eMedicine Specialties > General Surgery > Abdomen

Hepatocellular Carcinoma

David A Axelrod, MD, MBA, Assistant Professor of Surgery, Section Chief, Solid Organ Transplantation, Dartmouth-Hitchcock Medical Center
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

Updated: Sep 18, 2008

Introduction

Hepatocellular carcinoma (HCC) is a primary malignancy of the liver. Hepatocellular carcinoma is now the third leading cause of cancer deaths worldwide, with over 500,000 people affected.  The incidence of hepatocellular carcinoma 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 hepatocellular carcinoma.

The presentation of hepatocellular carcinoma has evolved significantly over the past few decades.  While, in the past, hepatocellular carcinoma generally presented at an advanced stage with right upper quadrant pain, weight loss, and signs of decompensated liver disease, hepatocellular carcinoma is now increasingly recognized at a much earlier stage as a consequence of the routine screening of patients with known cirrhosis, using cross-sectional imaging studies and serum alpha-fetoprotein measurements.

Resection may benefit certain patients, albeit mostly transiently. Many patients are not candidates given the advanced stage of their cancer at diagnosis or their degree of liver disease and, ideally, could be cured by liver transplantation. Globally, only a fraction of all patients have access to transplantation, and, even in the developed world, organ shortage remains a major limiting factor. In these patients, local ablative therapies, including radiofrequency ablation, chemoembolization, and potentially novel chemotherapeutic agents, may extend life and provide palliation.

Problem

Hepatocellular carcinoma is a primary cancer of the liver and occurs predominantly in patients with underlying chronic liver disease and cirrhosis. The cell of origin is believed to be the hepatic stem cells, although this remains the subject of investigation.1 Tumors progress with local expansion, intrahepatic spread, and distant metastases. In general, the tumors are discovered either during routine screening or when symptomatic because of their size or location. Tumors may present as a single mass lesion or as diffuse growth, which can be difficult to differentiate from the surrounding cirrhotic liver tissue and the regenerating liver nodules on imaging studies. The presentation may be caused in part by mass effect that can lead to obstruction of the biliary system or anywhere affecting the liver vasculature. Without aggressive surgical resection, ablative therapy, or liver transplantation, hepatocellular carcinoma results in liver failure and death.

Large hepatocellular carcinoma.

Photomicrograph of a liver demonstrating hepatocellular carcinoma.

Frequency

In the United States, hepatocellular carcinoma, with its link to the hepatitis C epidemic, represents the fastest growing cause of cancer mortality overall and the second fastest growing cause of cancer deaths among women, based upon data from the Surveillance Epidemiology and End Results (SEER) program.²  

Over the past 20 years, the incidence of hepatocellular carcinoma has more than doubled, from 2.6 to 5.2 per 100,000 population. Among African Americans, the increase has been even greater (ie, from 4.7 to 7.5 per 100,000 population overall and to 13.1 per 100,000 population among males). The mortality rate has similarly increased from 2.8 to 4.7 per 100,000 population over the past 5 years alone.
 
Worldwide, the incidence of hepatocellular carcinoma in developing nations is over twice the incidence of that in developed countries. In 2000, the age-adjusted incidence of hepatocellular carcinoma in men was 17.43 per 100,000 population in developing countries compared with only 8.7 per 100,000 population in the United States. Among women, the disparity was also significant (6.77 vs 2.86 per 100,000 population). The highest incidence of hepatocellular carcinoma is in East Asia, with incidence rates in men of 35 per 100,000 population, followed by Africa and the PacificIslands.
 
Mortality rates mirror the incidence rates for hepatocellular carcinoma. In developing countries, the mortality from hepatocellular carcinoma in men is more than double that in developed countries (16.86 vs 8.07 per 100,000 population).  In Asia and Africa, the mortality rates are 33.5 and 23.73 per 100,000 population, respectively.
 
In the United States, the average age at diagnosis is 65 years; 74% of cases occur in men.  The racial distribution includes 48% whites, 15% Hispanics, 14% African Americans, and 24% others (primarily Asians). The incidence of hepatocellular carcinoma increases with age, peaking at 70-75 years; however, an increasing number of young patients have been affected, as the demographic shifts from primarily alcoholic liver disease to those in the fifth to sixth decades of life as the consequences of viral hepatitis B and C acquired earlier in life and in conjunction with high-risk behavior. The combination of viral hepatitis and alcohol significantly increases the risk of cirrhosis and subsequent hepatocellular carcinoma.

