HEPATOCELLULAR CARCINOMA

Epidemiology

Hepatocellular carcinoma is the commonest primary malignant tumor of the liver. It is the fifth most common cancer in men and the eighth most common in women, and it ranks fourth in annual cancer mortality rates.^1,2 Information on incidence is derived from an increasing but still limited number of cancer registries, and it is possible to classify countries into broad risk categories only. Moreover, in low-income (developing) countries, especially in sub-Saharan Africa, hepatocellular carcinoma is underdiagnosed and underreported, in some cases by as much as 50%. Despite these sources of inaccuracy, hepatocellular carcinoma clearly has an unusual geographic distribution (Fig. 94-1). Moreover, the tumor is not necessarily uniformly common throughout countries with a high incidence, such as China³ and Mozambique.⁴ The incidence of hepatocellular carcinoma has increased considerably in Japan since the 1980s, and lesser increases have been recorded in developed Western countries, including North America and Western Europe.⁵ Interestingly, a study from Japan has shown that the rate of hepatocellular carcinoma began to decline in 2000, presumably because of the aging of the cohort of persons infected with hepatitis C virus (HCV).⁶ A similar downward trend has been noted in some European countries, including France and Italy.⁷ By contrast, in the United States, hepatocellular carcinoma is the cancer that has been increasing in incidence most rapidly since 2000, at a time when other major cancers such as cancers of the lung, breast, prostate, and colon are decreasing.⁸ Considerable racial and ethnic variation exits in the incidence of hepatocellular carcinoma in the United States. The incidence among Asians is highest, almost double that of white Hispanics and more than four times higher than that of whites.⁹

Figure 94-1. Incidence of hepatocellular carcinoma in different parts of the world. High, age-adjusted rate of more than 15 cases/100,000 population/year; intermediate, age-adjusted rate of 5 to 15 cases/100,000/year; low, age-adjusted rate of fewer than 5 cases/100,000/year.

Migrants from countries with a low incidence to areas with a high incidence of hepatocellular carcinoma usually retain the low risk of their country of origin, even after several generations in the new environment. The consequences for migrants from countries with a high incidence to those with a low incidence differ, depending on the major risk factors for the tumor in their country of origin and whether chronic hepatitis B virus (HBV) infection, if this is the major risk factor, is acquired predominantly by the perinatal or horizontal route (see later and Chapter 78).^2,10,11

Men are generally more susceptible than women to hepatocellular carcinoma. Male predominance is, however, more obvious in populations at high risk for the tumor (mean male-to-female ratio, 3.7 : 1.0) than in those at low or intermediate risk (2.4 : 1.0).^1,2 In industrialized countries, the number of men and number of women with hepatocellular carcinoma in the absence of cirrhosis are almost equal.

The incidence of hepatocellular carcinoma increases progressively with advancing age in all populations, although it tends to level off in the oldest age groups.^1,2 In Chinese and particularly in black African populations, however, the mean age of patients with the tumor is appreciably younger than in other populations. This finding is in sharp contrast to the age distribution in Japan, where the incidence of hepatocellular carcinoma is highest in the cohort of men ages 70 to 79 years.⁶ Hepatocellular carcinoma is rare in children.^12,13

Imaging

The diagnosis of hepatocellular carcinoma generally requires imaging evidence of a focal lesion in the liver, although large infiltrating lesions can also be diagnostic. Arterial hyperenhancement, particularly seen on dynamic contrast imaging of the liver, is observed because the blood supply of hepatocellular carcinoma comes from newly formed abnormal arteries (neoangiogenesis).^23,52,53 As a nodule transforms from low- to high-grade dysplasia and then to hepatocellular carcinoma, the primary blood supply shifts from portal to arterial—especially new abnormal arterial branches that produce characteristic findings on dynamic contrast imaging of the liver.²⁷

Ultrasonography

Ultrasonography detects most hepatocellular carcinomas but may not distinguish this tumor from other solid lesions in the liver. As with all imaging methods, the sensitivity increases with increasing size of the lesion. A systematic review of eight studies using histologic reviews of liver explants has shown that ultrasound has fair sensitivity (pooled estimate, 48%; 95% confidence interval [CI], 34% to 62%) with good specificity, estimated at 97% (95% CI, 95% to 98%).²⁴ Advantages of ultrasonography include safety, availability, and cost-effectiveness, although it has the drawbacks of being nonstandardized and examiner-dependent. Body habitus, particularly obesity, may limit the sensitivity of this test. Approximately two thirds of symptomatic hepatocellular carcinomas are uniformly hyperechoic, whereas the remainder are partly hyperechoic and partly hypoechoic.⁵⁴ Small tumors are uniformly hypoechoic. The ultrasonographic appearance is influenced by the presence of fat, calcium, and necrosis. Tumors located immediately under the right hemidiaphragm may be difficult to detect. In Japanese patients in particular, hepatocellular carcinoma may have a well-defined, even thick capsule, which can be seen on ultrasonography. Ultrasonography with Doppler technology is useful for assessing the patency of the inferior vena cava, portal vein and its larger branches, hepatic veins, and biliary tree.

Dynamic contrast-enhanced Doppler ultrasonography with intra-arterial infusion of CO₂ microbubbles and intravenous enhanced color Doppler ultrasonography are refinements that, by characterizing hepatic arterial and portal venous flow in tumorous nodules, facilitate the diagnosis of malignant and benign hepatic nodules.⁵⁵ These techniques are not often performed in the United States.

Computed Tomography

Multiphase, also called dynamic, helical computed tomography (CT) is the imaging technique of choice for the diagnosis of hepatocellular carcinoma.^24,54,55 CT during arterial portography is also helpful but rarely done because it is invasive. Phases in dynamic contrast-enhanced CT can include noncontrast, arterial, portal venous, and delayed phases. The classic and most diagnostic pattern for hepatocellular carcinoma is a combination of enhancement in the arterial phase (with the uninvolved liver lacking enhancement), loss of central nodule enhancement compared with the uninvolved liver (washout), and capsular enhancement in the portal-venous and delayed phases (Fig. 94-2).^25,56 When the lesion is larger than 2 cm in diameter, this pattern has almost 100% specificity for hepatocellular carcinoma.^36,37,56 When the nodule is 1 to 2 cm, guidelines recommend a second type of dynamic imaging (magnetic resonance imaging [MRI] or contrast ultrasonography) to confirm the diagnosis of hepatocellular carcinoma, although the specificity of one dynamic study is higher than 90%.⁵⁷ CT often finds so-called hypervascular-only lesions, which enhance in the arterial phase and become isodense to the surrounding liver in the portal-venous and delayed phases. These lesions may be dysplastic nodules, arterial portal shunts, atypical hemangiomas, hepatocellular carcinoma, confluent fibrosis, or aberrant venous drainage. When less than 2 cm in diameter, only about 30% are hepatocellular carcinomas, which grow over time. Other causes disappear or remain stable on follow-up studies. Current guidelines recommend biopsy of lesions larger than 1 cm if the serum AFP level is less than 200 ng/mL and serial imaging for lesions smaller than 1 cm.⁵⁸ Hepatocellular carcinoma may also have other patterns on CT, such as washout only on delayed imaging, a hypovascular nodule, or a fat-containing nodule.^27,58 Overall, the pooled estimate of sensitivity and specificity for detecting hepatocellular carcinoma by CT is 67.5% (95% CI, 55% to 80%) and 92.5% (95% CI, 89% to 96%), respectively. Dynamic CT is also useful for detecting invasion into the portal or hepatic veins and identifying the location and number of tumors; these findings are critical for planning treatment.

Figure 94-2. Dynamic computed tomography scan of a patient with hepatocellular carcinoma showing no lesion in the noncontrast phase, an enhancing lesion in the arterial phase of contrast administration, and a faint lesion in the portal venous phase seen better in the delayed phase.

Magnetic Resonance Imaging

Dynamic MRI using gadolinium contrast agents provides another way of distinguishing hepatocellular carcinoma from normal liver tissue. The performance of MRI and the findings on multiphase contrast enhancement are similar to those described for CT (Fig. 94-3). Typically, the signal intensity on T1-weighted images is low.^27,54 The pooled estimate of sensitivity and specificity for detecting hepatocellular carcinoma by MRI is 80.6% (95% CI, 70% to 91%) and 84.8% (95% CI, 77% to 93%), respectively.²⁴ MRI may be slightly superior overall to CT, although local expertise should dictate the choice of imaging technique.

