for Health Care Providers
Background - Liver Cancer
Hepatocellular carcinoma (HCC) in 2005 is a cancer that is becoming increasingly common in the United States.(1) Its effects on the health of Americans, and particularly veterans, likely will grow substantially over the next several decades, as the later health consequences of the hepatitis C epidemic play themselves out.(2)
HCC is the fifth most common cancer in the world and the most common type of liver cancer. The incidence of HCC in the United States is approximately 2.4 per 100,000 persons per year, and rising.(3) Chronic infection with hepatitis C virus (HCV) is now a major risk factor for the development of HCC in developed countries. Patients with advanced liver disease, particularly cirrhosis, are those at risk for HCC and should be screened every 6 months for its development. The risk of developing HCC for a patient with HCV-related cirrhosis is approximately 2-6% per year.(4)
Chronic hepatitis B virus (HBV) infection, chronic HCV-related cirrhosis, and cirrhosis of any etiology are the major risk factors for the development of HCC. Patients with HBV are known to be at risk for HCC even without cirrhosis, so all patients with chronic HBV (those who are hepatitis B surface antigen positive) should be considered for screening for HCC.(5) Individuals with chronic HBV who are at increased risk for HCC include men, anyone over age 45, and those with cirrhosis or a family history of HCC. (6)
In patients with HCV, only those with advanced liver disease (particularly cirrhosis) have been shown to be at high risk for HCC, so screening should be applied only to these patients.(7) Other HCC risk factors include inherited metabolic diseases such as hemochromatosis and tyrosinemia. Additional risk factors for HCC development include older age, alcohol use, and exposure to aflatoxin, particularly in developing countries.
Screening for HCC in at-risk patients is expensive and time consuming, and only recently has it been shown to lead to improved patient outcomes.(4, 8) Nonetheless, it is considered standard practice within the gastroenterology/liver community in developed areas of the world.(7) Screening generally is performed using both serum alpha fetoprotein (AFP) and hepatic imaging by ultrasound, computerized tomography (CT) scanning, or magnetic resonance imaging (MRI). Screening intervals generally are every 6 months. No screening strategy is perfect, and patients have been found at transplant to have tumors that were not seen on imaging, or to have no tumor in areas that were suspicious by imaging.(9)
No randomized controlled trial of screening/surveillance in patients at risk for HCC, with disease-specific or all-cause mortality as end points, has been published. Nor is one expected, as screening of cirrhotic patients for HCC with serial liver imaging and measurement of serum AFP is now considered standard practice. However, studies that reflect improved outcomes with these screening strategies are being published. An Italian group found that patients undergoing screening and aggressive therapy for HCC diagnosed after 1997 had smaller tumors and improved yearly mortality compared with patients who had been diagnosed during earlier time periods.(4)
Serum Testing for AFP
Between 50% and 85% of hepatocellular carcinomas produce AFP, which normally is not present at high levels in the blood of adults. Elevation of AFP in the blood is fairly sensitive for the detection of HCC. In one study of patients with chronic HCV, the sensitivity and specificity of an AFP of >20 ng/mL for the diagnosis of HCC were 67% and 89%, respectively.(10) It should be noted, however, that pregnancy, germ cell tumors, and even chronic inflammatory liver diseases also can elevate AFP levels. The positive predictive value of an AFP >20 ng/mL is poor since minor elevations are common in patients with chronic liver disease. In one prospective study of 200 patients with chronic HCV infection, 13% of those without cirrhosis and 47% of those with cirrhosis had a serum AFP level of >10 ng/mL.(11) When AFP has been studied in patients with HCV-related cirrhosis specifically, an AFP >200 ng/mL in the setting of a hepatic mass was found to be essentially diagnostic of HCC, although lower levels were not as specific.(12) African Americans with HCC also tended to have less AFP elevation than Caucasians with HCC, making AFP a less helpful marker in them.
Ultrasound is the standard imaging modality for HCC screening, and a skilled operator can often visualize tumors that are ≥1 cm in diameter.(13) Ultrasound sensitivity for detection of such tumors across several studies is in the range of 60%, with specificity of around 90%.(14) The cirrhotic liver can make visualization of small HCCs very difficult, however, so screening practices should be individualized based on available resources at each location where screening is performed.
Other Imaging Studies
Other radiological techniques including CT scans and MRI are even more sensitive than ultrasound in detecting small lesions in the liver. One study found the sensitivity of HCC detection to be 79.4% for ultrasound, 81.6% for CT scan, and 88.9% for MRI.(15) The cost effectiveness of these imaging studies compared with ultrasound remains to be demonstrated, however, as unrelated abnormalities of the liver that require evaluation are detected by the increasingly sensitive techniques.
