American Journal of Roentgenology

Diagnostic Imaging and Related Sciences

Published by

July 2014, Volume 203, Number 1

« Previous Article | Next Article »

FOCUS ON: Gastrointestinal Imaging

Review

Hepatocellular Carcinoma in the Noncirrhotic Liver

Santhosh Gaddikeri1, Michael F. McNeeley1, Carolyn L. Wang1, Puneet Bhargava2, Manjiri K.
Dighe1, Matthew M. C. Yeh3, Theodore Jay Dubinsky1, Orpheus Kolokythas4 and Neeraj
Lalwani1
Share

Affiliations: 1Department of Radiology, University of Washington, 1959 NE Pacific St,

Seattle, WA 98195.
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.
Citation: American Journal of Roentgenology. 2014;203: W34-W47. 10.2214/AJR.13.11511

ABSTRACT

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 entities 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,
cytogenetic, 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
features of this entity and of other diagnostic considerations for the noncirrhotic liver is
essential for improved patient care.

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

Hepatocellular carcinoma (HCC) accounts for approximately 90% of the primary hepatic
malignancies in adults worldwide [1]. Although 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 distinctive enough to suggest the diagnosis, an understanding of its appearance and
of the predisposing clinical risk factors is necessary to prevent misdiagnosis.

Epidemiology and Clinical Features

HCC 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 affected by
noncirrhotic HCC approximately twice as often as women, the male predilection for developing
HCC in a cirrhotic liver is considerably stronger [5] (Table 1). Fibrolamellar HCC, which is a
subtype of noncirrhotic HCC, commonly occurs between the 2nd and 3rd decades of life and
does not show any sex predilection [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 cases per 100,000
individuals, which is almost 100 times lower than classic HCC [7]. Up to one third of the HCCs
developing on a noncirrhotic background could be fibrolamellar HCC [8].

View Larger Version

TABLE 1: Summary of the Differences Between Hepatocellular Carcinoma (HCC) in a

Cirrhotic Liver and HCC in a Noncirrhotic Liver

Whereas classic HCC is often detected during surveillance imaging of patients with cirrhosis,
noncirrhotic HCCs commonly affect patients without known underlying liver disease.
Consequently, these tumors are often detected at an advanced stage and are more likely to cause
symptoms [5, 6]. Common presenting symptoms include abdominal pain (52%), distention
(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 conditions 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).

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
View larger version (293K)
factor–β.

View Larger Version

TABLE 2: Summary of Etiologic Factors Implicated in the Development of

Hepatocellular Carcinoma (HCC) in a Noncirrhotic Liver and Proposed Mechanisms of
Carcinogenesis
Viral Hepatitis

The hepatitis B virus (HBV) is a DNA virus that can induce hepatic carcinogenesis independent
of cirrhosis, which occurs in up to 30% of all HBV-related HCCs [10]. On infection, the HBV
genome integrates with the host hepatocellular DNA and may disrupt normal cellular
regulatory mechanisms by inducing genomic instability or producing genotoxins 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 noncirrhotic HCC.
Overexpression of insulinlike growth factor–2 (IGF-2) and PIK3CA mutations 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].
 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).
View larger version (55K)

The hepatitis C virus (HCV) is an RNA virus that does not integrate with the host genome 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—without 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 surveillance, and genetic
susceptibility.

Genotoxic Substances

Aspergillus flavus is a pathogenic fungus that is endemic to several African and Asian countries
and may contaminate cereals, legumes, 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 commonly underlies noncirrhotic HCC induction [19]. Concomitant
exposure to HBV infection leads to a 60-fold increased risk of noncirrhotic 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
carcinogenesis in patients who live in highly industrialized areas. Some specific mutations have
been linked with certain carcinogens; for example, vinyl chloride–induced noncirrhotic HCC
is linked to KRAS mutations, whereas HRAS mutations are associated with methylene chloride–
induced noncirrhotic HCCs [10].

Thorotrast, a liquid suspension of radioactive 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 discontinued and associated cases have become exceedingly 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 patients 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 hemochromatosis, 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 accumulating mutant proteins or an aggregation of a

substance within the hepatocytes activates a number of stress responses at the genetic 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 suppressor genes (p53), formation of reactive oxygen species and lipid
peroxidation, and acceleration of fibrogenesis, which when taken together induce the formation
of noncirrhotic HCC.

Metabolic syndrome (a synergistic concomitance of dyslipidemia, hypertension, obesity, and

type 2 diabetes mellitus) is an important and evolving risk factor for HCC. The hypothesized
mechanisms of carcinogenesis include lipid peroxidation (oxidative stress induced by free
radicals) and elevated levels of insulin and insulinlike growth factor–1 (IGF-1) [24, 25]. The
unopposed and persistent action of these carcinogens provokes cellular proliferation and
activation of hepatic progenitor cells and also stimulates p53 mutations and epigenetic
aberrations [26, 27].

