Introduction
Hepatocellular carcinoma (HCC) is a global problem being fourth in terms of cancer-related deaths1. Contrast-enhanced ultrasound (CEUS) is used as an add-on test to confirm focal liver lesions suspected as HCC at prior diagnostic tests such as ultrasound or alpha-foetoprotein, or both2,3. According to guidelines4,5,6, a single contrast-enhanced imaging techniques, with either computed tomography (CT) or magnetic resonance imaging (MRI) showing the typical hallmarks is sufficient to diagnose HCC in cirrhotic patients. However, a significant number of HCC show atypical imaging features, and therefore, are missed at imaging.
The advantages of CEUS over CT and MRI is the use of contrast agents not containing iodine and that are not nephrotoxic, and quick image acquisition. Despite the advantages, the use of CEUS in the diagnostic algorithm for HCC remains controversial, with disagreement on relevant guidelines.
Aims & Methods
The aim was to assess the diagnostic accuracy of CEUS for the diagnosis of HCC of any size and at any stage in adults with chronic liver disease, in a surveillance programme or in a clinical setting and to assess the diagnostic accuracy of CEUS for the diagnosis of resectable HCC in people with chronic liver disease and identify potential sources of heterogeneity in the results.
We included studies assessing the diagnostic accuracy of CEUS for the diagnosis of HCC in adults with chronic liver disease, with cross-sectional designs, using one of the acceptable reference standards, such as pathology of the explanted liver, and histology of resected or biopsied focal liver lesion with at least a six-month follow-up.
Standard Cochrane methods 7 were used to screen studies, extract data, and assess the risk of bias and applicability concerns, using the QUADAS-2 checklist8. We used the bivariate model and provided estimates of summary sensitivity and specificity. We assessed the certainty of the evidence using GRADE9,10. We presented uncertainty-of-the-accuracy estimates using 95% confidence intervals (CIs).
Results
We included 23 studies with 6546 participants. Studies were published between 2001 and 2021. We judged all 23 studies at high-risk of bias in at least one domain, and 13/23 studies at high concern for applicability. Most studies used different reference standards to exclude the presence of the target condition. The time interval between the index test and the reference standard was rarely defined. We also had major concerns on their applicability due to the participant characteristics.
CEUS for HCC of any size and stage: sensitivity 77.8% (95% CI 69.4% to 84.4%) and specificity 93.8% (95% CI 89.1% to 96.6%) (23 studies, 6546 participants; very low-certainty evidence).
CEUS for resectable HCC: sensitivity 77.5% (95% CI 62.9% to 87.6%) and specificity 92.7% (95% CI 86.8% to 96.1%) (13 studies, 1257 participants; low-certainty evidence).
The observed heterogeneity in the results remains unexplained.
Conclusion
Using CEUS, as an add-on test following abdominal ultrasound, to diagnose HCC of any size and stage, 22% of people with the tumor would be missed, and 6% of people without would unnecessarily undergo further testing or inappropriate treatment. As to resectable HCC, we found that 23% of people with resectable tumor would incorrectly be unresected, while 8% of people without HCC would undergo further inappropriate testing or treatment. The uncertainty resulting from the high risk of bias of the included studies, heterogeneity, and imprecision of the results and concerns on their applicability limit our ability to draw confident conclusions.
References
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5) Omata M, et al.Asia–Pacific clinical practice guidelines on the management of hepatocellular carcinoma: a 2017 update. Hepatology International 2017;11:317-70
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7) Macaskill P, et al. Chapter 10: Understanding meta-analysis Draft version (13 May 2022) for inclusion in: Deeks JJ, Bossuyt PM, Leeflang MM, TakwoingiY, editor(s). Cochrane Handbook for Systematic Reviews of Diagnostic Test Accuracy Version 2. London: Cochrane.
8) Whiting PF, Ret al. QUADAS-2 Group. QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies. Annals of Internal Medicine 2011;155(8):529-36.
9) McMaster University (developed by Evidence Prime) GRADEpro GDT. Version accessed 26 January 2022. Hamilton (ON): McMaster University (developed by Evidence Prime). Available at gradepro.org.
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Disclosure
nothing to disclose
