W34 AJR:203, July 2014

more prevalent in Europe and North America and are uncommon in Asia and Africa. The age-adjusted incidence of fibrolamellar HCC in the United States is approximately 0.02 cas-es per 100,000 individuals, which is almost 100 times lower than classic HCC [7]. Up to one third of the HCCs developing on a noncirrhot-ic background could be fibrolamellar HCC [8].

Whereas classic HCC is often detected dur-ing surveillance imaging of patients with cir-rhosis, noncirrhotic HCCs commonly affect patients without known underlying liver dis-ease. Consequently, these tumors are often de-tected at an advanced stage and are more likely to cause symptoms [5, 6]. Common presenting symptoms include abdominal pain (52%), dis-tention (9%), weight loss (9%), anorexia (6%), and chest pain (6%) [9]. Occasionally, these patients present with fever of unknown origin or abnormal liver function test results.

EtiopathogenesisA variety of congenital and acquired con-

ditions can induce the development of HCC without underlying cirrhosis, often through alterations in cell cycle regulation, oxidative stress, and increased levels of tumorigenic growth factors (Fig. 1 and Table 2).

Hepatocellular Carcinoma in the Noncirrhotic Liver

Santhosh Gaddikeri1Michael F. McNeeley1

Carolyn L. Wang1

Puneet Bhargava2

Manjiri K. Dighe1

Matthew M. C. Yeh3

Theodore Jay Dubinsky1

Orpheus Kolokythas4

Neeraj Lalwani1

Gaddikeri S, McNeeley MF, Wang CL, et al.

1 Department of Radiology, University of Washington, 1959 NE Pacific St, Seattle, WA 98195. Address correspondence to N. Lalwani (neerajl@uw.edu).

2 Department of Radiology, VA Puget Sound Health Care System, Seattle, WA.

3 Department of Pathology, University of Washington, Seattle, WA.

4 Institut für Radiologie, Kantonsspital Winterthur, Winterthur, Switzerland.

Gastrointest ina l Imaging • Review

WEB This is a web exclusive article.

AJR 2014; 203:W34–W47

0361–803X/14/2031–W34

© American Roentgen Ray Society

Hepatocellular carcinoma (HCC) accounts for approximately 90% of the primary hepatic malignan-cies in adults worldwide [1]. Al-

though HCC typically occurs in the setting of hepatic cirrhosis, as many as 20% of HCCs may involve a noncirrhotic liver [2]. Because the imaging features of HCC in a noncirrhotic liver, when interpreted in the appropriate clinical context, often are dis-tinctive enough to suggest the diagnosis, an understanding of its appearance and of the predisposing clinical risk factors is neces-sary to prevent misdiagnosis.

Epidemiology and Clinical FeaturesHCC in a noncirrhotic liver, which we refer

to here as “noncirrhotic HCC,” has a bimodal age distribution with peaks at the 2nd and 7th decades of life [3, 4]; although men are affect-ed by noncirrhotic HCC approximately twice as often as women, the male predilection for developing HCC in a cirrhotic liver is consider-ably stronger [5] (Table 1). Fibrolamellar HCC, which is a subtype of noncirrhotic HCC, com-monly occurs between the 2nd and 3rd decades of life and does not show any sex predilection [6]. Geographically, fibrolamellar HCCs are

Keywords: cirrhosis, CT, hepatocellular carcinoma, MRI, noncirrhotic liver, risk factors

DOI:10.2214/AJR.13.11511

Received June 26, 2013; accepted after revision November 6, 2013.

OBJECTIVE. Hepatocellular carcinomas (HCCs) that arise in noncirrhotic livers have several histologic and biochemical features that distinguish them from HCCs occurring in the setting of cirrhosis. Because the presentation, management, and prognosis of these enti-ties are distinct, the accurate preoperative characterization of these lesions is of great clinical significance. We review the pathogenesis, imaging appearance, and clinical implications of noncirrhotic HCCs as they pertain to the clinical radiologist.

CONCLUSION. HCCs that develop in noncirrhotic patients have distinct etiologic, cy-togenetic, histopathologic, and clinical features. Despite a larger tumor burden at the time of HCC diagnosis, noncirrhotic patients with HCC have better overall survival and disease-free survival than cirrhotic patients with HCC. Knowledge of the precise clinical and imaging fea-tures of this entity and of other diagnostic considerations for the noncirrhotic liver is essential for improved patient care.

Gaddikeri et al. HCC in the Noncirrhotic Liver

Gastrointestinal ImagingReview

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HCC in the Noncirrhotic Liver

Viral HepatitisThe hepatitis B virus (HBV) is a DNA vi-

rus that can induce hepatic carcinogenesis in-dependent of cirrhosis, which occurs in up to 30% of all HBV-related HCCs [10]. On in-fection, the HBV genome integrates with the host hepatocellular DNA and may disrupt nor-mal cellular regulatory mechanisms by induc-ing genomic instability or producing genotox-ins such as the HBx protein [11] (Fig. 2). High viral load titers (104–5 copies/mL) have been linked with PIK3CA mutations and have been shown to be an independent risk factor for non-cirrhotic HCC. Overexpression of insulinlike growth factor–2 (IGF-2) and PIK3CA muta-tions are linked to activation of the Akt/PKB (protein kinase = B) pathway, which has been postulated as a major pathway to elicit HBV-induced carcinogenesis [12].

