¹, and Xiance Zhao²
¹Affiliated Nantong Hospital 3 of Nantong University, Nantong Third People’s Hospital, Nantong, China, ²Philips Healthcare, Shanghai, China, Nantong, China

Synopsis

Keywords: Liver, Liver

Motivation: VETC and MVI have a synergistic effect on prognosis assessment and treatment selection of HCC. Preoperative noninvasive evaluation of VETC and MVI is important.

Goal(s): To explore the diagnosis value of nomograms based on preoperative gadoxetic acid (GA)-enhanced MRI features for MVI, VETC, and RFS in patients with HCC.

Approach: Retrospective study explored the relationship between the clinical and imaging features of MVI, VETC, and MVI+/VETC+ using the same dataset.

Results: Nomograms incorporating independent indicators showed good performance in the training and internal validation cohorts. Significant differences in recurrence rates between the nomogram-evaluated high- and low-risk stratification were found.

Impact: Through the in-depth exploration of the combination of MVI and VETC, we can deepen the understanding of tumor metastasis heterogeneity, and the diagnosis and treatment plan, prognosis prediction and risk stratification of tumor patients can be formulated.

Introduction

EMT-mediated metastasis promotes the progression of microvascular invasion (MVI).1 The histopathological grades of MVI, including M0, M1, and M2, are significantly negatively correlated with recurrence-free survival (RFS) in patients with HCC.^1,2 However, many patients with MVI-negative HCC are also at risk of early recurrence after radical resection,^3,4 suggesting that MVI is inadequate for explaining the mechanism of HCC recurrence and metastasis. Vessels encapsulating tumor clusters (VETC)-mediated metastasis cannot be explained by single-cell metastasis based on EMT.^5,6 In VETC+ HCC, tumor cell clusters are completely surrounded by CD34(+) endothelial cells, and the overall efficient metastasis is carried out. The cancer nest metastasize to the target organ with the bloodstream, and proliferate to form new metastases, leading to a higher rate of VETC+ HCC metastasis, more likely recurrence after surgery, and a worse prognosis for patients.^5,7 VETC and MVI are two different vascular patterns that underlie distinct molecular and cellular bases. Lin et al. reported that VETC is weighted slightly higher than MVI in a multivariable model in evaluating HCC recurrence.⁸ The presence of VETC suggests that HCC is more aggressive.⁹ Lu et al.¹⁰ found that VETC+/MVI+ patients had the worst overall survival (OS) and disease-free survival (DFS), while patients with VETC-/MVI- had the best long-term prognosis. No studies have focused at the independent risk factors only associated with VETC+/MVI+ HCCs and no studies have simultaneously predicted MVI+, VETC+, and VETC+/MVI+ in the same patient cohort.

Methods

240 patients with pathologically confirmed HCC (allocated to training and validation sets with a 7:3 ratio) who underwent GA-enhanced MRI examination followed by radical hepatectomy. Preoperative clinical characteristics and imaging features of subjective assessment by the radiologist were collected and analyzed. Regression-based nomograms to diagnose MVI, VETC, and VETC+/MVI+ were developed for HCC in the training set. Based on the nomograms, the RFS prognostic stratification system was further.

Results

Serum PIVKA-II level >40 mAU/mL, arterial peritumoral enhancement, intratumoral vessels, and nonsmooth tumor margins were independently associated with MVI-HCC. Independent risk factors for diagnosing VETC-HCC were PIVKA-II level >40 mAU/mL, the ≥50% arterial phase hypovascular component, peritumoral hypointensity on HBP, and lower RIR on HBP images. PIVKA-II level >40 mAU/mL, arterial peritumoral enhancement, and lower RIR on HBP images were significant factors for estimating VETC+/MVI+ HCCs. Three nomograms incorporating these indicators showed good performance in the training and internal validation cohorts. Significant differences in recurrence rates between the nomogram-evaluated high- and low-risk stratification were found.

