Hepatocellular carcinoma is the most common form of primary liver cancer in the United States with three-quarters of primary and secondary liver cancer cases. The trend for both estimated new and instances of death is increasing in parallel to the geographical underlying chronic liver disease or cirrhosis etiology.
Hepatocellular carcinoma develops from chronic liver disease caused by multiple risk factors. Hepatocellular carcinoma has a strong association with chronic hepatitis B and C virus (HBV and HCV) infections. Chronic hepatitis infections with other associated risk factors, including coinfection hepatitis D (HDV), alcohol consumption, cigarette smoking, may have a higher liver cancer risk.  Patients with chronic hepatitis of any cause (e.g., hemochromatosis or alpha-1 antitrypsin deficiency) or cryptogenic cirrhosis have an increased risk of Hepatocellular carcinoma. Environmental exposure to aflatoxin, contaminated water with blue-green algal toxin and betel nut contribute to hepatocellular carcinoma. Ethanol abuse and metabolic syndrome have been linked to liver cancer with persistent liver damage leading to steatosis, steatohepatitis, cirrhosis, and ultimately hepatocellular carcinoma. Protective factors of hepatocellular carcinoma have been associated with statins and coffee. Treatment of chronic hepatitis, metabolic syndrome, iron removal, alcohol cessation to prevent the development of cirrhosis may reduce Hepatocellular carcinoma development. HBV vaccination and HCV screening can reduce hepatocellular carcinoma incidence worldwide. Hepatocellular carcinoma surveillance guidelines are indicated for high-risk populations and vary per societies/institutions and usually recommend including ultrasonography (US), with or without alpha-fetoprotein (AFP), every 6 to 12 months.
Hepatocellular carcinoma is the fifth most common cancer occupying second place in cancer deaths worldwide. The majority of Hepatocellular carcinoma cases are due to chronic viral B and C hepatitis infections. In the United States, the Surveillance, Epidemiology and End Results (SEER) Database reported an increased incidence rate of 3.1% per year. Men have an incidence of 11.5 per 100,000 compared to 3.9 in women. Hepatocellular carcinoma death rates have also increased by 2.8% for males and 3.4% for females, per year. Hepatocellular carcinoma commonly presents in the older population after longstanding chronic liver disease. Regional and race/ethnical variations of hepatocellular carcinoma are dependent on the exposure risk factor. HBV is more prevalent worldwide, and HCV accounts for 30% of cases in the United States. HCV has a five-fold increased prevalence among individuals born in the United States between 1945 and 1965, raising their liver cancer-related mortality.
Although ngene sequencing studies have described multiple genes associations with hepatocellular carcinoma, most of the initiating genetic events that incite hepatocellular carcinoma remain unknown. Genomic instability, including chromosomal or single nucleotide polymorphism, could be the force of tumorigenesis in liver cancer. Recurrently somatic mutated genes (e.g., TERT promoter, TP53, CTNNB1, ARID1A, FGF) with implicated signaling pathways (JAK/STAT, WntB-catenin, PI3K-AKT-mTOR) have been identified as major drivers of the development of hepatocellular carcinoma. No potential driver or targeted therapy has emerged likely due to the genomic heterogeneity of hepatocellular carcinoma. The classical prognostic biomarkers of hepatocellular carcinoma include Ki-67 protein expression and TP53 gene mutation, which has repeatedly been demonstrated to correlate with poor prognosis.
The most important pathologic issue is the distinction between fibrolamellar variant with tumor encapsulation that presents in younger individuals. These lesions are more likely to be resectable, less frequently related to viral infection or cirrhosis, accompany normal AFP levels and an overall better prognosis, or the traditional hepatocellular cancer presenting in the older population with a chronic disease and less than 25% resectable cases.
Most patients are initially asymptomatic from hepatocellular carcinoma but often present with related symptoms due to chronic liver disease. Patients may complain of upper abdominal discomfort and distention, weight loss, fever, poor appetite, early satiety, diarrhea and other symptoms. Any acute liver decompensation with the development of ascites, encephalopathy, jaundice, or hematemesis should raise a suspicion for hepatocellular carcinoma. Patients with hepatocellular carcinoma may rarely present with unusual symptoms due to a paraneoplastic syndrome presentation that may include hypoglycemia, erythrocytosis, hypercalcemia, or severe watery diarrhea.