Figure 94-3. Multiphasic magnetic resonance imaging of the liver showing hepatocellular carcinoma with characteristic features, including hyperintensity (arrow) on T2-weighted image (top left panel) but not on T1-weighted image (top right panel), enhancement during the arterial phase of contrast administration (bottom left panel), with central washout of contrast and capsular enhancement during the venous and delayed phases (bottom middle and right panels).

Hepatic Angiography

Since the advent of CT and MRI, the diagnostic role of hepatic angiography has decreased. Digital subtraction angiography is helpful for recognizing small hypervascular hepatocellular carcinomas but may miss early, well-differentiated hypovascular tumors. Hepatocellular carcinomas often are densely vascular, although multinodular tumors may be relatively avascular.⁵⁹ The arteries in the tumor are irregular in caliber and do not taper in the usual way, and the smaller branches may show a bizarre pattern. The hepatic veins fill early, and retrograde filling of the portal veins results from the presence of arteriovenous anastomoses within the tumor. An additional finding is a delay in capillary emptying, which is seen as a blush. The center of some large tumors may be avascular as a result of necrosis or, less often, hemorrhage. Angiography is essential for delineating the hepatic arterial anatomy in planning embolization or chemoembolization of the tumor or infusion of cytotoxic drugs directly into the hepatic artery or its branches (see later).

Staging

Accurate staging of hepatocellular carcinoma is necessary for prognostication and also to assist with selection of therapy. Determining the optimal staging system for hepatocellular carcinoma has been controversial, in part because it needs to take into account both the severity of the underlying liver disease and the size and degree of spread of the tumor. As with all cancers, the TNM (tumor-node-metastasis) system can be used to stage hepatocellular carcinoma, but this system does not factor in the underlying liver disease. A study⁶⁶ comparing the usefulness of seven staging systems, including the Okuda, TNM, Cancer of the Liver Italian Program (CLIP), Barcelona Clinic Liver Cancer (BCLC), Chinese University Prognostic Index (CUPI), Japanese Integrated Staging (JIS), and Group d’Etude et Traitement du Carcinome Hépatocellulaire (GETCH) systems in a cohort of patients from the United States, has found the BCLC staging system to have the best independent predictive power for survival. The BCLC system has been adopted by the AASLD for use in its practice guidelines on management of hepatocellular carcinoma.²⁵ This staging classification also includes a treatment schedule based on stage (Fig. 94-4).⁶⁷

Figure 94-4. Barcelona Clinic Liver Cancer (BCLC) staging classification and treatment schedule. Staging is based on tumor size and spread, the patient’s performance status (PST) on a scale of 0 (good) to >2 (poor), and liver function as assessed by the Child-Pugh class (see Chapter 90). Patients with very early (stage 0) hepatocellular carcinoma (HCC) are optimal candidates for surgical resection. Patients with early (stage A) HCC are candidates for radical therapy (resection, cadaveric liver transplantation [CLT] or live-donor liver transplantation [LDLT], or local ablation via percutaneous ethanol injection [PEI] or radiofrequency ablation [RFA]). Patients with intermediate (stage B) HCC benefit from transarterial chemoembolization (TACE). Patients with advanced HCC, defined as the presence of macroscopic vascular invasion, extrahepatic spread, or cancer-related symptoms (PST 1 or 2) (stage C), benefit from sorafenib. Patients with end-stage disease (stage D) should receive symptomatic treatment. The treatment strategy will transition from one stage to another when treatment fails or is contraindicated. M, metastasis stage; N, nodal stage.

(Adapted from Llovet J, Di Bisceglie A, Bruix J, et al. Design and endpoints of clinical trials in hepatocellular carcinoma. J Natl Cancer Inst 2008; 100:698-711.)

Hepatitis B Virus

Some 387 million carriers of HBV exist in the world today, and hepatocellular carcinoma will develop in as many as 25% of them (see Chapter 78). HBV accounts for up to 80% of hepatocellular carcinomas, which occur with high frequency in East Asian and African populations.^68,69 Persistent HBV infection antedates the development of hepatocellular carcinoma by several to many years, an interval commensurate with a cause and effect relationship between the virus and the tumor. Indeed, in at-risk populations, the HBV carrier state is largely established in early childhood by perinatal or horizontal infection.^70,71 Approximately 90% of children infected at this stage of life become chronic carriers of the virus, and these early-onset carriers face a lifetime relative risk for developing hepatocellular carcinoma of more than 100, compared with uninfected controls.⁷²

An effective vaccine against HBV has been available since the early 1980s and, in countries in which this vaccine has been included in the expanded program of immunization for a sufficient length of time, the HBV carrier rate among children has decreased by 10-fold or more. Studies in Taiwan, where universal immunization was started in 1984 and where the rate of HBV carriage among children has decreased by more than 10-fold, have already shown a 70% reduction in the mortality rate from hepatocellular carcinoma in children in the vaccinated age groups.⁷³ This finding gives promise for the ultimate eradication of HBV-induced hepatocellular carcinoma and provides further evidence of the causal role of the virus in the development of this tumor.

HBV DNA is integrated into cellular DNA in approximately 90% of HBV-related hepatocellular carcinomas.⁷⁴ The sites of chromosomal insertion appear to be random, and whether viral integration is essential for hepatocarcinogenesis is still uncertain. The virus appears to be directly and indirectly carcinogenic.⁷⁵ Possible direct carcinogenic effects include cis-activation of cellular genes as a result of viral integration, changes in the DNA sequences flanking the integrated viral DNA, transcriptional activation of remote cellular genes by HBV-encoded proteins, particularly the X protein, and effects resulting from viral mutations. The transcriptional activity of the HBV X protein may be mediated by interaction with specific transcription factors, activation of the mitogen-activated protein (MAP) kinase and Janus kinase–signal transducer and activator of transcription (JAK/STAT) pathways, an effect on apoptosis, and modulation of DNA repair. Studies have shown a clear link between the amount of HBV replication (measured as serum level of HBV DNA [viral load]) and subsequent risk of hepatocellular carcinoma. The long-term risk of hepatocellular carcinoma increases markedly in patients with serum HBV DNA levels higher than 10⁴ copies/mL.⁷⁶ A randomized controlled trial of antiviral therapy has also shown a reduction in the incidence of hepatocellular carcinoma in association with reductions in serum levels of HBV DNA on therapy.⁷⁷

Indirect carcinogenic effects are the result of the chronic necroinflammatory hepatic disease, in particular cirrhosis, induced by the virus. The increased hepatocyte turnover rate resulting from continuous or recurring cycles of cell necrosis and regeneration acts as a potent tumor promoter. In addition, the distorted architecture characteristic of cirrhosis contributes to the loss of control of hepatocyte growth, and hepatic inflammation generates mutagenic reactive oxygen species. The transgenic mouse model of Chisari and coworkers has provided indirect support for the role of prolonged hepatocyte injury in hepatocarcinogenesis.⁷⁸

Hepatitis C Virus

Approximately 170 million people in the world today are chronically infected with HCV and are at greatly increased risk for the development of hepatocellular carcinoma. In Japan, Italy, and Spain, HCV is the cause of about 75% of hepatocellular carcinomas, and, in other industrialized countries, HCV infection, often in combination with alcohol abuse, is emerging as a major cause of the tumor.^68,79 Patients with HCV-induced hepatocellular carcinoma generally are older than those with HBV-related tumors, and it is likely that the HCV infection is acquired mainly in adult life.

Almost all HCV-induced hepatocellular carcinomas arise in cirrhotic livers, and most of the exceptions are in livers with chronic hepatitis and fibrosis. This observation strongly suggests that chronic hepatic parenchymal disease plays a key role in the genesis of HCV-related tumors. Because the HCV genome does not integrate into host DNA, the virus would have to exert a direct carcinogenic effect by some other means.

