G a s t r o i n t e s t i n a l I m a g i n g R ev i ew

Gaddikeri et al.
HCC in the Noncirrhotic Liver

Gastrointestinal Imaging
Review
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FOCUS ON:

Hepatocellular Carcinoma in the

Noncirrhotic Liver
Santhosh Gaddikeri1 OBJECTIVE. Hepatocellular carcinomas (HCCs) that arise in noncirrhotic livers have
Michael F. McNeeley 1 several histologic and biochemical features that distinguish them from HCCs occurring in
Carolyn L. Wang1 the setting of cirrhosis. Because the presentation, management, and prognosis of these enti-
Puneet Bhargava2 ties are distinct, the accurate preoperative characterization of these lesions is of great clinical
Manjiri K. Dighe1 significance. We review the pathogenesis, imaging appearance, and clinical implications of
noncirrhotic HCCs as they pertain to the clinical radiologist.
Matthew M. C. Yeh 3
CONCLUSION. HCCs that develop in noncirrhotic patients have distinct etiologic, cy-
Theodore Jay Dubinsky 1
togenetic, histopathologic, and clinical features. Despite a larger tumor burden at the time of
Orpheus Kolokythas 4 HCC diagnosis, noncirrhotic patients with HCC have better overall survival and disease-free
Neeraj Lalwani1 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
Gaddikeri S, McNeeley MF, Wang CL, et al.
for improved patient care.

H
epatocellular carcinoma (HCC)
accounts for approximately 90%
of the primary hepatic malignan-
cies in adults worldwide [1]. Al-
Keywords: cirrhosis, CT, hepatocellular carcinoma, MRI, though HCC typically occurs in the setting
noncirrhotic liver, risk factors of hepatic cirrhosis, as many as 20% of
HCCs may involve a noncirrhotic liver [2].
DOI:10.2214/AJR.13.11511 Because the imaging features of HCC in a
Received June 26, 2013; accepted after revision
noncirrhotic liver, when interpreted in the
November 6, 2013. appropriate clinical context, often are dis-
tinctive enough to suggest the diagnosis, an
1
Department of Radiology, University of Washington, understanding of its appearance and of the
1959 NE Pacific St, Seattle, WA 98195. Address
predisposing clinical risk factors is neces-
correspondence to N. Lalwani (neerajl@uw.edu).
sary to prevent misdiagnosis.
2
Department of Radiology, VA Puget Sound Health Care
System, Seattle, WA. Epidemiology and Clinical Features
3
HCC in a noncirrhotic liver, which we refer
Department of Pathology, University of Washington,
Seattle, WA.
to here as noncirrhotic HCC, has a bimodal
age distribution with peaks at the 2nd and 7th
4
Institut fr Radiologie, Kantonsspital Winterthur, decades of life [3, 4]; although men are affect-
Winterthur, Switzerland. ed by noncirrhotic HCC approximately twice
WEB as often as women, the male predilection for
This is a web exclusive article. developing HCC in a cirrhotic liver is consider-
ably stronger [5] (Table 1). Fibrolamellar HCC,
AJR 2014; 203:W34W47 which is a subtype of noncirrhotic HCC, com-
0361803X/14/2031W34
monly occurs between the 2nd and 3rd decades
of life and does not show any sex predilection
American Roentgen Ray Society [6]. Geographically, fibrolamellar HCCs are
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.
Etiopathogenesis
A 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).

W34 AJR:203, July 2014

 HCC in the Noncirrhotic Liver

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 De novo carcinogenesis
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Major molecular alterations
Multifocal or solitary
Tumor size
Demography
Clinical presentation
NoteMAPK = mitogen-activated protein kinase.
nodule HCC
Mutations or deletions of tumor suppressor genes such as p53, Lower rate of p53 mutation, higher prevalence of -catenin
Rb, IGF2R, and p16INK4 and activation of protooncogenes mutation, p14 inactivation, and DNA mismatch repair;
such as -catenin and ras-MAPK pathway; loss of heterozy- increased levels of Y654-catenin in fibrolamellar HCC; loss
gosity is frequent of heterozygosity is infrequent
Usually multifocal Usually solitary
Variable size, often small Large (mean size, 12.4 cm)
High male preponderance (male-female ratio, 8:1); common in Relatively lower male preponderance (male-female ratio, 2:1);
elderly age group bimodal distribution in 2nd and 7th decades
Hepatomegaly, abdominal pain, jaundice, and ascites Hepatomegaly, abdominal pain, asthenia, malaise, fever, weight
loss, and anorexia