The hepatitis C virus (HCV) is an RNA vi-rus that does not integrate with the host ge-nome but generates several gene products (core, NS3, NS4B, and NS5A) that have shown carcinogenic potential in animal cell cultures [13, 14]. Approximately 46% of HCV-related HCCs exhibit CTNNB mutations [10]; of these, the majority arise in the absence of underlying cirrhosis [15]. Accelerated liver fibrosis—with-out frank cirrhosis—is also implicated in the pathogenesis of noncirrhotic HCC [16].

The risk of HCC significantly increases (2–4 times) in patients with chronic HBV- or HCV-related hepatitis who also consume alcohol [17, 18]. Postulated mechanisms of pathogenesis include oxidative stress, DNA methylation, decreased immune surveil-lance, and genetic susceptibility.

Genotoxic SubstancesAspergillus flavus is a pathogenic fungus

that is endemic to several African and Asian countries and may contaminate cereals, le-gumes, spices, and fruits harvested in those locations. The aflatoxin B1 produced by A. flavus is associated with a selective mutation in the p53 tumor suppressor gene that com-monly underlies noncirrhotic HCC induction [19]. Concomitant exposure to HBV infec-tion leads to a 60-fold increased risk of non-cirrhotic HCC development [20].

Chemical and industrial carcinogens, such as nitrosamines, azo dyes, aromatic amines, vinyl chloride, organic solvents, pesticides, and arsenic, have been implicated in hepatic carci-nogenesis in patients who live in highly indus-trialized areas. Some specific mutations have been linked with certain carcinogens; for ex-ample, vinyl chloride–induced noncirrhotic HCC is linked to KRAS mutations, whereas HRAS mutations are associated with methy-lene chloride–induced noncirrhotic HCCs [10].

Thorotrast, a liquid suspension of radioac-tive thorium dioxide particles that was once used as a radiologic contrast agent, is a risk factor for noncirrhotic HCC, although it is classically associated with angiosarcoma and cholangiocarcinoma [21]. The thorium can retain in the body and emit carcinogenic alpha particles. Because of its carcinogenic potential, Thorotrast has long been discon-tinued and associated cases have become ex-ceedingly rare.

Excess iron within hepatocytes may act as a genotoxic cocarcinogen factor as suggested by the mild iron accumulation found in the

nonneoplastic liver parenchyma of most pa-tients with noncirrhotic HCC [22].

Heritable DiseasesHCC in a noncirrhotic liver may occur in

the setting of rare inherited metabolic and congenital diseases such as hemochroma-tosis, porphyria, α-1-antitrypsin deficiency, hypercitrullinemia, Wilson disease, type I glycogen storage disease (GSD-I), Alagille syndrome, and congenital hepatic fibrosis [2].

The postulated hypothesis suggests that ac-cumulating mutant proteins or an aggregation of a substance within the hepatocytes acti-vates a number of stress responses at the ge-netic and cellular levels that, in turn, induce proliferation and tumor formation [23]. For example, Hemochromatosis induces cellular proliferation and direct damage to the DNA, resulting in the inactivation of tumor suppres-sor genes (p53), formation of reactive oxygen species and lipid peroxidation, and accelera-tion of fibrogenesis, which when taken togeth-er induce the formation of noncirrhotic HCC.

Metabolic syndrome (a synergistic con-comitance of dyslipidemia, hypertension, obesity, and type 2 diabetes mellitus) is an im-portant and evolving risk factor for HCC. The hypothesized mechanisms of carcinogenesis include lipid peroxidation (oxidative stress in-duced by free radicals) and elevated levels of insulin and insulinlike growth factor–1 (IGF-1) [24, 25]. The unopposed and persistent ac-tion of these carcinogens provokes cellular proliferation and activation of hepatic progen-itor cells and also stimulates p53 mutations and epigenetic aberrations [26, 27].

TABLE 1: Summary of the Differences Between Hepatocellular Carcinoma (HCC) in a Cirrhotic Liver and HCC in a Noncirrhotic Liver

Difference HCC in Cirrhotic Liver HCC in Noncirrhotic Liver

Cause Underlying viral hepatitis or alcohol abuse leading to cirrhosis Underlying hereditary disorders, metabolic syndromes, viral hepatitis, or genotoxins exposure

Carcinogenesis Stepwise carcinogenesis: regenerative nodule → dysplastic nodule → HCC

De novo carcinogenesis

Major molecular alterations Mutations or deletions of tumor suppressor genes such as p53, Rb, IGF2R, and p16INK4 and activation of protooncogenes such as β-catenin and ras-MAPK pathway; loss of heterozy-gosity is frequent

Lower rate of p53 mutation, higher prevalence of β-catenin mutation, p14 inactivation, and DNA mismatch repair; increased levels of Y654–β-catenin in fibrolamellar HCC; loss of heterozygosity is infrequent

Multifocal or solitary Usually multifocal Usually solitary

Tumor size Variable size, often small Large (mean size, 12.4 cm)

Demography High male preponderance (male-female ratio, 8:1); common in elderly age group

Relatively lower male preponderance (male-female ratio, 2:1); bimodal distribution in 2nd and 7th decades

Clinical presentation Hepatomegaly, abdominal pain, jaundice, and ascites Hepatomegaly, abdominal pain, asthenia, malaise, fever, weight loss, and anorexia

Note—MAPK = mitogen-activated protein kinase.