Clinical signs and symptoms present in later stages of HCC. These signs and symptoms may include:
- right upper quadrant pain or fullness
- weight loss
- elevated liver function tests, particularly an elevated alkaline phosphatase
- increases in AFP levels
- infrequently: polycythemia, hypoglycemia, hypercalcemia, dysfibrinogenemia, or intraperitoneal bleeding due to tumor rupture
Because clinical presentations of HCC are not entirely specific, histological evaluation with a percutaneous biopsy sometimes is performed to aid in the diagnosis. This often is not done, however, in patients with known cirrhosis who are found to have a new mass lesion concerning for HCC during screening. Particularly, a nodule >2 cm in diameter in this setting has >95% likelihood of being an HCC.(16) According to European Association for the Study of Liver guidelines, confirmation of arterial hypervascularity of the lesion by 2 additional imaging techniques (CT, MRI, or angiography), or 1 additional imaging technique if the AFP is >400 ng/mL, is sufficient for a diagnosis of HCC without a biopsy.(17) Smaller lesions in a cirrhotic patient also often represent early HCCs. If a patient with a concerning lesion is being considered for referral for listing for liver transplantation, consultation with the referring center also can be undertaken prior to proceeding with a percutaneous biopsy of the lesion.
Staging is essential for the optimal management of HCC, as a wide variety of treatments are applied based on HCC stage. Residual hepatic function and tumor extent tend to be the two factors that most influence HCC prognosis. Hepatic function tends to be assessed by the Child-Pugh classification or the MELD score. Unfortunately, no single scoring system for HCC staging has been accepted as the best one. Staging systems that have been widely used are the Okuda system,(18) the tumor, node, metastasis (TNM) system of the International Union Against Cancer,(19) the Cancer of the Liver Italian Program (CLIP) score,(20) the Barcelona Clinic Liver Cancer (BCLC) system,(21) and several others. The TNM system takes into account only the extent of the tumor; the Okuda system adds serum albumin, serum bilirubin, and the extent of ascites; and the CLIP system includes Child-Pugh class, tumor morphology, whether or not the AFP is >400 ng/mL, and the presence or absence of portal vein thrombosis. The BCLC system is similar to the CLIP, but incorporates the performance status of the patient, and does not include AFP. A recent study comparing the predictive value of 7 staging systems in a group of HCC patients in the United States found that all 7 systems were valid, with survival declining in direct correlation with higher score, but that the BCLC system, incorporating performance status, had the best independent predictive power for survival.(22) Practitioners caring for many HCC patients likely will find it useful to have a working knowledge of several of the systems.
The median survival of HCC patients after diagnosis generally has been a little more than 1 year. Survival usually is between 3-6 months if a patient is diagnosed after the onset of symptoms. Median survivals as short as 8-10 weeks have been reported in some studies, including a retrospective study of 157 untreated patients, 18% of whom had extrahepatic metastases at the time of diagnosis.(23) Causes of death in these patients were upper gastrointestinal bleeding in 34%, cancer-related causes (cachexia and metastatic disease) in 32%, and hepatic failure in 25%.
Prevention of HCC
Prevention efforts in the area of HCC have been directed at prevention of underlying liver disease. Primary prevention of HCV infection includes thorough screening of the blood supply and risk-reduction interventions in injection drug users. Secondary prevention of the progression from HCV-related cirrhosis to HCC has been shown following interferon-alfa treatment of cirrhosis.(46, 47) Limiting alcohol intake and reducing obesity in patients with HCV also may lead eventually, through decreased liver disease progression, to a reduction in HCC.
HBV immunization programs have successfully reduced the incidence of HBV-associated HCC. In Taiwan, the rate of HCC in children aged 6-9 decreased from 5.2 per million before a neonatal vaccination program for HBV began in 1984 to 1.3 per million in the first vaccinated cohort.(48)
Kubo and colleagues randomized 30 HCV-positive men after HCC resection to either 2 years of interferon-alfa or no postoperative therapy.(49) The rate of tumor recurrence was significantly lower in the interferon-alfa group than in the control group, and the authors concluded that postoperative interferon-alfa therapy had a role in decreasing the incidence of recurrence after resection of HCV-related HCC. Agents such as polyprenoic acid and acyclic retinoids are also being investigated in the hopes of preventing second primaries following resection of HCC.(50)
Learn about treatment for hepatocellular carcinoma.
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