Cirrhosis

In all parts of the world, hepatocellular carcinoma frequently coexists with cirrhosis.⁸⁰ All causative forms of cirrhosis may be complicated by tumor formation. A long-term follow-up study of 2126 U.S. military veterans with cirrhosis found that hepatocellular carcinoma developed in 100 (4.7%) over an average period of 3.6 years.⁸⁰ The calculated rate was 1.3/100 patient-years. Risk factors for hepatocellular carcinoma included obesity, low platelet count, and the presence of antibody to hepatitis B core antigen. A similar study from Italy found an incidence of hepatocellular carcinoma of 3.7/100 patient-years among persons with HCV infection and 2.0/100 patient-years among persons with HBV infection. Older age and male gender were confirmed as risk factors among patients with cirrhosis.⁸¹

Aflatoxin B₁

Dietary exposure to aflatoxin B₁, derived from the fungi Aspergillus flavus and Aspergillus parasiticus, is an important risk factor for hepatocellular carcinoma in parts of Africa and Asia. These molds are ubiquitous in nature and contaminate a number of staple foodstuffs in tropical and subtropical regions (see Chapter 87). Epidemiologic studies have shown a strong correlation between the dietary intake of aflatoxin B₁ and incidence of hepatocellular carcinoma.⁸² Moreover, aflatoxin B₁ and HBV interact synergistically in the pathogenesis of hepatocellular carcinoma. Heavy dietary exposure to aflatoxin B₁ may contribute to hepatocarcinogenesis through an inactivating mutation of the third base of codon 249 of the TP53 tumor suppressor gene.^83,84

Other Liver Conditions

Hepatocellular carcinoma develops in as many as 45% of patients with hemochromatosis (see Chapter 74).⁸⁵ Malignant transformation was thought previously to occur only in the presence of cirrhosis (and is certainly more likely to do so), but this complication also has been reported in patients without cirrhosis.⁸⁶ Excessive free iron in tissues may be carcinogenic, perhaps by generating mutagenic reactive oxygen species.⁸⁷ Further support for this theory comes from the observations that black Africans with dietary iron overload are at increased risk of hepatocellular carcinoma⁸⁸ and that rats fed a diet high in iron develop iron-free dysplastic foci and hepatocellular carcinoma in the absence of cirrhosis.⁸⁹ Hepatocellular carcinoma develops occasionally in patients with Wilson disease, but only in the presence of cirrhosis (see Chapter 75).⁹⁰ Malignant transformation has been attributed to the cirrhosis but also may result from oxidant stress secondary to the accumulation of copper in the liver.⁹¹ Hepatocellular carcinoma also may develop in patients with other inherited metabolic disorders that are complicated by cirrhosis, such as α₁-antitrypsin deficiency and type 1 hereditary tyrosinemia, and in patients with certain inherited diseases in the absence of cirrhosis—for example, type 1 glycogen storage disease (see Chapter 76). Hepatocellular carcinoma develops in approximately 40% of patients with membranous obstruction of the inferior vena cava, a rare congenital or acquired anomaly (see Chapter 83). Continuous cycles of hepatocyte necrosis followed by regeneration resulting from the severe and unremitting hepatic venous congestion render the cells susceptible to environmental mutagens, as well as to spontaneous mutations.⁹²

More recently, the role of obesity, diabetes mellitus, and fatty liver disease have come to be recognized in the causation of hepatocellular carcinoma,^93–95 although the mechanisms whereby these overlapping conditions contribute to causing hepatocellular carcinoma is unknown. Certainly, cirrhosis caused by nonalcoholic steatohepatitis may give rise to hepatocellular carcinoma, but it appears that these risk factors may also be additive to chronic viral hepatitis and cirrhosis.

A statistically significant correlation between the use of oral contraceptive steroids and the occurrence of hepatocellular carcinoma has been demonstrated in countries in which the incidence of hepatocellular carcinoma is low and no overriding risk factor for development of the tumor is present.⁹⁶ Epidemiologic evidence of a link between cigarette smoking and the occurrence of hepatocellular carcinoma is conflicting, although most of the evidence suggests that smoking is a minor risk factor.⁹⁷ Heavy smokers have an approximately 50% higher risk than nonsmokers. The incidence of hepatocellular carcinoma is increased in patients with human immunodeficiency virus (HIV) infection compared with controls in the general population, presumably because of the increased rate of chronic viral hepatitis in the HIV-positive population.⁹⁸

Although the aforementioned risk factors have been identified, the precise mechanisms whereby they lead to hepatocellular carcinoma still need to be elucidated. Multiple cellular pathways are involved in causing unconstrained proliferation of hepatocytes and increased angiogenesis against a background of chronic liver disease. These pathways have become the targets for new molecular therapies against hepatocellular carcinoma (Table 94-5).⁹⁹

Table 94-5 Key Molecular Pathways Involved in Hepatocarcinogenesis

JAK/STAT, janus kinase/signal transducers and activators of transcription; mTOR, mammalian target of rapamycin.

Adapted from Roberts L. Emerging experimental therapies for hepatocellular carcinoma: What if you can’t cure? In: McCullough A, ed. AASLD Postgraduate Course, 2007. Boston: AASLD, 2007; p 185.

Surgical Resection

Surgical therapy, whether by tumor resection or liver transplantation, offers the best chance of cure for hepatocellular carcinoma. For resection to be considered, the tumor should be confined to one lobe of the liver, favorably located, and, ideally, the nontumorous liver tissue should not be cirrhotic. Expert surgical centers can achieve five- and ten-year survival rates of 40% and 26%, respectively, with a mean tumor diameter of 8.8 cm in noncirrhotic patients.¹⁰¹ Unfortunately, these patients represent less than 5% of Western cases.^102,103 Resection is also effective if the tumor is limited to the left lobe or a portion of the right lobe, thereby permitting a segmental resection if the patient has Child (Child-Pugh) class A cirrhosis, the serum bilirubin level is normal, and portal hypertension is not present (based on imaging, a normal platelet count, and lack of varices on endoscopy or on direct measurement of the hepatic venous pressure gradient). Using these criteria, five-year survival rates of 50% can be achieved. In parts of the world where liver transplantation is not available, surgical resection is a viable option, particularly for Child class A patients without portal hypertension and with a Model for End-stage Liver Disease (MELD) score of 9 (see Chapter 90). All the tumor nodules need to be removed with negative margins, and the patient needs to be left with enough functional liver volume (usually defined as ≅40%) to survive the postoperative period.^104–106 Overall, resection is feasible in only approximately 15% of patients. Resection performed at expert surgical centers carries an operative mortality rate of less than 5%, but at low volume centers the mortality rate is almost three times greater.¹⁰⁷ Unfortunately, recurrence after resection occurs in more than 50% in the long term, and salvage liver transplantation is rarely possible.¹⁰⁸

Liver Transplantation

Liver transplantation is performed in patients in whom the tumor is not resectable but is confined to the liver or in whom advanced cirrhosis and poor liver function preclude resection (see Chapter 95).²⁵ Liver transplantation is the ideal therapy for hepatocellular carcinoma because it provides the largest possible resection margin, removes the remaining liver, which is at high risk for de novo tumors, and replaces the dysfunctioning liver. Liver transplantation can fail in patients with extrahepatic tumor, which tends to grow rapidly under the influence of post-transplantation immunosuppression. Because the availability of donor livers is limited, the consensus is that the outcomes of liver transplantation for hepatocellular carcinoma should be similar to those for other indications for liver transplantation and superior to those for other treatments for hepatocellular carcinoma. Several large series have demonstrated that if one selects candidates based on the Milan criteria—a single lesion up to 5 cm in size or two to three lesions, each up to 3 cm, with no large-vessel vascular invasion or metastasis—the five-year survival rate is 70% to 75%, and the tumor recurrence rate is 10% to 15%.^{102,109–111} These criteria led to the hepatocellular carcinoma MELD exception pathway, which was adopted in the United States in 2002. As a result of the change, the frequency of hepatocellular carcinoma as an indication for liver transplantation rose from 4.6% to 26% of the total adult liver transplant population. Additionally, progression of the tumor beyond the Milan criteria before a patient undergoes transplantation has largely been eliminated.^38,112 In other parts of the world, waiting times before transplantation remain critical, and when the waiting time increases to one year, as many as one half of patients will not receive a transplant.¹⁰² An analysis of four-year survival rates for all patients transplanted in the United States has confirmed that overall outcomes for those transplanted with hepatocellular carcinoma are only minimally worse than for those transplanted for other indications.³⁸ Certain subgroups of patients do worse, including those with nodules 3 to 5 cm in diameter, a MELD score of 20, and a serum AFP level of ≥455 ng/mL.