Miscellaneous Factors

Approximately 5–10% of hepatic adenomas (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 malignant
degeneration of HCA exists in patients with glycogen storage disease, patients who take oral
contraceptive pills (OCPs) or male hormones, and patients with familial adenomatous
polyposis syndrome [10, 30].

Scarce information on the carcinogenesis associated with OCPs is available in the literature.
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 evaluated 23
patients with malignant transformation within HCA revealed that five patients had taken 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 rarity 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 degeneration [32]. Anabolic C17-alkylated androgenic steroids and
contraceptive steroids have been implicated as initiators or promoters of hepatic
carcinogenesis, particularly after long-term use [33]. Interestingly, patients with GSD-I
commonly have steatosis in the liver parenchyma surrounding the adenomas, which may also
be a contributory risk factor.

Budd-Chiari syndrome, nodular regenerative 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 enigma—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].

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 (41–76%). The scirrhous and mixed HCC-cholangiocarcinoma subtypes are
generally rare but occur more frequently in noncirrhotic livers, specifically in western
populations [2]. Well-differentiated HCC is frequent in noncirrhotic liver and shows
microscopic fat.

The fibrolamellar subtype of HCC occurs almost exclusively in noncirrhotic livers [2].
Fibrolamellar HCCs are characterized 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
calcify (35–68%) [10].

The hepatic parenchyma surrounding noncirrhotic HCC can be entirely normal but usually
shows some degree of inflammation (50%), fibrosis (41–65%), early steatosis (36%), or iron
accumulation [4, 39, 40]. Steatosis is frequently associated with conventional noncirrhotic
HCC, whereas background parenchymal inflammation is frequently identified with
fibrolamellar HCC [40].

Diagnosis

Role 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 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 classic 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 fibrolamellar 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-differentiated noncirrhotic HCCs typically are encapsulated with distinct
margins, whereas poorly differentiated and aggressive tumors tend to be nonencapsulated and
poorly circumscribed. Varying amounts of central or peripheral calcification, necrosis,
hemorrhage, and microscopic and macroscopic fat may be present. Occasionally, focal
intrahepatic biliary dilatation can be seen; this feature may be related to mass effect rather than
ductal invasion.

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.

View larger version (362K)

Fig. 4A —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).
View larger version (299K)
 Fig. 4B —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.

B, Equilibrium phase: Coronal image at same

level as A shows subtle washout in lesion
View larger version (401K) (circle).

Fig. 4C —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.

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.

View larger version (400K)

Fig. 5A —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).

View larger version (267K)

 Fig. 5B —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).

B, Axial opposed-phase image shows signal dropout

in mass (arrows) indicating presence of microscopic
fat.

View larger version (350K)

Fig. 5C —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).

C, Axial fat-suppressed T2-weighted image shows

variable intermediate signal intensity in mass
(arrows).

View larger version (204K)

 Fig. 5D —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).

View larger version (291K)

Fig. 5E —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).

E, Axial gadolinium-enhanced equilibrium phase fat-

suppressed T1-weighted image shows washout of
contrast material from mass and pseudocapsule
(arrows).

View larger version (337K)

Fig. 5F —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).

F, Photomicrograph (H and E, ×100) shows

well-differentiated HCC. There is moderate
View larger version (370K) fatty change within carcinoma.
 Fig. 6A —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)
View larger version (553K)
parenchyma; these findings are consistent with
known history of primary hemochromatosis.

Fig. 6B —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).

B, Axial diffusion-weighted image (b value = 1000

s/mm2) shows restricted diffusion in mass (arrow).

View larger version (226K)

 Fig. 6C —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).

View larger version (266K)

Fig. 6D —55-year-old man with history of

hemochromatosis, hepatitis C virus infection, and
alcohol abuse. Incidentally detected right hepatic
mass was evaluated on MRI.

D, Axial gadolinium-enhanced arterial phase fat-

suppressed T1-weighted image shows
homogeneous hypervascularity in mass (arrow).

View larger version (295K)

 Fig. 6E —55-year-old man with history of
hemochromatosis, hepatitis C virus infection, and
alcohol abuse. Incidentally detected right hepatic
mass was evaluated on MRI.

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.

View larger version (342K)

Fig. 7A —61-year-old man with chronic

hepatitis C virus infection.

A, Axial unenhanced fat-suppressed T1-

weighted image shows hypointense central
liver mass (arrows).

View larger version (281K)

Fig. 7B —61-year-old man with chronic

hepatitis C virus infection.

