Hepatocellular Cancer (Suspected)

Risk factors for hepatocellular carcinoma

• Cirrhotic patients (AASLD)
• Non-cirrhotic patients with active chronic hepatitis B infection
  • From Asian background
  • 40-50 years of age (AASLD)
• Non-cirrhotic patients with chronic hepatitis C and advanced liver fibrosis [EASL 3 - lesser grade of recommendation]
• Cirrhotic patients due to hepatitis B or C [APASL, 4 JSH, 5]
• Patients with active chronic hepatitis B or C [JSH, 5]
• Patients with a family history of HCC
• Non-viral aetiology of liver cirrhosis, e.g: [JSH, 5]
  • Alcoholic cirrhosis
  • Haemachromatosis
  • Primary biliary cirrhosis
  • Auto-immune hepatitis
  • Alpha-1 antitrypsin deficiency
  • Non-alcoholic steatohepatitis
• Evidence for surveillance in patients with the above conditions without cirrhosis is scanty 5

Current existing international guidelines

• Internationally, there are several consensus-based guidelines for the investigation of suspected HCC, including the American Association for the Study of Liver Disease (AASLD), 1 the European Association for the Study of the Liver (EASL), 2 the Asian Pacific Association for the Study of the Liver (APASL), 3 the Japan Society of Hepatology, 4 and the Italian Association for the Study of the Liver. 5 While differences exist among these, it is possible to discern many similarities. The AASLD and Italian guidelines, divide detected lesions into 1cm, whereas the EASL utilizes <1cm, 1-2cm and >2cm
• As the difference in recommendations between the latter two groups of the EASL guidelines is minor, this document has used the simpler categories of 1cm

Typical vascular pattern of HCC

• Most HCCs are hypervascular compared to the surrounding liver reflecting the predominant vascular supply to these lesions from branches of the hepatic artery, rather than the predominant portal venous supply of ‘normal’ liver
• Arterial enhancement followed by washout is considered the typical vascular pattern of HCC. This can be demonstrated on either 4-phase multi-detector CT or dynamic contrast-enhanced MRI or CEUS 1,6
• During the arterial phase, HCC enhances more intensely than the surrounding liver while during the venous phase HCC enhances less than the surrounding liver (known as 'wash-out')
• During the delayed phase, the 'wash-out' persists; sometimes the 'wash out' is only present during the delayed phase
• A recent systematic review indicated that for the evaluation of focal liver lesions, CT, MRI and CEUS had similar sensitivities for HCC 7
• In a further recent meta-analysis, comparing CT and MRI, MR imaging showed higher per-lesion sensitivity than multi-detector CT and was therefore recommended to be the preferred imaging modality for the diagnosis of HCCs in patients with chronic liver disease 8

• Ultrasound contrast agents (‘microbubbles’) comprise an albumen or phospholipid shell containing a stable perfluorocarbon or sulfur hexafluoride gas. They are predominantly blood-pool agents, the encapsulated microbubbles being small enough to pass through pulmonary and systemic circulations after IV injection and durable enough to re-circulate for several minutes
• Ultrasound contrast agents are mainly based on the dynamic assessment of macro- and micro-vasculature of organs and their pathologies. They are, in principle, comparable to the use of contrast agents for CT and MRI with the added advantage of the capability for imaging continuously during the passage of the contrast agent, thereby obtaining what is effectively a dynamic real-time ultrasound angiogram with greater temporal resolution than contrast-enhanced CT or MRI. In addition, quantitative assessment of contrast uptake can be measured by generating Time-Intensity Curves
• CEUS was endorsed by AASLD in its 2005 guidelines 9 but removed from the list of diagnostic techniques in 2011, 1 partly due to lack of availability of ultrasound contrast in the USA and partly due to false-positive diagnoses in patients with intrahepatic cholangiocarcinoma (ICC). ICC’s may show peripheral ring enhancement, difficult to distinguish from small HCCs. In addition, washout of ICCs may mimic HCC washout; some small HCCs may fail to show washout. Nevertheless, controversy persists, since CEUS typical for HCC has a PPV of >95% 10 and it is suggested that the CEUS pattern is enough to establish whether malignancy is present. 11-14 Only 1-3% of newly developed tumours in cirrhosis are ICCs 15
• CEUS improves diagnostic performance in differentiating HCCs from non-neoplastic nodules in cirrhotic patients compared with baseline ultrasound 16 and, if available, can be recommended as the first diagnostic step when liver lesions are detected on ultrasound surveillance, 17 especially as the procedure can be performed immediately without the need for further attendance or preparation and may therefore avoid further and more expensive examinations 18

