Primary liver cancers arise predominantly from the parenchymal liver cells or hepatocytes (90%) and are called hepatocellular carcinoma (HCC). The incidence of HCC continues to increase rapidly in the United States, with rates increasing the fastest in men (
1). Research on vaccinations for hepatitis B and their use have impacted the development of HCC in many regions of the world.
EPIDEMIOLOGY
In the United States, the incidence of clinically significant metastatic carcinoma to the liver is 20 times more common than primary liver cancer.
Based on November 2006 SEER data submission, the incidence for all races was 9.9 per 100,000 men and 3.5 per 100,000 women (http://seer.cancer.gov/statfacts/html/livibd.html).
There are fewer than 10,000 new patients annually, accounting for less than 2% of all malignancies.
There is marked geographic variation in the incidence of HCC, with the highest incidences occurring in sub-Saharan Africa and Asia. Over 40% of all cases of HCC occur in the People’s Republic of China, which has an annual incidence of 137,000 cases (2).
Men are affected twice as often as women (mean 3.7:1). The mean age at diagnosis is between 50 and 60 years.
ETIOLOGY
Cirrhosis is present in 80% of patients with HCC. Therefore, risk factors for cirrhosis are also risk factors for HCC.
Hepatitis B virus (HBV) infection increases the risk of developing HCC by 100-fold. HBV causes 80% of HCC in the world. HCC develops from chronic hepatitis due to HBV at a rate of 0.5% per year; 15% to 80% have HBs antigenemia.
Hepatitis C virus (HCV) infection accounts for 30% to 50% of HCC in the United States. In contrast to HBV infection, HCC in patients with hepatitis C occurs almost exclusively in those with cirrhosis.
Alcoholic cirrhosis accounts for 15% of HCC.
Hemochromatosis (HH), hereditary tyrosinemia, and autoimmune chronic active hepatitis are other causes of cirrhosis and are associated with a significant risk for developing HCC. In all, 3% to 27% of patients with long-standing HH develop HCC.
There is less convincing evidence for the risk of developing HCC from Aflatoxin B1 (chemical product of Aspergillus), androgenic steroids, thorotrast (radiology contrast agent), oral contraceptives, and nonalcoholic fatty liver disease. In diabetes mellitus, the risk was increased by approximately 2.5 times.
CLINICAL FEATURES The most common symptoms or signs of HCC are:
Pain (91%)
Weight loss (35%)
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Vomiting (8%)
Hepatomegaly (89%)
Abdominal swelling (43%)
Jaundice (7-41%).
Paraneoplastic manifestations can also occur. They include hypoglycemia, hypercalcemia, carcinoid, erythrocytosis, hypercholesterolemia, hyperthyroidism, and osteoporosis. The physical findings in most patients with HCC (splenomegaly, ascites, jaundice, or other manifestations of decompensated cirrhosis) reflect the underlying liver disease. Hepatomegaly or a bruit heard over the liver are occasionally present. DIAGNOSIS The diagnosis of HCC is often suspected in a patient with underlying liver disease (i.e., cirrhosis, chronic viral hepatitis), who develops a rising serum alfa-fetoprotein (AFP) level (
3). Recommendations for diagnosis of HCC have been issued in a guideline from the American Association for the Study of Liver Diseases (
3).
Nodules found on ultrasound surveillance that are smaller than 1 cm should be followed with ultrasound at intervals of 3 to 6 months. If there has been no growth over a period of up to 2 years, one can revert to routine surveillance.
Nodules between 1 and 2 cm found on ultrasound screening of a cirrhotic liver should be investigated further with two dynamic studies, whether computed tomography (CT) scan, contrast ultrasound, or magnetic resonance imaging (MRI) with contrast. If the appearances are typical of HCC (i.e., hypervascular with washout in the portal/venous phase) in two techniques the lesion should be treated as HCC. If the findings are not characteristic or the vascular profile is not coincidental among techniques, the lesion should be biopsied.
If the nodule is larger than 2 cm at initial diagnosis and has the typical features of HCC on a dynamic imaging technique, biopsy is not necessary for the diagnosis of HCC. Alternatively, if the AFP is >200 ng/mL biopsy is also not required. However, if the vascular profile on imaging is not characteristic or if the nodule is detected in a noncirrhotic liver, biopsy should be performed.