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Miscellaneous FactorsApproximately 5–10% of hepatic adeno-

mas (HCAs) show malignant potential, often in the setting of β-catenin mutation [28].

Malignant transformation can occur in 0–18% of HCAs [29]. A higher risk of malig-nant degeneration of HCA exists in patients with glycogen storage disease, patients who take oral contraceptive pills (OCPs) or male hormones, and patients with familial adeno-matous polyposis syndrome [10, 30].

Scarce information on the carcinogenesis associated with OCPs is available in the liter-ature. The risk of malignant degeneration has been directly linked with the duration of intake

of OCPs and the size (> 5 cm) of the tumor [31]. The results of one recent study that evalu-ated 23 patients with malignant transformation within HCA revealed that five patients had tak-en OCPs for more than 2 years [30].

Patients with GSD-I are prone to develop HCA (22–75%) and, rarely, HCC. The precise degree of risk is unknown because of the rar-ity of this condition. However, of 14 reported GSD-associated adenomas, four (28%) had a β-catenin mutation and two (14%) had both a β-catenin mutation and malignant degenera-tion [32]. Anabolic C17-alkylated androgenic steroids and contraceptive steroids have been implicated as initiators or promoters of hepat-

ic carcinogenesis, particularly after long-term use [33]. Interestingly, patients with GSD-I commonly have steatosis in the liver paren-chyma surrounding the adenomas, which may also be a contributory risk factor.

Budd-Chiari syndrome, nodular regenera-tive hyperplasia, and hepatoportal sclerosis have been implicated as risk factors for HCC in the absence of cirrhosis [4, 34].

Nonalcoholic steatohepatitis (NASH) has been acknowledged as the most common cause of chronic liver disease [35]. The enig-ma—whether NASH itself or NASH-induced cryptogenic cirrhosis leads to HCC—remains unsolved and long-term prospective studies are needed to elucidate this mystery [36].

HistopathologyAccording to the histologic classification

criteria of the World Health Organization [37], the trabecular form is the most common histologic subtype of HCC in both cirrhotic and noncirrhotic livers (41–76%). The scir-rhous and mixed HCC-cholangiocarcinoma subtypes are generally rare but occur more frequently in noncirrhotic livers, specifically in western populations [2]. Well-differentiat-ed HCC is frequent in noncirrhotic liver and shows microscopic fat.

The fibrolamellar subtype of HCC oc-curs almost exclusively in noncirrhotic liv-ers [2]. Fibrolamellar HCCs are charac-terized as polygonal neoplastic cells with abundant eosinophilic cytoplasm arranged in sheets, cords, or trabeculae divided by parallel sheets of fibrous tissue into lobules. Approximately 20–60% of fibrolamellar HCCs show a central scar [38] that may cal-cify (35–68%) [10].

The hepatic parenchyma surrounding non-cirrhotic HCC can be entirely normal but usually shows some degree of inflamma-tion (50%), fibrosis (41–65%), early steatosis (36%), or iron accumulation [4, 39, 40]. Ste-atosis is frequently associated with conven-tional noncirrhotic HCC, whereas background parenchymal inflammation is frequently iden-tified with fibrolamellar HCC [40].

DiagnosisRole of Serum α-Fetoprotein

Elevated serum levels of α-fetoprotein (AFP) are less commonly associated with noncirrhotic HCC (31–67% of cases) than with cirrhotic HCCs (59–84% of cases); the serum AFP value is typically normal in the setting of fibrolamellar HCC. Serum AFP levels that exceed 400 ng/dL are considered

TABLE 2: Summary of Etiologic Factors Implicated in the Development of Hepatocellular Carcinoma (HCC) in a Noncirrhotic Liver and Proposed Mechanisms of Carcinogenesis

Etiologic Factors Proposed Mechanisms

HBV DNA microdeletions

HBx protein

Overexpression of IGF-2

AXIN1 mutation

p53 inactivation

AKT pathway activation

HCV Less carcinogenic than HBV

HCV gene products (core, NS3, NS4B, and NS5A)

Induce TGF-β signaling

CTNNB mutations

Alcohol Synergistic role in the background of chronic HBV or HCV

Oxidative stress

DNA methylation

Decreased immune surveillance

Genetic susceptibility

Aflatoxin B1 Selective codon 249 mutation in p53 gene (hot spot mutation)

Concomitant HBV infection further increases risk of HCC by sixfold

Chemical and industrial carcinogens

Oxidative stress

Inactivation of tumor suppressor genes

Activation of oncogenes

Tissue iron overload Oxidative stress

Inherited diseases Activation of stress response at genetic and cellular levels

Free radical formation leading to lipid peroxidation and acceleration of fibrogenesis

Metabolic syndromes Oxidative stress by free radicals

p53 mutations and epigenetic aberrations

Hepatic adenoma to carcinoma β-catenin mutation

Sex hormones Implicated as initiators or promoters in hepatic carcinogenesis

Hepatic vascular abnormalities Exact mechanism not clearly described in the literature

Note—HBV = hepatitis B virus, IGF-2 = insulinlike growth factor–2, HCV = hepatitis C virus, TGF-β = transform-ing growth factor–β.

