In 2018, primary liver tumors will be diagnosed in approximately 42,220 new patients in the United States, and approximately 30,200 individuals will die from this disease.¹ Worldwide, primary liver tumors remain the second leading cause of death from cancer in males and the sixth leading cause of death from cancer in females.² Malignant lesions can arise from any of the various cell types that comprise the organ, which include hepatocytes, endothelial cells, and the cells of the intrahepatic bile ducts. The 2 most common hepatic neoplasms are hepatocellular carcinoma (HCC), which accounts for more than 75% of primary liver tumors, and intrahepatic cholangiocarcinoma (ICC), which accounts for 10% to 15%. The remaining primary hepatic neoplasms are hepatic angiosarcoma, epithelioid hemangioendothelioma, and hepatic lymphoma. The focus of this chapter will be on HCC and ICC.

In patients with primary hepatic malignancies, the malignancy itself and any underlying liver disease must be considered as 2 separate but interconnected pathologic processes. The extent of abnormalities associated with each pathologic process directly affects the clinical impact and treatment options.

Epidemiology

The incidence of HCC is greatest in areas where exposure to factors that cause chronic HCC injury is heaviest. The incidence of HCC is greatest in sub-Saharan Africa and East Asia, where the incidence is more than 20 cases per 100,000 individuals per year.² In the United States, the overall incidence of HCC is 6 cases per 100,000 individuals per year; the incidence is highest among Asian, African American, and Hispanic individuals.³ Globally, males have up to 5.7 times the HCC incidence observed in females.²

Risk Factors

There are several risk factors for development of HCC, many of them related to the development of chronic hepatocellular injury (Table 58-1). Some risk factors are independent, while others have potentiating effects. The risk factors most commonly observed in individuals with HCC are the hepatitis viruses: worldwide, 75% to 80% of primary liver tumors are associated with persistent liver infections, particularly hepatitis B (seen in 50%-55% of patients with HCC) or hepatitis C (25%-30%).⁴ The degree of liver change that results from hepatitis before development of HCC differs between hepatitis B and C. Among patients with hepatitis B, 20% of HCC cases develop before cirrhosis develops, whereas among patients with hepatitis C, HCC almost always arises in the background of significant cirrhosis and fibrosis. The mechanism proposed to explain this difference is that hepatitis B virus directly modulates oncogenes, whereas hepatitis C virus–induced HCC is related to the degree of inflammation.⁵

Today, with vaccination against hepatitis B and better detection of hepatitis B and C, approximately 60% of patients with HCC are not infected with hepatitis virus. Other risk factors for HCC include environmental exposures, chronic disease processes, and genetic conditions that predispose patients to development of cirrhosis and/or chronic liver inflammation.

Alcohol consumption is a major risk factor for the development of HCC. Metabolism of alcohol occurs through oxidative processes, resulting in lipogenesis and fatty liver development that can progress to cirrhosis.⁶ Additionally, reactive oxygen species are created in hepatocytes during alcohol metabolism and can lead to further liver damage.⁶ The degree of alcohol-induced liver damage and related risk of HCC development are dose dependent. Studies have found that exposure to 60 g of alcohol per day for more than 25 years increases the risk of HCC by almost 6 times (odds ratio [OR], 5.7; 95% confidence interval [CI], 2.4-13.7).⁷

Aflatoxin is a hepatic carcinogen produced by Aspergillus flavus and Aspergillus parasiticus that contaminates foods stored in warm and damp environments, such as corn, soybeans, and peanuts. The mycotoxin is thought to act by creating mutations in the TP53 gene.⁸ Regions of the world where aflatoxin exposure is highest coincide with regions of high hepatitis B prevalence, and the effects are potentiative. A study has found that individuals in Shanghai with concomitant hepatitis and aflatoxin exposure had 59.4 times the risk of developing HCC of the normal population. Hepatitis B alone was associated with only a seven-fold increase in risk, whereas aflatoxin exposure alone was associated with a four-fold increase in risk.⁹