The major risk factors for developing hepatocellular carcinoma vary by region and degree of national development. See Table 1. 

In the United States, the risk factors have historically included alcoholic cirrhosis, hepatitis B (HBV) infection, hemochromatosis, and now hepatitis C (HCV) infection.³   However, the obesity epidemic has resulted in a growing population of patients with nonalcoholic fatty liver disease (NAFLD), also referred to as nonalcoholic steatohepatitis (NASH).  Patients with NAFLD can progress to fibrosis, cirrhosis, and now hepatocellular carcinoma.⁴  These patients are expected to drive the hepatocellular carcinoma epidemic in the United States and other developed countries. In the developing world, viral hepatitis (primarily hepatitis B), continues to represent the major risk for the development of hepatocellular carcinoma. The impact of hepatitis B vaccination on the eventual rate of hepatocellular carcinoma remains to be determined.⁵   The results of the vaccination of newborns are encouraging.

Temporal trends suggest that the epidemic of hepatocellular carcinoma is likely to continue, reflecting the reservoir of the viral hepatitis endemic in the population. In the United States, the annual incidence of new acute HCV infections appears to have decreased since the mid 1980s. However, the delay between HCV infection and hepatocellular carcinoma development can be up to 30-40 years, leading to the belief that the epidemic of hepatocellular carcinoma is unlikely to begin to decrease until 2015-19.^6,7 Overall, it is estimated that 1.5% of the US population is infected with HCV, of whom 20-30% may develop cirrhosis. Among patients with cirrhosis, the incidence of hepatocellular carcinoma is 1-6%. This risk is compounded by concurrent alcohol abuse, which increases the risk of cirrhosis and hepatocellular carcinoma in patients with viral hepatitis.

Other trends driving the epidemic include the aging population, obesity, and, perhaps, improved survival of patients with cirrhosis through better management of ascites and portal hypertension. The worldwide burden of hepatocellular carcinoma is also likely to continue. While significant progress has been made worldwide through HBV vaccination as part of the expanded program for vaccination by the World Health Organization (WHO), the prevalence of chronic liver disease remains significant among the older population who is at risk of developing hepatocellular carcinoma.   
 
Table 1. Risk Factors for Primary Liver Cancer and Estimate of Attributable Fractions³

Etiology

See Pathophysiology.

Pathophysiology

The pathophysiology of hepatocellular carcinoma has not been definitively elucidated and is clearly a multifactorial event. In 1981, after Beasley linked HBV infection to hepatocellular carcinoma development, the cause of hepatocellular carcinoma was thought to have been identified.8  an RNA virus replicates in the cytoplasm and does not integrate in the host DNA. 

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.

The chart below provides an overview of the pathways and the modifiers that lead to hepatocellular carcinoma.

Hepatocellular carcinoma: pathobiology.

Presentation

See Medical therapy and Surgical therapy.

Indications

Because the outcome in patients with advanced hepatocellular carcinoma is uniformly dismal, early diagnosis is crucial in order to provide effective treatment. Early diagnosis of hepatocellular carcinoma is generally the result of routine screening protocols in high-risk patients, including patients with cirrhosis due to viral hepatitis (ie, HBV, HCV), patients with hemochromatosis, patients with alpha-1-antitrypsin deficiency, or patients who abuse alcohol. Among patients with cirrhosis, current recommendations include cross-sectional imaging studies every 6-12 months and serum alpha-fetoprotein (AFP) measurements. With aggressive screening, the rate of resectable hepatocellular carcinoma diagnosed in patients who are at high risk reaches 30-50%, which is nearly twice the rate of unscreened populations.¹²  Despite the significant risk of recurrence, even in treated patients, the screening protocols appear to be cost effective in this population.¹³

Serum AFP would appear to be an attractive option for screening given its low cost and morbidity. Unfortunately, it is only 40-64% sensitive because many tumors do not produce AFP at all or only at a very advanced stage. AFP levels can be subject to misinterpretation. AFP is principally the result 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 they 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). See Table 2.

