Advanced Imaging Techniques of the Magnetic Resonance in Characterization of Hepatocellular Carcinoma Type: A Systematic Review and Meta‑Analysis

Received: 26-Jul-2021 Accepted Date: Aug 09, 2021 ; Published: 16-Aug-2021

Introduction

Hepatocellular Carcinoma (HCC) is the most common primary malignancy of the liver [1]. HCC is the fifth most common type of cancer and the second leading cause of cancer-related death worldwide [2]. Approximately 70%-90% of HCCs are developed on the background of established liver cirrhosis or advanced fibrosis. Hepatitis B Virus (HBV) and/ or Hepatitis C Virus (HCV) infection, alcohol, and Nonalcoholic Aatty Liver Disease (NAFLD) are the most predominant risk factors for HCC worldwide [3]. A tremendous development of new imaging techniques has taken place during these last year’s [4]. Maximizing accuracy of imaging in the context of HCC is paramount in avoiding unnecessary histopathology, which may result in post-procedural complications up to 6.4%, and mortality up to 0.1% [5]. Noninvasive imaging modalities, including Ultrasound (US), Computed Tomography (CT), and Magnetic Resonance Imaging (MRI), have played pivotal roles in assessing HCC in recent decades [6]. Several clinical practice guidelines, the application of US is limited in obese patients and patients with very cirrhotic heterogeneous livers. In addition, the performance of US is usually deteriorated for deep, sub diaphragmatic, multiple, and treated lesions. In general, US is less accurate for diagnosing HCC than MRI [7]. Therefore, US is not yet recommended as the first-line diagnostic tool for HCC, according to current guidelines [6]. Multiphasic dynamic Computed Tomography (CT) is useful in the evaluation of nodular lesions in the cirrhotic liver [8]. Arterial phase imaging is most useful for the detection of HCC as its predominant blood supply is from the hepatic artery [9]. However, it is less sensitive for the detection of small HCC and for dysplastic nodules which appear isodense to the liver parenchyma due to their predominant blood supply from the portal vein [10]. CT arterio-portography and CT hepatic arteriography are more sensitive for the detection of HCC but the false positive rate is high due to benign hyper vascular lesions like arterioportal shunts [11]. Nowadays, magnetic resonance plays a key role in management of liver lesions, using a radiation-free technique and a safe contrast agent profile [12]. Magnetic Resonance Imaging (MRI) provides valuable imaging information for the preoperative and postoperative evaluation of HCC [13]. DWI is a functional MRI technique that allows quantitative measurements of proton diffusion in tissues [14]. HCC and other malignancies are usually characterized by increased cellularity and, thus, have restricted water proton diffusion [6]. Therefore, most HCCs are observed as a hyper intense lesion on high b value DWI with low Apparent Diffusion Coefficient (ADC) value on quantitative maps compared with background liver [15]. HCC and other malignancies are usually characterized by increased cellularity and, thus have restricted [16]. Perfusion weighted image Dynamic Contrast- Enhanced (DCEMRI) enables quantification of the vascular characteristics of tissue and tumor [17]. DCE-MRI requires IV injection of a gadoliniumbased contrast agent and uses high-temporal images that capture changes in MR Signal Intensity (SI) as a function of time. Tracer kinetic modeling based on DCE-MRI has been used to detect liver fibrosis and cirrhosis and to assess tumor angiogenesis [18].

Materials and Methods

This systematic review and meta-analysis was performed in compliance with the Preferred Reporting Items for Systematic Reviews and Meta- Analyses (PRISMA) guidelines [19].

Literature search

A systematic literature search using PubMed( https://pubmed.ncbi. nlm.nih.gov), Embase (https://www.embase.com), Web of Science (https://apps.webofknowledge com), SEMANTIC SCHOLAR, Google Scholar, PROQUEST, and Cochrane Library databases (https://www cochranelibrary.com) were performed independently by tow radiologists to identify articles published prior to June 2021, using the key words ‘hepatocellular carcinoma’, ‘liver cancer’, ‘liver cell carcinoma’, ‘magnetic resonance imaging’ ‘diffusion magnetic resonance imaging’, Meta-analysis • Systematic review susceptibility weighted image SWI. Related citations in eligible articles were also assessed for inclusion. The search was limited to English-language studies on human subjects. The time period for the studies was limited from January 1, 2010 to February 6, 2021. The detailed search strategy is described in supplementary Figure 1.

Figure 1. Flow chart of post-therapy assessment participants.