B, Axial gadolinium-enhanced arterial phase

fat-suppressed T1-weighted image shows
heterogeneous hypervascularity in mass
(arrows) with necrotic areas (asterisk).

View larger version (303K)

 Fig. 7C —61-year-old man with chronic
hepatitis C virus infection.

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).

View larger version (292K)

Fig. 7D —61-year-old man with chronic

hepatitis C virus infection.

D, Photomicrograph (H and E, ×200) shows

moderately to poorly differentiated HCC.
Carcinoma cells are arranged in sheets with
pleomorphic nuclei.

View larger version (378K)

Fig. 8A —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).

View larger version (404K)

 Fig. 8B —23-year-old man with history of acute
abdominal pain.

B, Axial arterial phase CT image shows hypervascular

mass with central stellate nonenhancing scar (arrow).

View larger version (382K)

Fig. 8C —23-year-old man with history of acute

abdominal pain.

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.

View larger version (466K)

Fig. 8D —23-year-old man with history of

acute abdominal pain.

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.
View larger version (308K)
 Fig. 9A —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).

View larger version (409K)

Fig. 9B —33-year-old woman who presented with

hepatic lesion incidentally discovered on chest CT.

B, Axial T1-weighted opposed-phase image shows no

signal drop (arrows) to support presence of
microscopic fat.

View larger version (400K)

 Fig. 9C —33-year-old woman who presented with
hepatic lesion incidentally discovered on chest CT.

C, Axial T2-weighted image shows intermediate

signal intensity within mass (arrows). No central scar
is evident.

View larger version (369K)

Fig. 9D —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).

View larger version (360K)

 Fig. 9E —33-year-old woman who presented with
hepatic lesion incidentally discovered on chest CT.

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.

View larger version (268K)

Fig. 10A —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.

View larger version (343K)

 Fig. 10B —39-year-old woman with hepatic lesion
found on ultrasound performed for right upper quadrant
pain.

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.

View larger version (359K)

Fig. 10C —39-year-old woman with hepatic lesion

found on ultrasound performed for right upper quadrant
pain.

C, Axial T2-weighted image shows intermediate signal

intensity of lesion (circle).

View larger version (329K)

 Fig. 10D —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).

View larger version (311K)

Fig. 10E —39-year-old woman with hepatic lesion

found on ultrasound performed for right upper quadrant
pain.

E, On delayed phase image, lesion (circle) is isointense

to liver parenchyma.

View larger version (329K)

 Fig. 10F —39-year-old woman with hepatic lesion
found on ultrasound performed for right upper quadrant
pain.

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.

View larger version (325K)

Extrahepatic extension of HCC via direct invasion of adjacent structures or metastasis is more
common in noncirrhotic patients than in cirrhotic patients (20.5% vs 6.5%, respectively) [5];
this tendency can be explained by the inherent biologic aggressiveness of noncirrhotic HCC
or, rather, by the typical delay in its diagnosis. The relative tendency for early portal vein
invasion by HCC in a cirrhotic liver versus HCC in a noncirrhotic liver remains controversial.
Tumor 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 noncirrhotic HCC
[9]. Fibrolamellar HCCs exhibit a distinct tendency for both nodal and peritoneal metastasis
[10, 43].

Ultrasound—On gray-scale ultrasound, the appearance of HCC in the noncirrhotic liver is

often nonspecific. Noncirrhotic HCC may appear hypoechoic, hyperechoic (due to fatty
metamorphosis or hemorrhage), or mixed echogenic (due to necrosis and hypervascularity).

CT—On unenhanced CT, noncirrhotic HCC tends to be hypoattenuating relative to the

surrounding liver parenchyma. Areas of central or peripheral calcification, necrosis, and
hemorrhage 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 material, the fibrolamellar HCC subtypes show
hyperenhancement during the late arterial phase, isoenhancement compared with neighboring
parenchyma during the portal venous phase, and contrast washout during the equilibrium
phase, as seen in classic HCC in a noncirrhotic liver (Figs. 4A and 4B). Capsular enhancement,
when present, is most apparent during the equilibrium phase. Fibrolamellar HCC may show
predominant heterogeneous arterial enhancement, the presence of a central scar (20–60%), and
a discontinuous capsule (35%) [44]. Some authors have reported that the central scar in
fibrolamellar HCC is usually avascular and shows little or no enhancement, 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
significant 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 proteinaceous 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 better 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 microscopic 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 isointense to
hypointense [51].

Noncirrhotic HCC can show restricted diffusion 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, regardless of the
degree of underlying fibrosis, may be more conspicuous on DWI than their lower-grade
counterparts. Dysplastic nodules and well-differentiated (low-grade) HCCs are relatively
hypovascular. These findings probably are a function of the hypercellularity of higher-grade
carcinomas and could possibly also reflect the increased nuclear-cytoplasmic ratio inherent to
aggressive tumors [55] (Fig. 7).