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diagnostic of HCC regardless of the presence or absence of underlying cirrhosis [5].

Cross-Sectional ImagingOn imaging, noncirrhotic HCC generally

shows imaging features characteristic of clas-sic HCC except for the lack of cirrhosis on the background. Additionally, noncirrhotic HCC often presents as a large solitary mass or a dominant mass with satellite lesions [41]. Rarely there can be multiple masses without a dominant lesion. The right lobe appears to be commonly involved with the exception of fi-brolamellar HCC, which is more common in the left lobe [42]. The size of noncirrhotic HCC can range from 2 to 23 cm, with the average size of 12.4 cm (Figs. 3–10). Well-differenti-ated noncirrhotic HCCs typically are encap-sulated with distinct margins, whereas poorly differentiated and aggressive tumors tend to be nonencapsulated and poorly circumscribed. Varying amounts of central or peripheral cal-cification, necrosis, hemorrhage, and micro-scopic and macroscopic fat may be present. Occasionally, focal intrahepatic biliary dilata-tion can be seen; this feature may be related to mass effect rather than ductal invasion.

Extrahepatic extension of HCC via di-rect invasion of adjacent structures or me-tastasis is more common in noncirrhotic pa-tients than in cirrhotic patients (20.5% vs 6.5%, respectively) [5]; this tendency can be explained by the inherent biologic aggres-siveness of noncirrhotic HCC or, rather, by the typical delay in its diagnosis. The rela-tive tendency for early portal vein invasion by HCC in a cirrhotic liver versus HCC in a noncirrhotic liver remains controversial. Tu-mor thrombus can be seen in the portal or hepatic veins, but it is less common (≈ 15%) [41]. Upper abdominal lymphadenopathy can be seen in up to 21% of cases of noncir-rhotic HCC [9]. Fibrolamellar HCCs exhibit a distinct tendency for both nodal and perito-neal metastasis [10, 43].

Ultrasound—On gray-scale ultrasound, the appearance of HCC in the noncirrhot-ic liver is often nonspecific. Noncirrhotic HCC may appear hypoechoic, hyperecho-ic (due to fatty metamorphosis or hemor-rhage), or mixed echogenic (due to necrosis and hypervascularity).

CT—On unenhanced CT, noncirrhotic HCC tends to be hypoattenuating relative to the sur-rounding liver parenchyma. Areas of central or peripheral calcification, necrosis, and hem-orrhage may be seen. Fibrolamellar HCC sub-types show internal calcification in 68% of the

cases [38] (Fig. 8). The calcification often (91–95%) involves the central scar [44].

After the administration of IV contrast ma-terial, the fibrolamellar HCC subtypes show hyperenhancement during the late arterial phase, isoenhancement compared with neigh-boring parenchyma during the portal venous phase, and contrast washout during the equi-librium phase, as seen in classic HCC in a non-cirrhotic liver (Figs. 4A and 4B). Capsular en-hancement, when present, is most apparent during the equilibrium phase. Fibrolamellar HCC may show predominant heterogeneous arterial enhancement, the presence of a cen-tral scar (20–60%), and a discontinuous cap-sule (35%) [44]. Some authors have reported that the central scar in fibrolamellar HCC is usually avascular and shows little or no en-hancement, and this imaging characteristic can be used to differentiate fibrolamellar HCC from focal nodular hyperplasia (FNH) [45] (Fig. 8). However, the results of some recent studies suggest that central scars in a signifi-cant number of fibrolamellar HCCs (25–56%) can retain contrast material [38, 42, 44, 46].

MRI—The appearance of noncirrhotic HCC on T1-weighted MRI sequences varies but is most commonly hypointense relative to the surrounding liver parenchyma. The presence of hemorrhage, fat, glycogen, copper, or protein-aceous matter within the lesion can increase its intensity on T1-weighted imaging [47].

Fat is seen in approximately 10–17% of noncirrhotic HCC and is a sign of a bet-ter prognosis [9, 48, 49]. An almost similar number of HCCs in cirrhotic livers (10%) may show the presence of fat [50].

Interestingly, intracellular fat accumulation is a relatively common feature (36% of cases) of well-differentiated noncirrhotic HCCs [47] (Fig. 5). Comparisons of in- and opposed-phase images can be helpful for detecting mi-croscopic fat within the tumor; parenchymal hypointensity on the in-phase series suggests underlying iron overload (Fig. 6).