Higher body mass index (BMI) has been associated with increased death rates from multiple malignances, including esophagus, colorectal, pancreas, and liver cancers. Women with a BMI of 35 to 40 kg/m² had almost twice the mortality rate from liver cancer of women with a lower BMI, and men with a BMI of 35 to 40 kg/m² had almost 5 times the liver cancer mortality rate of men with a lower BMI.¹⁰ Obesity can lead to the development of chronic liver changes, such as steatosis and steatohepatitis.¹¹ Obesity in the United States affects over 1 in 3 adults.¹⁰

Protective Factors

Statin use has been found to protect against the development of HCC. A meta-analysis of 10 studies with 1.46 million patients found that statin use was associated with an adjusted OR of 0.63 (95% CI, 0.52-0.76).¹² Despite the heterogeneity of the studies analyzed in this meta-analysis, this protective affect was seen not only in Asian but also in Western populations. Statins are thought to inactivate pro-growth pathways and activate apoptotic pathways through hydroxymethylglutaryl–coenzyme A (HMG-CoA) reductase-dependent and -independent pathways.¹²

Prevention of HCC is based on reduced exposure to the risk factors such as environmental exposures and hepatitis viruses. Vaccination against hepatitis B has reduced HCC rates in high-risk countries such as Taiwan.¹³ In patients with hepatitis B or C, close surveillance and treatment to prevent development of cirrhosis are of paramount importance and have been shown to improve outcomes associated with HCC.¹⁴

Pathology

HCC is thought to develop in a multistep progression from normal hepatocytes to malignancy (Fig. 58-1) through alterations in various molecular pathways. A consensus on the nomenclature for precancerous lesions and early HCC has been developed to standardized pathologic assessment of specimens.¹⁵ Dysplastic nodules are defined as nodular lesions larger than 5 mm. These are divided into low-grade and high-grade dysplastic nodules. Low-grade nodules have no cytologic atypia and often have a peripheral fibrous scar. High-grade nodules have architectural and/or cytologic atypia, increased cell density, and an irregular trabecular pattern.¹⁵ These lesions precede the development of HCC.

Early HCCs are larger than dysplastic nodules and characterized by 5 parameters: (1) cell density more than twice that of the surrounding tissue, with an increased nuclear/cytoplasm ratio and irregular thin-trabecular pattern; (2) portal tracts within the nodule (intratumoral portal tracts); (3) a pseudoglandular pattern; (4) diffuse fatty changes; and (5) unpaired arteries within the nodule.¹⁵ Despite these defining criteria, differentiation between high-grade dysplastic nodules and early HCC is challenging. One of the key distinguishing findings is the presence of stromal invasion in HCC.¹⁵

Gross Features

HCC can exhibit any of several growth patterns and was eloquently categorized by Eggel in 1901 into 3 separate types.^16,17 The nodular type is characterized by well-­circumscribed nodules and the absence of extranodal extension or multinodularity and has the lowest frequency of spread.¹⁷ Large HCCs that occupy the majority of the liver parenchyma are defined as massive and are often seen in livers that do not have cirrhosis (Fig. 58-2). Massive HCCs have a higher propensity for lymph node and intrahepatic metastases than nodular HCCs.¹⁷ Finally, diffuse HCCs are characterized by multiple small lesions covering the liver and are almost always associated with hematogenous extrahepatic metastases.¹⁷ Additional poor prognostic features often seen in patients with HCC are invasion of the portal and hepatic vein or bile duct.^18,19

Fibrolamellar HCC

Fibrolamellar carcinoma is a distinctive variant of HCC, accounting for less than 5% of all HCC cases. Unlike traditional HCCs, fibrolamellar carcinomas are seen in younger patients, affect males and females equally, and are not associated with chronic liver inflammation such as hepatitis or cirrhosis.²⁰ Fibrolamellar carcinomas are slow growing, present with abdominal pain or an abdominal mass, are often resectable, and consequently have a better prognosis; the 5-year overall survival after resection is 76%.²¹