When elevated, the AFP is 75-91% specific, and values greater than 400 ng/mL are generally considered diagnostic of hepatocellular carcinoma in the proper clinical context, including appropriate radiologic findings. Better biological markers, including AFP variants, are currently under investigation.^14,15   

Table 2. Serum Alpha-Fetoprotein (AFP) Determination in Liver Disease¹⁶

Relevant Anatomy

A complete understanding of the surgical and interventional approach to the liver requires a comprehensive understanding of its anatomy and vascular supply.^22,23 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 2 sources of inflow that travel in the hepatoduodenal ligament: the hepatic artery and the 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 aorta.  The hepatic artery supplies 30% of the blood flow to the normal liver parenchyma but greater than 90% to hepatic tumors, including both hepatocellular carcinoma 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 3 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 2-3 additional ducts draining the liver.  There is significant variation in the biliary anatomy, and, thus, careful preoperative imaging is vital prior to embarking on any major hepatic resection.²³

The vascular anatomy of the livers defines its functional segments.  Bismuth synthesized existing knowledge and new insight into the anatomy of the liver.²⁴ Bismuth defined the right and left hemiliver, which is divided by a line connecting the gallbladder fossa and the inferior vena cava, roughly paralleling the middle hepatic vein that is slightly to the left.²⁴ The right hemiliver (lobe) is divided into 4 segments (ie, 5, 6, 7, 8), each of which is supplied by a branch of the portal vein. The right lobe drains via the right hepatic vein. The left lobe is composed of 3 segments (ie, 2, 3, 4).  Segment 4 is the most medial and is adjacent to the middle hepatic vein. Segments 2 and 3 comprise the left lateral segment, are to the left of the falciform ligament, and drain via the left hepatic vein.  Finally, segment 1 (caudate lobe) is located behind the portahepatis and adjacent to the vena cava.
 
In general, resection of the liver is divided into 2 main categories.²⁵ Nonanatomic (wedge) resections are generally limited resections of a small portion of liver without respect to the vascular supply. Anatomic resections involve removing 1 or more of the 8 segments of the liver.  Commonly, a right hepatic lobectomy refers to the removal of segments 5-8, an extended right lobectomy (right trisegmentectomy) includes segments 4-8, a left hepatectomy includes segments 2-4, and a left trisegmentectomy includes segments 2, 3, 4, 5, and 8. A left lateral segmentectomy 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, as described in Surgical therapy.

Contraindications

See Medical therapy.

Workup

Laboratory Studies

Laboratory evaluation of patients with newly diagnosed hepatocellular carcinoma should include testing to determine the severity of the underlying liver disease and to elucidate the etiology of the underlying disease. Laboratory studies should include a complete blood count, electrolytes, liver function tests, coagulation studies (eg, INR, PTT), and alpha-fetoprotein determination.

Disease severity

• Anemia: Low hemoglobin may be related to bleeding from varices or other sources.
• Thrombocytopenia: A platelet count below 100,000/mL is highly suggestive of significant portal hypertension/splenomegaly. 
• Hyponatremia is commonly found in patients with cirrhosis and ascites and may be a marker of advanced liver disease.
• Increased serum creatinine level may reflect intrinsic renal disease or hepatorenal syndrome.
• Prolonged PT/INR reflects significant impairment of hepatic function that may preclude resection. 
• Elevated liver enzymes (AST/ALT) reflect active hepatitis due to viral infection, current alcohol use, or other causes.
• Increased bilirubin level usually indicates advanced liver disease.
• Hypoglycemia may represent end-stage liver disease (no glycogen stores).

Disease etiology

• HBsAg/anti-HBc, anti-HCV - Viral hepatitis (current/past)
• Increased iron saturation (>50%) - Underlying hemochromatosis
• Low alpha-1-antitrypsin levels - Alpha-1-antitrypsine deficiency
• Tumor/paraneoplastic phenomena
• Increased alpha fetoprotein - Levels greater than 400 ng/mL considered diagnostic with appropriate imaging studies 
• Hypercalcemia - Ectopic parathyroid hormone production possible in 5-10% of patients with hepatocellular carcinoma
• Thrombocytosis (normal/rapid increase in platelet count in patients with a history of thrombocytopenia)