Discussion

PIVKA-II elevation is related to undesirable biological behaviors such as histological vascular invasion, and metastasis of cancer cells, and has the potential to reflect the progression of HCC. ^11,12 Arterial peritumoral enhancement,¹³ intratumoral vessels,¹⁴ and unsmooth tumor margin^13-16 have been reported as independent risk factors for MVI, which is consistent with our results. Most massive macrotrabecular-massive (MTM) patterns exhibit VETC+ expression.^17-19 Rhee et al.¹⁸ and Cha et al.¹⁹ observed that MTM-HCC was accompanied by ≥ 50% of arterial phase hypovascular components, which is consistent with our study. This study found that peritumoral hypointensity in HBP images was significantly associated with VETC. Previous studies have shown that peritumoral hypointensity on HBP images was significantly associated with MVI and high tumor grade,^15,20 implying that this variable has the potential to reflect the malignant biological behavior of HCC. Our study found that VETC+ HCCs had significantly lower RIR on HBP images than VETC-negative HCCs, which is consistent with the study of Fan et al.,¹⁷ who found that a tumor-to-liver SI ratio of 0.585 or less on HBP images was a significant independent risk factor for predicting VETC+ HCCs. Moreover, Zheng et al.²¹ reported that HCCs with a lower tumor-to-liver signal ratio on HBP images exhibited greater aggressiveness, higher tumor grade, and shorter RFS. This supports the theory that VETC is a potent predictor of aggressive HCC.⁹ Multivariable logistic regression analysis showed that arterial peritumoral enhancement and lower RIR on HBP images were independent risk factors for MVI+/VETC+ HCCs. Yang et al.²² proposed that AFP >400 ng/mL, intratumor vascularity, and enhancement pattern can be used to characterize the positive VETC and/or MVI (VM patterns), and intratumor vascularity was associated with RFS. Notably, how our research differs from theirs may be related to the different groupings of cases included in the study by Yang et al.²², who put VETC+/MVI-, VETC-/MVI+ and MVI+/VETC+ together in a group. Another difference is that our study used GA-enhanced MRI.

Conclusion

Preoperative noninvasive models combining the GA-enhanced MRI signature and clinical variables have potential to preoperatively diagnose MVI, VETC, and VETC+/MVI+ in HCC.

Acknowledgements

Not applicable.

References

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Figures

Flow chart of the study population.

Gadoxetic acid-enhanced MR images in a 68-year-old woman demonstrated an approximately 4.1-cm MVI−/ VETC+ HCC in liver segment 6. a T2WI showed a moderately hyperintense lesion with smooth margin. b The mass showed diffusion restriction (b = 800 sec/mm2). c Arterial phase image showed a hypovascular component (≥ 50%). d In the hepatobiliary phase, the mass showed peritumoral hypointensity (arrow). e Photomicrograph (original magnification, ×200; CD34 stain) showed typical VETC pattern HCC appearance with tumor cells surrounded by rims of CD34(+) endothelial cells.

Images in a 62-year-old woman with MVI+/ VETC+ HCC (arrow) in liver segment 7. a The tumor was approximately 4.1 cm in diameter with uneven high signals on T2WI. b Diffusion restriction on DWI. c Stripe-like and significant peritumoral arterial phase hyperenhancement in the axial plane (arrow). d Hepatobiliary phase image showed a non-smooth tumor margin and peritumoral hypointensity (arrow). e Microscopy (hematoxylin–eosin stain, ×200) showed a cluster of carcinoma cells in microvessels. f Immunohistochemical staining for CD34 (Original magnifications ×200).

Nomograms for predicting MVI+ (d), VETC+ (e), and MVI+/VETC+ (f) in HCC. When using the nomogram, find the position of each variable on the horizontal axes and the corresponding points are identified vertically. Then, the points of all variables are added and converted into the probability on the bottom axis.

Kaplan-Meier plots for postoperative RFS according to nomogram-predicted and histological MVI and VETC status. RFS of (a) histologic MVI status and (b) nomogram-predicted MVI status. RFS of (c) histologic VETC status and (d) nomogram-predicted VETC status. RFS of (e) histologic MVI+/VETC+ status and (f) nomogram-predicted MVI+/VETC+ status. The classification of nomogram-predicted MVI, VETC and MVI+/VETC+ status was derived using the optimal threshold that maximized the Youden index of the corresponding receiver-operating characteristic analyses.

Proc. Intl. Soc. Mag. Reson. Med. 32 (2024)

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DOI: https://doi.org/10.58530/2024/4141