Biopsies of small lesions should be evaluated by expert pathologists. If the biopsy is negative for HCC, patients should be followed by ultrasound or CT scanning at 3 to 6 month intervals until the nodule disappears, enlarges, or displays diagnostic characteristics of HCC. If the lesion enlarges but remains atypical for HCC, a repeat biopsy is recommended.
Serum Markers The most commonly used marker for HCC is the serum AFP concentration. Several other serologic markers (such as des-gamma-carboxy prothrombin—these other markers are not used in routine clinical practice) may indicate the presence of HCC, and used alone or in combination with the serum AFP may improve the diagnostic accuracy. It is generally accepted that serum levels greater than 500 mcg/L (normal in most laboratories is between 10 and 20 mcg/L) in a high-risk patient is diagnostic of HCC. However, HCC is often diagnosed at a lower AFP level in patients undergoing screening (
4), as not all tumors secrete AFP, and serum concentrations are normal in up to 40% of small HCCs, epspecially where alcohol is the etiological factor (
5). AFP levels are normal in the majority of patients with fibrolamellar carcinoma, a variant of HCC. Imaging Studies The imaging tests most commonly used for the diagnosis of HCC are ultrasound, CT, MRI, and angiography. A classic appearance on one of these imaging modalities combined with an elevated serum AFP concentration in the appropriate clinical setting is usually sufficient for establishing the diagnosis of HCC.
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PET Scanning The ability of a PET scan to distinguish benign lesions from malignant lesions is unclear. A new tracer, (
11)C-acetate, appears to improve sensitivity and specificity when used in conjunction with F-FDG PET. Until further data are available, the role of PET scanning in the evaluation of patients with HCC remains uncertain (
6,
7).
Laparoscopy is recommended to improve staging and to prevent unnecessary laparotomy (8).
PATHOLOGY
Ninety percent of primary cancers of the liver are HCC, the remaining include cholangiocarcinoma, hepatoblastoma, angiosarcoma, and other sarcomas. There are many histologic types of HCC including trabecular, pseudoglandular or acinar, compact, scirrhous, clear cell, and fibrolamellar.
Fibrolamellar carcinoma is a histologic variant accounting for 1% of HCC. It occurs more commonly in women, is not associated with cirrhosis, and has a better prognosis than HCC.
STAGING
The TNM staging system (Table 7.1) has been criticized because it does not evaluate the underlying liver disease, which is clearly a major prognostic factor in patients regardless of tumor stage.
The Child-Pugh grading system has been incorporated into the management of HCC because it evaluates the status of the underlying liver function and influences treatment (Table 7.2).
TREATMENT Surgery
Surgery remains the only possibility for cure in HCC. Surgery is applicable to only about 5% of the U.S. population.
The treatment of HCC is determined by two factors: tumor extent and the severity of the underlying hepatic parenchymal disease.
| TABLE 7.1. The American Joint Committee on Cancer (AJCC) sixth edition TNM stage groupings |
| Stage I | T1 N0 M0 | T1: solitary tumor with no vascular invasion | 5-year survival rates—55% | | Stage II | T2 N0 M0 | T2: solitary tumor with vascular invasion or multiple tumors none >5 cm | 5-year survival rates—37% | | Stage IIIA | T3 N0 M0 | T3: multiple tumors 5 cm or involving a major branch of the portal or hepatic vein(s) | | | Stage IIIB | T4 N0 M0 | T4: tumor directly invading adjacent organs other than gallbladder or perforating visceral peritoneum | 5-year survival rates—15% | | Stage IIIC | Any T N1 M0 | N1: regional lymph node metastases | | Stage IV | Any T any N | M1 M1: distant metastases |
|
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| TABLE 7.2. Child-Pugh scoring system |
| Score attributed to each parameter | | Chemical and biochemical parameters | 1 | 2 | 3 | | Encephalopathy | None | 1-2 | 3-4 | | Ascites | None | Slight | Moderate | | Albumin (g/dL) | >3.5 | 2.8-3.5 | <2.8 | | Prothrombin time prolonged (s) | 1-4 | 4-6 | >6 | | INR | <1.7 | 1.7-2.3 | >2.3 | | Bilirubin (mg/dL) | 1-2 | 2-3 | >3 | | Class A = 5-6 points, Class B = 7-9 points, Class C = 10-15 points. These grades correlate with 1- and 2-year patient survival—grade A: 100% and 85%; grade B: 80% and 60%; and grade C: 45% and 35%. |
|
Partial hepatectomy: Only 13% to 35% are surgical candidates. Small tumors have the best outcomes. Recurrence is most commonly seen in the remnant liver. Repeat hepatectomy is possible in 10% to 29% of patients. Operative mortality is <5%, but is higher in the presence of cirrhosis. Long-term relapse-free survival rates average 40% or better, and 5-year survival rates as high as 90% are reported in carefully selected patients.