Viral Hepatitis Genotoxic Substances nonneoplastic liver parenchyma of most pa-

The 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 (1045 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 factor2 (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 fibrosiswith-
out frank cirrhosisis also implicated in the
pathogenesis of noncirrhotic HCC [16].
The risk of HCC significantly increases
(24 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.
Aspergillus 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 chlorideinduced noncirrhotic
HCC is linked to KRAS mutations, whereas
HRAS mutations are associated with methy-
lene chlorideinduced 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
tients with noncirrhotic HCC [22].
Heritable Diseases
HCC in a noncirrhotic liver may occur in
the setting of rare inherited metabolic and
congenital diseases such as hemochroma-
tosis, porphyria, -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 factor1 (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].

AJR:203, July 2014 W35

 Gaddikeri et al.
Miscellaneous Factors of OCPs and the size (> 5 cm) of the tumor
Approximately 510% of hepatic adeno- [31]. The results of one recent study that evalu-
mas (HCAs) show malignant potential, often ated 23 patients with malignant transformation
in the setting of -catenin mutation [28]. within HCA revealed that five patients had tak-
Malignant transformation can occur in en OCPs for more than 2 years [30].
018% of HCAs [29]. A higher risk of malig- Patients with GSD-I are prone to develop
nant degeneration of HCA exists in patients HCA (2275%) and, rarely, HCC. The precise
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with glycogen storage disease, patients who degree of risk is unknown because of the rar-
take oral contraceptive pills (OCPs) or male ity of this condition. However, of 14 reported
hormones, and patients with familial adeno- GSD-associated adenomas, four (28%) had a
matous polyposis syndrome [10, 30]. -catenin mutation and two (14%) had both a
Scarce information on the carcinogenesis -catenin mutation and malignant degenera-
associated with OCPs is available in the liter- tion [32]. Anabolic C17-alkylated androgenic
ature. The risk of malignant degeneration has steroids and contraceptive steroids have been
been directly linked with the duration of intake implicated as initiators or promoters of hepat-
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- 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 Oxidative stress
carcinogens
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 -catenin mutation
Sex hormones Implicated as initiators or promoters in hepatic carcinogenesis
Hepatic vascular abnormalities Exact mechanism not clearly described in the literature
NoteHBV = hepatitis B virus, IGF-2 = insulinlike growth factor2, HCV = hepatitis C virus, TGF- = transform-
ing growth factor.
W36 AJR:203, July 2014
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-
mawhether NASH itself or NASH-induced
cryptogenic cirrhosis leads to HCCremains
unsolved and long-term prospective studies
are needed to elucidate this mystery [36].
Histopathology
According 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 (4176%). 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 2060% of fibrolamellar
HCCs show a central scar [38] that may cal-
cify (3568%) [10].
The hepatic parenchyma surrounding non-
cirrhotic HCC can be entirely normal but
usually shows some degree of inflamma-
tion (50%), fibrosis (4165%), 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].
Diagnosis
Role of Serum -Fetoprotein
Elevated serum levels of -fetoprotein
(AFP) are less commonly associated with
noncirrhotic HCC (3167% of cases) than
with cirrhotic HCCs (5984% 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

diagnostic of HCC regardless of the presence
or absence of underlying cirrhosis [5].
Cross-Sectional Imaging
On imaging, noncirrhotic HCC generally
shows imaging features characteristic of clas-
sic HCC except for the lack of cirrhosis on
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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. 310). 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].
UltrasoundOn 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).
CTOn 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
AJR:203, July 2014 W37
HCC in the Noncirrhotic Liver
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 (2060%), 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 (2556%)
can retain contrast material [38, 42, 44, 46].
MRIThe 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 1017% 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-
 Gaddikeri et al.

mellar HCC may show contrast enhancement
in 2556% of the cases.
Differential Diagnosis
In an otherwise healthy individual or pa-
tients with undiagnosed liver disease, the
diagnosis of HCC is challenging. The most
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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.
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