Some authorities have advocated a modest expansion of the Milan criteria, with use of the so-called University of California, San Francisco (UCSF) criteria (a single lesion up to 6.5 cm in diameter or two or three lesions up to 4.5 cm each, with a total tumor diameter of 8 cm), based on excellent prospective outcomes from a small, single-center series, but these patients generally need a special exception from the regional review board in the United States.¹¹³ Other groups who use similar criteria have shown similarly good results.¹¹⁴ A larger multicenter study is needed before these criteria can be widely adopted.

Local Ablation

Local ablative therapies are potentially curative treatments for patients with small tumors, usually smaller than 3 to 5 cm in diameter, that are not amenable to resection or liver transplantation because of patient preference, the number and location of lesions, or significant hepatic dysfunction (Child class B or C; see Fig. 94-4).^25,115 The first of these techniques available was percutaneous ethanol injection (PEI), a relatively effective and safe method that is still used and is most effective for lesions smaller than 2 to 3 cm in diameter.¹¹⁶ PEI requires multiple sessions and, in patients with small tumors and intact hepatic function, can lead to survival rates similar to those for surgical resection, although no randomized studies have been performed to demonstrate equivalent outcomes.¹¹⁷ Complications are rare but include tumor seeding of the needle track. More recently, radiofrequency ablation (RFA) has supplanted PEI, because it is more effective, particularly with larger tumors (up to 3 to 5 cm), requires fewer sessions, and has similar complication rates.¹¹⁸ RFA can be performed percutaneously or by a laparoscopic or open surgical approach. Survival rates are similar to those for surgical resection, although recurrence rates are higher and complications are uncommon.^117,119 PEI is generally favored over RFA for lesions adjacent to a major vessel or large bile ducts. A randomized study has suggested that a combination of RFA and chemoembolization for tumors larger than 3 cm in diameter produces a survival benefit when compared with either treatment alone.¹²⁰ PEI and RFA have been used to stabilize tumor growth in patients awaiting liver transplantation, but their use for this purpose is controversial and probably unnecessary, unless the waiting time for transplantation is more than six months or the tumor burden is near the limits of acceptability for transplantation.^{102,121–123}

Chemoembolization

Transarterial chemoembolization (TACE) is a palliative treatment reserved for patients with relatively intact hepatic function (Child class A or B) and tumors not amenable to local ablative treatments because of size, number, or location (see Fig. 94-4).^25,121 Six randomized trials and a meta-analysis have compared embolization or chemoembolization with supportive care and have shown overall improved survival with treatment.^124–130 The effectiveness of TACE before liver transplantation has not been fully elucidated, but TACE can be considered if the waiting time for transplantation is more than six months or the tumor size is near the acceptable limit.^131,132 Theoretically, TACE can be used to reduce the size of the tumor to make resection or transplantation possible (downstaging) or to allow a more conservative resection, although study results are mixed as to whether this approach is effective.^133,134

Chemotherapy

A large number of anticancer drugs, including alkylating agents, antitumor antibiotics, antimetabolites, plant alkaloids, platinum derivatives, procarbazine, estrogen receptor modulators, and somatostatin, have been tried alone and in various combinations and by different routes of administration for the treatment of hepatocellular carcinoma, but response rates have invariably been less than 20%.^126,135 Several small-molecule, targeted anticancer agents have been developed and studied for the treatment of hepatocellular carcinoma. Sorafenib, an inhibitor of Raf kinase and the tyrosine kinase activity of vascular endothelial growth factor receptors (VEGFRs) and platelet-derived growth factor receptor (PDGFR), is the first of these new agents to show modest improvement in survival compared with supportive care.¹³⁶ The drug should be considered for patients with intact hepatic function (Child class A) and portal vein thrombosis, extrahepatic tumor, or failures of other therapies (see Fig. 94-4). Other targeted agents, alone and in combination with each other and with traditional chemotherapy, are being studied. Patients with advanced hepatic dysfunction (Child class C) or advanced tumor symptoms (Eastern Cooperative Oncology Group [ECOG] performance status > 2) have such a poor prognosis that only supportive care should be offered (see Fig. 94-4).²⁵

New Alternative Techniques

New local ablative techniques include cryoablation, microwave ablation, and laser ablation and are being studied in hepatocellular carcinoma, but these techniques have not been adequately compared with PEI and RFA; thus, their use should be limited to clinical trials. Use of other local regional therapies include stereotactic radiotherapy and radioembolization with ⁹⁰Y microspheres, but should be limited to clinical trials or as a last resort until they are compared with chemoembolization.

Epidemiology

Intrahepatic cholangiocarcinoma represents approximately 10% to 20% of all primary liver cancers and 20% to 25% of cholangiocarcinomas. The geographic variation in prevalence rates is marked, ranging from 0.2 to 96/100,000 in men and from 0.1 to 38/100,000 in women, because of differences in the frequencies of known risk factors in various populations.¹⁴² The highest prevalence rates are found in parts of Asia, most notably certain regions of Thailand, Hong Kong, China, Japan, and Korea. Chronic infestation of the biliary tree with one of the liver flukes is thought to be the cause of these high rates.¹⁴³ The overall prevalence rate in the United States is 0.85/100,000, with a 1.5-fold higher rate in men than women. The rate in whites is about equal to that in African Americans and about half that in Asians.

Although the underlying predisposing factor for most cases of cholangiocarcinoma is unknown, a number of risk factors have been recognized. The strongest association is with Opisthorchis viverrini, a liver fluke endemic in parts of Southeast Asia and acquired by ingestion of raw or uncooked fish.^142,144,145 The association with Clonorchis sinensis, a related liver fluke, is weaker.¹⁴⁶ An association with the radiographic contrast agent thorium dioxide (Thorotrast), which was banned in the 1950s, has been well established.¹⁴⁷ Primary sclerosing cholangitis is linked to a diagnosis of cholangiocarcinoma at a young age, with a lifetime risk of 8% to 20% (see Chapter 68).^148–150 Congenital and acquired abnormalities of the biliary tract that may result in bile stasis, chronic inflammation, and infection, as in biliary atresia,¹⁵¹ von Meyenburg complexes,¹⁵² Caroli’s disease,¹⁵³ choledochal cyst,¹⁵³ and intrahepatic cholelithiasis, have been associated with the development of cholangiocarcinoma. Cirrhosis, particularly caused by HCV, also has been associated with cholangiocarcinoma.¹⁵⁴

Intrahepatic cholangiocarcinoma is rare before the age of 40 years, and historically the worldwide approximate average age at presentation is 50 years. Epidemiologic data indicate that the age at presentation has shifted to more than 65 years. Additionally, the incidence and mortality rates are increasing worldwide.¹⁴⁰ Surveillance, Epidemiology and End Results (SEER) registry data from the United States have shown a 165% increase between the late 1970s and the late 1990s.¹⁴² This increase may be a result, in part, of the increased prevalence of cirrhosis, particularly HCV-associated cirrhosis.¹⁵⁴

Molecular Pathogenesis

Malignant transformation of the bile duct cells generally occurs in an environment of inflammation or cholestasis (or both), usually as a result of one of the known risk factors. The proposal has been made that a combination of these environmental factors and genetic predisposition—for example, defects in oncogenes or bile salt transporters—leads to an accumulation of genetic defects that results in carcinoma.^140,155 A polymorphism in the gene for the natural killer cell receptor G2D (NKG2D) has been associated with an increased risk of cholangiocarcinoma in patients with primary sclerosing cholangitis.¹⁵⁶ At the molecular level, numerous changes have been described, including mutations of the K-ras gene, the gene for interleukin-6, and allelic loss or mutations of TP53 and p16, as well as many others (see Chapter 69).

Clinical Features

Peripheral cholangiocarcinoma seldom produces symptoms until the tumor is advanced. The clinical features are then similar to those of hepatocellular carcinoma, including malaise, weight loss, abdominal pain, and jaundice, which may be more frequent and prominent than with hepatocellular carcinoma.^153,157 The clinical presentation of perihilar and extrahepatic cholangiocarcinoma is with progressive painless jaundice, acholic stools, pruritus with or without weight loss, and, rarely, cholangitis.¹⁵⁸ Patients with primary sclerosing cholangitis may present with worsening jaundice caused by a dominant bile duct stricture, weakness, and weight loss.

