Hepatocellular carcinoma (HCC) is a primary malignancy of the liver (see the image below) that occurs predominantly in patients with underlying chronic liver disease and cirrhosis. However, up to 25% of patients have no history of cirrhosis or risk factors for it.
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Large hepatocellular carcinoma. Image courtesy of Arief Suriawinata, MD, Department of Pathology, Dartmouth Medical School.
The incidence of HCC has been rising worldwide over the last 20 years and is expected to increase until 2030 in some countries, including the United States.[1] The incidence of HCC is highest in Asia and Africa, where the endemic high prevalence of hepatitis B and hepatitis C strongly predisposes to the development of chronic liver disease and subsequent development of HCC.
Current international vaccination strategies for hepatitis B virus (HBV), and advances in the management of hepatitis C virus (HCV) infections, promise to have a major impact on the incidence of HCC, but their benefit will be realized slowly because of the very long latency period—20-30 years—from hepatic damage to HCC development.
Meanwhile, however, there is a growing problem with cirrhosis due to nonalcoholic fatty liver disease (NAFLD), specifically nonalcoholic steatohepatitis (NASH). NASH, which typically develops in the setting of obesity, type 2 diabetes, dyslipidemia, and hypertension, appears to lead the list of risk factors for HCC in the United States.[2, 3]
The presentation of HCC has evolved significantly over the past few decades. Whereas in the past, patients with HCC generally presented at an advanced stage, with right-upper-quadrant pain, weight loss, and signs of decompensated liver disease, HCC is now increasingly recognized at a much earlier stage as a consequence of the routine screening of patients with known cirrhosis, using ultrasonography with or without serum alpha-fetoprotein (AFP) measurements.
The diagnosis of HCC can often be established on the basis of noninvasive imaging, without biopsy confirmation. Even when biopsy is needed, imaging is usually required for guidance.[4] Laboratory evaluation of patients with newly diagnosed HCC should include testing to determine the severity of the underlying liver disease and to elucidate the etiology of the underlying disease, such as the following:
CBC
Electrolytes
Liver function tests
Coagulation studies
AFP determination
See Workup for more information.
Liver transplantation remains the best option for patients with HCC. Unfortunately, the supply of good-quality deceased-donor organs is limited. Thus, other treatments, including resection, radiofrequency ablation (RFA), and, potentially, systemic therapy with sorafenib (or, if sorafenib fails, with regorafenib, nivolumab, lenvatinib, pembrolizumab, cabozantinib, or ramucirumab), should be used to bridge patients to transplant or to delay recurrence if possible. See Treatment.
For patient education resources, see Hepatitis, the Cirrhosis of the Liver Directory, and the Liver Cancer Directory.
A complete understanding of the surgical and interventional approach to the liver requires a comprehensive understanding of its anatomy and vascular supply.[5, 6] The liver is the largest internal organ, representing 2-3% of the total body weight in an adult. It occupies the right upper quadrant of the abdomen, surrounding the inferior vena cava, and attaches to the diaphragm and parietal peritoneum by various attachments that are commonly referred to as ligaments.
The vascular supply of the liver includes two sources of inflow that travel in the hepatoduodenal ligament, as follows:
Hepatic artery
Portal vein
The hepatic artery is generally derived from the celiac axis, which originates on the ventral aorta at the level of the diaphragm. Common variations include a replaced right hepatic artery, which originates from the superior mesenteric artery, a replaced left hepatic artery, which is derived from the left gastric artery, or a completely replaced common hepatic artery, which can originate from the superior mesenteric artery or the aorta. The hepatic artery supplies 30% of the blood flow to the normal liver parenchyma but greater than 90% to hepatic tumors, including both HCC and metastatic lesions.
The other major inflow vessel is the portal vein which carries 70-85% of the blood into the liver. The portal vein is confluence of the splenic vein and the superior mesenteric vein, which drain the intestines, pancreas, stomach, and spleen.
The primary venous drainage of the liver is through three large hepatic veins that enter the inferior vena cava adjacent to the diaphragm. The right hepatic vein is generally oval in shape, with its long axis in the line of the vena cava. The middle and left hepatic veins enter the inferior vena cava through a single orifice in about 60% of individuals. In addition, there are 10-50 small hepatic veins that drain directly into the vena cava.
The biliary anatomy of the liver generally follows hepatic arterial divisions. The common bile duct gives off the cystic duct and becomes the hepatic duct. The hepatic duct then divides into two or three additional ducts draining the liver. There is significant variation in the biliary anatomy, and thus, careful preoperative imaging is vital before any major hepatic resection.[5]
The vascular anatomy of the liver defines its functional segments. Bismuth synthesized existing knowledge and new insight into the anatomy of the liver.[7] Bismuth defined the right and left hemilivers, which are defined by a line connecting the gallbladder fossa and the inferior vena cava, roughly paralleling the middle hepatic vein that is slightly to the left.[7]
The right hemiliver (lobe) is divided into four segments (ie, 5, 6, 7, 8), each of which is supplied by a branch of the portal vein. The right hemiliver drains via the right hepatic vein. The left hemiliver (lobe) is composed of three segments (ie, 2, 3, 4). Segment 4 is the most medial and is adjacent to the middle hepatic vein. Segments 2 and 3 make up the left lateral section, are to the left of the falciform ligament, and drain via the left hepatic vein. Finally, segment 1 (caudate lobe) is located behind the porta hepatis and adjacent to the vena cava.
In general, resection of the liver is divided into the following two main categories[8] :
Nonanatomic (wedge) resections are generally limited resections of a small portion of liver, without respect to the vascular supply
Anatomic resections involve removing one or more of the eight segments of the liver
Commonly, a right hepatectomy refers to the removal of segments 5-8, an extended right hepatectomy (right trisectionectomy) includes segments 4-8, a left hepatectomy includes segments 2-4, and an extended left hepatectomy (left trisectionectomy) includes segments 2, 3, 4, 5, and 8. A left lateral sectionectomy includes only segments 2 and 3. The caudate lobe can be removed as an isolated resection or as a component of one of the more extensive resections noted above. The extent of resection that can be tolerated is based upon the health of the remnant liver.
The pathophysiology of HCC has not been definitively elucidated and is clearly a multifactorial event. In 1981, after Beasley linked hepatitis B virus (HBV) infection to HCC development, the cause of HCC was thought to have been identified.[9] However, subsequent studies failed to identify HBV infection as a major independent risk factor, and it became apparent that most cases of HCC developed in patients with underlying cirrhotic liver disease of various etiologies, including patients with negative markers for HBV infection.
The disease processes, which result in malignant transformation, include a variety of pathways, many of which may be modified by external and environmental factors and eventually lead to genetic changes that delay apoptosis and increase cellular proliferation (see the image below).
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Hepatocellular carcinoma: pathobiology.
Inflammation, necrosis, fibrosis, and ongoing regeneration characterize the cirrhotic liver and contribute to HCC development. In patients with HBV, in whom HCC can develop in livers that are not frankly cirrhotic, underlying fibrosis is usually present, with the suggestion of regeneration. By contrast, in patients with hepatitis C virus (HCV) infection, HCC almost invariably presents in the setting of cirrhosis. This difference may relate to the fact that HBV is a DNA virus that integrates in the host genome and produces HBV X protein, which may play a key regulatory role in HCC development by promoting cell proliferation.[10] HCV is an RNA virus that replicates in the cytoplasm and does not integrate in the host DNA.
Some of the factors associated with the development of HCC in HBV-infected individuals are as follows[11] :
Elevated serum HBV DNA viral load
HBV genotype – Risk of HCC appears to be higher with HBV genotypes C and F
HBV mutations – Such as in preS, basic core promoter (BCP), or HBx regions
Host factors – Such as polymorphisms in KIF1B, HLA-DQ, STAT4, and GRIK1
HBV integration into growth-control genes (eg, TERT), pro-oncogenic genes, or tumor suppressor genes and the oncogenic activity of truncated HBx
Genomic sequencing studies for HCC have been performed, and potential driver genes in HCC have been catalogued. Frequently mutated genes identified in large-scale studies, and their functions, include the following[12] :
TERT - Maintaining telomere length
TP53 - Tumor suppressor
CTNNB1 - Transcriptional regulator
ARID1A, ARID2[13] - Chromatin remodeling
Whereas various nodules are frequently found in cirrhotic livers, including dysplastic and regenerative nodules, no clear progression from these lesions to HCC occurs. Prospective studies suggest that the presence of small-cell dysplastic nodules conveyed an increased risk of HCC, but large-cell dysplastic nodules were not associated with an increased risk of HCC. Evidence linking small-cell dysplastic nodules to HCC includes the presence of conserved proliferation markers and the presence of nodule-in-nodule on pathologic evaluation. This term describes the presence of a focus of HCC in a larger nodule of small dysplastic cells.[14]
Some investigators have speculated that HCC develops from hepatic stem cells that proliferate in response to chronic regeneration caused by viral injury.[15] The cells in small dysplastic nodules appear to carry markers consistent with progenitor or stem cells.
Tumors are multifocal within the liver in 75% of cases. Late in the disease, metastases may develop in the lung, portal vein, periportal nodes, bone, or brain (see images below).
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Hepatocellular carcinoma (HCC). Dilated collateral superficial abdominal veins in a 67-year-old man with cirrhosis, HCC, and portal vein occlusion.
In general, cirrhosis of any etiology is the major risk factor for HCC.[16, 17] About 80% of patients with newly diagnosed HCC have preexisting cirrhosis. Major causes of cirrhosis in the United States are nonalcoholic fatty liver disease (NAFLD), alcohol abuse, hepatitis C infection, and hepatitis B infection.[2]
Metabolic factors
Obesity and diabetes have been implicated as risk factors for HCC, most likely through the development of nonalcoholic steatohepatitis (NASH).[18, 19, 20] In the analysis of a large managed care database, the incidence of HCC linked to nonalcoholic fatty liver disease rose by 10 times from 0.03-0.46 per 100,000 between the years 1997 and 2005.[21] Currently, HCC non-alcoholic fatty liver disease has the greatest proportion of the burden of the main risk factors for HCC in the United States.[2, 3, 22]
Alcohol
In the United States, about 30% of HCC cases are thought to be related to excessive alcohol use. Chronic alcohol use (> 80 g/d or > 6-7 drinks per day) for more than 10 years increases risk of HCC 5-fold.
Approximately 50% of US HCC patients have histories of alcohol abuse. As many as 50% of alcoholics may have subclinical HCC at autopsy.
Alcohol abusers are at increased risk of HCC if they stop drinking alcohol, because heavy drinkers typically do not survive long enough to develop cancer. The risk of HCC in patients with decompensated alcoholic cirrhosis is approximately 1% per year.
Hepatitis B virus infection
The global prevalence of chronic hepatitis B virus (HBV) infection is estimated to be 257 million persons[23] ; chronic HBV infection is the most common cause of HCC worldwide. In the United States, about 20% of HCC cases are thought to be related to chronic HBV infection. Chronic HBV infection in the setting of cirrhosis increases the risk of HCC 1000-fold. The mechanism by which HBV causes HCC is thought to be from a combination of chronic inflammation and integration of the viral genome into the host DNA.