Total hepatectomy and liver transplantation: Transplantation is indicated in patients with severe cirrhosis or where extensive resection leaving minimal liver reserve is required.
Orthotopic liver transplantation (OLT) is a suitable option for unresectable patients who have a solitary HCC ≤5 cm in diameter or up to three separate lesions none of which is larger than 3 cm, no evidence of gross vascular invasion, and no regional nodal or distant metastases (The Milano/Mazzaferro criteria). Based on these criteria, 4-year survival was reported as 75% to 85% (9).
Survival outcomes may be further improved by living donor transplantation, although this remains controversial.
Disadvantages of transplantation are the expense, the lack of specialty centers performing operations, and the lack of donor livers.
Ablative Techniques
Although there is no absolute tumor size beyond which radiofrequency ablation (RFA) should not be considered, the best outcomes are in patients with a single tumor <4 cm in diameter. For cirrhotic patients, some clinicians restrict RFA to those with Child-Pugh class A or B severity only.
Ablation of large tumors (>5 cm) has been shown to be associated with very high local recurrence rates.
Percutaneous ethanol or acetic acid into tumors is frequently used for up to three localized tumors of <5 cm that are not surgical candidates usually due to cirrhosis. It is relatively inexpensive and well tolerated.
RFA is performed percutaneously using ultrasound guidance and causes focal coagulative necrosis of tumors via thermal energy. It is most efficacious for tumors <3 cm where complete necrosis can occur in up to 90% of tumors.
Cryotherapy is also safe and more effective than RFA for larger tumors, but is less suited to a percutaneous approach.
Hepatic artery chemoembolization (transarterial chemoembolization [TACE]) is based on the principal that 80% of the blood supply to tumors is from the hepatic artery, which supplies only 20% to 30% of normal liver parenchyma. Ligation or embolization of the hepatic artery can induce temporary tumor responses, but when combined with chemotherapy can be more efficacious.
TACE is used most often for the treatment of large unresectable HCCs that are not amenable to other treatments such as resection or RFA; its use as a “bridging therapy” prior to transplant is less well defined. Bland particle embolization alone (i.e., without chemotherapy) has also been used for both unresectable and locally recurrent HCC.
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This approach is currently progressing, resulting in an improved median survival rate and quality of life. In a study of 16 patients with stage II-IV unresectable or recurrent HCC, hepatic arterial infusion (HAI) of oxaliplatin was administered. HAI-oxaliplatin was shown to be feasible, well-tolerated, and to demonstrate activity in patients with advanced HCC (10).
Absolute contraindications to this technique include the absence of hepatopetal blood flow (portal vein thrombosis), encephalopathy, and biliary obstruction.
Radiation
Liver can only tolerate about 20 Gy. However, safe and effective doses can be given to palliate the pain.
Radioactive isotopes have demonstrated efficacy in the adjuvant treatment of HCC.
Stereotactic radiotherapy: Stereotactic body radiation therapy (SBRT) is a technique in which a single (sometimes called sterotactic radiosurgery) or limited number of high-dose radiation fractions are delivered to a small, precisely defined target by using multiple, nonparallel radiation beams. The beams converge precisely on the target lesion, minimizing radiation exposure to adjacent normal tissue. This targeting allows treatment of small- or moderate-sized tumors in extracranial sites in either a single or limited number of dose fractions.