Diagnosis

In patients with perihilar cholangiocarcinoma and extrahepatic cholangiocarcinoma, obstructive jaundice is evident, with elevated serum levels of bilirubin, alkaline phosphatase, gamma glutamyl transpeptidase (GGTP), and often aminotransferases. In patients with peripheral cholangiocarcinoma, often only the alkaline phosphatase level is elevated. CA 19-9 is the most frequently used serum tumor marker for cholangiocarcinoma but has significant limitations because CA 19-9 levels are also elevated in pancreatic, colorectal, gastric, and gynecologic cancers and in acute bacterial cholangitis.¹⁵⁹ CA 19-9 is always undetectable in the 7% of the population that is Lewis blood group–negative. In patients with unexplained biliary obstruction without primary sclerosing cholangitis, the sensitivity of CA 19-9 is 53%, and the negative predictive value is 72% to 92%, for a cutoff value of 100 U/mL. In patients with primary sclerosing cholangitis, the sensitivity ranges from 38% to 89% and specificity from 50% to 98%. The addition of carcinoembryonic antigen (CEA) probably does not improve the performance of CA 19-9 in the setting of primary sclerosing cholangitis.

Initial imaging with ultrasound helps identify biliary obstruction. Dynamic contrast-enhanced CT or MRI further aids in localizing the lesion and determining the possibility of resection.^140,160 MRI with magnetic resonance cholangiography (MRCP) is a superior modality because of a higher sensitivity than CT for detecting lesions and localizing biliary obstruction. The tumor is hypodense on T1-weighted images and moderately intense on T2-weighted images. Endoscopic retrograde cholangiopancreatography (ERCP) or transhepatic cholangiography allows for localization of the tumor, sampling of tissue and bile, and relief of biliary obstruction if the tumor is unresectable. A perihilar tumor may demonstrate a classic appearance on ERCP, but for other biliary strictures, particularly in patients with primary sclerosing cholangitis, determining whether cholangiocarcinoma is present may be difficult. Cytology has a 30% sensitivity, which improves to 40% to 70% with the addition of brushings and biopsies. Newer cytologic techniques that assess the cells for aneuploidy and chromosomal aberrations may improve the diagnostic yield but are not widely available (see Chapter 69). Endoscopic ultrasound (EUS) with fine-needle aspiration (FNA) in patients without primary sclerosing cholangitis has the advantage of improving sensitivity and specificity for diagnosis of the primary lesion and nodal metastasis but the disadvantage of causing peritoneal seeding, and thus should be avoided if surgical resection is contemplated. Percutaneous biopsies also carry the risk of peritoneal seeding and are generally avoided if the tumor is potentially resectable.

Pathology

Peripheral cholangiocarcinoma usually is a large and solitary tumor, but it may be multinodular.¹⁶¹ It is grayish-white, firm, and occasionally umbilicated and can produce a focal hepatic mass, a tumor growing along and infiltrating the bile ducts, or an intraductal papillary lesion.¹⁶⁰ The tumor is poorly vascularized and rarely bleeds internally or ruptures. Perihilar cholangiocarcinoma may take the form of a firm intramural tumor that encircles the bile duct, a bulky mass centered on the duct or hilar region that radiates into the hepatic tissue, or a spongy friable mass within the lumen of the duct. Metastatic nodules may be distributed irregularly throughout the liver. The bile ducts peripheral to the tumor may be dilated, resulting in some cases in biliary cirrhosis. Metastases in regional lymph nodes occur in about 50% of cases.

Microscopically, cholangiocarcinoma exhibits acinar or tubular structures that resemble those of other adenocarcinomas.¹⁶¹ Most tumors are well differentiated. Secretion of mucus may be demonstrable, but bile production is not seen. The tumor cells provoke a variable desmoplastic reaction, and, in many tumors, the collagenized stroma may be the most prominent feature. Distinguishing the tumor from metastatic adenocarcinoma may be difficult, and some experts have advocated assuming that an adenocarcinoma in the liver is cholangiocarcinoma if no primary tumor can be found elsewhere.¹⁶²

Treatment and Prognosis

Early diagnosis of intrahepatic cholangiocarcinoma is unusual, and the annual mortality rate is almost identical to the annual incidence of the tumor.^153,157 Long-term survival after diagnosis in the United States based on the SEER database is dismal, with a one-year survival rate of 28% and a five-year survival rate less than 5%. The five-year survival rate has not improved since the late 1980s.¹⁴²

In a person with suspected or proven intrahepatic cholangiocarcinoma, staging is recommended to determine surgical resectability, which is the only opportunity for cure. The staging evaluation usually includes dynamic MRI and MRCP of the abdomen (or dynamic helical CT, if MRI is unavailable) and a chest x-ray or CT.¹⁴⁰ Positron emission tomography (PET) has been assessed in small series and does not clearly add to other modalities. EUS with FNA of suspicious lymph nodes may detect otherwise unrecognized metastasis in up to 20% of cases.¹⁶⁰ Surgical resectability of intrahepatic cholangiocarcinoma should be determined in conjunction with an experienced hepatobiliary surgeon and requires the ability to achieve clear surgical margins, which usually necessitates a major hepatectomy. Criteria for resection include absence of all the following: evidence of extrahepatic metastasis; main portal vein or hepatic artery invasion or encasement; bilateral segmental bile duct involvement; and contralateral hepatic lobar atrophy. Additionally, the patient must be medically fit to undergo surgery and have sufficient hepatic reserve. Without clear margins of resection, surgery provides benefits similar to those of endoscopic or biliary drainage. Patients well selected for surgical resection achieve a one- to two-year median survival and a 29% to 36% five-year survival rate.

If resection is not possible and major biliary obstruction is present, biliary drainage, either endoscopic or percutaneous, should be performed, because drainage appears to improve symptoms and survival (see Chapter 70).¹⁶² Placement of an expandable metal stent is generally preferred to plastic stents if the expected survival of the patient is more that three to six months.¹⁴⁰ The rates of response and survival following radiation therapy and chemotherapy are modest, as suggested by predominantly small uncontrolled series, so these modalities generally should be restricted to clinical trials. Photodynamic therapy in addition to biliary stent placement may provide benefit. Liver transplantation alone results in unacceptably high recurrence rates and limited survival.¹⁶⁰ In a single center report, aggressive preoperative therapy of unresectable hilar cholangiocarcinoma with external beam radiation, brachytherapy, and chemosensitization, followed by liver transplantation in patients who survived the treatment and had contained disease, produced a five-year survival rate of 82%.¹⁶³

Epidemiology

In children, hepatoblastoma is the third most common malignant tumor and the most common malignant hepatic tumor. It occurs almost exclusively in the first three years of life; boys are affected twice as often as girls.^164,165

Clinical Features

Most children with hepatoblastoma come to medical attention because of abdominal swelling.¹⁶⁶ Other reasons include failure to thrive, weight loss, poor appetite, abdominal pain, irritability, and intermittent vomiting and diarrhea. The tumorous liver almost always is enlarged and firm and may be tender. Its surface is smooth or nodular. Hepatoblastomas rarely rupture. Distant metastases are evident, usually in the lung, in 20% of patients at the initial visit.¹⁶⁷ The tumor occasionally causes isosexual precocity in boys as a result of the ectopic production of human chorionic gonadotropin.¹⁶⁸

Diagnosis

AFP is present in high concentrations in the serum of 80% to 90% of patients with hepatoblastoma and is a useful clue to diagnosis.¹⁶⁹ The few patients with a low serum AFP level appear to have a worse prognosis.¹⁷⁰ Anemia is common, as is thrombocytosis, which is attributed to raised serum thrombopoietin levels. Pulmonary metastases and, rarely, mottled calcification in the tumor may be seen on plain radiography. Ultrasonography is the most widely used initial imaging technique, although the findings are not specific. CT and MRI are used to define the extent of the tumor and plan definitive surgery. The tumor is seen as an avascular mass on hepatic arteriography.¹⁷¹

Pathology

Hepatoblastomas are the malignant derivatives of incompletely differentiated hepatocyte precursors. Their constituents are diverse, reflecting both the multipotentiality of their mesodermal origin and the progressive stages of embryonic and fetal development. Hepatoblastomas are classified morphologically into an epithelial type, composed predominantly of epithelial cells of varying maturity, and a mixed epithelial and mesenchymal type, which contains, in addition, tissues of mesenchymal derivation.^166,169 The tumors usually are solitary, ranging in diameter from 5 to 25 cm, and always well circumscribed (about half are encapsulated). They vary in color, ranging from tan to grayish-white, and contain foci of hemorrhage, necrosis, and calcification. Vascular channels may be prominent on the capsular surface. Epithelial hepatoblastomas are solid, whereas tumors of the mixed variety often are separated into lobules by white bands of collagen tissue.

