Welcome to the NORD Physician Guide to Hepatocellular Carcinoma (HCC). The NORD Online Physician Guides are written for physicians by physicians with expertise on specific rare disorders. This guide was written by Jonathan M. Schwartz, MD, Professor of Clinical Medicine, Division of Gastroenterology and Liver Diseases, Albert Einstein College of Medicine, Montefiore Medical Center Bronx, NY. (see acknowledgements for additional information).
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Hepatocellular carcinoma (HCC) is the most common primary liver tumor and results in approximately 700,000 deaths annually worldwide.
HCC often occurs in patients with chronic liver diseases such as hepatitis B, hepatitis C and alcoholic or non-alcoholic fatty liver disease.
There is randomized controlled evidence of a survival benefit to screening and surveillance in patients at risk.
Patients with early stage disease represent about one third of patients, and can be treated with “curative” techniques such as surgical resection, liver transplantation or tumor ablation by radiofrequency or microwave techniques.
What is Hepatocellular carcinoma (HCC)?
Hepatocellular carcinoma (HCC) is the most common primary liver tumor and results in approximately 700,000 deaths annually worldwide (1). The incidence of HCC has been rising in the United States over the past four decades. Based on the National Health and Nutrition Examination Survey data, there were 1.4 new cases per 100,000 people annually in the 1970’s. Currently, there are an estimated six new cases per 100,000 of the population annually (2, 3). Despite the relatively low prevalence of HCC, the disease has a high case-fatality rate, leading to over 29,000 deaths annually (4).
HCC often occurs in patients with chronic liver diseases such as hepatitis B, hepatitis C and alcoholic or non-alcoholic fatty liver disease (5). The rising incidence of HCC can likely be attributed to an aging population of patients with hepatitis C infection that have developed liver injury over the past few decades. HCC is typically evolves in patients with advanced hepatic fibrosis or cirrhosis; however HCC has recently been observed in non-cirrhotic patients with the metabolic syndrome and non-alcoholic fatty liver disease (6).
Early diagnosis enables potentially curative treatments, and although limited, there is randomized controlled evidence of a survival benefit to screening and surveillance in patients at risk (7, 8). The American Association for the Study of Liver Diseases thus recommends hepatic imaging every six months among patients at risk for HCC (9) (Table I). The diagnosis of HCC is typically made on the basis of imaging findings.
Treatment of HCC is determined by both tumor characteristics (number and size) and the extent of hepatic reserve as assessed by the Child-Turcotte-Pugh classification (10). These parameters, in conjunction with ECOG performance status, have been used to develop the validated Barcelona Liver Cancer Staging system (BCLC) (11). The BCLC staging system is used as a guideline to treat HCC. Patients with early stage disease represent about one third of patients, and can be treated with “curative” techniques such as surgical resection, liver transplantation or tumor ablation by radiofrequency or microwave techniques. Intermediate stage disease (multifocal tumors in the absence of tumor invasion of the portal vein or extra-hepatic metastases) is typically treated with transarterial chemoembolization or radioembolization using 90Yttrium, whereas patients with advanced tumor burden, portal venous invasion or metastatic disease with good performance status derive a survival benefit from the oral multi-kinase inhibitor, sorafenib (12, 13). Ongoing clinical trials show promising results for patients who do not respond to sorafenib (13, 14).
Patients with hepatocellular carcinoma are frequently asymptomatic especially if the disease is diagnosed at an early stage. Symptoms and signs associated with cirrhosis such as hepatic encephalopathy may be exacerbated by HCC, and new onset of hepatic decompensation (development of ascites, variceal bleeding or hepatic encephalopathy) is often associated with a diagnosis of HCC. Furthermore, patients with hepatic decompensation as manifest by ascites, hepatic encephalopathy or portal hypertension related intestinal bleeding may develop disease progression as a consequence of HCC.
Patients with advanced HCC may present with insidious abdominal pain (typically in the right upper quadrant), weight loss and constitutional signs or symptoms such as fatigue, weight loss, anorexia or infrequently fever or diarrhea. Pain related to bony metastases or symptoms due to pulmonary or central nervous system metastases may occur in advanced disease.
HCC diagnosed through screening or surveillance is often diagnosed at an early and treatable stage. Patients with hepatitis B infection and cirrhosis from all causes should be enrolled in such a program (see Table 1).
Table 1. Screening and Surveillance for HCC
Screening and surveillance with abdominal imaging, typically ultrasonography, is performed every six months. Once a nodule is detected on ultrasonography, cross sectional imaging using triple phased CT or contrast enhanced MRI is frequently diagnostic, and biopsy of liver nodules is usually unnecessary. Radiographic features of HCC include increased tumor vascularity as observed in the arterial phase. There is subsequent portal venous phase “washout” which is observed when blood leaves the tumor when the surrounding non-tumorous hepatic parenchyma is enhanced by the contrast agent. Additional imaging features include a pseudo capsule or may identify tumor invasion of the portal vein or lymph node enhancement. These imaging findings have been systematically characterized in the Liver Imaging Reporting and Data Systems (LIRADS) diagnostic criteria that also incorporates tumor growth (Figure 1—LIRADs) (15). Contrast enhanced MRI and CT can provide valuable information regarding the number and size of typical HCC lesions in addition to the presence of portal or hepatic venous tumor invasion and lymph node or extra-hepatic spread. Since a proportion of HCC are hypovascular and given the possibility of other liver tumors such as cholangiocarcinoma or metastatic tumors, imaging guided biopsy is recommended to diagnose tumors without typical imaging features of HCC.