The ethical approval for this study was obtained from Tehran University of medical sciences ethical committee in our institution IR.TUMS.SPH. REC.1399.324 during 14 Mars 2021. The study included (35) articles studied consecutive with HCC. In our study, Embase, MEDLINE, PubMed, the Cochrane library, Elsevier, Springer and free journals were searched using the search queries: HCC , conventional MRI, Locally Advance MRI, diffusion weighted imaging DWI, perfusion MRI , IVIM and SWI. Only original articles that performed during the years 2010 to 2020 presented in English language that relevant to our objectives were considered for inclusion. We searched more in databases using function of Related Articles in PubMed and browsed the scholar.google.com using same terns. Also we searched the references of all retrieved articles manually for relevant related articles. Then we compared the retrieved articles and accepted recent publication for the overlapping patients ‘series. Furthermore, we assessed for potential eligibility by screening for relevance on title and reading the abstracts first and then full text article and then start to apply agreed upon inclusion and exclusion criteria.

Inclusion and exclusion criteria

Studies meeting the following criteria were included: (a) population: Patients at high risk for HCC [1,2,5]; (b) index test: liver MRI with conventional protocol or advanced protocol; (c) reference standard: HCC histopathology and clinical diagnosis such as imaging follow-up or laboratory markers; Studies meeting any of the following criteria were excluded: (a) studies not reporting sufficient data to clearly establish outcomes; (b) studies for which it was not possible to obtain separate outcomes using with conventional protocol or advanced protocol; (c) studies with hepatic lesions previously treated with systemic therapy; (d) studies with case–control designs; (e) studies with partially overlapping cohorts; (f) case reports or series including fewer than ten patients; and (g) protocols, conference abstracts, reviews, guidelines, books, letters, editorials, and errata.

Data extraction and quality assessment

The following data were extracted from each eligible study: (a) Study characteristics: Authors, year of publication, institution, country, duration, and study design (prospective vs. retrospective); (b) patient characteristics: number of patients, sex, age, underlying liver disease, (c) lesion characteristics: lesion number, lesion size,; (d) MRI techniques: magnetic field, MRI protocol, (e) reference standard; The methodological quality of the selected studies was assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool [11]. The risk of bias and applicability of each eligible study were assessed according to the four different domains of patient selection, index test, reference standard, and flow and timing. Studies without a high risk of bias in any domain were considered to have a low-to-moderate overall risk of bias. Likewise, studies without a high concern for applicability in any domain were considered to have a low-tomoderate overall concern for applicability. The data extraction and quality assessment were independently conducted by the two reviewers, with any disagreements being resolved by discussion with the third reviewer.

The two radiologists reviewed all 2380 abstracts after duplication removal and subsequently the full text of the 120 articles was obtained if the following inclusion criteria was fulfilled: 1) Included the diagnostic accuracy of conventional MRI only or with advance protocol for HCC; 2) constituted original research rather than a meta‑analysis, a review article, case report or case series; 3) published in English; and 4) results are from humans and not animals 5) included both MRI with conventional protocol and advanced protocol 6) included sufficient data, with>20 patients to calculate True Positive (TP), False Positive (FP), False Negative (FN) and True Negative (TN) for constructing a 2 × 2 contingency table; and 7) patients at high risk for HCC using pathological analysis (surgical resection, explant and/or biopsy) or imaging from follow‑up according to the guidelines for standardization of liver imaging, diagnosis, classification and reporting of hepatocellular carcinoma. In addition, articles from the same institution, which included an overlap period of patient recruitment, were considered to have an overlapping population. In these cases, the study, which had the larger number of HCCs cases, was included.

If there were disagreements between the two investigators, the consensus amongst the two radiologists was used to resolve the disagreement. Disagreements were resolved following discussions between the two investigators, until at least own of the investigators reached the same conclusion. A total of 85 studies were excluded according to the following exclusion criteria:1) They were not relevant to the present meta‑analysis if they fit one of the followings conditions: Cancer type includes malignant cancer other than HCC, such as cholangiocarcinoma, hepatoepidermoid carcinoma and metastatic cancer; diagnosis of HCC using a combination of multiple imaging modalities;2) they evaluated previously treated HCCs; 3) the sensitivity and specificity was not evaluated; 4) there was a lack of sufficient data to construct a 2 × 2 contingency table; and vi) there was study population overlap. A total of 35 studies were included for analysis. In addition, the reference list of these 35 studies was reviewed.