On T2-weighted fast spin-echo images, noncirrhotic HCCs are usually isointense to hyperintense; however, lower-grade or well-differentiated tumors may be isoin-tense to hypointense [51].

Noncirrhotic HCC can show restricted dif-fusion on diffusion-weighted imaging (DWI) with a higher b value and may also show low apparent diffusion coefficient values (Fig. 6). DWI improves the detection of noncirrhotic HCC (especially tumors < 2 cm) and helps to differentiate it from potential mimics [52, 53]; however, DWI is less reliable for detecting

HCC lesions than it is for detecting hepatic metastases [54]. Higher-grade HCCs, regard-less of the degree of underlying fibrosis, may be more conspicuous on DWI than their low-er-grade counterparts. Dysplastic nodules and well-differentiated (low-grade) HCCs are rel-atively hypovascular. These findings probably are a function of the hypercellularity of high-er-grade carcinomas and could possibly also reflect the increased nuclear-cytoplasmic ra-tio inherent to aggressive tumors [55] (Fig. 7).

Dynamic fat-saturated gadolinium-en-hanced T1-weighted imaging shows an en-hancement pattern similar to multiphase CT, with hyperenhancement during the arterial phase, isoenhancement during the portal ve-nous phase, and washout during the equilibri-um phase. Moderately or poorly differentiated HCCs are often hypointense on T1-weighted imaging and show discernible washout during the portal phase [56] (Fig. 7). Moreover, the rapidity of washout has been correlated with the poorer differentiation of the tumor [56]. HCC may be surrounded by a capsule com-posed of fibrous connective tissue. Alterna-tively, the presence of prominent hepatic si-nusoids or nonbridging peritumoral fibrosis may cause the appearance of a pseudocapsule on cross-sectional imaging in 80% of the cas-es. In this situation, iodinated or gadolinium-based contrast agents can be retained in the peritumoral space, resulting in late circumfer-ential enhancement on the equilibrium phase (Fig. 6). The incidence of vascular invasion appears to be similar, roughly one third, in the presence of either entity [41, 57].

Noncirrhotic HCC can invade veins in 15% of the cases [41]. Classically, the cen-tral scar has been described in fibrolamel-lar HCC, FNH, HCA, and large hemangio-ma, but HCC can also show a central scar [43, 58]. Noncirrhotic HCCs more common-ly (50%) show a central scar on MR images than HCCs in cirrhotic livers (6%) [41].

The fibrolamellar subtype of noncirrhotic HCC is usually hypointense on T1-weighted images, hyperintense on T2-weighted imag-es, and heterogeneously enhancing after gad-olinium administration. The capsule appears hypointense on both T1-weighted and T2-weighted images [44]. The central scar has been classically described as hypointense on T2-weighted images. However, in clinical practice fibrolamellar HCC with T2-weight-ed hyperintense scars are frequently encoun-tered, which may be attributed to coexisting necrosis or altered vascularity [42]. As we described earlier, the central scar in fibrola-

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mellar HCC may show contrast enhancement in 25–56% of the cases.

Differential DiagnosisIn an otherwise healthy individual or pa-

tients with undiagnosed liver disease, the diagnosis of HCC is challenging. The most common symptoms that prompt the diagno-sis of HCC are abdominal pain or discomfort in the right upper quadrant, jaundice, nausea, or toxic syndrome (weight loss, fever, mal-aise, asthenia, and anorexia). Rarely, noncir-rhotic HCC presents as life-threatening he-moperitoneum from tumor rupture [44].

Major differential considerations for an HCC in a noncirrhotic liver include fibrola-mellar HCC, HCA, and FNH.

Fibrolamellar Hepatocellular CarcinomaFibrolamellar HCC commonly involves

the left lobe and measures 5–20 cm. A cen-tral scar and radiating septa, central calci-fications or necrosis, and satellite nodules are common and useful identifying features. Metastatic lymphadenopathy is seen in up to 65% of the cases. Cross-sectional imaging shows a central scar that is hypointense on T2-weighted MRI as opposed to a hyperin-

tense scar, which is seen in FNH. On con-trast-enhanced MRI, there is arterial het-erogeneous hyperenhancement of the whole tumor except for the central scar. Washout is seen on the portal venous and equilibri-um phases, and the central scar does not en-hance in the equilibrium phase.

Hepatocellular AdenomaUp to 75% of adenomas occur in the right

lobe of the liver. Cross-sectional imaging shows variegated appearance of the tumor due to the presence of fat, necrosis, or hem-orrhage. The tumor tends to be hypoatten-uating on unenhanced CT images; howev-er, in the setting of a diffuse fatty liver, the tumor may appear hyperattenuating when compared with the adjacent liver parenchy-ma. Contrast-enhanced images show hyper-enhancement on arterial phase imaging and washout on portal venous phase and equilib-rium phase imaging.