Combined HCC and Cholangiocarcinoma

Combined HCC and cholangiocarcinoma is a type of liver tumor that contains elements of both HCC and cholangiocarcinoma and accounts for less than 1% of all primary liver tumors. The pathogenesis is malignant transformation of hepatic progenitor cells with dual differentiation leading to formation of a lesion capable of bile production, trabecular growth, glandular structures, and intracellular mucin production.^22,23 Five-year overall and disease-specific survival rates for patients with combined HCC and cholangiocarcinoma fall in between those for patients with HCC and those for patients with cholangiocarcinoma.²⁴

Clinical Presentation and Diagnosis

Unlike other malignancies, HCC often presents incidentally as patients are being followed for underlying liver disease or when there is enough tumor progression to cause a mass effect. Direct obstruction of the bile ducts can lead to obstructive jaundice; compression of the liver capsule can cause right upper quadrant pain; and bleeding from the tumor can cause anemia if the bleeding is minimal or severe hemorrhagic shock if the bleeding is major. Additional generalized constitutional symptoms of HCC include anorexia, weight loss, and malaise. In patients with cirrhosis in whom HCC is discovered incidentally, general physical examination findings caused by portal hypertension include ascites, jaundice, varices, and splenomegaly. Other, rarer presentations include development of fevers secondary to tumor necrosis and paraneoplastic syndromes such as hypoglycemia, hypercalcemia, hypercholesterolemia, watery diarrhea, erythrocytosis, and cutaneous manifestations, which are present in multiple gastrointestinal malignancies but not necessarily specific for HCC (Table 58-2).^25-28

One of the unique features of HCC is its hypervascularity. HCC derives the majority of its blood supply from the hepatic artery as opposed to the portal vein.²⁹ This feature allows accurate identification of HCC on imaging, particularly on high-quality multiphase (unenhanced, arterial phase, portal venous phase, and delayed venous phase) cross-sectional imaging. The pathognomonic radiographic profile is enhancement in the arterial phase followed by washout in the delayed venous phase (Fig. 58-3). Additional common findings are delayed enhancement of the fibrous pseudocapsule, presence of septations, and an internal mosaic pattern.

The decision whether to use computed tomography (CT) or magnetic resonance imaging (MRI) for diagnosis of HCC is largely dependent on the institution and the physician’s level of comfort with interpreting the results. A meta-analysis of 15 studies comparing CT to MRI found that MRI was associated with better sensitivity (91% vs 81%) and specificity (95% vs 93%), especially for smaller HCC lesions.³⁰ Regardless of the modality used, if the lesion is larger than 1 cm and exhibits the classic appearance of HCC on radiographs, no additional workup or biopsy is needed for diagnosis. If the imaging findings are not definitive, the next step is repeat imaging with another modality (CT if MRI was used and vice versa). If the imaging findings remain ambiguous after repeat imaging, a needle biopsy can be performed unless the patient is a candidate for liver transplant. In candidates for liver transplant, biopsy should be avoided until evaluation by a transplant team to avoid peritoneal seeding even though the risk of seeding is low when needle biopsy is performed by a physician with appropriate experience. For lesions smaller than 1 cm, hepatic ultrasonography should be performed every 3 months.³¹ If there are concerning changes or findings, further investigation is warranted (Fig. 58-4).

Screening

Screening for HCC should be reserved for patients at high risk for development of HCC and should not be performed in the general population. Individuals with cirrhosis of the liver should undergo evaluation with liver sonography every 6 to 12 months according to the American Association for the Study of Liver Diseases.³²

The tumor marker most commonly used for monitoring and diagnosis of patients at high risk for HCC is α-fetoprotein (AFP). AFP is a glycoprotein produced by the fetal liver and yolk sac. AFP can be elevated in a variety of disease processes and other malignancies, including tumors of gonadal origin, gastric cancer, pregnancy, acute or chronic hepatitis, and cirrhosis.^33-36 Typically an AFP value of greater than 20 µg/L is considered abnormal, but with this cutoff value, there are significant variations in the sensitivity and specificity of AFP level according to the population examined (patients with cirrhosis or chronic hepatitis vs patients with normal livers).³⁷ Therefore, the status of the underlying liver must be taken into account in interpreting the AFP level. Furthermore, up to 40% of patients with small HCCs have normal AFP levels.³⁸

