Hepatocellular Carcinoma

Hepatocellular carcinoma is usually a complication of cirrhosis.

The presence of HBV increases risk of HCC by > 100-fold among HBV carriers. Incorporation of HBV-DNA into the host’s genome may initiate malignant transformation, even in the absence of chronic hepatitis or cirrhosis.

Other disorders that cause hepatocellular carcinoma include cirrhosis due to chronic hepatitis C virus (HCV) infection, hemochromatosis, and alcoholic cirrhosis. Similar to HBV infection, HCC can develop in patients with noncirrhotic nonalcoholic steatohepatitis. Patients with cirrhosis due to other conditions are also at increased risk.

Environmental carcinogens may play a role; eg, ingestion of food contaminated with fungal aflatoxins is believed to contribute to the high incidence of HCC in subtropical regions.

Most commonly, patients are asymptomatic and tumors are diagnosed on routine screening. Patients with advanced HCC may present with abdominal pain, weight loss, right upper quadrant mass, and unexplained hepatic deterioration. Fever may occur. In a few patients, the first manifestation of HCC is bloody ascites, shock, or peritonitis, caused by hemorrhage of the tumor. Occasionally, a hepatic friction rub or bruit develops.

Occasionally, systemic metabolic complications, including hypoglycemia, erythrocytosis, hypercalcemia, and hyperlipidemia, occur. These complications may manifest clinically.

• Alpha-fetoprotein (AFP) measurement

• Imaging (CT, ultrasound, or MRI)

Clinicians suspect hepatocellular carcinoma (HCC) if

• Unexplained decompensation of chronic liver disease develops.

• An imaging test detects an incidental liver mass, especially if patients have cirrhosis.

However, screening programs enable clinicians to detect many HCCs before symptoms develop.

Diagnosis is based on AFP measurement and an imaging test. In adults, AFP signifies dedifferentiation of hepatocytes, which most often indicates HCC; 40 to 65% of patients with the cancer have high AFP levels (> 400 ng/mL [400 mcg/L]). High levels are otherwise rare, except in teratocarcinoma of the testis, a much less common tumor. Lower values are less specific and can occur with hepatocellular regeneration (eg, in hepatitis). Other blood tests, such as AFP-L3 (an AFP isoform) and des-gamma–carboxyprothrombin (DCP), are biomarkers for risk stratification of hepatocellular carcinoma. AFP-L3 and DCP have insufficient sensitivity (40 to 62%) to detect early-stage HCC when used alone; however, these biomarkers offer additive diagnostic value to AFP and imaging and may help clarify etiology of indeterminate lesions given their specificity (81 to 90%) for HCC (1).

Depending on local preferences and capabilities, the first imaging test may be contrast-enhanced CT, ultrasound, or MRI. Contrast imaging must be ordered as a triple-phase protocol because the third, or delayed-contrast phase, is essential for a radiographic diagnosis of HCC.

Radiographic criteria known as the LI-RADS (liver imaging reporting and data system) are used to diagnosis HCC with high sensitivity with key radiographic features, including presence of arterial hyperenhancement, pseudocapsule around the lesion, washout of contrast on delayed-phase imaging, and interval growth of the lesion from the prior scan (2).

If imaging shows characteristic findings and AFP is elevated, the diagnosis is clear. However, rarely, liver biopsy, often guided by ultrasound or CT, is indicated for definitive diagnosis in equivocal cases.

• Transplantation if tumors are within the Milan criteria (1 tumor < 5 cm or 3 tumors < 3 cm without vascular invasion and alpha-fetoprotein < 500 mcg/L).

• Surgical resection in selected patients.

• Sometimes, liver-directed ablative therapy and systemic chemotherapy/immunotherapy

Treatment of hepatocellular carcinoma (HCC) depends on its stage (1) and the underlying severity of liver disease.

The Milan criteria (single tumors < 5 cm or ≤ 3 tumors that are all ≤ 3 cm and that are limited to the liver, without microvascular invasion, and if AFP is < 500 mcg/L) are used to identify patients with HCC who are good candidates for liver transplantation (2). Transplantation for HCC can be curative and appears to result in as good a prognosis as liver transplantation performed for noncancerous disorders. The American Association for the Study of Liver Diseases (AASLD) 2023 guidelines use the Milan criteria for selection of patients for liver transplantation (3).

Clinical Calculators

Milan Criteria in Liver Transplantation for Hepatocellular Carcinoma

In selected patients with singular tumors, no vascular invasion, and no portal hypertension, surgical resection is potentially curative, with 5-year survival rates > 60% (4, 5).

If the tumor is large (> 5 cm), is multifocal, has invaded the portal vein, or is metastatic (ie, stage III or higher), transplantation is not an immediate option. However, with a combination of liver-directed therapy (eg, transhepatic arterial chemoembolization [TACE] and systemic chemotherapy), a carefully selected subset of patients can be downstaged to Milan criteria and may then be eligible for reconsideration for liver transplantation. Management of advanced HCC is best if discussed by a multidisciplinary tumor board.