Stereotactic approaches to RT are increasingly being used for treatment of metastatic liver tumors.
Selective internal irradiation: For example, iodine-131 (131I)-labeled lipiodol or yttrium-90 (90Y)-tagged glass microspheres are delivered selectively to the tumor via the hepatic artery. Early reports suggest that radioembolization using intrahepatic artery administration of (90Y)-tagged glass microspheres is safe, and induces objective responses in patients with unresectable HCC. However, long-term follow-up of these studies and additional experience are needed with this technique.
Chemotherapy
Hepatocellular cancer has been considered to be a relatively chemotherapy-refractory tumor.
Systemic therapy is appropriate for patients with advanced unresectable disease who are unsuitable for locoregional therapy.
Single-agent chemotherapy has demonstrated response rates of approximately 15% to 30%, which increases to 20% to 35% with combination therapy. Cisplatin and anthracycline combinations have been studied most extensively, but there is no reference regimen for this disease (11). Despite objective responses that are occasionally complete, median survival in all of these studies has been short (4-11 months), with the exception of those in which resection/transplantation is attempted after chemotherapy.
Interferon-alfa (IFNa) and chemoimmunotherapy: Combinations of chemotherapy with IFNa appear active.
The PIAF regimen (intravenous cisplatin, recombinant interferon-alfa 2b, doxorubicin, and 5-fluorouracil) demonstrated a 50% objective response rate in 50 patients with unresectable disease from Hong Kong (12), but failed to show superiority versus Doxorubicin (13).
Molecularly Targeted Therapy
Sorafenib (a multikinase inhibitor with antiangiogenic, proapoptotic, and Raf kinase-inhibitory activity) was well tolerated and is the first agent to demonstrate a statistically significant improvement in overall survival (OS) for patients with advanced HCC. The OS was significantly longer in the sorafenib-treated patients (10.7 vs. 7.9 months; HR = 0.69, P = 0.0006), as was the time to progression (5.5 vs. 2.8 months; HR = 0.58, P = 0.000007). This effect is clinically meaningful and establishes sorafenib as first-line treatment for patients with advanced HCC (14). It has also demonstrated encouraging results with doxorubicin (15).
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VEGF Receptor Targeting
Bevacizumab: Bevacizumab (an anti-VEGFR monoclonal antibody [MoAb]) alone is active in HCC. A preliminary report of a trial documented a partial response in 2 of 27, and disease stabilization in 18 patients (16).
The combination of bevacizumab with gemcitabine and oxaliplatin (GEMOX) was safe and moderately effective in a small phase 2 trial.
Sunitinib: Sunitinib is an orally active TKI that targets a variety of TKs in addition to VEGFR, including platelet-derived growth factor receptors (PDGFRs), KIT, RET, and FLT3. Some antitumor activity is suggested with early studies (17).
Anti-EGFR Strategies
Small-molecule TK inhibitors: Limited activity for erlotinib (Tarceva), a small-molecule TKI with specificity for EGFR, was suggested in a phase 2 study of 38 patients with unresectable or metastatic HCC, one-half of whom had previously received cytotoxic chemotherapy (18).
Cetuximab: Cetuximab (Erbitux) is a MoAb that binds to the EGFR. Early results suggest activity for cetuximab in combination with GEMOX (19).
PREVENTION AND NOVEL THERAPIES
Hormone therapy: Tamoxifen, megestrol, antiandrogen therapy, and octreotide have been extensively investigated but do not have a beneficial effect on patients with HCC. HMG-CoA reductase inhibitors such as pravastatin have shown conflicting results (20).
IFNa reduces the onset of liver damage and its progression to cirrhosis in 10% to 30% of patients with chronic hepatitis B.
Refrigerated storage of food grains and transportation of grains in refrigerated vehicles should help reduce the risk of ingesting aflatoxin.
Acyclic retinoid polyprenoic acid, reduces the incidence of second primary of HCC after initial resection and requires further investigation.
Screening of high-risk populations with AFP at 4-month intervals and with ultrasound at yearly intervals has been shown to identify patients with earlier stages of HCC and may improve survival in high-risk groups (21).