It is anticipated that with implementation of worldwide vaccination, the incidence of hepatitis B–related HCC will decrease. In a study from Taiwan, where universal hepatitis B vaccination in newborns and children was instituted in 1984, the average annual incidence of HCC per 100,000 children age 6-14 years declined from 0.70 in 1981-1986 to 0.36 in1990-1994 (P< 0.01).[24] By the end of 2018, hepatitis B vaccine for infants had been introduced nationwide in 189 countries; in addition,109 countries had introduced one dose of hepatitis B vaccine to newborns within the first 24 hours of life, and the global coverage was 42%.[25]
Hepatitis C virus infection
Hepatitis C virus (HCV) infection is a global pandemic affecting 71 million persons.[23] Approximately 80% of individuals infected with HCV develop chronic infection; this rate is higher than occurs with HBV infection.
HCV infection has become the most common cause of HCC in Japan and Europe, and it is also responsible for the recent increased incidence in the United States.[6] More than 3 million Americans have chronic HCV infection. In the United States, about 30% of HCC cases are thought to be related to HCV infection. Some 5-30% of individuals with HCV infection develop chronic liver disease. In this group, about 30% progress to cirrhosis, and in these, about 1-2% per year develop HCC.
The lifetime risk of HCC in patients with HCV is approximately 5%, appearing 30 years after infection. However, studies suggest that antiviral treatment of chronic HCV infections may significantly reduce the risk of HCC.[26]
Co-infection with HBV further increases the risk; many patients are co-infected with both viruses. Alcohol use in the setting of chronic HCV doubles the risk of HCC compared with HCV infection alone.
Hemochromatosis
Patients with hemochromatosis, especially in the presence of cirrhosis, are at an increased risk of developing HCC. About 30% of all iron-related deaths in hemochromatosis are due to HCC.
Aflatoxin
This hepatic carcinogen is a byproduct of fungal contamination of foodstuffs in sub-Saharan Africa and East and Southeast Asia. Aflatoxin causes DNA damage and mutations of the p53 gene. Humans are exposed through the ingestion of moldy foods found in susceptible grains. Dietary levels in endemic areas correlate directly with incidence of hepatocellular carcinoma.
In the United States, liver cancer is the most rapidly increasing cancer in both men and women, with incidence rates more than tripling since 1980; from 2006 to 2015, the rate increased by about 3% per year. For 2020, the American Cancer Society (ACS) estimates that 42,810 new cases of liver cancer (including intrahepatic bile duct cancers) will be diagnosed; approximately three-fourths of those will be HCC.[27]
Liver and intrahepatic bile duct cancers are the fifth most common cause of cancer deaths in men in the US, and the seventh most common in women. The ACS estimates that 30,160 deaths will occur from liver cancer in 2020.[27] According to Surveillance, Epidemiology, and End Results (SEER) program data, liver and intrahepatic bile duct cancers account for 2.4% of all new cancer cases but 5.2% of all cancer deaths.[28]
In the US, the median age at diagnosis is 64 years; 74% of cases occur in men. Incidence rates per 100,000 persons are 13.6 in men and 4.7 in women. Incidence rates increase with age; 36.4% of cases are in persons age 55-64 years and 27.6% in those 65-74 years.[28] Globally, the incidence of liver cancer among men and women who are younger than 30 years and those aged 30 to 59 years has declined, largely due to national hepatitis B virus (HBV) vaccination programs.[29, 30]
By racial and ethnic group, rates are highest in Hispanics, followed by Asians/Pacific Islanders, then American Indians/Alaska Natives, blacks, and whites.[28]
Worldwide, liver cancer was the fifth most common cancer and the third most common cause of cancer deaths in 2108, with an estimated 841,080 new cases and 781,631 deaths. The incidence was highest in East Asia, at 17.7 per 100,000 population (26.8 in males and 8.7 in females), followed by Micronesia, northern Africa, Southeast Asia, and Melanesia. The incidence was lowest in south-central Asia (2.5 per 100,000) and western Asia (4.0 per 100,000). By comparison, the incidence rate was 6.6 per 100,00 in North America and 5.3 per 100,000 in western Europe. Overall, the incidence rate of liver cancer is approximately three times higher in males than in females. Mortality figures mirror the incidence figures.[1]
In the United Kingdom, both the incidence and mortality rates of hepatocellular carcinoma (HCC) have risen dramatically. Rates of HCC increased from 2.7 per 100,000 in 1997 to 8.8 per 100,000 in 2016 in men, and from 0.8 per 100,000 to 2.2 per 100,000 in women.[31]
Steady declines in HCC mortality are predicted for East Asia. In contrast, Northern and Central Europe, North America, and Latin America are showing unfavorable trends.[32] According to an analysis of data from the Global Burden of Disease (GBD) Study, the number of liver cancer cases increased nearly threefold in older men and more than twofold in older women (aged 60 years or more) from 1990 to 2017. The increase consisted mainly of cases secondary to nonalcoholic steatohepatitis (NASH; popularly known as fatty liver disease).[29, 30]
Overall prognosis for survival is poor, with a 5-year relative survival rate of 18.4%. By stage, the relative 5-year survival is 32.6% in patients diagnosed with localized disease, 10.8% with regional disease, and 2.4% with distant disease. Length of survival depends largely on the extent of cirrhosis in the liver; cirrhotic patients have shorter survival times and more limited therapeutic options. Portal vein occlusion, which occurs commonly, portends an even shorter survival. As many patients die of liver failure as from tumor progression.
The influence of diabetes, obesity, and glycemic control continues to be evaluated in studies of the etiology and outcomes of HCC. For example, in a study of patients who had undergone curative resection for solitary HCV-related HCC, the tumor-free survival rate at 3 years was more than twice as high in patients in patients who had a normal hemoglobin A1c than in those whose hemoglobin A1c was 6.5% or higher (66% versus 27%).[33]
Complications from HCC are those of hepatic failure; death occurs from cachexia, variceal bleeding, or (rarely) tumor rupture and bleeding into the peritoneum. Signs and symptoms of hepatic failure may signify tumor recurrence and/or progression.
Various studies have reported extrahepatic metastasis in up to 30–50% of cases of HCC, with lungs the commonest site, followed by lymph nodes and bones. Unusual extrahepatic metastatic sites include the following[34] :
The diagnosis of hepatocellular carcinoma (HCC) can often be established on the basis of noninvasive imaging, without biopsy confirmation. Even when biopsy is needed, imaging is usually required for guidance.[4]
Because the outcome in patients with advanced HCC is uniformly dismal, early diagnosis is crucial in order to provide effective treatment. Consequently, routine screening for HCC is recommended in patients with cirrhosis from any cause; some guidelines also recommend testing in other patients at high risk (see Guidelines). Screening is typically performed using ultrasonography (US), with or without serum alpha-fetoprotein (AFP) measurement, generally every 6 months.
AFP is elevated in 75% of cases. The level of elevation correlates inversely with prognosis. An elevation of greater than 400 ng/mL predicts for HCC with specificity greater than 95%. In the setting of a growing mass, cirrhosis, and the absence of acute hepatitis, many centers use a level greater than 1000 ng/mL as presumptive evidence of HCC (without biopsy). AFP alone is inadequate for screening purposes because of the high rate of false positives in active hepatitis; it has only 40-64% sensitivity because many tumors do not produce AFP at all or do so only at a very advanced stage.[35]
US as a screening method is reported to have 60% sensitivity and 97% specificity in the cirrhotic population, and it has been demonstrated to be cost-effective.[36, 37] Findings on US should then be confirmed with further imaging studies—multiphase computed tomography (CT) or magnetic resonance imaging (MRI)—and potentially biopsy.
With aggressive screening, the rate of resectable HCC diagnosed in patients who are at high risk reaches 30-50%, which is nearly twice the rate of unscreened populations.[38] Despite the significant risk of recurrence, even in treated patients, the screening protocols appear to be cost effective in this population.[39]
On CT, HCC generally appears as a focal nodule with early enhancement on the arterial phase with rapid washout of contrast on the portal venous phase of a three-phase contrast scan. MRI of HCC generally demonstrates high signal intensity on T2 imaging. Biopsy is indicated in patients with HCCs that are larger than 2 cm with low AFP or in whom ablative treatment or transplant is contraindicated. In patients with elevated AFP and consistent imaging characteristics, patients can be treated presumptively for HCC without a biopsy. Patients should also undergo evaluation for extrahepatic disease (primarily pulmonary metastasis) with cross-sectional imaging, as the presence of extrahepatic disease would preclude curative locoregional therapy. For more information, see Hepatocellular Carcinoma Imaging.
Laboratory evaluation of patients with newly diagnosed HCC should include testing to determine the severity of the underlying liver disease, such as the following:
Complete blood cell count (CBC)
Electrolyte levels
Liver function tests (LFTs)
Coagulation studies (eg, international normalized ratio [INR], partial thromboplastin time [PTT])
Increased AFP - Levels higher than 400 ng/mL are considered diagnostic with appropriate imaging studies
Hypercalcemia - Ectopic parathyroid hormone production is possible in 5-10% of patients with HCC
Alpha fetoprotein
AFP levels may be elevated because of production by the tumor or by regenerating hepatocytes. Therefore, AFP levels are also frequently elevated in chronic active hepatitis C (levels of 200-300 ng/mL are not uncommon), but in those patients the levels tend to fluctuate and do not progressively increase. AFP levels can also be elevated because of other conditions, such as following liver resection (transient until regeneration complete), recovery following toxic injury, or seroconversion following hepatitis B infection (typically inducing transient exacerbation of inflammation).
When elevated, the AFP is 75-91% specific, and values greater than 400 ng/mL are generally considered diagnostic of HCC in the proper clinical context, including appropriate radiologic findings.[40] (See Table 2 below.) Better biologic markers, including AFP variants, are being investigated.[41, 42]
Table 2. Serum Alpha-Fetoprotein (AFP) Determination in Liver Disease[40]
Accurate diagnosis and surgical planning require adequate cross-sectional imaging studies. Although US is commonly used for screening, it does not provide sufficient anatomic detail for planning surgical resection or ablation. Correlation between ultrasonographic findings and explant liver pathology has revealed that a significant number of small lesions may not be detected with ultrasound screening. Pooled estimates from one meta-analysis suggested that US is only 60% sensitive.[36]
US identification of HCC can be difficult in the background of regenerative nodules in the cirrhotic liver. In general, HCC appears as a round or oval mass with sharp, smooth boundaries. The lesions have a range of echogenicity, from hypoechoic to hyperechoic, depending on the surrounding parenchyma and the degree of fatty infiltration. The border between the HCC and the liver can become indistinct with nodular HCC. The use of Doppler analysis to characterize the lesion can be helpful, in that HCC is more likely to have a significant arterial blood supply and neovascularization as compared to regenerative nodules. (See the image below.)
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Ultrasonographic image of hepatocellular carcinoma.
Triple-phase CT (including an arterial phase, a portal venous phase, and a late washout phase) has been found to be highly accurate in the diagnosis and characterization of HCCs but, like US, may miss smaller lesions. Pooled estimates reveal a sensitivity of 68% and a specificity of 93%.[36] Disadvantages of CT include cost, radiation exposure, and the need for iodinated contrast.
