Hepatocellular carcinoma: Options for diagnosing and managing a deadly disease
ABSTRACTHepatocellular carcinoma (HCC) is an important cause of death in patients with liver disease, and its incidence appears to be rising in the United States. Because early diagnosis improves the chances of survival, it is important to identify patients who would benefit from surveillance. Once HCC is suspected on surveillance, noninvasive diagnostic tests are available to make an accurate diagnosis. Treatment should be individualized, based on the characteristics of the tumor and the degree of liver dysfunction.
KEY POINTS
- Surveillance for HCC is indicated in all patients with cirrhosis, regardless of the cause of the cirrhosis.
- Liver biopsy is not needed to make the diagnosis if the findings on four-phase multidetector computed tomography or dynamic contrast-enhanced magnetic resonance imaging are typical of HCC (arterial hyperenhancement with venous-phase or delayed-phase washout).
- Many treatments are available, including surgical resection, liver transplantation, ablative therapy, perfusion-based therapy, chemotherapy, and palliative therapy.
Surveillance methods
The tests most often used in surveillance for HCC are serum alpha-fetoprotein levels and liver ultrasonography.
Serum alpha-fetoprotein levels by themselves have not been shown to be useful, whereas the combination of alpha-fetoprotein levels and ultrasonography has been shown to reduce the death rate when used for surveillance in a randomized trial.12 A 2012 study reported that the combination of alpha-fetoprotein testing and ultrasonography had a higher sensitivity (90%) than ultrasonography alone (58%), but at the expense of a lower specificity.13
Alpha-fetoprotein has a low sensitivity (ie, 54%) for HCC.14 Tumor size is one of the factors limiting the sensitivity of alpha-fetoprotein, 14 and this would imply that this test may not be helpful in detecting HCC at an early stage. Alpha-fetoprotein L3, an isoform of alpha-fetoprotein, may be helpful in patients with alpha-fetoprotein levels in the intermediate range, and it is currently being studied.
Liver ultrasonography is operator-dependent, and it may not be as accurate in overweight or obese people.
Computed tomography (CT) and magnetic resonance imaging (MRI) are not recommended for surveillance. Serial CT poses risks of radiation-induced damage, contrast-related anaphylaxis, and renal failure, and MRI is not cost-effective and can also lead to gadolinium-induced nephrogenic systemic fibrosis in patients with renal failure.
Currently, the American Association for the Study of Liver Diseases9 recommends ultrasonography only, every 6 months, for surveillance for HCC. However, it may be premature to conclude that alpha-fetoprotein measurement is no longer required for surveillance, and if new data emerge that support its role, it may be reincorporated into the guidelines.
DIAGNOSING HEPATOCELLULAR CARCINOMA
Lesions larger than 1 cm on ultrasonography
The finding of a liver lesion larger than 1 cm on ultrasonography during surveillance warrants further testing.
Noninvasive testing with four-phase multidetector CT or dynamic contrast-enhanced MRI is the next step. Typical findings on either of these imaging studies are sufficient to make a diagnosis of HCC, as they have a high specificity and positive predictive value.15 Arterial hyperenhancement with a venous-phase or delayed-phase washout of contrast medium confirms the diagnosis (Figure 2).9 If one of the two imaging studies is typical for HCC, liver biopsy is not needed.
Other imaging studies, including contrast-enhanced ultrasonography, have not been shown to be specific for this diagnosis.16
Liver biopsy is indicated in patients in whom the imaging findings are atypical for HCC.9,17 Biopsy has very good sensitivity and specificity for cancer, but false-negative findings do occur.18 Therefore, a negative biopsy does not entirely exclude HCC. In this situation, patients should be followed by serial ultrasonography, and any further growth or change in character should be reevaluated.
Lesions smaller than 1 cm
For lesions smaller than 1 cm, the incidence of HCC is low, and currently available diagnostic tests are not reliable.15,19 Lesions of this size should be followed by serial ultrasonography every 3 to 4 months until they either enlarge to greater than 1 cm or remain stable at 2 years.9 If they remain stable at the end of 2 years, regular surveillance ultrasonography once every 6 months can be continued.
CURATIVE AND PALLIATIVE THERAPIES
Therapies for HCC (Table 2) can be divided into two categories: curative and palliative.
Curative treatments include surgical resection, liver transplantation, and radiofrequency ablation. All other treatments are palliative, including transarterial chemoembolization and medical therapy with sorafenib.
The choice of treatment depends on the characteristics of the tumor, the degree of liver dysfunction, and the patient’s current level of function. The Barcelona Clinic Liver Cancer classification is widely used in making these decisions, as it incorporates both clinical features and tumor stage.9 Figure 3 shows a simplified management algorithm.
SURGICAL RESECTION
Surgical resection is the preferred treatment for patients who have a solitary HCC lesion without cirrhosis.9 It is also indicated in patients with well-compensated cirrhosis who have normal portal pressure, a normal serum bilirubin level, and a platelet count greater than 100 × 109/L.20,21 In such patients, the 5-year survival rate is about 74%, compared with 25% in patients with portal hypertension and serum bilirubin levels higher than 1 mg/dL.21
Surgical resection is not recommended for patients with decompensated cirrhosis, as it can worsen liver function postoperatively and increase the risk of death.19,20 In Western countries, where cirrhosis from hepatitis C is the commonest cause of HCC, most patients have poorly preserved hepatic function at the time of diagnosis, leaving only a minority of patients as candidates for surgical resection.
After surgical resection of HCC, the recurrence rate can be as high as 70% to 80% at 5 years.22,23 Studies have consistently found larger tumor size and vascular invasion to be factors that predict recurrence.24,25 Vascular invasion was also found to predict poor survival after recurrence.24 Studies have so far not shown any conclusive benefit from post-surgical adjuvant chemotherapy in reducing the rate of recurrence of HCC.26,27
How to treat recurrent HCC after surgical resection has not been clearly established. Radiofrequency ablation, transarterial chemoembolization, repeat resection, and liver transplantation have all improved survival when used alone or in combination.28 However, randomized controlled trials are needed to establish the effective treatment strategy and the benefit of multimodal treatment of recurrent HCC.