Results

Study selection. A flow chart following the Preferred Reporting Items for Systematic Reviews and Meta-analysis principles was used to demonstrate the selection procedure (Figure 1).

A total of 2,380 articles were initially identified. There was a total of 2,260 articles remaining following the removal of duplicates and a further 120 articles were excluded, following screening of the abstract. Amongst the remaining 85 studies, a total of 35 studies were included in the Meta analysis using the inclusion criteria.

Summary of included studies

The summarized characteristics and the diagnostic performance of conventional MRI and Advance MRI for the included 35 studies are shown in Tables 1 and 2, respectively. A total of 3,757 HCCs with a diameter 2 cm and 3,682 benign liver lesions, with a diameter 2 cm was included in the meta analysis. The DWI, HCC, MRI and were all calculated on a per lesion basis. Of the included studies, 27 originated from Asia, 7 from Europe and one from USA. In addition, 23 of the studies were retrospective, and 12 were prospective. The reference standard for the diagnosis of HCC included pathological analysis (surgical resection, explant and/or biopsy) and imaging from follow-up. MR imaging field strength was 3 T and 1.5 T.

Quality assessment and publication bias: Figure 2 demonstrates the overall evaluation for the quality of the included studies using QUADAS.2. The quality of the index test was high (90%, 9/35 studies); however, patient selection had a low score (70%, 7/35 studies), which could be due to a lack of avoidance of a case control design or the inappropriate exclusions during patient selection.

Figure 2.Quality assessment of the included studies using the Quality Assessment of Diagnostic Accuracy Studies. The red bar indicates high risk of bias; the yellow bar indicates unclear risk of bias; and the green bar indicates low risk of bias. In the lower part, details of quality assessment were shown. Green circle with â??+â?? indicates low risk of bias or low concern for applicability; yellow circle with â???â?? indicates unclear risk of bias or unclear concern for applicability; red circle with â??â??â?? indicates high risk of bias or low concern for applicability. Funnel plot of comparison.

This also increased concerns regarding the applicability of patient selection. For all the 35 included studies, some of them used pathological finding as the only reference standard to diagnose HCC. For the others, Histopathology was used as a reference standard for patients when pathology analysis was not available. Liver transplantation (n¼10), surgical resection (n¼26), or fine needle aspiration biopsy (n¼55). Of the 91 nodules, 60 nodules were pathologically confirmed as WD-HCCs and 31 nodules were confirmed as HGDNs.

Therefore, the concerns of bias for applicability of reference standards was low for studies using imaging follow up as one of the reference standards for patients when pathology was not used. The risk of bias for flow and timing was high for 1 study since the interval between MRI scan and the pathological analysis exceeded 117 days for some of the patients, and was unclear for 2 studies for the lack of information regarding the time interval between MRI scan and the references standard (Figure 3 and Table 3).

Figure 3. Deeks' funnel plot for assessment of publication bias. Potential publication exists if the calculated P<0.05.

Heterogeneity between studies the 35 included studies demonstrated significant heterogeneity with P<0.00001 using X2 test. The heterogeneity for the sensitivity (I2 of 93) was higher compared with that for specificity (I2 of 93). In addition, there was no threshold effect found (correlation,.0.46; proportion of heterogeneity due to threshold effect, (0.46), (P=0.65).

Synthesis of general diagnostic

Figure 4 demonstrates the forest plots of sensitivity and specificity, Tables 4-6 comparison of the diagnostic performance of conventional MRI, The pooled sensitivity and specificity were 0.81 (95% CI, 0.77-0.94) and 0.78 (95% CI, 0.84-0.92), respectively, +Advance MRI. The pooled sensitivity and specificity were 0.93 (95% CI, 0.83-0.89) and 0.86 (95% CI, 0.79-0.96), respectively. The positive and negative likelihood ratio was 0.02 (95% CI, 0.06-0.09), respectively.

Figure 4. Forest plots of sensitivity and specificity.

SROC, The confidence region (smaller circle with dash line) represents the ellipsoid 95% confidence region in SROC space for the summary point estimate of diagnostic performance. SROC, summary receiver operating characteristics curve; AUC, area under the curve; SPEC, Specificity; SENS, Sensitivity (Figure 5).

Figure 5. Sensitivity was significantly higher for studies not using hepatobiliary phase compared with those using hepatobiliary phase (P<0.001). Specificity was significantly higher for studies using a 3 T magnetic field compared with those using 1.5 T magnetic field (P=0.03). There were no significant differences in either the sensitivity or in specificity for the remaining study characteristics (all P>0.05).