Classic CT findings of HCC include a hypervascular pattern with arterial enhancement and rapid washout during the portal venous phase.[43] (See the images below.) In contrast, regenerative nodules generally appear isoattenuating or hypoattenuating when compared with the remaining parenchyma. Other characteristics that support the diagnosis of HCC include visualization of a tumor capsule, demonstration of an internal mosaic resulting from variable attenuation within the tumor, and portal vein branch invasion. Unfortunately, all of these characteristics are more easily demonstrated in large lesions. Consequently, small lesions are frequently missed on CT examination.
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Arterial phase CT scan demonstrating enhancement of hepatocellular carcinoma.
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Portal venous phase CT scan demonstrating washout of hepatocellular carcinoma.
MRI provides an excellent method for characterizing HCC without radiation and the need for iodinated contrast. Technologic improvements have reduced scanning time and improved the specificity of the study. Pooled analysis demonstrated a sensitivity of 81% and a specificity of 85%.[36]
HCC demonstrates a variety of features on MRI, depending on the tumor architecture, grade, and amount of intratumoral fat and glycogen.[43] (See the image below.) The lesion ranges from isointense to hyperintense (bright) on T1-weighted images. Similarly, T2 images may vary from isointense to hyperintense. Well-differentiated tumors are more commonly hyperintense on T1 images and isointense on T2 images, whereas moderately or poorly differentiated tumors tend to be hyperintense on T2 images and isointense on T1 images. Although imaging characteristics may be suggestive, a significant overlap may occur between the tumor and regenerative nodules.
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MRI of a liver with hepatocellular carcinoma.
The benefits of contrast-enhanced studies must be balanced against the risks if any anatomic or functional renal impairment is possible. Iodinated contrast for CT may worsen renal failure, and gadolinium enhancement on MRI has been linked to a syndrome of severe systemic fibrosis in a patient with renal failure.[44]
The decision to biopsy a lesion suspected of being hepatocellular carcinoma is the subject of ongoing controversy. In patients with large tumors who are not candidates for resection or transplantation, biopsy is frequently not indicated to confirm the diagnosis prior to initiating palliative procedures, because clinical and imaging evidence is convincing and biopsy is potentially risky.
In patients with lesions smaller than 1 cm, fewer than 50% of the lesions will be malignant, and the false-negative result rate is high. Thus, conservative management with close follow-up and no biopsy is recommended.[38]
In patients with 1- to 2-cm lesions, a biopsy should be performed; these patients have a significant risk of malignancy. If the result is positive, they are candidates for resection, transplantation, or ablative therapy. As in the smaller lesions, there is a significant false-negative result rate, and close follow-up is indicated in patients with a negative biopsy result.
Patients with lesions larger than 2 cm, cirrhosis, characteristic imaging studies, and elevated AFP values can be managed without biopsy. In these patients, the risk of tumor seeding must be taken into account. Whereas some groups require biopsy before transplantation,[38] others are willing to proceed on clinical characteristics alone.[45] In patients with more atypical findings on imaging studies, the value of AFP should not be overemphasized, because an excessive number of patients submitted to transplantation did not have HCC.[41]
In patients with cirrhosis who are being considered for resection, survival following resection has been previously correlated with the degree of portal hypertension. In some centers, determination of the wedged hepatic vein pressure is advocated to then determine the safety of resection. Resection can, in general, be safely undertaken in patients with a wedged hepatic venous pressure gradient of less than 10.[38] Patients should also have a platelet count lower than 100,000/μL and a normal bilirubin level. In patients with small tumors but significant hepatic dysfunction, transplantation is the preferred option.
Histology is quite variable: tumors range from well differentiated to anaplastic. The fibrolamellar subtype is associated with a better prognosis, possibly because it is not associated with cirrhosis and is more likely to be resectable. The presence of intracellular bile or staining for AFP may be helpful in distinguishing HCC from other hepatic malignancies (eg, cholangiocarcinoma). Various other immunohistochemical markers are available to establish the diagnosis of HCC. Nguyen et al reported that arginase-1 and hepatocyte paraffin antigen 1 (Hep Par 1) had the highest sensitivity for well-differentiated HCC, whereas arginase-1 and glypican-3 had the highest sensitivity for poorly differentiated HCC.[46]
Aberrations of chromosome 1 and 8 are common features of HCC that can be detected by fluorescent in situ hybridization (FISH) technique. The role of FISH in the diagnosis of hepatocellular carcinoma is still under investigation.
The prognosis of HCC is a reflection of both tumor characteristics (ie, size, location, tumor biology) and the degree of underlying liver disease. The traditional pathologic TNM (tumor-node-metastasis) staging system, while helpful in determining a prognosis in patients undergoing resection, is not as useful in planning treatment, because it fails to include measures of the severity of the liver disease. However, the tumor size is predictive of outcome, as it predicts the likelihood of major venous involvement.[47]
Likewise, the Child-Pugh-Turcotte score predicts perioperative survival after resection, but it does not incorporate tumor size, number, and location, which have important implications for respectability and treatment. Among the scales that integrate the tumor and liver disease characteristics, the Barcelona Clinic Liver Cancer (BCLC) system,[38] the Japan Integrated Staging System, and the Cancer of the Liver Italian Program (CLIP) are the most widely used staging systems.
BCLC algorithm
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The Barcelona-Clinic Liver Cancer (BCLC) approach to hepatocellular carcinoma management. Adapted from Llovet JM, Fuster J, Bruix J, Barcelona-Clinic ....
The BCLC system is very useful in deciding among potential treatment options and correlates best with patient outcome among the major staging systems.[48]
In the BCLC system, stage 0 patients have lesions smaller than 2 cm, normal bilirubin levels, and normal portal pressure measurements. These patients can often undergo resection safely with excellent long-term survival.
Patients with larger tumors (ie, single tumors < 5 cm or multiple [≤ 3] tumors < 3 cm) are considered for resection if they have preserved liver function or for transplantation if they have decompensated cirrhosis.
In patients whose tumor exceeds these measurements, palliative therapy can be offered depending upon hepatic reserve. Fewer than 10% of these patients survive longer than 3 years.
CLIP scoring system
A score of 0-2 is assigned for each of the 4 features listed below; a cumulative score ranging from 0-6 is the CLIP score.
Child-Pugh class:
Class A = 0
Class B = 1
Class C = 2
Tumor morphology:
Uninodular and extension less than 50% = 0
Multinodular and extension less than 50% = 1
Massive and extension greater than 50% = 2
Alpha-fetoprotein:
Less than 400 = 0
Greater than 400 = 1
Portal vein thrombosis:
Absent = 0
Present = 1
Estimated survival based on CLIP score
Patients with a total CLIP score of 0 have an estimated survival of 31 months; those with score of 1, about 27 months; score of 2, 13 months; score of 3, 8 months; and scores 4-6, approximately 2 months.
For more information, see Hepatocellular Carcinoma Staging.
Management of hepatocellular carcinoma (HCC) is best performed in a multidisciplinary setting. Patients should be cooperatively managed by hepatologists, transplant and hepatobiliary surgeons, medical oncologists, interventional radiologists, and palliative care specialists. Specifically, this is crucial to ensure that patients who are candidates for liver transplantation are referred in a timely manner, while their tumors are within the Milan criteria.[38]
Treatment options for hepatocellular carcinoma depend on the following[49] :
Size, number, and location of tumors
Presence or absence of cirrhosis
Operative risk based on extent of cirrhosis and comorbid diseases
Overall performance status
Portal vein patency
Presence or absence of metastatic disease
Before instituting definitive therapy, it is best to treat the complications of cirrhosis, as follows:
Sodium restriciton, diuretics, and paracentesis for ascites
Lactulose for encephalopathy
Ursodiol for pruritus
Sclerosis or banding for variceal bleeding
Antibiotics for spontaneous bacterial peritonitis
Surgical resection and liver transplantation provide the only chances of cure but have limited applicability. The main prognostic factors for resectability are tumor size and liver function. Only about 5% of hepatocellular carcinoma patients are suitable for transplantation; these patients may have a 5-year survival of greater than 75% with tumor recurrence rates as low as 15% at 5 years.[50]
Thus, other treatments should be used to bridge patients to transplant or to delay recurrence if possible; these include resection; radiofrequency ablation (RFA); and, potentially, systemic therapy with sorafenib (or, if sorafenib fails, with regorafenib, nivolumab, lenvatinib, pembrolizumab, cabozantinib, or ramucirumab). In patients who experience a recurrence following resection or transplantation, aggressive surgical treatment appears to be associated with the best possible outcome.[51]
See also Hepatocellular Carcinoma Treatment Protocols.
In patients who are not candidates for liver transplantation or resection, tumor ablation can be offered to extend life and potentially to downstage the tumor so as to permit transplantation or resection. Alternatively, patients who have advanced disease may benefit from palliative care interventions rather than be subjected to often ineffective therapies.
Transcatheter arterial chemoembolization
The most commonly offered therapy is transcatheter arterial chemoembolization (TACE).[52, 53] TACE is performed by an interventional radiologist who selectively cannulates the feeding artery to the tumor and delivers high local doses of chemotherapeutic agents, including doxorubicin, cisplatin, or mitomycin C. To prevent systemic toxicity, the feeding artery is occluded with gel foam or coils to prevent flow.
Because most HCCs derive 80-85% of their blood flow from the hepatic artery, the therapy can be well targeted, leaving the normal parenchyma, which is primarily supplied by portal blood, minimally affected. A reduction in tumor burden can be achieved in 16-61% of treated patients.
The impact of TACE on clinical outcome remains unclear.[54] Some studies suggested no benefit, but others reported a marked improvement in survival, including an increase in the 2-year survival rate from 27% to 63% in a group of 112 patients.[55] One meta-analysis of seven randomized controlled trials with 516 patients suggested a survival advantage for chemoembolization (odds ratio for death, 0.53) as compared with medical therapy.
A phase 2 study using data from the TACTICS trial (33 institutions, N = 156) found evidence that adding sorafenib to TACE may yield significantly longer progression-free survival (PFS) than TACE alone in patients with unresectable HCC.[56] Adverse events were consistent with findings from previous TACE combination trials. The patients in this trial received sorafenib for a median of 38.7 weeks, compared with a range of 17-21 weeks in earlier combination studies.
Because TACE is reasonably well tolerated and has minimal morbidity, it can be offered to well-compensated patients with cirrhosis as a method to reduce their disease burden and to potentially extend their life.
The most common complication is postembolization syndrome, which is characterized by fever, elevated alanine aminotransferase (ALT), and abdominal pain; it occurs in 32-80% of treated patients.[57] However, in patients with advanced cirrhosis and hepatic decompensation, TACE is contraindicated, because the ischemic damage associated with embolization can lead to a rapid decline in liver function with worsening encephalopathy, increased ascites, and, potentially, death.