Imaging Studies

Accurate diagnosis and surgical planning require adequate cross-sectional imaging studies. While ultrasound is commonly used for screening, it does not provide sufficient anatomic detail for planning surgical resection or ablation. Recently, correlation between ultrasonographic findings and explant liver pathology revealed that a significant number of small lesions may not be detected using ultrasound screening. Pooled estimates from a recent meta-analysis suggest that ultrasound is only 60% sensitive.²⁰

Ultrasonographic identification of hepatocellular carcinoma can be difficult in the background of regenerative nodules in the cirrhotic liver. In general, hepatocellular carcinoma appears to be 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 hepatocellular carcinoma and the liver can become indistinct with nodular hepatocellular carcinoma. The use of Doppler analysis to characterize the lesion can be helpful, as hepatocellular carcinoma is more likely to have a significant arterial blood supply and neovascularization as compared to regenerative nodules.

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.

Diagnostic Procedures

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 less than 1 cm, less than half will be malignant, and the false-negative result rate is high. Thus, conservative management with close follow-up and no biopsy is recommended.¹²   

In patients with 1- to 2-cm lesions, a biopsy should be performed, as 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 greater 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. While some groups require biopsy prior to transplantation,¹² others are willing to proceed on clinical characteristics alone.²⁸ 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 hepatocellular carcinoma.¹⁴

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 10.¹² Patients should also have a platelet count greater than 100,000/mL and a normal bilirubin level. In patients with small tumors but significant hepatic dysfunction, transplantation is the preferred option.

Staging

The prognosis of hepatocellular carcinoma is a reflection of both tumor characteristics (ie, size, location, tumor biology) and the degree of underlying liver disease. The traditional pathological TNM (tumor, node, metastasis) staging system, while helpful in determining a prognosis in patients undergoing resection, is not as useful in planning treatment, as 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.²⁹

Likewise, the Child-Pugh-Turcotte score predicts perioperative survival following 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),¹² the Japan Integrated Staging System, and the Cancer of the Liver Italian Program (CLIP) are the most widely used staging systems. The BCLC system is very useful in deciding among potential treatment options and correlates best with patient outcome among the major staging systems.30  

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.

Treatment

Medical Therapy

Nonsurgical therapies

In patients who are not candidates for liver transplantation or resection, tumor ablation can be offered to extend life and to potentially downstage the tumor 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. 

The most commonly offered therapy is transcatheter arterial chemoembolization (TACE).^31,32 TACE is performed by an interventional radiologist who selectively cannulates the feeding artery to the tumor and delivers high local doses of chemotherapy, 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 hepatocellular carcinomas 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 the clinical outcome remains unclear, with some studies suggesting no benefit. However, other investigators have 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.33  A recent meta-analysis of 7 randomized controlled trials with 516 patients suggested a survival advantage of chemoembolization (Odds Ratio for death 0.53 p=.017) compared with medical therapy.35  Early reports suggest that a small number of patients can be successfully downstaged and subsequently transplanted using this approach. Risks include radiation damage to nearby organs, such as the gastrointestinal tract.

The use of systemic or regional chemotherapy has also been attempted in patients with hepatocellular carcinoma. Unfortunately, hepatocellular carcinoma is minimally responsive to systemic chemotherapy. Among the agents tried, doxorubicin-based regimens appear to have the greatest efficacy with response rates of 20-30% and a minimal impact on survival. There is also no apparent benefit to chemotherapy in the adjuvant setting following resection or radiofrequency ablation (RFA).36 In an effort to provide care in this difficult population, a variety of hormonal and biologic agents have been tried with minimal success, including tamoxifen, antiandrogens (eg, cyproterone, ketoconazole), interferon, interleukin 2 (IL-2), and octreotide.³⁷ Currently, liver-directed therapies (eg, resection, transplantation, RFA) offer the only genuine hope for extended survival in patients with advanced hepatocellular carcinoma.
 
Recently, the novel agent, sorafenib (Nexavar), was evaluated in patients with hepatocellular carcinoma in phase II and phase III clinical trials.³⁸  Sorafenib is an oral agent that has antiangiogenic, pro-apoptotic, and raf-kinase inhibitory properties. Preclinical trials have implicated the Raf/MAPK-ERK (MED)/extracellular signal regulated kinase (ERK) in hepatocellular carcinoma carcinogenesis.39

Additionally, Raf-1 activity was found to be up-regulated in HCV infected hepatocytes, which increases the risk of neoplastic transformation. Hepatocellular carcinoma development has been tied to pro-angiogenic factors, including vascular endothelial growth factor (VEGF), given its highly vascular nature. Sorafenib is unique in its ability to target multiple pathways by blacking RAF/MEK/ERK signaling at the level of raf-kinase as well as by inhibiting vascular endothelial growth factor receptor (VEGFER) and platelet-derived growth factor receptor beta (PDGFR-beta).   