Focal Nodular Hyperplasia FNH is usually solitary but can be mul-

tiple in 25% of cases. FNH is usually iso-attenuating or isointense to the surround-ing liver parenchyma on unenhanced CT

or unenhanced T1-weighted MRI, respec-tively. There can be a reversal in the im-aging appearance in the presence of a dif-fuse fatty liver. The central scar (present in 77% cases) is typically hyperintense on T2-weighted images. Contrast-enhanced im-aging shows homogeneous arterial phase hyperenhancement of the tumor except for the scar. On portal venous and equilibrium phase images, FNH may show the same en-hancement as the surrounding liver paren-chyma with an enhancing scar. Delayed scar enhancement and hyperintensity on T2-weighted imaging have been described as important features for distinguishing be-tween FNH and fibrolamellar HCC; how-ever, in practical life the differentiation of these two entities can be very challenging and significant overlap of imaging findings may exist [46]. Gadobenate dimeglumine (MultiHance, Bracco Diagnostics) or ga-doxetate disodium (Eovist, Bayer Health-Care) can be used to confirm the FNH, which shows contrast retention in the hepa-tobiliary phase. HCC becomes hypointense to remainder of the liver.

The key features for differentiating among these entities are summarized in Table 3.

TABLE 3: Differential Diagnosis of Hepatocellular Carcinoma (HCC) in Noncirrhotic Liver: Key Characteristics of Hepatocellular Adenoma (HCA), Focal Nodular Hyperplasia (FNH), and Noncirrhotic HCC

Patient, Disease, and Imaging Characteristics HCA FNH Noncirrhotic HCC

Age Adult (fertile age group) Adult (fertile age group) Bimodal distribution: peaks at 2nd and 7th decades

Sex (male-female ratio) 1:10 1:8 2:1

Malignant transformation Can occur Never —

Risk factors Steroid therapy; GSD-I Congenital; rarely steroids Variegateda

T1-weighted MRI Variegated appearance due to presence of fat and hemorrhage (Fig. 9A)

Isointense (Fig. 10A) Variable depending on the presence or absence of fat and hemorrhage

In- and opposed-phase MRI Signal may decrease on opposed-phase imaging due to microscopic fat (Fig. 9B)

No microscopic fat (Fig. 10B) Signal may decrease on opposed-phase imaging due to microscopic fat; often seen with well-differentiated HCC

T2-weighted MRI Mildly hyperintense (Fig. 9C) Hypo- to isointense lesion with central hyperintense scar (80%); atypical FNH may lack central scar (20%) (Fig. 10C)

Typically intermediate signal intensity to hyperintense; iso- or hypointensity could be well-differentiated HCC

Diffusion restriction Rare Never Often

Arterial phase Hypervascular (Fig. 9D) Hypervascular with nonenhancing scar (Fig. 10D)

Hypervascular

Equilibrium phase Variable washout (Fig. 9E) No washout; may see scar enhancement

Washout with enhancing pseudocapsule

Gadoxetate disodium–enhanced imaging (hepatobiliary phase)

No contrast retention (Fig. 9F) Classically retains contrast material (Fig. 10E)

No contrast retention

Note—Dash (—) indicates not applicable. GSD-I = type I glycogen storage disease.aRefer to text.

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Treatment and PrognosisSurgical resection is the treatment of choice

for HCCs in a noncirrhotic liver. Relative preservation of liver function allows wide re-section margins without significant periopera-tive mortality (0–6%) or morbidity (8–40%) even in the setting of very large tumors [2].

The 5-year overall survival after surgi-cal resection of noncirrhotic HCC is much higher (44–58% of patients) than for resec-tion of HCC in the setting of cirrhosis (23–48% of patients). However, recurrences may be seen in 27–73% cases, especially in the first 2 years after surgery. Therefore, strin-gent postoperative follow-up is necessary.

The ideal treatment strategy for recur-rent disease remains controversial. Currently, there is no strong evidentiary support for ad-juvant chemotherapy to prevent recurrence af-ter surgical resection [59, 60]. Many recurrent noncirrhotic HCCs are amenable to repeat hepatectomy, with achievable 5-year survival rates of 50%, but a second recurrence is com-mon [61]. Second and third hepatectomies for recurrent noncirrhotic HCC appear to be equally safe and effective when compared with primary resections. However, orthotopic liver transplantation may be necessary when partial resections fail to control the disease.

Sorafenib (Nexavar, Bayer HealthCare) is a U.S. Food and Drug Administration–ap-proved oral multikinase inhibitor that antag-onizes tumor cell proliferation and neoan-giogenesis [62]. Sorafenib may be beneficial in the treatment of unresectable tumors; however, its effect on long-term outcomes as an adjunct to surgical resection of non-cirrhotic HCCs remains undetermined. Be-cause of their high levels of Y654–β-catenin and increased receptor tyrosine kinase sig-naling, fibrolamellar subtypes may be highly responsive to Sorafenib therapy.

Fibrolamellar HCCs generally show fewer cytogenetic aberrations and fewer chromo-somal abnormalities than other hepatocellu-lar tumors and, therefore, are less aggressive and are associated with better outcomes than other noncirrhotic HCCs and HCCs occur-ring in cirrhosis. Surgical resection remains the mainstay of treatment of fibrolamellar HCC, and the 5-year survival rate for fibrola-mellar HCC is even better than that for oth-er noncirrhotic HCCs—ranging from 37% to 76% after complete surgical resection.