Brachytherapy
Another treatment option involves the local delivery of low-dose brachytherapy to the tumor. One such treatment, TheraSphere (BTG, Ottawa, Ontario, Canada), uses 20- to 40-μm glass beads that are loaded with radioactive yttrium and delivered angiographically. The radiotherapy is then delivered over 10-12 days with a total dose of about 150 Gy. The maximum distance affected is 1 cm.[58]
Early reports suggested that a small number of patients can be successfully downstaged and subsequently transplanted by using this approach. Risks include radiation damage to nearby organs (eg, the gastrointestinal tract).
Chemotherapy
Systemic chemotherapy remains the mainstay of therapy for patients with advanced HCC who are not candidates for surgical resection, liver transplantation, or localized tumor ablation. Unfortunately, HCC is minimally responsive to systemic chemotherapy. Resistance to chemotherapy may be caused by the universal expression of the multidrug resistance gene protein on the surface of the malignant cells, leading to active efflux of chemotherapeutic agents.
Chemotherapy is usually not well tolerated and seems to be less efficacious in patients with HCC who have underlying hepatic dysfunction. Younger patients with well-compensated cirrhosis due to chronic hepatitis B or C infections have better outcomes with chemotherapy than older patients with alcoholic cirrhosis and other comorbid diseases.
The most active drugs tested for single-agent therapy have been doxorubicin, cisplatin, and fluorouracil. Response rates are about 10%, and treatment shows no clear impact on overall survival.[59] The combination of gemcitabine and oxaliplatin (GEMOX) helped to shrink large hepatomas to the point where some could be resected, according to a multicenter retrospective study in France.[60]
There is also no apparent benefit to chemotherapy in the adjuvant setting following resection or radiofrequency ablation (RFA).[57] In an effort to provide care in this difficult population, various hormonal and biologic agents have been tried with minimal success, including tamoxifen, antiandrogens (eg, cyproterone and ketoconazole), interferon, interleukin (IL)-2, and octreotide.[61] Currently, liver-directed therapies (eg, resection, transplantation, and RFA) offer the only genuine hope for extended survival in patients with advanced HCC.
Sorafenib
Sorafenib is an oral agent that has antiangiogenic, proapoptotic, and Raf-kinase inhibitory properties.[62, 63, 64] In 2007, it was approved by the US Food and Drug Administration (FDA) for use in patients with unresectable HCC. Sorafenib is regarded as a standard medical treatment for advanced HCC.[65, 66] In addition, data from the TACTICS trial suggest that adding it to TACE may lead to improved survival as compared with TACE alone in patients with unresectable HCC.[56]
The following additional systemic drug options exist for patients with HCC who have stopped responding to initial treatment with sorafenib:
Regorafenib
Nivolumab
Lenvatinib
Pembrolizumab
Cabozantinib
Ramucirumab
Atezolizumab plus bevacizumab
Regorafenib
In April 2017, regorafenib was approved by the FDA for use in patients with HCC who have been previously treated with sorafenib. Approval was based on the RESORCE trial results (N = 573) in patients with progressive HCC who had undergone treatment with sorafenib.[67] In this trial, regorafenib improved overall survival (OS) in comparison with placebo (10.6 vs 7.8 months). Median PFS was also significantly better with regorafenib than with placebo (3.1 vs 1.5 months), as were the disease control rate (65.2% vs 36.1%) and the complete or partial response rate (10.6% vs 4.1%).
Nivolumab
In September 2017, nivolumab (Opdivo) was approved by the FDA for patients with HCC who have been previously treated with sorafenib. Accelerated approval was based on the CheckMate-040 trial, a phase 1/2, open-label, multicenter trial evaluating nivolumab in patients with advanced HCC who progressed on or were intolerant of sorafenib.[68] Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
In the CheckMate-040 trial, 154 patients received nivolumab 3 mg/kg IV every 2 weeks. Of the 154 patients, 22 (14.3%) responded to nivolumab, with complete response seen in 3 (1.9%).[68] The duration of response ranged from 3.2 months to greater than 38.2 months. In those who responded, 91% had responses lasting at least 6 months, and 55% had responses lasting at least 12 months. Common adverse reactions occurring in greater than 20% of patients in nivolumab clinical trials include fatigue, rash, musculoskeletal pain, pruritus, diarrhea, nausea, asthenia, cough, dyspnea, constipation, decreased appetite, back pain, arthralgia, upper respiratory tract infection, and pyrexia.
Lenvatinib
In August 2018, the FDA approved lenvatinib, a vascular endothelial growth factor (VEGF) inhibitor, for first-line treatment of unresectable HCC. Approval was based on the phase III REFLECT trial, which showed that lenvatinib was noninferior to sorafenib for first-line treatment of HCC.[69] Median OS was 13.6 months with lenvatinib vs 12.3 months with sorafenib. Median PFS was 7.4 months for lenvatinib versus 3.7 months for sorafenib. Time to progression was 8.9 months for lenvatinib vs 3.7 months for sorafenib.
Pembrolizumab
In November 2018, the FDA granted pembrolizumab an accelerated approval for patients with HCC previously treated with sorafenib. Approval was based on the KEYNOTE-224 trial, in which single-agent pembrolizumab induced an objective response of 17% among 104 patients with advanced HCC previously treated with sorafenib.[70] The overall response rate was 1%, and the partial response rate was 16%; meanwhile, 44% of patients had stable disease, 33% had progressive disease, and 6% were considered not assessable. Pembrolizumab treatment resulted in durable responses and favorable PFS and OS in patients with advanced HCC previously treated with sorafenib.
Cabozantinib
In January 2019, cabozantinib was approved for HCC in patients previously treated with sorafenib. Cabozantinib is an inhibitor of multiple tyrosine kinases, including RET, MET, and VEGFR-2. Approval was based on the phase III CELESTIAL trial (N = 707). OS was improved by 2.2 months with cabozantinib (10.2 months) as compared with placebo (8.0 months). The improvement in median OS with cabozantinib represented a 24% reduction in the risk of death (HR, 0.76).[71]
Ramucirumab
In May 2019, ramucirumab, a VEGFR2 antagonist, was approved by the FDA for HCC. It is indicated as monotherapy in patients with HCC who have an alpha fetoprotein (AFP) level of 400 ng/mL or higher and have been previously treated with sorafenib. Approval was based on the REACH‑2 randomized double-blind placebo-controlled study (N = 292).[72] Patients were randomized (2:1) to receive ramucirumab 8 mg/kg plus best supportive care (BSC) or placebo plus BSC every 2 weeks as an intravenous infusion until disease progression or unacceptable toxicity. Estimated median OS was 8.5 months (range, 7.0-10.6) for ramucirumab and 7.3 months (range, 5.4-9.1) for placebo (HR 0.71).
Atezolizumab plus bevacizumab
In a global, open-label, phase 3 trial in systemic treatment–naive patients with unresectable hepatocellular carcinoma, both OS and PFS were better with atezolizumab plus bevacizumab than with sorafenib. OS at 12 months was 67.2% (95% CI, 61.3 to 73.1) in patients (n = 329) treated with atezolizumab–bevacizumab and 54.6% (95% CI, 45.2 to 64.0) in patients (n = 156) treated with sorafenib. Median PFS was 6.8 months (95% CI, 5.7 to 8.3) versus 4.3 months (95% CI, 4.0 to 5.6), respectively. The hazard ratio for disease progression or death with atezolizumab–bevacizumab compared with sorafenib was 0.59 (95% CI, 0.47 to 0.76; P < 0.001).[108]
Other nonsurgical measures
For most patients, treatment options other than palliative care are limited. For patients with Child-Pugh class C cirrhosis and contraindications for transplantation, any intervention has the potential to result in progressive hepatic decompensation. In these patients, treatment focuses on pain control, ascites, edema, and portosystemic encephalopathy management.
Pain control may provoke worsening of portosystemic encephalopathy, in that some patients are sensitive to narcotics and sometimes benzodiazepines. Insomnia may be the consequence of depression and fear, but it can also be a reflection of portosystemic encephalopathy. The latter can be worsened by (narcotic-induced) constipation that should be prevented. Lactulose can be helpful, and the ideal dosage should lead to not more than and not fewer than two or three bowel movements daily.
Aspirin and aspirinlike products, as a rule, are contraindicated in the patient with fluid retention because prostaglandin inhibition can strongly enhance retention of water and salt. In addition, consequences of platelet dysfunction may occur.
Fluid overload is best managed with a combination of spironolactone (50-400 mg/day), replaced by amiloride (10-20 mg/day) in case of painful gynecomastia, and furosemide (40-160 mg/day). Excessive diuresis leading to a weight loss of more than 1-2 lb daily usually causes worsening renal and electrolyte problems. Large-volume paracentesis in excess of 5-7 L, even accompanied by intravenous albumin, can result in renal decompensation and worsening of portosystemic encephalopathy.
In terminal patients, hypoglycemia can be confused with hepatic coma and can be managed with glucose infusions. Patients with large tumors have a short life expectancy, and every effort should be made to preserve and enhance quality of life. Early referral to palliative care practitioners should be considered.
In May 2018, the second-generation orally administered thrombopoietin receptor agonist avatrombopag was approved by the FDA for the treatment of thrombocytopenia in patients with chronic liver disease who are scheduled to undergo a medical or dental procedure. Approval was based on the ADAPT-1 and ADAPT-2 trials.[73]
In view of the absence of effective chemotherapy and the insensitivity of HCC to radiotherapy, complete tumor extirpation represents the only opportunity for a long-term cure. Resection of the tumor by partial hepatectomy (see the videos below) can be accomplished in a limited number of patients (generally < 15-30%) in most Western series due to the degree of underlying cirrhosis.
View Video
Right hepatectomy. Part 1: Dissection of portal vein. Courtesy of Memorial Sloan-Kettering Cancer Center, featuring Leslie H. Blumgart, MD. (From Blumgart LH. Video Atlas: Liver, Biliary & Pancreatic Surgery. Philadelphia, PA: Saunders; 2010.)
View Video
Right hepatectomy. Part 2: Devascularization of right liver. Courtesy of Memorial Sloan-Kettering Cancer Center, featuring Leslie H. Blumgart, MD. (From Blumgart LH. Video Atlas: Liver, Biliary & Pancreatic Surgery. Philadelphia, PA: Saunders; 2010.)
View Video
Right hepatectomy. Part 3: Suturing and dividing. Courtesy of Memorial Sloan-Kettering Cancer Center, featuring Leslie H. Blumgart, MD. (From Blumgart LH. Video Atlas: Liver, Biliary & Pancreatic Surgery. Philadelphia, PA: Saunders; 2010.)
In patients with decompensated liver disease, liver transplantation offers the potential for a long-term cure in patients with limited tumor burden. Alternative treatments, including local ablative therapy, TACE, and transarterial brachytherapy, can be considered in patients who are not candidates for curative procedures.
Surgical resection
Advances in the technique of liver resection, better patient selection, improved postoperative care, and expert anesthetic management have resulted in a dramatic reduction in perioperative morbidity and mortality. Liver resection is the operation of choice for patients with tumors smaller than 5 cm in the absence of cirrhosis. These patients can often tolerate resection of up to 50% of the total liver volume. In these patients, an operative mortality of less than 2% can be expected in experienced centers.[45]
In patients with cirrhosis, the extent of liver resection that can be tolerated is significantly more limited. Clinically evident portal hypertension (defined as a hepatic vein–to–right atrial pressure gradient in excess of 10), esophageal varices, or splenomegaly with a platelet count lower than 100,000/μL predicts poor outcome with significant resection. In general, resection of more than two segments is contraindicated in patients with Child class B or C cirrhosis. However, among patients who do undergo successful resection, long-term survival is possible, with 5-year survival rates as high as 74% in patients without significant decompensation.