Initial phase II clinical trials reported in 2004 demonstrated safety and clinical efficacy in 137 patients with Child Class A or B cirrhosis.³⁸  Patients were treated with oral sorafenib 400 mg twice daily for 4-week cycles. Tumor response was variable; 2.2% of patients had a partial response, 5.8% of patients had a minimal response, and 33% of patients had stable disease for more than 16 weeks. Overall toxicity was limited; grade 3 toxicities included fatigue (9.5%), diarrhea (8%), and hand-foot syndrome (5.1%).

The efficacy of sorafenib has been recently investigated in a phase III trial, reported in abstract form at the 2007 American Society of Clinical Oncology meeting. LLovet and colleagues randomized 602 patients with Child Class A cirrhosis and hepatocellular carcinoma to sorafenib versus placebo.⁴⁰  The overall results were encouraging. Treatment with sorafenib significantly improved survival (hazard ratio for all cause mortality: 0.69, p=0.0006). Treatment was also associated with an increased time to disease progression (5.5 mo vs 2.8 mo) and disease control rate (43% vs 32%). Overall toxicity did not differ between treatment and placebo arm (52% vs 54%). Based on this trial, sorafenib has become the most promising chemotherapeutic agent in the treatment of hepatocellular carcinoma in patients with preserved liver function. Various somewhat similar agents are under investigation.

For most patients, treatment options other than palliative care are limited. For patients with Child Class C cirrhosis and contraindications to 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, as 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 less than 2-3 bowel movements daily.

Aspirin and aspirin-like 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 daily), replaced by amiloride (10-20 mg daily) in case of painful gynecomastia, and furosemide (40-160 mg daily). Excessive diuresis leading to a weight loss of more than 1-2 lbs 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.

Surgical Therapy

Given the absence of effective chemotherapy and the insensitivity of hepatocellular carcinoma to radiotherapy, complete tumor extirpation represents the only opportunity for a long-term cure. Resection of the tumor by partial hepatectomy can be accomplished in a limited number of patients (generally <15-30%) in most Western series due to the degree of underlying cirrhosis. 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, transarterial chemoembolization, and transarterial brachytherapy, can be considered in patients who are not candidates for curative procedures.
 
Surgical resection of hepatocellular carcinoma

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 less 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 rate of less than 2% can be expected in experienced centers.^28,12

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 of greater than 10, esophageal varices, or splenomegaly with a platelet count of less than 100,000/mm³ predict poor outcome with significant resection. In general, resection of more than 2 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 of up to 74% in patients without significant decompensation.

Following liver resection, up to 75% of patients will develop intrahepatic recurrence within 5 years.^41,42 This recurrence can be either de novo hepatocellular carcinoma or local spread. Pathologic characteristics associated with a higher rate of recurrence include tumor at the resection margin, presence of cirrhosis, vascular invasion, advanced tumor grade, number of tumor nodules, and microvascular portal vein thrombosis. Other clinical factors associated with a higher rate of hepatocellular carcinoma recurrence include a preresection serum AFP level of greater than 10,000 ng/mL, large intraoperative transfusion requirements, preoperative AST greater than twice normal, and diagnosis of hepatitis C. In patients with recurrence and preserved liver function, re-resection may be indicated. In one single center series, operative resection was associated with prolonged survival (44 mo vs 10.6 mo) when compared to patients managed medically.43
             
Liver transplantation

Compared with resection for hepatocellular carcinoma, 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 hepatocellular carcinoma was unrewarding with high rates of recurrence in the allograft (transplanted liver) and extrahepatically.44 Reports from the national transplant tumor registry in 1991 revealed a 5-year survival rate of only 18%.45 In the survivors, only 9% remained tumor free at 2 years. These dismal survival data led to a moratorium on transplantation for hepatocellular carcinoma in the early 1990s. However, further investigations have 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 recent reassessment of the hepatocellular carcinoma as an indication for OLT.