Sensitivity was significantly higher for studies not using hepatobiliary phase compared with those using hepatobiliary phase (P<0.001). Specificity was significantly higher for studies using a 3 T magnetic field compared with those using 1.5 T magnetic field (P=0.03). There were no significant differences in either the sensitivity or in specificity for the remaining study characteristics (all P>0.05) (Figure 6).

Larger values of the test result variable(s) indicate stronger evidence for a positive actual state. The positive actual state is 0.

The test result variable(s): Interpretation has at least one tie between the positive actual state group and the negative actual state group. The smallest cutoff value is the minimum observed test value minus 1, and the largest cutoff value is the maximum observed test value plus 1. All the other cutoff values are the averages of two consecutive ordered observed test values. Diagonal segments are produced by ties.

Discussion

The aim of the present meta‑analysis was to assess the diagnostic performance of advance MRI combined with conventional MRI for the diagnosis of HCC lesions. The results suggested that advance MRI with conventional MRI had a high sensitivity of 0.93 (0.83-0.89), and specificity of 0.86 (0.79-0.96). The meta‑regression analysis revealed that the heterogeneity of Sensitivity was significantly higher for studies not using hepatobiliary phase compared with those using hepatobiliary phase (P<0.001). Specificity was significantly higher for studies using a 3T magnetic field compared with those using 1.5 T magnetic field (P=0.03). There were no significant differences in either the sensitivity or in specificity for the remaining study characteristics (all P>0.05). However, a threshold effect was not identified. Non‑contrast enhanced Ultrasonography (US) is a common choice for HCC screening in patients who with chronic liver disease, as it is cost‑effective [20]. However, there is low sensitivity when compared with that in contrast‑ enhanced Computer Tomography (CT) and MRI [21]. Contrast‑enhanced US has emerged as a promising method to diagnose small HCCs however, additional studies are required to confirm its clinical value [20,22]. Multiple meta‑analyses have found that contrast‑enhanced MRI out performs contrast enhanced CT in the diagnosis of HCCs with higher sensitivity and overall accuracy [23]. Previous meta‑analysis indicated that contrast‑enhanced MRI had moderately high sensitivity and high specificity in the diagnosis of small HCC [24]. However, gadolinium contrast cannot be used in patients with chronic renal failure due to risk of nephrogenic systemic fibrosis and in those with history allergy to gadolinium [25]. This creates a need for imaging sequences without the use of gadolinium which can be used for diagnosing HCC in patients with contraindication for gadolinium [26]. In DCEMR, hepatic lesions, which show arterial phase enhancement without venous washout such as dysplastic nodules, and arterio- portal shunts are often encountered which hoften posea diagnostic difficulty indiscriminating HCC from these pseudo-enhancing lesions [27].

The present meta‑analysis suggested that Advance MRI combined with conventional MRI increased the sensitivity and specificity in the diagnosis of HCC. However, the prognosis is poor when HCC is diag- nosed at an advanced stage. Hence, diagnosing HCC at an early stage is very important. ADC has been used to diagnose benign and malignant hepatic lesions [28].

An increasing number of studies have suggested that ADC is more accurate in grading smaller HCCs [29], and for monitoring early treatment responses of HCC to radiofrequency ablation (39).

In the 35 studies included in the present meta‑analysis, one of them study Zhi-bo Hou et al. used a predetermined threshold SWI with DWI value to diagnose small HCC was found Conventional MRI, sen, spes, accuracy 81.24 83.71 80.34 and he found SWI+ DWI increase sens, spes accuracy 91.26 93.55 91.47 respectively.

Conclusion

The present meta‑analysis suggests that Advance MRI may increase the sensitivity, and specificity for the diagnosis of HCCs. The aim of the present meta‑analysis was to assess the diagnostic performance of advance MRI combined with conventional MRI for the diagnosis of HCC lesions. The results suggested that advance MRI with conventional MRI had a high sensitivity of 0.93 (0.83-0.89), and specificity of 0.86 (0.79-0.96).

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Citation: Vahid Changizi, Ahmed Jasim Abbas, Hayder Jasim Taher and Hayder Suhail Najim, et al. “Advanced Imaging Techniques of the Magnetic Resonance in Characterization of Hepatocellular Carcinoma Type: A Systematic Review and Meta Analysis.” Clin Schizophr Relat Psychoses 15S(2021). Doi: 10.3371/CSRP.CVAA.16.0821.

Copyright: ©2021 Changizi V, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.