Two types of epithelial cells are present in the tumor.¹⁷² Cells of the first type resemble fetal hepatocytes and are arranged in irregular plates, usually two cells thick, with bile canaliculi between individual cells and sinusoids between plates. Cells of the second type are embryonal and are less differentiated than the fetal type. Mixed hepatoblastomas contain mesenchymal tissue consisting of areas of a highly cellular primitive type of mesenchyme intimately admixed with epithelial elements. Cartilage and striated muscle may be present. Hepatoblastomas may show foci of squamous cells, with or without keratinization, and foreign body–type giant cells. Vascular invasion may be evident. Metastases most commonly involve lung, abdominal lymph nodes, and brain.

Cause and Pathogenesis

Hepatoblastoma may occur sporadically or in association with hereditary syndromes such as familial adenomatous polyposis (FAP) and Beckwith-Wiedemann syndrome, suggesting a possible role for chromosomes 5 and 11 in the genesis of the tumor. The FAP tumor suppressor gene down-regulates β-catenin. Sporadic hepatoblastoma is not associated with any known environmental risk factor, and its pathogenesis is unclear. Most patients with hepatoblastoma have mutations of the FAP gene, and a similar number have activating mutations of the β-catenin gene, raising the possibility that the wnt signaling pathway plays a role in the development of the tumor.¹⁷³

Treatment and Prognosis

Hepatoblastomas are rapidly progressive. If the lesion is solitary and sufficiently localized to be resectable, surgery often is curative, with five-year survival rates as high as 75%.¹⁶⁶ The current practice is to pretreat the patient with cisplatin and doxorubicin. When the tumor is judged to be inoperable, neoadjuvant chemotherapy may reduce the size of the tumor sufficiently to permit resection. Encouraging results also have been obtained with liver transplantation in patients with bilobar multifocal tumors without extrahepatic extension.¹⁷⁴ If surgery is not possible or the tumor recurs after surgery, the prognosis generally is poor.

Epidemiology

Although rare, angiosarcoma is the most common malignant mesenchymal tumor of the liver.^175,176 It occurs almost exclusively in adults and is most prevalent in the sixth and seventh decades of life.^177,178 Men are affected four times as often as women.

Pathogenesis

Despite its rarity, hepatic angiosarcoma is of special interest because specific risk factors have been identified, although no cause is discerned in most cases. In early reports, the tumor became evident approximately 20 years after the patient had been exposed to thorium dioxide (see Chapter 87).¹⁷⁹ Angiosarcoma also has occurred in German vintners who used arsenic-containing insecticides and drank wine adulterated with arsenic.¹⁸⁰ A few patients with angiosarcoma had taken potassium arsenite (Fowler’s solution) for many years to treat psoriasis.¹⁸¹ Hepatic angiosarcoma in workers exposed to vinyl chloride monomer (VCM) was first reported in 1974.^177,182,183 The monomer is converted by enzymes of the endoplasmic reticulum to reactive metabolites that form DNA adducts and guanosine-to-adenine transitions in the K-ras and TP53 genes. Angiosarcomas have occurred after exposures of 11 to 37 years (or after shorter periods with a heavy initial exposure). The mean age of patients at diagnosis is 48 years. In addition to angiosarcoma, persons exposed to VCM may be at increased risk of hepatocellular carcinoma and soft tissue sarcoma.

Clinical Features

The most common presenting symptom is upper abdominal pain. Other frequent complaints are abdominal swelling, rapidly progressing liver failure, malaise, weight loss, poor appetite, and nausea.^176,177 Vomiting occurs occasionally. The duration of symptoms generally ranges from one week to six months, but a few patients have had symptoms for as long as two years before seeking medical attention.

The liver almost always is enlarged and usually is tender. Its surface may be irregular, or a definite mass may be felt. An arterial bruit occasionally is heard over the enlarged liver. Splenomegaly may be present and is attributed to the hepatic fibrosis and consequent portal hypertension that also may complicate exposure to VCM. Ascites is frequent, and the fluid may be blood-stained. The patient often has jaundice. Fever and dependent edema are less common. Approximately 15% of patients present with acute hemoperitoneum following tumor rupture. Rarely, pulmonary or skeletal metastases are present.

Diagnosis

A rising serum bilirubin level and other evidence of progressive hepatic dysfunction may be present, especially in the later stages of the tumor. Plain radiography may show pulmonary metastases, a raised right hemidiaphragm, or, rarely, skeletal metastases. In patients who received thorium dioxide, radiopaque deposits of the material may be evident in the liver and spleen.¹⁷⁹ One or more mass lesions may be demonstrated on ultrasonography, CT, or MRI, but diffusely infiltrating tumor may not be visualized. Hepatic arteriography reveals a characteristic appearance.¹⁸⁴ The hepatic arteries are displaced by the tumor, which shows a blush and “puddling” during the middle of the arterial phase that persist for many seconds, except in the central area, which may be hypovascular.

Complications and Prognosis

Hepatic angiosarcomas grow rapidly, and the prognosis is poor; death ensues within six months. Patients may have thrombocytopenia resulting from entrapment of platelets within the tumor (Kasabach-Merritt syndrome), disseminated intravascular coagulation with secondary fibrinolysis,¹⁸⁵ or microangiopathic hemolytic anemia as a result of fragmentation of erythrocytes within the tumor circulation.¹⁸⁶

Pathology

Angiosarcomas usually are multicentric.¹⁸⁷ Their hallmark is the presence of blood-filled cysts, although solid growth also is seen. The lesions are fairly well circumscribed but not encapsulated. Larger masses are spongy and bulge beneath Glisson’s capsule.

The earliest microscopic change is the presence of hypertrophic sinusoidal lining cells with hyperchromatic nuclei in ill-defined loci throughout the liver. With progression of the lesion, sinusoidal dilatation and disruption of hepatic plates occur, and the malignant cells become supported by collagen tissue. Enlarging vascular spaces lined by malignant cells cause the tumor to become cavernous. The malignant endothelial cells usually are multilayered and may project into the cavity in intricate fronds and tufts supported by fibrous tissue. The fronds commonly are elongated, with ill-defined borders. The cytoplasm is clear and faintly eosinophilic. Nuclei are hyperchromatic and vary greatly in size and shape; some cells are multinucleated. Evidence of phagocytosis may be seen. Foci of extramedullary hematopoiesis are common, and invasion of the portal and central veins occurs in most cases. Distant metastases are present in 50% of tumors.

Treatment

Operative treatment usually is precluded by the advanced stage of the tumor. Even when surgery is undertaken, the patient commonly survives only one to three years, although long-term survival may be achieved in the few patients with a solitary tumor.¹⁷⁶ The results of irradiation and chemotherapy are poor.

Epidemiology

Epithelioid hemangioendothelioma is a rare tumor whose incidence is not known. A case series of 137 cases has been collected at a specialized referral center.¹⁸⁸ Two thirds of patients were female, and the tumor occurred at all ages in adulthood.

Clinical Features

Patients typically present with nonspecific symptoms, such as abdominal pain and weight loss.

Diagnosis

Imaging studies show a characteristically highly vascular mass, which may infiltrate throughout the liver. Case reports indicate that the tumor can be visualized on PET. Correct diagnosis requires histologic examination of tissue obtained by biopsy.

Complications and Prognosis

The tumor has low-grade malignant potential and must be distinguished from hemangiosarcoma, because it has a much better prognosis if treated appropriately and aggressively. Epithelioid hemangioendothelioma may metastasize, both within and beyond the liver.