ConclusionHCCs that develop in noncirrhotic patients

have distinct etiologic, cytogenetic, histo-

pathologic, and clinical features. Despite a larger tumor burden at the time of HCC di-agnosis, noncirrhotic patients with HCC have better overall survival and disease-free survival than cirrhotic patients with HCC. Knowledge of the precise clinical and imag-ing features of this entity and of other diag-nostic considerations for the noncirrhotic liv-er is essential for improved patient care.

AcknowledgmentWe sincerely acknowledge the input

and guidance provided by S. R. Prasad (Professor of Radiology, M. D. Anderson Cancer Center, Houston, TX).

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7:3129–3140(Figures start on next page)

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HCC in the Noncirrhotic Liver

• Activation of protooncogenes (e.g., N-ras, c-myc, c-fos) • Activation of growth factors (e.g., IGF-1, IGF-2, TGF-α, TGF-β)• Inactivation of tumor suppressor genes (p53, p16, Rb, LOH 1p, 1q, 2q, 4q, 5q, 6q, 8p, 8q, 9p, 9q, 10q, 11p, 13q, 16p, 16q, 17p, 22 APC)

• Integrins• E-cadherin • β-catenin• CMAR• NM23• KAI1

Virus• HBV• HCV

Radiation:Thorotrast

• Chemicals• Aflatoxin B1• Alcohol• Smoking• Vinyl chloride

• Defects in terminal differentiation• Defects in growth control• Resistance to cytotoxicity• Defects in apoptosis

Genetic predisposition (e.g., hemochromatosis, Wilson disease, α-1-antitrypsin deficiency, metabolic syndromes)

Necroinflammatory disease, reactive oxygen and nitric oxide species

Selective clonalexpansion

Preneoplasticlesion

Malignanttumor

Clinical HCC HCC with distantmetastases

Normal cell Initiated cell

Fig. 1—Illustration shows cascade of genetic events involved in carcinogenesis of hepatocellular carcinoma (HCC) in noncirrhotic liver. HBV = hepatitis B virus, HCV = hepatitis C virus, IGF-1 = insulinlike growth factor–1, IGF-2 = insulinlike growth factor–2, TGF-α = transforming growth factor–α, TGF-β = transforming growth factor–β.

HBV genomeintegration in host

cells

Modifies the expression of

several growth-control genes

Genotoxic viralproduct

(HBx protein)

Host DNAmicrodeletions

High viral load(104–5 copies/mL) Development

of HCC

Accumulation of mutations in basal

core promoter

Fig. 2—Flowchart shows hepatitis B virus–induced hepatocarcinogenesis in noncirrhotic liver. High viral load and continued accumulation of various genetic mutations have independent positive influences on etiopathogenesis of hepatocellular carcinoma (HCC).

Fig. 3—76-year-old man who presented with atypical chest pain and right upper quadrant pain. On routine workup in emergency department, nonspecific liver lesion was identified. Single-phase coronal CT image shows heterogeneously enhancing mass (≈ 6 cm) in right hepatic lobe; note peripherally enhancing pseudocapsule (double arrows) and scattered foci (single arrow) of hypodensities consistent with necrosis. Liver is noncirrhotic in morphology. On further workup, α-fetoprotein level and hepatitis panel results were normal; biopsy verified well-differentiated HCC.

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AFig. 4—64-year-old man with history of α-1-antitrypsin deficiency. Hypervascular lesion was incidentally identified on chest CT and was later evaluated on dedicated three-phase liver CT. A, Arterial phase: Coronal CT image shows hypervascular mass at hepatic dome (arrow). B, Equilibrium phase: Coronal image at same level as A shows subtle washout in lesion (circle). C, Axial chest CT image obtained using lung window settings shows bilateral panacinar emphysema. Mass was proven to be hepatocellular carcinoma in noncirrhotic liver on biopsy. Histologically there was extensive fibrosis but no lobular regeneration.

B

C

A

Fig. 5—59-year-old woman with chronic hepatitis B virus infection and solitary left lobe mass in background of noncirrhotic liver. Mass that was incidentally seen on ultrasound was evaluated on MRI. Histologically this mass was characterized as well-differentiated hepatocellular carcinoma (HCC). A, Axial in-phase image shows isointense to mildly hyperintense mass in left hepatic lobe (arrows). B, Axial opposed-phase image shows signal dropout in mass (arrows) indicating presence of microscopic fat. C, Axial fat-suppressed T2-weighted image shows variable intermediate signal intensity in mass (arrows).