Physical examination may reveal signs of chronic liver disease or cirrhosis stigmata, including hepatomegaly, splenomegaly, ascites, jaundice, or engorgement of collateral veins (caput medusa, also known as the palm tree sign, which are dilated superficial epigastric veins) which could be a sign of cirrhosis.
Patients with suspected or confirmed hepatocellular carcinoma will need general laboratory workup for further risk score stratification. Laboratory testing will help to evaluate the severity of liver disease including hypoalbuminemia, hyperbilirubinemia, and hypoprothrombinemia with the clinical inclusion of ascites and encephalopathy to classify according to the Child-Pugh assessment scale. The American Association for the Study of Liver Disease (AASLD) has issued diagnostic algorithms for solid liver lesions by size. US surveillance frequently identifies high-risk patients and is further characterized by dynamic contrasted-enhanced magnetic resonance imaging (MRI) or four-phase computer tomography (CT). Negative features for hepatocellular carcinoma on MRI should be followed by a serial ultrasound every three months. Biopsy for diagnosis is not required for patients with increased hepatocellular carcinoma risk when MRI is diagnostic (e.g., T2 signal intensity) or CT (e.g., arterial enhancement with washout). An AFP increase, especially above 500 mcg/L should raise suspicion for hepatocellular carcinoma. Other approved tumor markers not routinely used are Lens culinaris agglutinin-reactive AFP (AFP-L3) and Des-gamma-carboxy prothrombin (DCP); that in combination with AFP can have a 90% positive predictive value but can be missed in 9% of hepatocellular carcinoma patients. If the diagnosis remains unclear, a biopsy may be appropriate. Diagnosed hepatocellular carcinoma will require further staging imaging with CT to evaluate for metastasis.
Liver cancer has multiple proposed prognostic staging systems, but no single system is considered ideal. The most commonly used is the Barcelona Clinic Liver Cancer system (four stages A to D) that includes a more robust evaluation of the performance status evaluation (0, 1, 2 or greater than 2), constitutional symptoms by the Child-Pugh stage (A, B, or C), and the Okuda system evaluation. The Okuda criteria include tumor size less than or greater than 50%, ascites clinically detectable or absent, albumin less than or greater than 3 mg/dL, bilirubin less than or greater than 3 mg/dL, assigning positive points that correlates with stages I, II, and III in untreated patients with median overall survival of (mOS) 8.3, 2.0, and 0.7 months, respectively. Barcelona Clinic Liver Cancer system is divided into the following:
Very early stage (0) and early stage (A) may be considered for resection or even liver transplant with a curative rate of 30% and 5-year survival 40% to 70%. After a complete resection for hepatocellular carcinoma, based upon the 2010 TNM (tumor, node, metastasis) staging system, five-year survival rates are Stage I (55%), Stage II (37%) and Stage III (16%). Patient with advanced disease may benefit from prognostic survival evaluation by calculating the Cancer of the Liver Italian Program (CLIP) score which sums points of each of the sub-scores (Child-Pugh stage, Tumor morphology uni-nodular versus multi-nodular and extension less than or greater than 50%, AFP less than or greater than 400, and portal vein thrombosis present or absent) with a mOS of 36, 22, 9, 7, and 3 months for patients in categories 0, 1, 2, 3, and 4 to 6, respectively.
The only proven curative approach in most patients is surgery (resection or transplant). Unfortunately, most patients are not candidates for surgery (70%). Resectable candidates have early hepatocellular carcinoma stage (less than IIIB and liver disease Child-Pugh stage A only). Resection can achieve relapse-free survival of 40% and 5-year OS of 90%, but the surgery carries a mortality rate of 5% to 10% in patients with cirrhosis. Transplant candidates are evaluated according to the Milan criteria (single tumor smaller than 5 cm or two to three tumors none exceeding 3 cm and no vascular invasion and/or extrahepatic spread) plus High MELD-Na score to ensure that available organs are directed to transplant candidates according to urgency. A liver transplant can achieve relapse-free survival of 80% and 4-year OS 75%. Waiting time for transplant may be months, and hence bridging therapies are performed (chemoembolization, radiofrequency ablation, or partial hepatectomy). Neoadjuvant therapy is not considered a standard of care and adjuvant therapy by the Adjuvant Treatment in the Prevention of Recurrence of Hepatocellular Carcinoma (STORM) (sorafenib) trial showed no benefit. Patients should be offered enrollment in clinical trials when available. If chronic viral hepatitis is present, treatment should be included in the multidisciplinary discussion.