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 Carcinoma
Fibrolamellar HCC commonly involves
the left lobe and measures 520 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-
Hepatocellular Adenoma
Up 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
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 Isointense (Fig. 10A) Variable depending on the presence or
presence of fat and hemorrhage absence of fat and hemorrhage
(Fig. 9A)
In- and opposed-phase MRI Signal may decrease on opposed- No microscopic fat (Fig. 10B) Signal may decrease on opposed-phase
phase imaging due to microscopic imaging due to microscopic fat; often
fat (Fig. 9B) seen with well-differentiated HCC
T2-weighted MRI Mildly hyperintense (Fig. 9C) Hypo- to isointense lesion with Typically intermediate signal intensity to
central hyperintense scar (80%); hyperintense; iso- or hypointensity
atypical FNH may lack central scar could be well-differentiated HCC
(20%) (Fig. 10C)
Diffusion restriction Rare Never Often
Arterial phase Hypervascular (Fig. 9D) Hypervascular with nonenhancing Hypervascular
scar (Fig. 10D)
Equilibrium phase Variable washout (Fig. 9E) No washout; may see scar Washout with enhancing pseudocapsule
enhancement
Gadoxetate disodiumenhanced No contrast retention (Fig. 9F) Classically retains contrast material No contrast retention
imaging (hepatobiliary phase) (Fig. 10E)
NoteDash () indicates not applicable. GSD-I = type I glycogen storage disease.
aRefer to text.

W38 AJR:203, July 2014


Treatment and Prognosis
Surgical 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 (06%) or morbidity (840%)
even in the setting of very large tumors [2].
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The 5-year overall survival after surgi-
cal resection of noncirrhotic HCC is much
higher (4458% of patients) than for resec-
tion of HCC in the setting of cirrhosis (23
48% of patients). However, recurrences may
be seen in 2773% 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 Administrationap-
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-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 HCCsranging from 37% to
76% after complete surgical resection.
Conclusion
HCCs that develop in noncirrhotic patients
have distinct etiologic, cytogenetic, histo-
AJR:203, July 2014 W39
HCC in the Noncirrhotic Liver
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.
Acknowledgment
We 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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(Figures start on next page)
 HCC in the Noncirrhotic Liver

Chemicals
Aflatoxin B1 Defects in terminal
Alcohol differentiation
Smoking Defects in growth control Genetic predisposition (e.g.,
Vinyl chloride Resistance to cytotoxicity hemochromatosis, Wilson disease,
Defects in apoptosis -1-antitrypsin deficiency,
metabolic syndromes)
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Selective clonal
expansion

Normal cell Initiated cell Preneoplastic Malignant Clinical HCC HCC with distant
lesion tumor metastases

Necroinflammatory disease, Integrins

Virus E-cadherin
Radiation: reactive oxygen and nitric oxide species
HBV -catenin
Thorotrast
HCV CMAR
NM23
Activation of protooncogenes (e.g., N-ras, c-myc, c-fos) KAI1
Activation of growth factors (e.g., IGF-1, IGF-2, TGF-, TGF-)
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)

Fig. 1Illustration 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 factor1, IGF-2 = insulinlike growth factor2, TGF- = transforming growth factor, TGF- = transforming growth factor.

HBV genome
integration in host
cells

Genotoxic viral
Host DNA product
microdeletions Modifies the
expression of (HBx protein)
several growth-
control genes

Accumulation of
High viral load mutations in basal
(1045 copies/mL) Development
of HCC core promoter

Fig. 2Flowchart shows hepatitis B virusinduced 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. 376-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, -fetoprotein level and hepatitis
panel results were normal; biopsy verified well-
differentiated HCC.

AJR:203, July 2014 W41

 Gaddikeri et al.
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A B
Fig. 464-year-old man with history of -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.

A B C
Fig. 559-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).
(Fig. 5 continues on next page)

W42 AJR:203, July 2014

 HCC in the Noncirrhotic Liver
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D E F
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.

A B
Fig. 655-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 (CE).
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).
(Fig. 6 continues on next page)

AJR:203, July 2014 W43

 Gaddikeri et al.
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C D E
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.

A B C

Fig. 761-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.
D

W44 AJR:203, July 2014

 HCC in the Noncirrhotic Liver
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A B C
Fig. 823-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.

A B C
Fig. 933-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.
(Fig. 9 continues on next page)

AJR:203, July 2014 W45

 Gaddikeri et al.

Fig. 9 (continued)33-year-old woman who

presented with hepatic lesion incidentally discovered
on chest CT.
D, Gadoxetate disodiumenhanced 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
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nodular hyperplasia. Single arrow = contrast

excretion in common bile duct.

D E

A B C
Fig. 1039-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).
(Fig. 10 continues on next page)

W46 AJR:203, July 2014

 HCC in the Noncirrhotic Liver
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D E F
Fig. 10 (continued)39-year-old woman with hepatic lesion found on ultrasound performed for right upper quadrant pain.
D, Gadoxetate disodiumenhanced 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.

AJR:203, July 2014 W47

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