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D

Fig. 5 (continued)—59-year-old woman with chronic hepatitis B virus infection and solitary left lobe mass in background of noncirrhotic liver. Mass that was incidentally seen on ultrasound was evaluated on MRI. Histologically this mass was characterized as well-differentiated hepatocellular carcinoma (HCC). D, Axial gadolinium-enhanced arterial phase fat-suppressed T1-weighted image shows heterogeneous hypervascularity in mass that is more pronounced in center (arrow). E, Axial gadolinium-enhanced equilibrium phase fat-suppressed T1-weighted image shows washout of contrast material from mass and pseudocapsule (arrows). F, Photomicrograph (H and E, ×100) shows well-differentiated HCC. There is moderate fatty change within carcinoma.

FE

A B

Fig. 6—55-year-old man with history of hemochromatosis, hepatitis C virus infection, and alcohol abuse. Incidentally detected right hepatic mass was evaluated on MRI. Mass was histologically consistent with well- to moderately differentiated hepatocellular carcinoma. Note the smooth outline of liver (C–E).A, Axial in-phase T1-weighted image shows diffuse hypointensity of pancreatic (double arrows) and hepatic (single arrow) parenchyma; these findings are consistent with known history of primary hemochromatosis. B, Axial diffusion-weighted image (b value = 1000 s/mm2) shows restricted diffusion in mass (arrow).

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C

Fig. 6 (continued)—55-year-old man with history of hemochromatosis, hepatitis C virus infection, and alcohol abuse. Incidentally detected right hepatic mass was evaluated on MRI. C, Axial unenhanced fat-suppressed T1-weighted image shows mild intrinsic hyperintensity in mass (arrow). D, Axial gadolinium-enhanced arterial phase fat-suppressed T1-weighted image shows homogeneous hypervascularity in mass (arrow). E, Axial gadolinium-enhanced equilibrium phase fat-suppressed T1-weighted image shows washout of contrast material and enhancing pseudocapsule (arrow). Mass was histologically consistent with well- to moderately differentiated hepatocellular carcinoma.

ED

A

Fig. 7—61-year-old man with chronic hepatitis C virus infection. A, Axial unenhanced fat-suppressed T1-weighted image shows hypointense central liver mass (arrows). B, Axial gadolinium-enhanced arterial phase fat-suppressed T1-weighted image shows heterogeneous hypervascularity in mass (arrows) with necrotic areas (asterisk). C, Axial gadolinium-enhanced fat-suppressed T1-weighted image in equilibrium phase shows washout of contrast material (circle). Mass was histologically verified as poorly differentiated hepatocellular carcinoma (HCC). D, Photomicrograph (H and E, ×200) shows moderately to poorly differentiated HCC. Carcinoma cells are arranged in sheets with pleomorphic nuclei.

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AFig. 8—23-year-old man with history of acute abdominal pain. A, Axial unenhanced CT image shows large mildly hypodense mass in right lobe of liver with central calcifications (arrow). B, Axial arterial phase CT image shows hypervascular mass with central stellate nonenhancing scar (arrow). C, Axial equilibrium phase CT image shows contrast washout from mass and persistently nonenhancing central scar (arrow). Imaging findings are consistent with fibrolamellar hepatocellular carcinoma, which was confirmed at biopsy. D, Photomicrograph (H and E, ×100) shows fibrolamellar carcinoma. Thick collagen bundles are present within tumor. Tumor cells are arranged in trabeculae, are polygonal, and have ample granular cytoplasm with prominent nucleoli.

CB

D

A

Fig. 9—33-year-old woman who presented with hepatic lesion incidentally discovered on chest CT. A, Axial T1-weighted in-phase image shows isointense mass in hepatic segment VI (arrows). B, Axial T1-weighted opposed-phase image shows no signal drop (arrows) to support presence of microscopic fat. C, Axial T2-weighted image shows intermediate signal intensity within mass (arrows). No central scar is evident.

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Fig. 9 (continued)—33-year-old woman who presented with hepatic lesion incidentally discovered on chest CT. D, Gadoxetate disodium–enhanced arterial phase image shows avid enhancement of mass (arrow). E, On hepatospecific phase image, mass (arrows) retains contrast material and appears iso- to hyperintense to surrounding parenchyma; these findings strongly favor diagnosis of atypical focal nodular hyperplasia. Single arrow = contrast excretion in common bile duct.

E

A

Fig. 10—39-year-old woman with hepatic lesion found on ultrasound performed for right upper quadrant pain. A, Axial T1-weighted in-phase image shows iso- to hyperintense lesion (circle) in hepatic segment VI. B, Axial T1-weighted opposed-phase image shows signal intensity of lesion (circle) has decreased, which is consistent with presence of microscopic fat within lesion. C, Axial T2-weighted image shows intermediate signal intensity of lesion (circle).

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D

Fig. 10 (continued)—39-year-old woman with hepatic lesion found on ultrasound performed for right upper quadrant pain. D, Gadoxetate disodium–enhanced arterial phase image shows hypervascularity of lesion (circle). E, On delayed phase image, lesion (circle) is isointense to liver parenchyma. F, On hepatospecific phase image, mass (circle) appears hypointense to surrounding parenchyma and does not retain contrast material. Imaging findings are highly suggestive of adenoma. Well-differentiated hepatocellular carcinoma is less likely in this case because of lack of washout in delayed phase. Arrow = contrast excretion in common bile duct.

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ved