After liver resection, as many as 75% of patients will develop intrahepatic recurrence within 5 years.[74, 75] This recurrence can be either de-novo HCC or local spread. Pathologic characteristics associated with a higher rate of recurrence include the following:
Tumor at the resection margin
Presence of cirrhosis
Vascular invasion
Advanced tumor grade
Number of tumor nodules
Microvascular portal vein thrombosis
Other clinical factors associated with a higher rate of HCC recurrence include the following:
Preresection serum alpha-fetoprotein (AFP) level higher than 10,000 ng/mL
Large intraoperative transfusion requirements
Preoperative aspartate aminotransferase (AST) level greater than twice normal
Diagnosis of hepatitis C
In patients with recurrence and preserved liver function, repeat resection may be indicated. In one single-center series, operative resection was associated with prolonged survival (44 months vs 10.6 months) in comparison with medical management.[76]
Resection of HCCs that are 2 cm or smaller has been shown to be safe and effective in both Asian and Western populations, though recurrence is common. The presence of satellites and platelet count are associated with survival in these patients, and the presence of satellites, cirrhosis and nonanatomic resection are associated with recurrence.[77]
Liver transplantation
Compared with resection for HCC, orthotopic liver transplantation (OLT) offers several potential advantages. Complete hepatectomy eliminates the possibility of local recurrence at the resection margin and, moreover, removes the cirrhotic liver, which is clearly predisposed to tumor formation. Liver transplantation also eliminates concerns about the capacity of the postresection liver remnant to provide adequate liver volume.
The initial experience with liver transplantation for patients with HCC was unrewarding with high rates of recurrence in the allograft (transplanted liver) and extrahepatically.[78] Reports from the national transplant tumor registry in 1991 revealed a 5-year survival rate of only 18%.[79] In the survivors, only 9% remained tumor-free at 2 years.
These dismal survival data led to a moratorium on transplantation for HCC in the early 1990s. However, further investigations suggested that these results were likely the result of poor patient selection and transplantation in the face of extensive tumor burden. In patients with incidentally discovered small tumors, the results were actually quite good, leading to the subsequent reassessment of HCC as an indication for OLT.
The approach to patients with HCC was dramatically altered by the 1996 publication of the results from Mazzaferro et al in Milan,[80] who demonstrated that patients with limited HCC tumor burden could achieve posttransplant patient survival rates equivalent to patients without malignancies. Mazzaferro defined the Milan criteria, which have been used to determine candidacy for OLT.
In the experience of the Milan investigators, patients with established cirrhosis and either a single HCC no larger than 5 cm in diameter or as many as three HCCs no larger than 3 cm had a 4-year overall survival rate of 85% and a tumor-free survival rate of 92%. By comparison, patients with a large tumor burden had a 4-year survival rate of 50%. After this report, OLT was established as the therapy of choice for patients with significant cirrhosis and limited tumor burden.[80, 81, 82, 83]
These results were subsequently duplicated by several other transplant centers (see Table 3 below).[80]
Table 3. Patient Survival Rates Following Liver Transplantation for Hepatocellular Carcinoma
View Table
See Table
In addition to tumor burden, survival after transplantation has also been correlated with a variety of anatomic and pathologic features. Poor prognosis has been associated with the following[52, 84, 85] :
In these patients, tumor recurrence is highly likely. Whereas fibrolamellar histology has been associated with improved prognosis following resection, posttransplant survival appears to be equivalent to hepatocellular carcinoma in general. Finally, clinically evident reinfection with hepatitis B virus (HBV) or hepatitis C virus (HCV) has been correlated with tumor recurrence. In patients with hepatitis C, active viral recurrence is associated with a 40% risk of tumor development in the transplanted organ.[86]
The application of OLT to HCC has also been limited by access to deceased donor organs. Until 2002, patient waiting time was the primary driver of liver allocation, leading to high dropout rates among patients listed for transplant. In their report in 2002, Yao et al reported that as a result of tumor progression, as many as 37.8% of waitlist patients were no longer eligible at 12 months.[87]
Beginning in February 2002, liver allografts have been allocated according to the patients’ likelihood of dying from their liver disease. In general, liver allografts are allocated to patients according to their Model for End Stage Liver Disease (MELD) score. MELD is a complex equation, including creatinine, bilirubin, and international normalized ratio (INR), which accurately predicts mortality from complications of cirrhosis (see the MELD Score calculator). Under the MELD system, the patient with the highest MELD score and, therefore, the highest risk of dying without a liver transplant, is transplanted first.
Because patients with HCC are more likely to die from their malignancy than they are from their liver disease, surgeons feared that patients with HCC would be disadvantaged under the MELD system. To ensure access to deceased donor organs, patients with HCC with stage 1 or 2 tumors were assigned higher MELD scores based on tumor stage rather than tumor function. Patients with stage 3 or greater were precluded from transplantation. This change in allocation systems led to a dramatic reduction in waiting time and near-elimination of patients dropping out from tumor progression. Early reports suggested that the waitlist dropout rates were less than 5% at 8 months.
The priority accorded to patients with HCC has been challenged, and a number of authors have suggested that these patients have been disproportionately advantaged compared to the rest of the waiting list. This has led to a reduction in the MELD point upgrade.[88]
Additional strategies to provide OLT to patients with HCC have included the use of living-donor liver transplantation and split-liver transplant. These techniques expand the organ pool and appear to offer equivalent survival to whole-organ transplant. They have also been used in patients undergoing transplantation whose tumor burden exceeds the Milan criteria.
On the basis of this experience, several centers have advocated expanding the maximum tumor burden that can be considered for MELD upgrades to include patients with one tumor no larger than 6.5 cm or three or fewer tumors no larger than 4.5 cm with a total tumor diameter no larger than 8 cm. Transplantation in this population resulted in a survival rate of 90% at 1 year and 72.5% at 5 years.[89] Further refinement in both listing criteria and degree of MELD upgrade accorded to patients with HCC is likely in the future.
Ablative therapies
Curative treatment of patients with HCC who are not candidates for resection or OLT is limited. However, local ablative therapies can be used either as a bridge to transplant by reducing the risk of tumor progression or as a palliative procedure to extend disease-free survival. Ablative procedures, including ethanol injection, RFA, and cryotherapy, can be performed percutaneously, laparoscopically, or via an open surgical approach.
Percutaneous ethanol injection (PEI) was the first ablative technique used for HCC. PEI involves the injection of alcohol directly into the tumor leading to complete ablation of up to 70% of lesions, which are less than or equal to 3 cm. It is generally performed under the guidance of ultrasonography (US) and requires four to six sessions to complete the ablation.
In patients with Child class A cirrhosis, 40-55% survival can be achieved with PEI at 3 years.[90] PEI has not been compared with surgery in a randomized fashion; however, in retrospective reviews, the 3-year survival rates with PEI and surgery were 71% and 79%, respectively, in patients with Child class A cirrhosis and 40% and 41% in those with Child class B disease.
Although generally well tolerated, PEI can result in death and rare instances of tumor seeding. Unfortunately, PEI-treated lesions have a high rate of local recurrence (ie, 33% for tumors ≤3 cm, 43% for larger tumors).
In the United States, PEI has largely been supplanted by RFA, in which a conducting needle is placed within the tumor and current travels to a large dispersive electrode (grounding pad). The electric current leads to agitation of the ions in the tissue, heat generation, and desiccation of the tissues surrounding the probe. The coverage of the electric field can be extended with water cooling, multiple deployable tines within the needle, and other modified electrodes.[91]
Treatment with RFA is generally performed at a single session (in contrast to the multiple sessions required for PEI). The procedure can be done under the guidance of US, computed tomography (CT), or laparoscopy, depending upon the patient’s health, the location of the tumor, and the expertise available in the center.
When compared with PEI in a prospective trial, RFA was associated with a trend toward improved 24-month patient survival rates (98% vs 88%), but this trend did not achieve statistical significance.[90] However, significant differences in recurrence-free survival rates clearly favor RFA at 24 months (64% vs 43%). Complication rates are low, with a 0.3% mortality and a 2.2% incidence of major complications. Tumor seeding occurred in 0.5% of 1610 lesions treated in a large study reported by Llovet et al.[89]
RFA success may also be limited by the presence of large blood portal or hepatic vein branches adjacent to the tumor. Flowing blood can act as a heat sink and limit the ability to heat the tissue to a sufficient temperature. The temporary use of selective arterial/venous occlusion can be used to reduce the amount of heat sink.
RFA can also be used as an adjunctive therapy for patients waiting for transplantation.[92] In these patients, tumor progression can be delayed without the increased morbidity associated with liver transplantation following open resection.
Preliminary data are available in a variety of newer technologies, including microwave ablation, laser ablation, and focal external beam radiation. Unfortunately, no randomized trial data are available for this population. Cryoablation of tumors using a liquid nitrogen filled probe had been used historically for ablation. However, as a result of higher complication rates and lower efficacy rates, it has largely fallen out of the clinical armamentarium.[52]
Patients should avoid alcohol and other hepatic toxins because prognosis is related to worsening cirrhosis and tumor stage. The consumption of fish and fish-associated fatty acids is associated in a dose-dependent fashion with a lower risk of the development of HCC, regardless of hepatitis status.[93]
Although it is currently one of the most common worldwide causes of cancer death, a major impact on the incidence of hepatocellular carcinoma should be achieved through current vaccination strategies for hepatitis B virus (HBV) infection. Assuming that present HBV vaccination trends continue, between 2020 and 2050, the number of new HBV infections is estimated to drop by 70%.[29]
Additional primary prevention approaches include decreasing harmful use of alcohol, implementation of safe injection and transfusion practices, improved diagnoses of chronic infections, and increased treatment for HBV and HCV including increased accessibility and affordability of the highly effective HCV antiviral medication.[29]
Analysis of patients from the Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) trial found that in patients with chronic hepatitis C who did not have a sustained virologic response to therapy, long-term pegylated interferon therapy does not reduce the incidence of HCC.[94]
The Centers for Disease Control and Prevention (CDC) recommends one-time HCV testing for everyone born from 1945 to 1965 because this cohort accounts for about three-fourths of HCV-infected individuals in the US. Preventive measures for HBV and HCV infection recommended by the CDC include screening of donated blood, organs, and tissues; adherence to infection control practices during medical and dental procedures; needle-exchange programs for injection drug users; and practicing safe sex.[95]
Other preventive approaches include programs to reduce obesity and type 2 diabetes.[19] A nationwide study in Sweden reported low-dose aspirin use reduced the risk of HCC in patients with chronic viral hepatitis by 31% and reduced the risk of liver-related death by 27%.[96, 97]
Despite optimal treatment, HCC continues to have a high recurrence rate. It recurs in 50-80% of patients following resection, with the majority of recurrences developing within 2 years.[98] Careful follow-up in the postoperative period is mandatory. Early recurrence after resection is associated with a dismal prognosis, reducing 5-year survival rates from 70% to 30%.[98] Factors that increase the likelihood of recurrence include the presence of multiple foci of HCC, liver capsule invasion, and tumor size greater than 5 cm. Vascular invasion, both microscopic and macroscopic, also correlates with a higher risk of recurrence.