• CT and MRI are performed before and after intravenous contrast agents in multiple phases of enhancement. It is usual practice to acquire images in the arterial, portal venous and delayed post-contrast phases. In recent years agents have become available for MRI that exhibit a delayed hepatobiliary phase 19
• Two recent systematic reviews and meta-analyses have been published examining the performance of available modaliites for diagnosis of HCC 7,8 with the following findings from these studies and others
  • For the evaluation of focal liver lesions, the sensitivites of CT, MR and CEUS are similar 7
  • The sensitivity on a per lesion basis was higher for MRI than CT 8
  • Specificity of CT and MRI ranged from 84-94% 7,8
  • MRI using a gadolinium contrast agent that has a delayed hepatobiliary agent (a liver-specific agent) is very useful for the diagnosis of HCC 20,21 superior to MRI using a gadolinium contrast agent with only an extracellular phase 7,8,22 and is superior to CT 23
  • MRI should be the preferred imaging modality for the diagnosis of HCC in patients with chronic liver disease 8, preferably with a liver-specific contrast agent
• Diffusion Weighted MRI
  • The addition of Diffusion Weighted Imaging (DWI) to other MRI acquisitions has shown mixed results in distinguishing HCC from non-neoplastic cirrhotic nodules and other benign lesions 22,24-27

• CT and MRI are performed before and after intravenous contrast agents in multiple phases of enhancement. It is usual practice to acquire images in the arterial, portal venous and delayed post-contrast phases. In recent years agents have become available for MRI that exhibit a delayed hepatobiliary phase 19
• Two recent systematic reviews and meta-analyses have been published examining the performance of available modaliites for diagnosis of HCC 7,8 with the following findings from these studies and others
  • For the evaluation of focal liver lesions, the sensitivites of CT, MR and CEUS are similar 7
  • The sensitivity on a per lesion basis was higher for MRI than CT 8
  • Specificity of CT and MRI ranged from 84-94% 7,8
  • MRI using a gadolinium contrast agent that has a delayed hepatobiliary agent (a liver-specific agent) is very useful for the diagnosis of HCC 20,21 superior to MRI using a gadolinium contrast agent with only an extracellular phase 7,8,22 and is superior to CT 23
  • MRI should be the preferred imaging modality for the diagnosis of HCC in patients with chronic liver disease 8, preferably with a liver-specific contrast agent
• Diffusion Weighted MRI
  • The addition of Diffusion Weighted Imaging (DWI) to other MRI acquisitions has shown mixed results in distinguishing HCC from non-neoplastic cirrhotic nodules and other benign lesions 22,24-27

• In the appropriate clinical context (patient at high risk of HCC) the typical radiological appearances of HCC (arterial enhancement and delayed wash-out) have very high specificity (almost 100%) , and therefore biopsy in this situation is rarely necessary 13,28
• Biopsy is required when the radiological appearances are non-diagnostic
• The accuracy for early HCC is approximately 90% 29
• Immediate complications include post-procedural pain and haemorrhage. The risk of major complications is 0.05% with a mortality of 0.01% 30
• A delayed complication is needle track seeding with tumour. A meta-analysis found the incidence to be 2.7% overall with a median time to seeding of 17 months 31

Hepatocellular Cancer (surveillance)