Key messages
In adults with chronic liver disease, contrast-enhanced ultrasound (CEUS) can miss diagnosing hepatocellular carcinoma in around 22.2% of people who would not then receive timely or appropriate treatment, and would fail to diagnose hepatocellular carcinoma in 6.2% of people who could receive unnecessary further testing or treatment.
In the subset of people who are able have the hepatocellular carcinoma removed by surgery, CEUS probably misses hepatocellular carcinoma in 22.5% of people who could undergo surgery to remove part of their liver while it would erroneously find cancer in 7.3% of people who would undergo unnecessary further test or surgery.
As there were some problems with the way the studies were conducted, CEUS to detect hepatocellular carcinoma may appear more accurate than it actually is.
Why is improving the diagnosis of hepatocellular carcinoma important?
Hepatocellular carcinoma is cancer originating in the liver. It is sixth in terms of occurrences of cancer and fourth in terms of cancer-related deaths worldwide. It occurs mostly in people with chronic liver disease regardless of the exact cause. People with blood test or ultrasound results that suggest they may have hepatocellular carcinoma may go on to have further tests, such as imaging or a biopsy (where a small piece of the liver is removed and examined). If the cancer is detected early, people may have part of the liver removed or have a liver transplant. In advanced hepatocellular carcinoma, they may need chemotherapy. If hepatocellular carcinoma is missed at diagnostic testing, people will not receive appropriate treatment. However, incorrectly diagnosing hepatocellular carcinoma when it is not present means that people may undergo unnecessary testing or treatment.
What is contrast-enhanced ultrasound and how can it diagnose hepatocellular carcinoma?
CEUS can detect abnormalities in the liver that might be due to cancer and, using contrast agents, confirm the diagnosis of hepatocellular carcinoma. These contrast agents are safe. CEUS is used in clinical practice to confirm the presence of hepatocellular carcinoma in people in whom suspicion was raised by prior performed abdominal ultrasound or a blood test to measure alpha-foetoprotein.
The role of CEUS in the diagnosis of hepatocellular carcinoma remains controversial between guidelines. Previous systematic reviews have assessed the performance of CEUS in detecting hepatocellular carcinoma but they have included different studies and found different results.
What did we want to find out?
We wanted to find out if CEUS is accurate enough to diagnose hepatocellular carcinoma in adults with chronic liver disease (a progressive deterioration of liver functions for more than six months). We were interested first in hepatocellular carcinoma of any size and severity and, second, in hepatocellular carcinomas that were suitable for surgical removal (resection).
What did we do?
We searched for studies that assessed the accuracy of diagnostic tests of CEUS scans compared to the best available tests to confirm hepatocellular carcinoma in adults with chronic liver disease. The best available test is examination of the liver, or part of it, under a microscope.
What did we find?
We found 23 studies with 6546 adults.
Around 690 (69%) out of 1000 adults with chronic liver disease had a confirmed hepatocellular carcinoma of any size and severity. Considering these 1000 people, CEUS:
– correctly detected liver cancer in 537 people;
– missed liver cancer in 153 people;
– incorrectly detected cancer in 19 people;
– correctly detected no cancer in 291 people.
Around 690 (69%) out of 1000 adults with chronic liver disease had a confirmed hepatocellular carcinoma that could be removed by surgery. Considering these 1000 people, CEUS:
– correctly detected liver cancer in 535 people;
– missed liver cancer in 155 people;
– incorrectly detected cancer in 23 people;
– correctly detected no cancer in 287 people.
What are the limitations of the evidence?
Our confidence in the evidence is limited as the studies used different methods to select study participants and used different reference standards. This means that CEUS scans may be more or less accurate than what the evidence suggests.
How up to date is this evidence?
The evidence is up to date to 5 November 2021.
We found that by using CEUS, as an add-on test following abdominal ultrasound, to diagnose hepatocellular carcinoma of any size and stage, 22% of people with hepatocellular carcinoma would be missed, and 6% of people without hepatocellular carcinoma would unnecessarily undergo further testing or inappropriate treatment. As to resectable hepatocellular carcinoma, we found that 23% of people with resectable hepatocellular carcinoma would incorrectly be unresected, while 8% of people without hepatocellular carcinoma 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.
Hepatocellular carcinoma occurs mostly in people with chronic liver disease. Worldwide, it ranks sixth in terms of incidence of cancer, and fourth in terms of cancer-related deaths. Contrast-enhanced ultrasound (CEUS) is used as an add-on test to confirm the presence of focal liver lesions suspected as hepatocellular carcinoma after prior diagnostic tests such as abdominal ultrasound or measurement of alpha-foetoprotein, or both. According to guidelines, a single contrast-enhanced imaging investigation, with either computed tomography (CT) or magnetic resonance imaging (MRI), may show the typical hepatocellular carcinoma hallmarks in people with cirrhosis, which will be sufficient to diagnose hepatocellular carcinoma. However, a significant number of hepatocellular carcinomas show atypical imaging features, and therefore, are missed at imaging.
Dynamic CEUS images are obtained similarly to CT and MRI images. CEUS differentiates between arterial and portal venous phases, in which sonographic hepatocellular carcinoma hallmarks, such as arterial hyperenhancement and subsequent washout appearance, are investigated. The advantages of CEUS over CT and MRI include real-time imaging, use of contrast agents that do not contain iodine and 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.
There is no clear evidence of the benefit of surveillance programmes in terms of overall survival as the conflicting results can be a consequence of an inaccurate detection, ineffective treatment, or both. Therefore, assessing the diagnostic accuracy of CEUS may clarify whether the absence of benefit could be related to underdiagnosis. Furthermore, an assessment of the accuracy of CEUS for the diagnosis of hepatocellular carcinoma is needed for either diagnosing hepatocellular carcinoma or ruling it out in people with chronic liver disease who are not included in surveillance programmes.
1. To assess the diagnostic accuracy of contrast-enhanced ultrasound (CEUS) for the diagnosis of hepatocellular carcinoma of any size and at any stage in adults with chronic liver disease, in a surveillance programme or in a clinical setting.
2. To assess the diagnostic accuracy of CEUS for the diagnosis of resectable hepatocellular carcinoma in people with chronic liver disease and identify potential sources of heterogeneity in the results.
We used standard, extensive Cochrane search methods. The last date of search was 5 November 2021.
We included studies assessing the diagnostic accuracy of CEUS for the diagnosis of hepatocellular carcinoma 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.
We used standard Cochrane methods to screen studies, extract data, and assess the risk of bias and applicability concerns, using the QUADAS-2 checklist. We used the bivariate model and provided estimates of summary sensitivity and specificity. We assessed the certainty of the evidence using GRADE. We presented uncertainty-of-the-accuracy estimates using 95% confidence intervals (CIs).
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 characteristics of the participants.
– CEUS for hepatocellular carcinoma 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 hepatocellular carcinoma: 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. The sensitivity analyses, including only studies with clearly prespecified positivity criteria and only studies in which the reference standard results were interpreted with no knowledge of the results about the index test, showed no differences in the results.