Among patients undergoing liver transplantation, the rate of recurrence is dependent upon the characteristics of the tumor in the explanted liver.[99] Overall recurrence in patients transplanted within the Milan criteria is 4-10%.[80] The majority of these recurrences occur early (8-14 months); however, as many as 30% of recurrences may occur late.[100] In these patients, 23% develop only intrahepatic recurrence, 39% develop both intrahepatic and extrahepatic recurrence, and 39% develop only extrahepatic recurrence. Common extrahepatic sites of metastatic disease include lung, bone, central nervous system, and adrenal glands.
Resection in the posttransplant population can be accomplished in as many as one third of patients. In those patients who undergo successful resection, 4-year survival rates increase from 14% to 57%, justifying an aggressive approach.[101]
Unfortunately, no established guidelines exist regarding the frequency of imaging procedures in the postoperative period. In general, CT should be performed at 1 month post resection to ensure complete tumor clearance. After this initial scan, serum AFP measurements and repeat imaging studies (eg, US, CT, or magnetic resonance imaging [MRI]) should be obtained every 3-6 months, depending on the likelihood of recurrence. After 2-3 years, it appears safe to increase the follow-up interval.
Guidelines Contributor: Elwyn C Cabebe, MD Physician Partner, Valley Medical Oncology Consultants; Medical Director of Oncology, Clinical Liason Physician, Cancer Care Committee, Good Samaritan Hospital
Guidelines for the screening, surveillance, and diagnosis of hepatocellular carcinoma (HCC) have been issued by the following organizations:
American Association for the Study of Liver Diseases (AASLD)
National Comprehensive Cancer Network (NCCN)
American College of Gastroenterology (ACG)
European Association for the Study of the Liver (EASL)–European Organisation for Research and Treatment of Cancer (EORTC)
European Society for Medical Oncology (ESMO)
Surveillance and diagnosis
In its 2018 guidelines for the management of HCC, the AASLD recommends surveillance for HCC in adults with cirrhosis, because it improves overall survival. Surveillance should be conducted with ultrasonography (US), with or without alpha-fetoprotein (AFP) testing, every 6 months. Computed tomography (CT) and magnetic resonance imaging (MRI) are not recommended as the primary modality for surveillance but may be used in select patients with a high likelihood of having an inadequate US or if US is attempted but inadequate.
Although the risk of HCC is reduced in patients with hepatitis C virus (HCV) infection who have a sustained virologic response after direct-acting antiviral therapy, the risk is not eliminated, and continuing surveillance is recommended. However, the AASLD advises that risk for HCC is too low to justify surveillance in patients with HCV infection or nonalcoholic fatty liver disease (NAFLD) who do not have cirrhosis. The AASLD recommends not performing surveillance of patients with Child-Pugh class C cirrhosis unless they are on the transplant waiting list, given their low anticipated survival.[4]
Similarly, the NCCN guidelines recommend screening with US, with or without AFP testing, every 6 months in patients with cirrhosis due to any of the following[49] :
Hepatitis B or C
Alcohol
Genetic hemochromatosis
NAFLD
Stage 4 primary biliary cholangitis
Alpha-1-antitrypsin deficiency
Other causes
Unlike the AASLD, the NCCN also recommends surveillance in hepatis B virus (HBV) carriers without cirrhosis. The following patients are at additional risk:
Carriers with family history of HCC
Asian males ≥40 y
Asian females ≥50 y
African/North American blacks
ESMO guidelines include the following recommendations on screening for HCC[102] :
Cost-effectiveness studies suggest that surveillance of HCC is warranted in all cirrhotic patients, irrespective of its etiology, as long as their liver function and comorbidities allow curative or palliative treatments.
Surveillance of hepatitis-infected patients without cirrhosis is also advocated, especially in HBV carriers with serum viral load > 10 000 copies/mL or HCV-infected patients with bridging fibrosis.
The AASLD recommendations for follow-up of abnormal screening results include the following[4] :
For nodules identified on US that are < 1 cm, repeat US at intervals of 3-6 months; if no growth is observed over a period of up to 2 years, revert to routine surveillance.
A lesion of ≥10 mm on ultrasound or an AFP level > 20 ng/mL should trigger recall procedures for the diagnosis of HCC.
Noninvasive diagnosis of HCC requires multiphase imaging evaluated using stringent criteria. The American College of Radiology has published guidelines on the performance interpretation, and reporting of multiphase CT and MR exams through its CT/MRI Liver Imaging Reporting And Data System (CT/MRI LI-RADS).[103]
For multiphase CT and MRI, key imaging features include the following:
Size ≥1 cm
Arterial phase hyperenhancement
Depending on exact size, a combination of washout, threshold growth, and capsule appearance
If these criteria are not present but HCC or other malignancy is considered probable, then a liver biopsy should be considered for diagnosis. In patients without cirrhosis, the diagnosis of HCC cannot be made by imaging, even if the scan shows hypervascularity in the arterial phase with washout in the portal venous or delayed phase; biopsy is required in these cases.[4]
The NCCN notes that biopsy may be considered in the following circumstances[49] :
When a lesion is suspicious for malignancy, but multiphasic CT or MRI results do not meet imaging criteria for HCC
In patients who are not considered to be at high risk for HCC (ie, patients who do not have cirrhosis, chronic HBV, or a previous history of HCC)
In patients with conditions associated with formation of nonmalignant nodules that may be confused with HCC on imaging (eg, cardiac cirrhosis; congenital hepatic fibrosis; cirrhosis due to a vascular disorder such as Budd-Chiari syndrome, hereditary hemorrhagic telangiectasia, or nodular regenerative hyperplasia)
In patients with elevated CA 19-9 or carcinoembryonic antigen (CEA), in order to rule out intrahepatic cholangiocarcinoma
The AASLD guidelines include the following recommendations regarding biopsy[4] :
If the diagnosis of HCC cannot be established from routine histology, staining for several biomarkers, including the diagnostic panel of glypican-3 (GPC3), heat shock protein 70 (HSP70), and glutamine synthetase, can be used to help distinguish HCC from high-grade dysplastic nodules.
If the biopsy is negative, the lesion should be followed by imaging at 3- to 6-month intervals until the nodule disappears, enlarges, or develops features characteristics of HCC.
If the lesion enlarges but remains atypical for HCC, the biopsy should be repeated.
The 2014 ACG guidelines for the diagnosis and management of focal liver lesions (FLLs) include the following recommendations[104] :
Patients with cirrhosis in whom an ultrasound shows a lesion of > 1 cm should undergo an MRI or triple-phase CT scan.
Patients with chronic liver disease who are at a very high risk for HCC and who present with a solid FLL must be considered to have HCC until proved otherwise.
HCC can be diagnosed with CT or MRI if the typical characteristics are present.
If an FLL in a patient with cirrhosis does not have typical characteristics of HCC, then a biopsy should be performed.
The 2018 ESMO guidelines contain the following recommendations regarding diagnosis of HCC[102] :
The diagnosis of HCC is based on histological analysis and/or contrast-enhanced imaging findings.
The diagnosis can be established if the typical vascular hallmarks of HCC (hypervascularity in the arterial phase with washout in the portal venous or delayed phase) are identified in a nodule of > 1 cm diameter using one of those two modalities in a cirrhotic patient.
Based on techniques such as diffusion-weighted imaging and the use of hepatobiliary contrast agents, MRI may allow identification and stratification of nodules as high-risk nodules (either HCC not displaying the typical imaging hallmarks features or high-grade dysplastic nodules).
For contrast-enhanced ultrasound (CEUS), an overlap between the vascular profile of HCC and cholangiocarcinoma has been described. However, recent data suggest CEUS as a suitable technique to diagnose HCC noninvasively in the setting of liver cirrhosis.
When tumor biopsy fails to demonstrate a correlate for a focal lesion, a second tumor biopsy, a different contrast-enhanced imaging modality or (if amenable) direct resection of the lesion may be considered, according to tumor size.
Histopathological diagnosis of tumor biopsies relies on standard (hematoxylin and eosin [H&E]) and special stains (eg, reticulin), and—if required—immunohistochemistry (IHC).
It is important to distinguish combined HCC/cholangiocarcinoma from HCC, because treatments for the two differ; however, the mixed differentiation features might not be visible in the biopsy. In addition, although HCC is commonly negative for cytokeratin 19 (CK19), significant expression of CK19 may be present in HCC and is considered as a sign of poor prognosis in HCC.
In highly differentiated HCC, definitive signs of malignancy (interstitial or vascular invasion) are frequently absent from biopsy. Further consented histological criteria (trabecular alterations—more than two cell broad trabeculae, pseudoglands, reticulin loss, capsule formation) and cytological criteria (increased nuclear/cytoplasmic ratio; ie, ‘nuclear crowding’, increased cytoplasmic basophilia) support the diagnosis of HCC.
IHC should be carried out in unclear cases: capillarization of sinusoids could be assessed using CD34 IHC.
Further immunohistochemical markers have been shown to improve the diagnosis of highly differentiated HCC, including glutamine synthetase, GPC3, circulating tumor cells (CTC) , EZH2, and HSP70.
Staging
The tumor-node-metastasis (TNM) classification of the American Joint Cancer Committee/Union for International Cancer Control/ (AJCC/UICC) is useful only in patients who undergo surgical resection, which is a small minority of patients. Only the NCCN guidelines follow TNM for staging.[49]
Since most patients have unresectable disease and prognosis depends more on the state of the liver than on the size of the tumor, the AASLD and ESMO guidelines recommend the Barcelona Clinic Liver Cancer (BCLC) system for prognostic prediction and treatment stratification.[4, 104]
The BCLC staging system attempts to overcome the limitations of previous staging systems by identifying prognostic stages (0 and A through D) based on five variables:
Tumor stage
Functional status of the liver
Physical status
Cancer-related symptoms
See Table 4, below.
Table 4. Barcelona Clinic Liver Cancer staging
View Table
See Table
The BCLC staging system also links each HCC stage to appropriate treatment modalities, as follows:
Patients with early-stage HCC (stage 0 and A) may benefit from curative therapies (ie, liver transplantation, surgical resection, radiofrequency ablation).
Patients with intermediate-stage(stage B) or advanced-stage (stage C) disease may benefit from palliative treatments (ie, transcatheter arterial chemoembolization and sorafenib)
Patients with end-stage disease (stage D) are offered supportive care and palliation
Treatment
AASLD guidelines divide therapeutic options into curative and noncurative interventions.[4] Curative therapies, which offer the chance of long-term response and improved survival, include the following:
Surgical resection
Orthotopic liver transplantation
Ablative techniques (eg, thermal ablation)
Noncurative therapies, which attempt to prolong survival by slowing tumor progression, include the following:
Transarterial chemoembolization (TACE)
Transarterial radioembolization (TARE)
Stereotactic body radiation therapy (SBRT)
Systemic chemotherapy
The guidelines agree that resection is the treatment of choice for solitary tumors in non-cirrhotic patients or cirrhotic patients with well-preserved liver function. Pre- or post-resection adjuvant therapy is not recommended.