Figure I. LIRADS Classification of HCC
Histologically, HCC has features of cells that resemble normal hepatocytes and is assessed according to differentiation (well, moderate or poorly differentiated). The degree of differentiation of HCC is assessed by the resemblance of neoplastic cells to normal hepatocytes (16).
Given the potential for sampling error, a negative biopsy result should be followed by careful surveillance imaging and a there should be a low threshold to repeat a biopsy if there is a concern regarding the accuracy of tissue sampling. There is a small possibility of tumor seeding during the biopsy (17), hence in the absence of a clinical protocol, biopsy should not be routinely performed among patients with typical imaging features of HCC.
Patients with sub-centimeter nodules on screening or surveillance imaging should have repeat imaging every three months until a lesion is one or more centimeters in size, at which point, the lesion(s) should be characterized with contrast enhanced MRI or CT imaging. Patients with chronic kidney disease represent a particular challenge since MRI contrast agents are contraindicated in end stage renal disease given the risk of nephrogenic (18) systemic fibrosis. Furthermore, contrast CT can accelerate renal dysfunction, however it can be used once patients are on dialysis.
Staging and Treatment(s)
HCC typically occurs in patients with cirrhosis and varying degrees of hepatic dysfunction. Treatment of HCC thus requires a careful assessment of hepatic function in addition to tumor parameters. Patients are often managed by multidisciplinary teams at tertiary referral medical centers. These teams include hepatologists, medical oncologists, hepatobiliary and transplant surgeons, imaging and interventional radiologists and radiation oncologists and nurse coordinators.
Most staging systems incorporate tumor burden and indices of hepatic function such as the Child-Pugh classification. The Barcelona Cancer of the Liver (BCLC) staging system (see figure 2) has been prospectively validated and is a robust staging system that incorporates tumor burden, Child-Pugh status and ECOG performance status. The BCLC staging system also associates the different stages of disease with a guideline for evidenced based therapies.
Figure 2. Barcelona Clinic Cancer of the Liver Staging and Treatment Algorithm
Patients with early stage disease (BCLC stage A) typically have preserved hepatic function and a solitary tumor without portal venous invasion or extra hepatic metastases. Such patients are typically eligible for “curative” therapies which include surgical resection (Child Pugh Class A cirrhotics with unifocal tumors in the absence of portal hypertension or hyperbilirubinemia), liver transplantation (unifocal tumors up to 5 cm with portal hypertension or up to three tumors none larger than 3 cm without portal invasion or extra hepatic disease) or tumor ablation by radiofrequency or microwave techniques. There is also an emerging role for focused external beam radiation to ablate tumors that cannot be ablated by other techniques (19).
BCLC Stage B patients with multifocal disease and preserved hepatic function (Child Pugh Class A or B) and good ECOG performance status in the absence of extrahepatic disease or portal invasion derive a survival benefit from transarterial embolization, typically with adriamycin based embolic material (either drug eluting beads or delivered as a lipiodol based emulsion) or using radioactive Yttrium embolization in select patients (20, 21).
Patients with extra hepatic metastases, portal vein or hepatic vein tumor invasion with good ECOG performance status and preserved hepatic function typically have a poor short term probability of survival. Randomized controlled trials have shown a significant survival benefit using the oral multikinase inhibitor, sorafenib (12, 22). Sorafenib inhibits angiogenesis and cell proliferation in this context.
Unfortunately patients with poor ECOG performance status, advanced hepatic dysfunction and advanced hepatic tumors only benefit from the best supportive measures.
Unfortunately, there does not appear to be a survival benefit when sorafenib is used as an adjunct to surgical resection, liver transplantation, ablative or transarterial embolic techniques (site reference: Storm, SPACE, etc).
Techniques to improve patient eligibility for curative therapies such as surgical resection or liver transplantation are being pursued. These include contra-lateral portal venous embolization to induce hepatic hypertrophy and subsequent safe hepatic resection (23).There is also evolving data that patients with tumors that exceed the current size criteria for liver transplantation do well after down staging to within the Milan Criteria followed by subsequent liver transplantation (24).
Several phase 3 investigations of therapies for patients with tumor progression on sorafenib are ongoing. There appears to be a survival advantage using the kinase inhibitor tivantinib among patients with tumors that express the tumor marker Met (14). In addition, there may also be a survival benefit from a modified version of sorafenib (regerafenib) among patients who do not respond to sorafenib (13).
Immunotherapeutic agents also show promise and early phase clinical trials.
Information on current clinical trials is posted at https://www.clinicaltrials.gov/. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials sponsored by private sources, contact: www.centerwatch.com
For more information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
NORD does not endorse or recommend any particular studies.
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