The approach to patients with hepatocellular carcinoma has been dramatically altered following the 1996 publication of the results from Mazzaferro and colleagues in Milan.⁴⁶ They demonstrated that patients with limited hepatocellular carcinoma 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 their experience, patients with established cirrhosis and a single hepatocellular carcinoma (≤5 cm in diameter) or up to 3 hepatocellular carcinomas (all ≤3 cm in diameter) have 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%. Following this report, OLT was established as the therapy of choice for patients with significant cirrhosis and limited tumor burden.^46,47,48,49  

These results have also now been duplicated by several other transplant centers.⁴⁶ See Table 3. 

Table 3. Patient Survival Rates Following Liver Transplantation for Hepatocellular Carcinoma  

Additional strategies to provide OLT to patients with hepatocellular carcinoma have included the use of living donor living 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. Based on this experience, several centers have advocated expanding the maximum tumor burden that can be considered for MELD upgrades to include patients with 1 tumor up to 6.5 cm or 3 or fewer tumors less than or equal to 4.5 cm with a total tumor diameter of less than or equal to 8 cm. Transplantation in this population resulted in a survival rate of 90% at 1 year and 72.5% at 5 years.⁵⁸ Further refinement in both listing criteria and degree of MELD upgrade accorded to patients with hepatocellular carcinoma is likely in the future.

Ablative therapies

Curative treatment of patients with hepatocellular carcinoma 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, radiofrequency ablation, and cryotherapy, can be performed percutaneously, laparoscopically, or using an open surgical approach. 

Percutaneous ethanol injection (PEI) was the first ablative technique used for hepatocellular carcinoma. 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. The alcohol is generally performed with ultrasound guidance and requires 4-6 sessions to complete the ablation. In patients with Child Class A cirrhosis, 40-55% survival can be achieved at 3 years.56 PEI has not been compared with surgery in a randomized fashion; however, in retrospective reviews, the 3-year survival rate with PEI and surgery were 71% and 79% 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, the use of PEI has been largely replaced with 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.⁵⁷ Treatment is generally performed at one session (compared with multiple sessions using PEI). Guidance with ultrasound, CT, or laparoscopy can be used depending upon the patient's health, tumor location, and center expertise.
 
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 did not achieve statistical significance.⁵⁶ However, significant differences in recurrence-free survival rates clearly favor RFA at 24 months (64% vs 43%, p=.012). Complication rates are low with a 0.3% risk of 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 and colleagues.58   

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. In these patients, tumor progression can be delayed without the increased morbidity associated with liver transplantation following open resection.

Follow-up

Despite optimal treatment, hepatocellular carcinoma continues to have a high recurrence rate. Hepatocellular carcinoma recurs in 50-80% of patients following resection, the majority of which occur within 2 years.⁵⁹  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%.⁵⁹ Factors that increase the likelihood of recurrence include the presence of multiple foci of hepatocellular carcinoma, liver capsule invasion, and tumor size (>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 dependant upon the characteristics of the tumor in the explanted liver. Overall recurrence in patients transplanted within the Milan criteria is 4-10%.⁴⁶ The majority of these recurrences occur early (8-14 mo); however, up to 30% of recurrences may occur late.⁶⁰  In these patients, 23% develop intrahepatic-only recurrence, 39% develop both intrahepatic and extrahepatic recurrence, and 39% develop extrahepatic–only recurrence. Common extrahepatic sites of metastatic disease include lung, bone, CNS, and adrenal glands. Resection in the posttransplant population can be accomplished in up to one third of patients. In those patients who undergo successful resection, 4-year survival rates increase from 14% to 57%, justifying an aggressive approach.⁶⁴

Unfortunately, no established guidelines exist regarding the frequency of imaging procedures in the postoperative period. In general, a CT scan at 1 month postresection should be obtained to ensure complete tumor clearance. Following this initial scan, serum alpha-fetoprotein measurements and repeat imaging studies (eg, ultrasound, CT, 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.

Complications

See Medical therapy and Surgical therapy.

Outcome and Prognosis

See Medical therapy and Surgical therapy.