Dynamic fat-saturated gadolinium-enhanced T1-weighted imaging shows an enhancement

pattern similar to multiphase CT, with hyperenhancement during the arterial phase,
isoenhancement during the portal venous phase, and washout during the equilibrium 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 composed of fibrous connective tissue. Alternatively, the presence of
prominent hepatic sinusoids or nonbridging peritumoral fibrosis may cause the appearance of
a pseudocapsule on cross-sectional imaging in 80% of the cases. In this situation, iodinated or
gadolinium-based contrast agents can be retained in the peritumoral space, resulting in late
circumferential 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 central scar has
been described in fibrolamellar HCC, FNH, HCA, and large hemangioma, but HCC can also
show a central scar [43, 58]. Noncirrhotic HCCs more commonly (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 images, and heterogeneously enhancing after gadolinium
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-weighted hyperintense scars
are frequently encountered, which may be attributed to coexisting necrosis or altered
vascularity [42]. As we described earlier, the central scar in fibrolamellar HCC may show
contrast enhancement in 25–56% of the cases.

Differential Diagnosis

In an otherwise healthy individual or patients with undiagnosed liver disease, the diagnosis of
HCC is challenging. The most common symptoms that prompt the diagnosis of HCC are
abdominal pain or discomfort in the right upper quadrant, jaundice, nausea, or toxic syndrome
(weight loss, fever, malaise, asthenia, and anorexia). Rarely, noncirrhotic HCC presents as life-
threatening hemoperitoneum from tumor rupture [44].

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

Fibrolamellar Hepatocellular Carcinoma

Fibrolamellar HCC commonly involves the left lobe and measures 5–20 cm. A central scar and
radiating septa, central calcifications 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 hyperintense scar, which is seen in FNH. On contrast-enhanced MRI, there is arterial
heterogeneous hyperenhancement of the whole tumor except for the central scar. Washout is
seen on the portal venous and equilibrium phases, and the central scar does not enhance in the
equilibrium phase.
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 hemorrhage. The
tumor tends to be hypoattenuating on unenhanced CT images; however, in the setting of a
diffuse fatty liver, the tumor may appear hyperattenuating when compared with the adjacent
liver parenchyma. Contrast-enhanced images show hyper-enhancement on arterial phase
imaging and washout on portal venous phase and equilibrium phase imaging.

Focal Nodular Hyperplasia

FNH is usually solitary but can be multiple in 25% of cases. FNH is usually iso-attenuating or
isointense to the surrounding liver parenchyma on unenhanced CT or unenhanced T1-weighted
MRI, respectively. There can be a reversal in the imaging appearance in the presence of a
diffuse fatty liver. The central scar (present in 77% cases) is typically hyperintense on T2-
weighted images. Contrast-enhanced imaging shows homogeneous arterial phase
hyperenhancement of the tumor except for the scar. On portal venous and equilibrium phase
images, FNH may show the same enhancement as the surrounding liver parenchyma with an
enhancing scar. Delayed scar enhancement and hyperintensity on T2-weighted imaging have
been described as important features for distinguishing between FNH and fibrolamellar HCC;
however, 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 gadoxetate disodium (Eovist, Bayer Healthcare) can be used to confirm
the FNH, which shows contrast retention in the hepatobiliary phase. HCC becomes hypointense
to remainder of the liver.

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

View Larger Version

TABLE 3: Differential Diagnosis of Hepatocellular Carcinoma (HCC) in Noncirrhotic

Liver: Key Characteristics of Hepatocellular Adenoma (HCA), Focal Nodular
Hyperplasia (FNH), and Noncirrhotic HCC
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 perioperative
mortality (0–6%) or morbidity (8–40%) even in the setting of very large tumors [2].
The 5-year overall survival after surgical resection of noncirrhotic HCC is much higher (44–
58% of patients) than for resection 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, stringent postoperative follow-up is necessary.

The ideal treatment strategy for recurrent disease remains controversial. Currently, there is no
strong evidentiary support for adjuvant chemotherapy to prevent recurrence after 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 common [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–approved oral
multikinase inhibitor that antagonizes tumor cell proliferation and neoangiogenesis [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 noncirrhotic HCCs remains
undetermined. Because of their high levels of Y654–β-catenin and increased receptor tyrosine
kinase signaling, fibrolamellar subtypes may be highly responsive to Sorafenib therapy.

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

Conclusion

HCCs that develop in noncirrhotic patients have distinct etiologic, cytogenetic,

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 features of
this entity and of other diagnostic considerations for the noncirrhotic liver is essential for
improved