Pathology

Tumors are often multiple and may be diffuse throughout the liver. Histologically, they are characterized by the presence of dendritic and epithelioid cells that contain vacuoles, representing intracellular lumina. These cells stain positively for endothelial markers, such as factor VIII–related antigen, CD34, or CD31.

Treatment

The primary treatment modality for epithelioid hemangioendothelioma is surgical, including resection or liver transplantation. Transplantation appears to be effective for this tumor, even in the presence of advanced or even metastatic disease. The tumor does not appear to be sensitive to radiation or chemotherapy.

HEPATOCELLULAR ADENOMA

Epidemiology and Pathogenesis

Hepatocellular adenomas (or hepatic adenomas) were extremely rare before the use of oral contraceptive steroids became widespread. They are still rare in men, and the development of this tumor in women who are taking or have taken contraceptive steroids strongly implies a cause and effect relationship.^200,201 Nevertheless, in light of the large number of women who use this form of contraception, the risk of hepatocellular adenoma is small, and its occurrence implies some form of genetic predisposition (see later). The association is particularly strong with prolonged use of oral contraceptive steroids; the estimated risk for women who use oral contraceptive agents continuously for five to seven years is five times the normal rate, and this risk increases to 25 times with use for longer than nine years. Using preparations with high hormone potency further increases the risk. Contraceptive pill–associated hepatocellular adenomas are more likely to develop in older than younger women.

Hepatocellular adenomas have been linked to both types of synthetic estrogen and all forms of progestogen contained in oral contraceptive preparations.²⁰² Current evidence favors estrogens as the culprit, although progestogens may contribute through their enzyme-inducing properties. The growth of hepatocellular adenomas appears to be hormone-dependent, as evidenced by an increase in size during pregnancy and occasional cases of regression (and even disappearance) of the tumor after cessation of oral contraceptive use. Although hormonal replacement therapy has not proved to be associated with the development of hepatic adenoma, avoidance of this form of therapy in women with a history of oral contraceptive–related hepatic adenoma is prudent, unless compelling reasons to the contrary exist.

Hepatocellular adenomas and adenomatosis also may occur in those receiving long-term anabolic androgenic steroids⁶³ and in those with certain inherited metabolic disturbances, especially type 1 glycogen storage disease, in which one or more hepatocellular adenomas occur in approximately 60% of patients (see Chapter 76).²⁰¹

Genetic alterations have been identified in hepatocellular adenomas. Bilallelic mutations of the TCF1 gene that codes for hepatocyte nuclear factor 1α (HNF-1α) have been identified in up to 60% of patients with adenoma.²⁰³ A second pathway, the wnt pathway, which also is activated in about 25% of patients with hepatocellular carcinoma, is activated in at least some cases of adenoma.²⁰⁴ β-Catenin activation via this pathway appears to confer a higher risk of malignant transformation.²⁰⁵ The third identified pathway for formation of hepatocellular adenomas includes acute inflammatory responses demonstrable by histologic examination of the tumor²⁰⁵ and associated with obesity and alcohol (Fig. 94-5).

Figure 94-5. Schematic representation of the different molecular pathways altered in hepatocellular adenoma. Left, Main risk factors and known genetic predispositions. Center, Altered molecular pathways and their frequencies. Right, Principal clinical and pathologic features of the subtypes of adenomas. Arrows indicate the significant relationships. *Some tumors may be simultaneously inflammatory and β-catenin activated. CYP1B1, cytochrome P450 1B1; HCC, hepatocellular carcinoma; HNF1α, hepatocyte nuclear factor 1α (gene symbol TCF1); MODY3, maturity-onset diabetes of the young type 3; mut, mutation.

(Adapted from Rebouissou S, Bioulac-Sage P, Zucman-Rossi J. Molecular pathogenesis of focal nodular hyperplasia and hepatocellular adenoma. J Hepatol 2008; 48:163-70.)

Pathology

Hepatocellular adenoma generally occurs as a solitary, relatively soft, light brown to yellow tumor. It is sharply circumscribed but does not have a true capsule, although a pseudocapsule is formed by compression of the surrounding liver tissue (Fig. 94-6A).²¹¹ Hepatocellular adenomas arise in an otherwise normal liver. Occasionally, two or more tumors are present. Adenomas range in diameter from 1 to 30 cm and are commonly 8 to 15 cm in diameter. They are larger on average in women taking contraceptive steroids than in those not taking contraceptive steroids; they usually occupy a subcapsular position and project slightly from the surface of the liver. A pedunculated variety is seen occasionally. The cut surface of the tumor may show ill-defined lobulation but is never nodular or fibrotic. Foci of hemorrhage or necrosis are frequent, and bile staining may be evident.

Figure 94-6. A, Surgical specimen of a large hepatocellular adenoma. The tumor is yellowish and slightly lobular, with a pseudocapsule and areas of necrosis and hemorrhage. B, Photomicrograph of a hepatocellular adenoma showing the resemblance to normal liver tissue, with cords of normal-looking, although generally slightly larger, hepatocytes, as well as Kupffer cells (but fewer in number than normal) lining the sinusoids. Bile ducts and central veins are not seen, but the presence of abnormal vascular structures is evident. (Hematoxylin and eosin.)

(A courtesy of Elizabeth Brunt, MD, St. Louis, MO; B courtesy of Professor A.C. Paterson, Johannesburg, South Africa.)

Microscopically, hepatocellular adenoma may mimic normal liver tissue to an astonishing degree (see Fig. 94-6B).²¹¹ The tumor is composed of sheets or cords of normal-looking or slightly atypical hepatocytes that show no features of malignancy. Few or no portal tracts or central veins are present, and bile ducts are conspicuously absent. Only an infrequent fibrous or vascular septum traverses the lesion. An essentially normal reticulin pattern is demonstrable throughout the adenoma. The walls of arteries and veins are thickened. Some areas with vascular abnormalities are infarcted, and thrombi may be seen. Peliosis hepatis may be found in relation to the tumor.

CAVERNOUS HEMANGIOMA

Diagnosis

The ultrasonographic appearance is variable and nonspecific, although the lesion usually is echogenic.^215,216 Provided that the cavernous hemangioma is larger than 3 cm in diameter, single photon emission computed tomography (SPECT) with colloid ^99mTc-labeled red blood cells shows the tumor to be highly vascular and has a sensitivity and accuracy similar to those of MRI.²¹⁷ Almost all cavernous hemangiomas can be diagnosed by bolus-enhanced CT with sequential scans.²¹⁸ The center of the lesion remains hypodense, whereas the peripheral zone, which varies in thickness and may have a corrugated inner margin, is enhanced. MRI has a high degree of specificity and a central role in the diagnosis of small hemangiomas (Fig. 94-7).^219,220 With small hemangiomas, the contrast material may assume a ring-shaped or C-shaped configuration, with an avascular center resulting from fibrous obliteration; this appearance is pathognomonic.

Figure 94-7. Magnetic resonance imaging of a small cavernous hemangioma in the liver (arrow). A, T1-weighted image showing a rounded mass with a uniform increase in T1 signal intensity (low signal). B, Heavily T2-weighted image showing a mass with a uniform increase in signal intensity (bright signal relative to the water signal of cerebrospinal fluid).

(Courtesy of Dr. P. Sneider, Johannesburg, South Africa.)

Thrombocytopenia resulting from sequestration and destruction of platelets in large hemangiomas (Kasabach-Merritt syndrome) is seen occasionally in infants but rarely in adults.^214,221 Malignant transformation has not been reported.

Because of the risk of severe bleeding, percutaneous needle biopsy should not be performed if a cavernous hemangioma is suspected. Moreover, a needle biopsy is of limited diagnostic value.