The guidelines further concur that liver transplantation is the best available curative option for patients with early-stage non-resectable HCC who meet the Milan criteria (single tumors ≤5 cm in diameter or no more than three nodules ≤3 cm in diameter in patients with multiple tumors). Ablation should be considered as definitive treatment for patients with stage 0-A tumors who are not candidates for resection or transplantation. NCCN and AASLD guidelines also recommend ablation as a possible bridge therapy for patients awaiting transplantation.[4, 49]
The AASLD recommends TACE as first-line noncurative therapy for BCLC stage B HCC. For stage BCLC disease, sorafenib or lenvatinib is recommended as first-line therapy.[4]
For patients with unresectable HCC who are not candidates for transplantation, NCCN recommendations for first-line systemic therapy are as follows[49] :
Sorafenib is the preferred therapy for Child-Pugh Class A (category 1) or B7 HCC
Lenvatinib is a preferred therapy for Child-Pugh Class A only
Systemic chemotherapy (category 2B)
Recommended agents for subsequent-line therapy if disease progression occurs are as follows[49] :
Regorafenib (Child-Pugh Class A only) (category 1)
Cabozantinib (Child-Pugh Class A only) (category 1)
Few systemic options exist for patients with hepatocellular carcinoma (HCC). Sorafenib is indicated for patients with unresectable or advanced HCC; other recent options are regorafenib, nivolumab, lenvatinib, pembrolizumab, cabozantinib, and ramucirumab.
Clinical Context:
Regorafenib is a tyrosine kinase inhibitor. It is indicated for hepatocellular carcinoma in patients who have been previously treated with sorafenib.
Clinical Context:
Cabozantinib is an inhibitor of multiple tyrosine kinases, including RET, MET, and VEGFR-2. It is indicated for HCC in patients previously treated with sorafenib.
Tyrosine kinase inhibitors have shown inhibitory activity of membrane-bound and intracellular kinases involved in normal cellular functions and in pathological processes.
Clinical Context:
Lenvatinib is a receptor tyrosine kinase (RTK) inhibitor that inhibits the kinase activities of VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). It also inhibits other RTKs that have been implicated in pathogenic angiogenesis, tumor growth, and cancer progression in addition to their normal cellular functions, including fibroblast growth factor (FGF) receptors FGFR1, 2, 3, and 4; the platelet-derived growth factor receptor alpha (PDGFR-α); KIT; and RET. It is indicated for first-line treatment of unresectable HCC.
Clinical Context:
Vascular endothelial growth factor receptor 2 (VEGFR2) antagonist that specifically binds VEGF receptor 2 and blocks binding of VEGFR ligands, VEGF-A, VEGF-C, and VEGF-D. As a result, ramucirumab inhibits ligand-stimulated activation of VEGF2, thereby inhibiting ligand-induced proliferation, and migration of human endothelial cells. It is indicated as monotherapy for hepatocellular carcinoma (HCC) in patients with alpha fetoprotein (AFP) of 400 ng/mL or higher who have been previously treated with sorafenib.
Clinical Context:
Nivolumab is a programmed death receptor-1 (PD-1) blocking antibody. It is indicated for hepatocellular carcinoma in patients who have been previously treated with sorafenib.
Clinical Context:
Pembrolizumab is a monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response, including the antitumor immune response. Binding of PD-1 ligands, PD-L1 and PD-L2, to the PD-1 receptor found on T cells, inhibits T cell proliferation and cytokine production. It is indicated for patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib.
PD-1 and related target PD-ligand 1 (PD-L1) are expressed on the surface of activated T cells under normal conditions. PD-L1/PD-1 interaction inhibits immune activation and reduces T-cell cytotoxic activity when bound.
What is hepatocellular carcinoma (HCC)?How common is hepatocellular carcinoma (HCC)?At what stage is hepatocellular carcinoma (HCC) typically recognized?What is included in the diagnostic workup for hepatocellular carcinoma (HCC)?What are the limits of liver transplantation as a treatment for hepatocellular carcinoma (HCC)?What anatomy of the liver must be understood for the treatment of hepatocellular carcinoma (HCC)?How are the different forms of hepatectomies characterized?What is the pathogenesis of hepatocellular carcinoma (HCC)?What is the role of genetics in the pathobiology of hepatocellular carcinoma (HCC)?What is the role of nodules in the pathogenesis of hepatocellular carcinoma (HCC)?What is the role of cirrhosis in the etiology of hepatocellular carcinoma (HCC)?What are the metabolic risk factors for hepatocellular carcinoma (HCC)?What is the role of alcohol abuse in the etiology of hepatocellular carcinoma (HCC)?What is the role of hepatitis B virus (HBV) in the etiology of hepatocellular carcinoma (HCC) staging?What is the role of hepatitis C virus (HCV) in the etiology of hepatocellular carcinoma (HCC) tumors?What is the role of hemochromatosis in the etiology of hepatocellular carcinoma (HCC)?What is the role of aflatoxin in the etiology of hepatocellular carcinoma (HCC)?What are less common causes of hepatocellular carcinoma (HCC)?What is the incidence of hepatocellular carcinoma (HCC) in the US?What is the global incidence of hepatocellular carcinoma (HCC) worldwide?Which patient groups have the highest prevalence of hepatocellular carcinoma (HCC)?What is the prognosis for hepatocellular carcinoma (HCC)?What are the possible complications of hepatocellular carcinoma (HCC)?What are the signs and symptoms of hepatocellular carcinoma (HCC)?Which physical exam findings are characteristic of hepatocellular carcinoma (HCC)?Which conditions are included in the differential diagnoses of hepatocellular carcinoma (HCC)?What are the differential diagnoses for Hepatocellular Carcinoma (HCC)?How is hepatocellular carcinoma (HCC) diagnosed?How is hepatocellular carcinoma (HCC) screening performed?Which CT scan results are characteristic of hepatocellular carcinoma (HCC)?What is the role of lab evaluation in the management of hepatocellular carcinoma (HCC)?Which lab test results are useful in determining severity of hepatocellular carcinoma (HCC)?Which lab test findings are associated with specific etiologies of hepatocellular carcinoma (HCC)?What is the role of serum alpha-fetoprotein (AFP) in the screening and diagnosis of hepatocellular carcinoma (HCC)?What is the role of ultrasonographty in the workup of hepatocellular carcinoma (HCC)?What is the role of triple-phase CT in the diagnosis of hepatocellular carcinoma (HCC)?Which CT findings are characteristic of hepatocellular carcinoma (HCC)?What is the role of MRI in the diagnosis of hepatocellular carcinoma (HCC)?What is the role of liver biopsy in the diagnosis of hepatocellular carcinoma (HCC)?Which histologic findings are characteristic of hepatocellular carcinoma (HCC)?How is hepatocellular carcinoma (HCC) staged?How is hepatocellular carcinoma (HCC) treated?What are the nonsurgical options for hepatocellular carcinoma (HCC)?What is the role of transcatheter arterial chemoembolization (TACE) in the treatment of hepatocellular carcinoma (HCC)?What is the efficacy of transcatheter arterial chemoembolization (TACE) in the treatment of hepatocellular carcinoma (HCC)?What are complications of treating hepatocellular carcinoma (HCC) with transcatheter arterial chemoembolization (TACE)?What is the role of brachytherapy in the treatment of hepatocellular carcinoma (HCC)?What is the role of chemotherapy in the treatment of hepatocellular carcinoma (HCC)?What is the role of sorafenib in the treatment of hepatocellular carcinoma (HCC)?What are second-line treatments for hepatocellular carcinoma (HCC) no longer responsive to sorafenib?What are the roles of regorafenib, nivolumab, lenvatinib, pembrolizumab, cabozantinib, and ramucirumab in the treatment of hepatocellular carcinoma (HCC)?What are the treatment options when transplantation is contraindicated in patients with cirrhosis and hepatocellular carcinoma (HCC)?What are possible complications of pain medications in the treatment of hepatocellular carcinoma (HCC)?What is the role of aspirin in the treatment of hepatocellular carcinoma (HCC)?How is fluid overload managed in hepatocellular carcinoma (HCC)?How is glucose managed in hepatocellular carcinoma (HCC)?What is the role of avatrombopag in the treatment of hepatocellular carcinoma (HCC)?What is the role of surgery in the treatment of hepatocellular carcinoma (HCC)?What are the curative treatment options in hepatocellular carcinoma (HCC)?What is the role of surgical resection in the treatment of hepatocellular carcinoma (HCC)?What is the role of surgical resection in patients with cirrhosis and hepatocellular carcinoma (HCC)?Which pathological factors increase the risk of hepatocellular carcinoma (HCC) recurrence following surgical resection?Which clinical factors are associated with a higher rate of hepatocellular carcinoma (HCC) recurrence?When is repeat liver resection indicated in the treatment of hepatocellular carcinoma (HCC)?What are the advantages to orthotopic liver transplantation (OLT) for treatment of hepatocellular carcinoma (HCC)?Why were survival rates low for hepatocellular carcinoma (HCC) following liver transplantation in the 1990s?What are the survival rates for hepatocellular carcinoma (HCC) following liver transplantation?Which factors are associated with poor prognosis of hepatocellular carcinoma (HCC)?How are livers allocated for transplantation in the treatment of hepatocellular carcinoma (HCC)?What is the role of living donor and split-liver transplantations in the treatment of hepatocellular carcinoma (HCC)?What is the role of ablative therapies for hepatocellular carcinoma (HCC)?What is the role of percutaneous ethanol injection (PEI) in the treatment of hepatocellular carcinoma (HCC)?What is the role of radiofrequency ablation (RFA) in the treatment of hepatocellular carcinoma (HCC)?What new technologies are being investigated for the treatment of hepatocellular carcinoma (HCC)?Which dietary modifications are used in the treatment of hepatocellular carcinoma (HCC)?How is hepatocellular carcinoma (HCC) prevented?Which specialist consultations are beneficial to patients with hepatocellular carcinoma (HCC)?How common is recurrence of hepatocellular carcinoma (HCC)?What is the efficacy of posttransplant resection to treat recurrent hepatocellular carcinoma (HCC)?What are the guidelines for frequency of postoperative imaging procedures for hepatocellular carcinoma (HCC)?Which organizations have released guidelines on hepatocellular carcinoma (HCC)?How do the guidelines on hepatocellular carcinoma (HCC) screening vary?What are the ACR guidelines on diagnostic imaging for hepatocellular carcinoma (HCC)?How do the guidelines on hepatocellular carcinoma (HCC) diagnosis vary?What are the guidelines on hepatocellular carcinoma (HCC) staging?What are the AASLD treatment guidelines for hepatocellular carcinoma (HCC)?What are the NCCN treatment guidelines for hepatocellular carcinoma (HCC)?Which medications are used in the treatment of unresectable hepatocellular carcinoma (HCC)?Which medications in the drug class Antineoplastics, VEGF Inhibitor are used in the treatment of Hepatocellular Carcinoma (HCC)?Which medications in the drug class Antineoplastics, Tyrosine Kinase Inhibitor are used in the treatment of Hepatocellular Carcinoma (HCC)?Which medications in the drug class PD-1/PD-L1 Inhibitors are used in the treatment of Hepatocellular Carcinoma (HCC)?