Because AFP measurements alone have variable sensitivity and specificity in the diagnosis of HCC, imaging remains the mainstay of surveillance.^31,39 The combination of characteristic imaging findings with an elevated AFP level does have high positive predictive value.^40,41 In Japan, where the prevalence of HCC is much higher than in the United States, the Japanese Society of Hepatology recommends liver sonography and serum AFP and plasma des-gamma-carboxy prothrombin measurement every 3 to 4 months and CT or MRI every 6 to 12 months for patients with cirrhosis related to hepatitis B or C.⁴² For patients with chronic hepatitis B or C or with cirrhosis not due to hepatitis B or C, the Japanese Society of Hepatology recommends liver sonography and serum AFP and plasma des-gamma-carboxy prothrombin measurement every 6 months with or without cross-sectional imaging when such imaging would be appropriate.⁴²

Staging

The treatment of HCC involves consideration of 2 separate pathologic processes, the primary liver tumor and any underlying liver disease. To help stratify patients for treatment, there are 2 general systems of staging, pathologic and clinical. The pathologic staging systems are based on surgical outcomes and include the American Joint Committee on Cancer/International Union Against Cancer (AJCC/UICC) TNM staging system, Liver Cancer Study Group of Japan staging system, Japanese Integrated Staging score, and Chinese University Prognostic Index.^43-46 The clinical systems include the Okuda system, Cancer of the Liver Italian Program (CLIP) scoring system, and Barcelona Clinic Liver Cancer (BCLC) staging system.

The seventh edition of the AJCC/UICC staging system (Table 58-3) takes into account prognostic factors after resection of HCC, including tumor size (cutoff 5 cm), solitary versus multiple tumors, and presence or absence of vascular invasion. The most important prognostic factor is vascular invasion. Tumors without vascular invasion are defined as T1; those with vascular invasion as at least T2; and those with major vascular invasion, defined as invasion of a major branch of the portal or hepatic vein, as T3. Five-year overall survival rates after liver resection for patients with stages I, II, and III HCC are 55%, 37%, and 16%, respectively (Fig. 58-5).⁴⁷

Although there were significant improvements between the sixth and seventh editions of the AJCC/UICC staging system, additional stratification of the current stage categories may lead to better assessment of patient prognosis. An international multicenter study showed that neither microvascular invasion nor tumor differentiation affects surgical outcomes in patients with HCCs smaller than 2 cm. This subset of patients can be reclassified into a separate group that is associated with improved prognosis.⁴⁸ Evaluation of the underlying liver disease is assessed through a fibrosis score, which is stratified into 2 tiers. Although this score is not incorporated into the overall staging, it does provide prognostic value with respect to overall survival, as patients with associated liver disease have a worse prognosis.⁴⁹

Clinical staging systems are more useful than pathologic staging systems for choosing the appropriate treatment regimen, particularly when surgery is not feasible. The Okuda system (Table 58-4) is based on tumor size, presence of ascites, albumin level, and bilirubin level and categorizes patients into 3 stages.⁵⁰ Unfortunately, the Okuda system was derived from a cohort with primarily advanced HCC and used limited tumor-specific factors. As a result, it has little validity in patients with early HCC and groups patients with vascular invasion and multifocal disease into a single group.

The CLIP scoring system (Table 58-5) is based on the Child-Turcotte-Pugh (CTP) score (Table 58-6), tumor morphology, serum AFP level, and presence or absence of portal vein thrombosis.⁵¹ Although the CLIP system stratifies patients with respect to prognosis better than the Okuda system does, the CLIP system still groups a wide range of patients with heterogeneous outcomes together and does not accurately account for vascular invasion.⁴³

The BCLC staging system (Fig. 58-6) was designed to incorporate more prognostic factors and better stratify patients with early HCC.⁵² The system created 5 stages based on the primary tumor size and number of nodules, liver function, performance status, presence of constitutional symptoms, vascular invasion, and extrahepatic spread. Limitations of this system include lack of a patient-centered approach, failure to outperform other systems in larger studies, and relatively few patients judged to be candidates for resection or interventional therapy.^52,53 In Figure 58-6, candidates for resection according to the BCLC staging system are highlighted in red.⁵⁴