Small hepatocellular carcinoma: using MRI to predict histological grade and Ki-67 expression
Introduction
Hepatocellular carcinoma (HCC) is the fifth most common malignancy and the third most common cause of cancer-related deaths worldwide.1, 2, 3, 4 Due to the poor prognosis for patients with HCC, it is crucial to identify HCC at an early stage and select the optimal treatment in order to achieve satisfactory outcome. Cirrhosis is the most important clinical risk factor for HCC, and approximately 80% of cases of HCCs develop against a background of cirrhotic liver.5 Studies have showed that human hepatocarcinogenesis involves the stepwise progression of the tumour from a high-grade dysplastic nodule (DN) in a cirrhotic liver to advanced HCC.6, 7, 8 With the optimisation of medical imaging technologies, especially the widely use of magnetic resonance imaging (MRI), the rate of early detection is increasing, especially for small HCC (≤3 cm).
Although small HCCs usually have better outcomes than larger HCCs, a subset of small HCCs have been identified as more aggressive, with poorer clinical prognosis. Investigators have reported that the histological grade of HCCs is a valuable prognostic factor; higher histological grades indicate worse survival probability.9, 10 The nuclear protein, Ki-67, is associated with cell proliferative activity, which may be an indicator of tumour aggressiveness, and is expressed in all phases of the cell cycle except G0, with particularly high expression observed in the G2/M phase.11 High expression of Ki-67 is associated with a higher tumour grade12 and higher mortality.13 Studies have showed that patients with a higher level of Ki-67 expression had a worse prognosis.14, 15 Identification of small HCCs with high histological grade or high Ki-67 expression may help in the selection of appropriate treatment, improving remission rates. The caveat of these prognostic factors is that neither the histological grade nor Ki-67 expression is routinely available through biopsy due to the invasiveness and concern of procedure-related complications. As such, there is a need for non-invasive methods to evaluate Ki-67 expression or histological grade.
Studies have evaluated the correlation between blood supply and histological grade for HCCs,6, 16, 17 some demonstrated that the arterial blood supply decreases as the histological grade progresses in the late stage of HCC development (17). Signal intensity (SI) in dynamic contrast-enhanced MRI was hypothesised to help predict histological grade. Huang et al. reported that apparent diffusion coefficient (ADC) values are significantly negatively correlated with Ki-67 expression,18 but for small HCCs, the correlation between them remains unknown. The purpose of the present study was to investigate the association between histological tumour grade and Ki-67 expression and a battery of preoperative MRI findings, including quantitative and qualitative parameters, for the detection of aggressive small HCCs.
Section snippets
Patient population
The study protocol conformed to the ethical guidelines of the Declaration of Helsinki as reflected in a priori approval by the institutional review board, who waived the requirement for informed consent. Patient medical records were reviewed between January 2011 and December 2017 and 949 patients with histopathologically confirmed HCCs (by surgery or biopsy) were identified. The patients were included consecutively according to the following inclusion criteria1: undergoing routine
Demographic and pathologic characteristics of small HCCs
Baseline demographic and pathological characteristics (Table 1) demonstrated that 10 of the 60 HCCs examined were well-differentiated (WD) HCCs, 43 were moderately differentiated (MD) HCCs, and seven were poorly differentiated (PD) HCCs. Twenty-five of the 60 HCCs had low Ki-67 expression, and the remaining 35 HCCs had high Ki-67 expression. Tumour size (1.93±0.61 cm) ranged from 0.67 to 3 cm in diameter. There were 34 lesions had an AFP value of <20 ng/ml, and the remaining 26 lesions had a
Discussion
This study demonstrated that AFP levels of the selected patients with small HCCs were associated with histological grade, where higher AFP levels were more frequently observed in tumours with higher histological grade, as supported by a previous study.19 Arterial rim enhancement was observed more frequently in the higher histological grade HCCs, especially in MD and PD HCCs. Prior studies have described that arterial rim enhancement can be an indicator for poor differentiation and worse
Conflict of interest
The authors declare no conflict of interest.
Acknowledgements
This study received funding from the Fujian Provincial Health and Family Planning Commission (CN; award number: 2017-CX-27), Fujian Provincial Department of Science and Technology (CN; award number: 2015J0105), and Fujian Medical Elite Cultivation Program (CN; award number: 2015-ZQN-ZD-19).
References (36)
- et al.
Global epidemiology of hepatocellular carcinoma: an emphasis on demographic and regional variability
Clin Liver Dis
(2015) - et al.
Epidemiology and management of hepatocellular carcinoma
Infect Dis Clin N Am
(2010) - et al.