INFANTILE HEMANGIOENDOTHELIOMA

OTHER BENIGN TUMORS OF THE LIVER

Other rare benign tumors of the liver include angiomyolipoma,²³⁵ bile duct adenoma, biliary cystadenoma, and biliary adenofibroma.^236,237

FOCAL NODULAR HYPERPLASIA

Focal nodular hyperplasia is a circumscribed, usually solitary lesion composed of nodules of benign hyperplastic hepatocytes surrounding a central stellate scar.²³⁸

Diagnosis

Serum AFP levels are normal. The mass lesion seen on ultrasonography and CT is not specific for focal nodular hyperplasia,^246,247 unless the central scar and feeding artery are seen (Fig. 94-8). MRI may be useful for the diagnosis of focal nodular hyperplasia.²⁴⁸

Figure 94-8. Contrast-enhanced computed tomography scan of the liver during arterial phase showing a typical focal nodular hyperplasia (arrow) with enhancement of the mass lesion and the central stellate scar apparent by its lack of enhancement.

OTHER NODULAR DISORDERS

Nodular regenerative hyperplasia is characterized by nodularity of the liver without fibrosis (see Chapter 35).²⁵⁰ This rare condition may be associated with a number of diseases, such as rheumatoid arthritis and Felty’s syndrome. Although generally diffuse, the nodularity occasionally is focal, in which case the lesion may be mistaken for a tumor. Patients with nodular regenerative hyperplasia typically present clinically with portal hypertension. Partial nodular transformation is characterized by nodules that are limited to the perihilar region of the liver. These patients also present with portal hypertension.

Macroregenerative nodules may occur in advanced cirrhosis or after massive hepatic necrosis. In the presence of cirrhosis, they are believed to be premalignant and may, in addition, be mistaken for hepatic tumors during hepatic imaging.⁶⁰

Inflammatory pseudotumor is a rare entity, resulting from focal infection, that may be mistaken for a hepatic tumor (see Chapter 82).²⁵¹ It occurs particularly in young men, who present with intermittent fever, abdominal pain, jaundice, vomiting, and diarrhea. Leukocytosis, an elevated erythrocyte sedimentation rate, and polyclonal hyperglobulinemia are present in approximately 50% of patients. The lesion may be solitary or multiple and shows a mixture of chronic inflammatory cells, with plasma cells predominating. Focal fatty infiltration, or focal fatty sparing in the presence of diffuse fatty infiltration, may also be mistaken for a hepatic tumor (see Chapter 85).²⁵²

FIBROCYSTIC DISEASES OF THE LIVER

Fibrocystic diseases of the liver originate from abnormal persistence or defects in the progressive remodeling of the ductal plate during development, resulting in dilated fluid-filled spaces, including hepatic and choledochal cysts, portal fibrosis, and ductal plate malformations (see Chapter 62).^253,254 Fibrocystic disorders of the liver described here include simple hepatic cysts, polycystic liver disease (PCLD), von Meyenburg complexes, and Caroli’s disease (type V choledochal cyst). (The other diseases are congenital hepatic fibrosis and type IV choledochal cysts; see Chapter 62.)

Polycystic Liver Disease

PCLD is a rare condition in which multiple cysts form in the hepatic parenchyma; usually it comes to clinical attention in adulthood (Fig. 94-9). PCLD usually presents in association with autosomal dominant polycystic kidney disease (ADPKD)^258,259 but can appear as isolated polycystic liver disease.^260,261

Figure 94-9. Magnetic resonance imaging of the abdomen in a patient with severe polycystic liver disease. This coronal T2-weighted image shows a massively enlarged liver with numerous bright fluid-filled cysts.

(Courtesy of Dr. N. Cem Balci, St. Louis, Mo.)

The cysts range in diameter from a few millimeters to 10 cm or more. They contain clear, colorless, or straw-colored fluid and are lined by a single layer of cuboidal or columnar epithelium, resembling that of bile ducts.^258–262 Rarely, the cysts may be lined by squamous epithelium; these cysts may be complicated by the development of squamous cell carcinoma. In addition to the nature of the lining epithelium, evidence for a biliary origin of these cysts is suggested by the composition of the cystic fluid, which has a low glucose content and contains secretory immunoglobulin A and gamma glutamyl transpeptidase. The cysts are thought to arise as a result of ductal plate malformation. This process gives rise to von Meyenburg complexes (see later), which become disconnected from the biliary tree during development and growth and dilate progressively to form cysts.

PCLD is fairly common in patients with ADPKD. It occurs in approximately 24% of patients in the third decade of life to 80% in the sixth decade of life, but the kidney disease usually dominates the clinical course.²⁶³ Cysts also may be present in the pancreas, spleen and, less often, other organs. Symptomatic liver disease correlates with advancing age, severity of renal cysts, and renal dysfunction.²⁶⁴ Women tend to have larger and more numerous cysts, and a correlation with the number of pregnancies has been found. The use of exogenous female sex hormones may accelerate the rate of growth and size of the cysts. PCLD may coexist with other fibrocystic liver diseases, such as congenital hepatic fibrosis (in which the patient is likely to present with portal hypertension), Caroli’s disease, or von Meyenburg complexes.^258–262 PCLD also is associated with other conditions such as berry aneurysms, mitral valve prolapse, diverticular disease, and inguinal hernias.

Isolated PCLD not associated with ADPKD is rare, representing 7% of all PCLD in autopsy series.²⁶⁵ It usually is asymptomatic.²⁶⁶ Like ADPKD-associated PCLD, isolated PCLD is associated with pregnancy and appears to be more symptomatic in women than men.

ADPKD is a common genetic disease with a frequency of 1:1,000 in whites.²⁶⁷ Two genes are responsible. The gene affected in ADPKD1 is PKD-1, which is located on chromosome 16q13-q23 and expresses a ubiquitous protein, polycystin-1.^268,269 The gene responsible for ADPKD2 is PKD-2, which is located on chromosome 4 and expresses polycystin-2. The two polycystins are transmembrane glycoproteins that complex and localize in the primary cilium, a microtubule-based structure found on renal and biliary tubule epithelium and thought to act as a flow sensor and regulator of Ca²⁺ influx.²⁷⁰ Although the mutation is inherited as an autosomal dominant trait, a second somatic mutation is thought to be necessary to produce the monoclonally derived cysts.²⁷¹

Isolated PCLD has been shown in North American and Finnish families to be linked to the gene PRKCSH (also known as protein kinase C substrate 80K-H) on chromosome 19 locus p13.2-13.1 and to SEC63 on chromosome 6q21, although other associated genes undoubtedly exist.^268,272,273 The gene products hepatocystin and SEC63p are thought to be involved in the folding and quality control of glycoproteins and protein translocation in the endoplasmic reticulum, respectively.²⁷⁴ The genes appear to be autosomal dominant, and a second somatic mutation is thought to be needed to cause disease.

The hepatic cysts in polycystic liver disease, whether or not they occur in association with renal cysts, rarely cause morbidity, and many affected persons are asymptomatic.^258–262 The livers of these patients contain only a few cysts or cysts smaller than 2  cm in diameter. Symptoms occur in patients with more numerous and larger cysts (10% to 15% of patients, usually women), generally with markedly enlarged livers. Abdominal discomfort or pain, postprandial fullness, awareness of an upper abdominal mass, a protuberant abdomen, and shortness of breath may be present. Severe pain may be experienced with rupture or infection of a cyst, bleeding into a cyst, or torsion of a pedunculated cyst. Jaundice is evident in approximately 5% of patients and is caused by compression of the major intrahepatic or extrahepatic bile ducts. Ascites, if present, is the result of portal hypertension, which generally is caused by associated congenital hepatic fibrosis but occasionally by compression of the hepatic veins by the cysts. Gastroesophageal variceal bleeding has rarely been reported.²⁷⁵

Liver biochemical test results generally are normal, with intact hepatic function, although serum alkaline phosphatase and GGTP levels may be increased. A raised right hemidiaphragm may be evident on a plain x-ray of the chest in patients with severe PCLD. The diagnosis of PCLD is confirmed by ultrasound, CT, or MRI (see Fig. 94-9).

On the rare occasions when cysts require treatment, fenestration (unroofing) should be performed.^258,276 Cyst fenestration originally was done at laparotomy but is now performed laparoscopically. A high recurrence rate is observed for cysts treated in this way. Cysts also have been treated by percutaneous injection of a sclerosing substance such as alcohol or doxycycline, but most patients have too many small cysts to warrant this approach. Patients who fail to respond to cyst fenestration may be considered for partial hepatic resection. Liver transplantation (sometimes combined with renal transplantation) is generally reserved for patients with hepatic failure or severe symptoms that interfere with activities of daily living.²⁷⁷