Future and Controversies

The threat of hepatocellular carcinoma is expected to continue to grow in the coming years.¹²  The peak of the hepatocellular carcinoma associated with HCV infection has not yet occurred. There is also a growing problem with cirrhosis, which develops in the setting of nonalcoholic steatohepatitis (NASH).  NASH typically develops in the setting of obesity, type 2 diabetes, dyslipidemia, and hypertension, and it will undoubtedly remain a significant problem, given the obesity epidemic occurring in the United States.⁴ Thus, developing effective and efficient care for patients with end-stage liver disease and hepatocellular carcinoma must become a significant focus. 

Management of hepatocellular carcinoma 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.¹²    

Overall, transplantation remains the best option for patients with hepatocellular carcinoma. Unfortunately, there is a limited supply of good quality deceased donor organs. Thus, alternative treatments, including resection, RFA, and, potentially, systemic therapy with sorafenib, should be used to bridge patients to transplant or to delay recurrence if possible. In patients who experience a recurrence following resection or transplantation, aggressive surgical treatment appears to be associated with the best possible outcome. 

Other strategies to limit this epidemic will pay off in the long term. The vaccination campaign against hepatitis B has already resulted in a reduced incidence of hepatocellular carcinoma in Taiwan.⁶² Moreover, failure to complete HBV vaccination continues to lead to hepatocellular carcinoma in patients. 

Other strategies to reduce the incidence of hepatocellular carcinoma include the treatment of HBV and HCV infection to eradicate the virus with rapidly effective therapies, including pegylated interferons, nucleoside analogues (HBV), and ribavirin (HCV). Promising protease inhibitors are in ongoing clinical trials,63 and adequate screening of high-risk patients is needed to treat small lesions early.  

Other preventative approaches include programs to reduce obesity and type 2 diabetes. Major efforts are also needed to specifically warn patients with chronic liver disease to discontinue alcohol abuse. Hemochromatosis should be recognized in a timely manner.

See related CME at Diabetes May Increase Risk for Hepatocellular Carcinoma in Patients With Hepatitis C.

Multimedia

Media file 1: Large hepatocellular carcinoma.

Media file 2: Photomicrograph of a liver demonstrating hepatocellular carcinoma.

Media file 3: MRI of a liver with hepatocellular carcinoma.

Media file 4: Ultrasonographic image of hepatocellular carcinoma.

Media file 5: Arterial phase CT scan demonstrating enhancement of hepatocellular carcinoma.

Media file 6: Portal venous phase CT scan demonstrating washout of hepatocellular carcinoma.

Media file 7: 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.

Media file 8: Hepatocellular carcinoma: pathobiology.

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Keywords

hepatocellular carcinoma, HCC, hepatoma, hepatocellular cancer, liver carcinoma, liver cancer, liver tumor

Contributor Information and Disclosures

Author

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.

Coauthor(s)

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.

Medical Editor

Burt Cagir, MD, FACS, Assistant Professor of Surgery, State University of New York, Upstate Medical Center; Consulting Staff, Director of Surgical Research, Robert Packer Hospital; Associate Program Director, Department of Surgery, Guthrie Clinic
Burt Cagir, MD, FACS is a member of the following medical societies: American College of Surgeons, American Medical Association, and Society for Surgery of the Alimentary Tract
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

CME Editor

Paolo Zamboni, MD, Professor of Surgery, Chief of Day Surgery Unit, Chair of Vascular Diseases Center, University of Ferrara, Italy
Paolo Zamboni, MD is a member of the following medical societies: American Venous Forum and New York Academy of Sciences
Disclosure: Nothing to disclose.

Chief Editor

John Geibel, MD, DSc, MA, Vice Chairman, Professor, Department of Surgery, Section of Gastrointestinal Medicine and Department of Cellular and Molecular Physiology, Yale University School of Medicine; Director of Surgical Research, Department of Surgery, Yale-New Haven Hospital
John Geibel, MD, DSc, MA is a member of the following medical societies: American Gastroenterological Association, American Physiological Society, American Society of Nephrology, Association for Academic Surgery, International Society of Nephrology, New York Academy of Sciences, and Society for Surgery of the Alimentary Tract
Disclosure: AMGEN Royalty Other; AstraZeneca Grant/research funds Other

The authors would like to acknowledge Arief Suriawinata, MD, of the Department of Pathology at DartmouthMedicalSchool for the gross images and the photomicrographs contained in this article.

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