Luca Cicalese, MD, FACS, Professor of Surgery, John Sealy Distinguished Chair in Transplantation Surgery, Director, Texas Transplant Center and Hepatobiliary Surgery, Department of Surgery, University of Texas Medical Branch School of Medicine
Disclosure: Nothing to disclose.
Specialty Editors
Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Chief Editor
John Geibel, MD, MSc, DSc, AGAF, Vice Chair and Professor, Department of Surgery, Section of Gastrointestinal Medicine, Professor, Department of Cellular and Molecular Physiology, Yale University School of Medicine; Director of Surgical Research, Department of Surgery, Yale-New Haven Hospital; American Gastroenterological Association Fellow; Fellow of the Royal Society of Medicine
Disclosure: Nothing to disclose.
Additional Contributors
Burt Cagir, MD, FACS, Clinical Professor of Surgery, Geisinger Commonwealth School of Medicine; Director, General Surgery Residency Program, Guthrie Robert Packer Hospital; Attending Surgeon, Guthrie Robert Packer Hospital and Corning Hospital
Disclosure: Nothing to disclose.
Acknowledgements
David A Axelrod, MD, MBA Assistant Professor of Surgery, Section Chief, Solid Organ Transplantation, Dartmouth-Hitchcock Medical Center
David A Axelrod, MD, MBA is a member of the following medical societies: American College of Surgeons, American Society of Transplant Surgeons, and New Hampshire Medical Society
Disclosure: Nothing to disclose.
Dirk J van Leeuwen, MD, PhD Professor of Medicine, Dartmouth Medical School; Consulting Staff, Director of Hepatology, Associate Director, Hepatopancreatico-biliary Center, Dartmouth-Hitchcock Medical Center; Consulting Gastroenterologist, White River Junction Veterans Administration Medical Center
Dirk J van Leeuwen, MD, PhD is a member of the following medical societies: American Association for the Study of Liver Diseases, American Gastroenterological Association, Dutch Society of Gastroenterology/Enterology, Dutch Society of Hepatology, European Association for the Study of the Liver, and New Hampshire Medical Society
Disclosure: Nothing to disclose.
References
International Agency for Research on Cancer. Liver. World Health Organization. Available at http://gco.iarc.fr/today/data/factsheets/cancers/11-Liver-fact-sheet.pdf. 2018; Accessed: March 2, 2020.
Bamia C, Stuver S, Mucci L. Cancer of the Liver and Biliary Tract. Adami HO, Hunter DJ, Lagiou P, Mucci L, eds. In: Textbook of Cancer Epidemiology. 3rd ed. New York, NY: Oxford University Press; 2018. 277-308.
Fong Y, Dupuy DE, Feng M, Abou-Alfa G. Cancer of the Liver. DeVita VT Jr, Lawrence TS, Rosenberg SA, eds. In: DeVita, Hellman, and Rosenberg's Cancer: Principles & Practice of Oncology. 11th ed. Philadelphia PA: Wolters Kluwer; 2018.
World Hepatitis Day. Centers for Disease Control and Prevention. Available at https://www.cdc.gov/features/worldhepatitisday/index.html. July 25, 2019; Accessed: March 2, 2020.
Immunization Coverage. World Health Organization. Available at https://www.who.int/news-room/fact-sheets/detail/immunization-coverage. December 5, 2019; Accessed: March 2, 2020.
Cancer Facts & Figures 2020. American Cancer Society. Available at https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2020/cancer-facts-and-figures-2020.pdf. Accessed: March 2, 2020.
Cancer Stat Facts: Liver and Intrahepatic Bile Duct Cancer. Surveillance, Epidemiology, and End Results Program. Available at https://seer.cancer.gov/statfacts/html/livibd.html. Accessed: March 2, 2020.
Harrison, P. Liver Cancer Increase Driven Mainly by NASH in Men Over 60. Medscape Medical News. March 23, 2020. Available at https://www.medscape.com/viewarticle/927374
Davenport, L. Liver Cancer Rates Tripled Over 20 Years in England. Medscape News UK. November 5, 2019. Available at https://www.medscape.com/viewarticle/920826#vp_2
van Leeuwen DJ, Shumate CR. Space-occupying lesions of the liver. van Leeuwen DJ, Reeders JWAJ, Ariyama J, eds. Imaging in Hepatobiliary and Pancreatic Disease: A Practical Clinical Approach. London: WB Saunders; 2000.
[Guideline] NCCN Clinical Practice Guidelines in Oncology: Hepatobiliary Cancers. National Comprehensive Cancer Network. Available at https://www.nccn.org/professionals/physician_gls/pdf/hepatobiliary.pdf. Version 4.2019 — December 20, 2019; Accessed: March 2, 2020.
Centers for Disease Control and Prevention. Viral Hepatitis. CDC.gov. Available at https://www.cdc.gov/hepatitis/populations/index.htm.. May 11, 2017; Accessed: March 28, 2020.
Jenkins, K. Liver Cancer Risk Reduced by Aspirin in Chronic Viral Hepatitis. Medscape Medical News. March 13, 2020. Available at https://www.medscape.com/viewarticle/926795
Large hepatocellular carcinoma. Image courtesy of Arief Suriawinata, MD, Department of Pathology, Dartmouth Medical School.
Hepatocellular carcinoma: pathobiology.
Hepatocellular carcinoma (HCC). Dilated collateral superficial abdominal veins in a 67-year-old man with cirrhosis, HCC, and portal vein occlusion.
Ultrasonographic image of hepatocellular carcinoma.
Arterial phase CT scan demonstrating enhancement of hepatocellular carcinoma.
Portal venous phase CT scan demonstrating washout of hepatocellular carcinoma.
MRI of a liver with hepatocellular carcinoma.
The Barcelona-Clinic Liver Cancer (BCLC) approach to hepatocellular carcinoma management. Adapted from Llovet JM, Fuster J, Bruix J, Barcelona-Clinic Liver Cancer Group. The Barcelona approach: diagnosis, staging, and treatment of hepatocellular carcinoma. Liver Transpl. Feb 2004;10(2 Suppl 1):S115-20.
Right hepatectomy. Part 1: Dissection of portal vein. Courtesy of Memorial Sloan-Kettering Cancer Center, featuring Leslie H. Blumgart, MD. (From Blumgart LH. Video Atlas: Liver, Biliary & Pancreatic Surgery. Philadelphia, PA: Saunders; 2010.)
Right hepatectomy. Part 2: Devascularization of right liver. Courtesy of Memorial Sloan-Kettering Cancer Center, featuring Leslie H. Blumgart, MD. (From Blumgart LH. Video Atlas: Liver, Biliary & Pancreatic Surgery. Philadelphia, PA: Saunders; 2010.)
Right hepatectomy. Part 3: Suturing and dividing. Courtesy of Memorial Sloan-Kettering Cancer Center, featuring Leslie H. Blumgart, MD. (From Blumgart LH. Video Atlas: Liver, Biliary & Pancreatic Surgery. Philadelphia, PA: Saunders; 2010.)
Large hepatocellular carcinoma. Image courtesy of Arief Suriawinata, MD, Department of Pathology, Dartmouth Medical School.
Photomicrograph of a liver demonstrating hepatocellular carcinoma. Image courtesy of Arief Suriawinata, MD, Department of Pathology, Dartmouth Medical School.
MRI of a liver with hepatocellular carcinoma.
Ultrasonographic image of hepatocellular carcinoma.
Arterial phase CT scan demonstrating enhancement of hepatocellular carcinoma.
Portal venous phase CT scan demonstrating washout of hepatocellular carcinoma.
The Barcelona-Clinic Liver Cancer (BCLC) approach to hepatocellular carcinoma management. Adapted from Llovet JM, Fuster J, Bruix J, Barcelona-Clinic Liver Cancer Group. The Barcelona approach: diagnosis, staging, and treatment of hepatocellular carcinoma. Liver Transpl. Feb 2004;10(2 Suppl 1):S115-20.
Hepatocellular carcinoma: pathobiology.
Right hepatectomy. Part 1: Dissection of portal vein. Courtesy of Memorial Sloan-Kettering Cancer Center, featuring Leslie H. Blumgart, MD. (From Blumgart LH. Video Atlas: Liver, Biliary & Pancreatic Surgery. Philadelphia, PA: Saunders; 2010.)
Right hepatectomy. Part 2: Devascularization of right liver. Courtesy of Memorial Sloan-Kettering Cancer Center, featuring Leslie H. Blumgart, MD. (From Blumgart LH. Video Atlas: Liver, Biliary & Pancreatic Surgery. Philadelphia, PA: Saunders; 2010.)
Right hepatectomy. Part 3: Suturing and dividing. Courtesy of Memorial Sloan-Kettering Cancer Center, featuring Leslie H. Blumgart, MD. (From Blumgart LH. Video Atlas: Liver, Biliary & Pancreatic Surgery. Philadelphia, PA: Saunders; 2010.)
Hepatocellular carcinoma (HCC). Dilated collateral superficial abdominal veins in a 67-year-old man with cirrhosis, HCC, and portal vein occlusion.
Hepatocellular carcinoma. Plain radiograph immediately following chemoembolization, demonstrating catheter placement and Ethiodol enhancement of tumors.
Alpha-Fetoprotein (ng/mL)
Interpretation
> 400-500
- HCC likely if accompanied by space-occupying solid lesion(s) in cirrhotic liver or levels are rapidly increasing.
- Diffusely growing HCC, may be difficult to detect on imaging.
- Occasionally in patients with active liver disease (particularly HBV or HCV infection) reflecting inflammation, regeneration, or seroconversion
Normal value to < 400
- Frequent: Regeneration/inflammation (usually in patients with elevated transaminases and HCV) - Regeneration after partial hepatectomy
- If a space-occupying lesion and transaminases are normal, suspicious for HCC
Normal value
Does not exclude HCC (cirrhotic and noncirrhotic liver)
Author (Year)
N
Survival Rate
1 year
5 years
Mazzefero (1996)
48
84%
74%
Bismuth (1999)
45
82%
74%
Llovet (1999)
79
86%
75%
Jonas (2001)
120
90%
71%
Stage
Criteria
0 – Very Early
Child-Pugh class A
Single < 2 cm nodule
ECOG PS 0-1
A – Early
Child-Pugh class A-B
Single or 2-3 nodules < 3 cm
ECOG PS 0-1
B – Intermediate
Child-Pugh class A-B
Multinodular
ECOG PS 0-1
C - Advanced
Child-Pugh class A-B
Portal vein invasion, N1, M1
ECOG PS 0-2
D - Terminal
Child-Pugh class C
Any T, N, or M
ECOG PS > 2
ECOG PS = Eastern Cooperative Oncology Group Performance Status
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