Epidemiology and natural history of hepatocellular carcinoma
Best Pract Res Clin Gastroenterol
(2005) - et al.
Tumour recurrence after liver transplantation for hepatocellular carcinoma: recurrence pathway and prognostic factors
Transpl Proc
(2007) - et al.
Vascular invasion and histopathologic grading determine outcome after liver transplantation for hepatocellular carcinoma in cirrhosis
Hepatology
(2001) - et al.
Correlations between ADC values and molecular markers of Ki-67 and HIF-1alpha in hepatocellular carcinoma
Eur J Radiol
(2015) - et al.
Diffusion-weighted magnetic resonance imaging predicts malignant potential in small hepatocellular carcinoma
Dig Liver Dis
(2016) - et al.
MRI findings of rapidly progressive hepatocellular carcinoma
Magn Reson Imaging
(2010) - et al.
Diagnostic performance of apparent diffusion coefficient for predicting histological grade of hepatocellular carcinoma
Eur J Radiol
(2011) - et al.
Diffusion-weighted imaging of prostate cancer on 3T MR: relationship between apparent diffusion coefficient values and Ki-67 expression
Acad Radiol
(2013)
Value of pretherapeutic DWI in evaluating prognosis and therapeutic effect in immunocompetent patients with primary central nervous system lymphoma given high-dose methotrexate-based chemotherapy: ADC-based assessment
Clin Radiol
Tumour-associated autoantibodies are useful biomarkers in immunodiagnosis of alpha-fetoprotein-negative hepatocellular carcinoma
World J Gastroenterol
Rate of local tumour progression following radiofrequency ablation of pathologically early hepatocellular carcinoma
World J Gastroenterol
CT and MRI diagnosis and staging of hepatocellular carcinoma: part I. Development, growth, and spread: key pathologic and imaging aspects
Radiology
Imaging of multistep human hepatocarcinogenesis by CT during intra-arterial contrast injection
Intervirology
Hepatocarcinogenesis and LI-RADS
Abdom Radiol
Cell cycle analysis of a cell proliferation-associated human nuclear antigen defined by the monoclonal antibody Ki-67
J Immunol
Akt phosphorylation is a risk factor for early disease recurrence and poor prognosis in hepatocellular carcinoma
Cancer
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Prediction for Aggressiveness and Postoperative Recurrence of Hepatocellular Carcinoma Using Gadoxetic Acid-Enhanced Magnetic Resonance Imaging
2023, Academic RadiologyCitation Excerpt :Diffusion-weighted image: targetoid DWI appearance, defined as a rim-like high SI with a central hypointense areas in a DWI (b = 800 sec/mm2) (21). Arterial phase (Fig 1): (a)rim enhancement, defined as an irregularly shaped rim-like peripheral hyper enhancement with a central hypoenhancing area; (b) peritumoral enhancement, defined as a crescent-shaped or polygonal enhancement outside the tumor margin (18,25,27); (c) intratumoral vessels, defined as visible tumoral vessels in arterial phase (AP) images; (d) substantial hypoenhancing component, defined as a ≥50% tumor area with distinctly less enhancement than the liver parenchyma (25,28); and (e) tumor capsule, defined as a thin low-SI rim in AP images with delayed contrast enhancement around the tumor margin (29). Portal phase: non-peripheral washout, defined as a non-peripheral visually-assessed temporal reduction in enhancement on the whole or in part, relative to the liver parenchyma (25).
Poorly differentiated hepatocellular carcinoma: resection is equivalent to transplantation in patients with low liver fibrosis
2022, HPBCitation Excerpt :These include Kyoto criteria (PIVKA-II cutoffs),36 HALT-HCC score (tumor burden score and history of locoregional therapy),37 and extended Toronto criteria (excluding poorly differentiated tumors).10 Biomarker correlates of tumor grade may provide an adjunct to biopsy for patient risk stratification, as AFP, PIVKA-II, stemness markers such as K-19 and EpCAM, long non-coding RNA ARHGEF7-AS2, RGS5, Ki-67 expression in conjunction with serologies (i.e. neutrophil–platelet–monocyte/lymphocyte ratios) have all been associated with aggressive behavior, microvascular invasion, and, ultimately, poorly differentiated HCC.27,38–46 In fact, elevated AFP level has recently been incorporated as exclusion criterion in the UNOS National Liver Review Board HCC exception criteria, and a model incorporating AFP into selection recently demonstrated the potential to enhance Milan Criteria.47
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These authors contributed equally to this work and are co-first authors.