Ablative treatments (eg, transhepatic arterial chemoembolization [TACE], yttrium-90 microsphere embolization [selective internal radiation therapy, or SIRT], drug-eluting bead transarterial embolization, radiofrequency ablation) provide palliation and slow tumor growth; they are used when patients are awaiting liver transplantation. For small tumors < 2 cm, radiofrequency ablation (RFA) is potentially curative.

Systemic therapies, including immunotherapy, improve HCC outcomes. For advanced HCCs, traditional systemic therapy was with sorafenib, which only modestly improves outcomes (, including immunotherapy, improve HCC outcomes. For advanced HCCs, traditional systemic therapy was with sorafenib, which only modestly improves outcomes (6). Several newer chemotherapy agents provide more prolonged survival or cause fewer adverse effects than sorafenib; these include lenvatinib, regorafenib, and immunotherapy such as atezolizumab plus bevacizumab or tremelimumab plus durvalumab. Hence, these agents are now preferred first-line therapies over sorafenib. ). Several newer chemotherapy agents provide more prolonged survival or cause fewer adverse effects than sorafenib; these include lenvatinib, regorafenib, and immunotherapy such as atezolizumab plus bevacizumab or tremelimumab plus durvalumab. Hence, these agents are now preferred first-line therapies over sorafenib.

Progression-free survival is higher with lenvatinib than with sorafenib and is an alternate first-line therapy. Progression-free survival is higher with lenvatinib than with sorafenib and is an alternate first-line therapy.

Atezolizumab and bevacizumab are available as combination therapy for patients with advanced HCC who have not received prior systemic therapy. Atezolizumab is a humanized monoclonal antibody immune checkpoint inhibitor (PD-L1), whereas bevacizumab is a monoclonal antibody targeting vascular endothelial growth factor (VEGF). Increasing evidence supports these medications as first-line therapy for systemic treatment in HCC (Atezolizumab and bevacizumab are available as combination therapy for patients with advanced HCC who have not received prior systemic therapy. Atezolizumab is a humanized monoclonal antibody immune checkpoint inhibitor (PD-L1), whereas bevacizumab is a monoclonal antibody targeting vascular endothelial growth factor (VEGF). Increasing evidence supports these medications as first-line therapy for systemic treatment in HCC (7, 8), with better overall survival and similar adverse event rates with bevacizumab/atezolizumab than sorafenib, lenvatinib, or nivolumab (), with better overall survival and similar adverse event rates with bevacizumab/atezolizumab than sorafenib, lenvatinib, or nivolumab (8).The 2020 American Society of Clinical Oncology guidelines and the 2023 American Association and Study of Liver Disease HCC guidelines recommend use of atezolizumab and bevacizumab or tremelimumab plus durvalumab as first-line therapy for patients with Child-Pugh class A liver disease and Eastern Cooperative Oncology Group (ECOG) status 0–1 ().The 2020 American Society of Clinical Oncology guidelines and the 2023 American Association and Study of Liver Disease HCC guidelines recommend use of atezolizumab and bevacizumab or tremelimumab plus durvalumab as first-line therapy for patients with Child-Pugh class A liver disease and Eastern Cooperative Oncology Group (ECOG) status 0–1 (9, 10).

Because of an increased risk of bleeding with atezolizumab and bevacizumab, patients should have variceal ligation prior to initiation of therapy.  Immunotherapy is not recommended in patients with HCC recurrence post transplant because stimulation of the host immune system may lead to higher rates of rejection (Because of an increased risk of bleeding with atezolizumab and bevacizumab, patients should have variceal ligation prior to initiation of therapy.  Immunotherapy is not recommended in patients with HCC recurrence post transplant because stimulation of the host immune system may lead to higher rates of rejection (11). A new regimen combines tremelimumab, an anticytotoxic T-lymphocyte–protein 4 (or "CTLA-4") plus durvalumab (an anti-PD-L1). In the Himalaya trial, tremelimumab plus durvalumab improved survival more than prior first-line sorafenib monotherapy (). A new regimen combines tremelimumab, an anticytotoxic T-lymphocyte–protein 4 (or "CTLA-4") plus durvalumab (an anti-PD-L1). In the Himalaya trial, tremelimumab plus durvalumab improved survival more than prior first-line sorafenib monotherapy (12). This combination is available for patients with unresectable HCC and is often used as an alternative for patients with Child-Pugh class A cirrhosis and excellent performance status who cannot receive bevacizumab. ). This combination is available for patients with unresectable HCC and is often used as an alternative for patients with Child-Pugh class A cirrhosis and excellent performance status who cannot receive bevacizumab.

Use of vaccine against HBV eventually decreases the incidence, especially in endemic areas. Preventing the development of cirrhosis of any cause (eg, via treatment of chronic hepatitis C, early detection of hemochromatosis, prevention and management of metabolic syndrome, or management of alcohol use disorder) can also have a significant effect.