For non-surgical candidates, a variety of local treatment options could be offered. Radiofrequency ablation could offer complete remission in 80% of cases (tumors less than 3 cm and 50% of tumors larger than 3 cm). Radiofrequency ablation can be performed in tumors smaller than 4 cm and Child-Pugh A/B liver disease severity. Transarterial chemoembolization is most often used for large or multifocal disease (larger than 5 cm or more than three tumors) not suitable for local ablation with early liver disease. Transarterial chemoembolization offers a survival benefit but only in selected patients with tumors that are smaller than 2 cm and CLIP1 and those cohorts of patients have a median of survival of 50 months. Transarterial chemoembolization absolute contraindications include portal vein thrombosis, encephalopathy, and biliary obstruction and other relative limiting factors. Transarterial chemoembolization plus radiofrequency ablation may be better according to a retrospective analysis with a five-year OS of 44% compared to 20% with only transarterial chemoembolization or 28% with only radiofrequency ablation. Percutaneous ethanol injection [PEI] is considered for poor Child-Pugh B/C liver stage. Other thermal ablation therapies are cryoablation or microwave. Multiple radiation therapy modalities are available (EBRT-SBRT-IMRT-Cyberknife-(90Y or 131I) radioembolization-Proton Beam) without clear guidelines or consensus.
Systemic therapy for hepatocellular carcinoma patients with advanced disease is single-agent multikinase inhibitor which is sorafenib and no role for chemotherapy.
The Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol (SHARP) study, a multicenter, phase 3, double-blind, placebo-controlled trial with 602 patients with unresectable hepatocellular carcinoma compared sorafenib (at a dose of 400 mg twice per day) to placebo and results revealed time to progression of 5.5 months versus 2.8 months and mOS of 10.7 months versus 7.9 months, in favor of sorafenib and statistically significant for both outcomes. Of note, the SHARP study only included hepatocellular carcinoma patients with Child-Pugh A, and a subgroup analysis showed HCV positive patients had a longer median survival of 14 months. Sorafenib was for long the only approved hepatocellular carcinoma option in the advanced disease setting until the Regorafenib After Sorafenib in Patients with Hepatocellular Carcinoma (RESORCE) study with regorafenib (a multikinase inhibitor) revealed positive results. This was a randomized, double-blind, placebo-controlled, multicenter phase 3, that enrolled 573 patients with Hepatocellular carcinoma whose disease has progressed after treatment with sorafenib greater than 400 mg/day and CP-A (97%). The trial compared 160 mg regorafenib once daily for 3 weeks on and 1 week off, or best supportive care plus placebo, with 28 days cycles. The results revealed a statistically significant median of survival of 10.6 months in the regorafenib group when compared with 7.8 months in the control arm. The Regorafenib After Sorafenib in Patients with Hepatocellular Carcinoma (RESORCE) study included 87% of patients with hepatocellular carcinoma and a Barcelona Clinic Liver Cancer system stage C. Another option for patients with hepatocellular carcinoma whose disease progressed on sorafenib therapy is ramucirumab (a recombinant monoclonal antibody which inhibits vascular endothelial growth factor receptor 2). In the REACH study, a median of survival was improved with ramucirumab (9.2 months) compared with placebo (7.6 months) but did not reach statistical significant (p = 0.1391). Nonetheless, a sub-analysis demonstrated a significant median of survival benefit for patients with an AFP level of 400 ng/mL or greater and Child-Pugh A for 7.8 months for ramucirumab compared with 4.2 months for placebo (HR, 0.67; 95% CI; 0.51, 0.90). REACH-2 study of ramucirumab in patients with advanced hepatocellular carcinoma with underlying Child-Pugh A cirrhosis and baseline AFP levels of 400 ng/mL or more is currently recruiting to evaluate this hypothesis. Ongoing clinical trials and future therapies are focused on immunotherapy (nivolumab and durvalumab) and small molecule tyrosine kinase inhibitors (cabozantinib).
Managing liver cancer requires a multidisciplinary team that includes an oncologist, hepatobiliary surgeon, pathologist, radiologist, gastroenterologist, palliative care nurses, dietitian, and an internist. Unfortunately, the majority of patients are not candidates for surgery. Many local treatments are available but they only increase life span by 6-18 months. Biological agents are available but most are prohibitively expensive and do not affect survival significantly. Most patients may benefit from palliative care and it is important to involve the team early on. The surgeon and radiologist may be consulted to manage some of the complications of metastatic liver disease. The overall outlook for patients with liver cancer is very poor.
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