Characteristics of common solid liver lesions and recommendations for diagnostic workup Nimer Assy, Gattas Nasser, Agness Djibre, Zaza Beniashvili,… [600905]

www.wjgnet.com REVIEW
Characteristics of common solid liver lesions and
recommendations for diagnostic workup
Nimer Assy, Gattas Nasser, Agness Djibre, Zaza Beniashvili, Saad Elias, Jamal ZidanOnline Submissions: wjg.wjgnet.com World J Gastroenterol 2009 July 14; 15(26): 3217-3227
[anonimizat] World Journal of Gastroenterology ISSN 1007-9327
doi:10.3748/wjg.15.3217 © 2009 The WJG Press and Baishideng. All rights reserved.
Nimer Assy, Liver Unit, Ziv Medical Center, Zefat 13100,
Israel, Faculty of Medicine, Technion Institute of Technology,
Haifa 32000, Israel
Gattas Nasser, Liver Unit, Ziv Medical Center, Zefat 13100,
Israel
Agness Djibre, Department of Medicine, Western Galilee
Hospital, Nahariya 22100, Israel
Zaza Beniashvili, Liver Unit, Ziv Medical Center, Zefat 13100,
Israel
Saad Elias, Department of Medicine, Ziv Medical Center,
Zefat 13100, Israel
Jamal Zidan, Institute of Oncology, Ziv Medical Center,
Zefat 13100, Israel; Faculty of Medicine, Technion Institute of
Technology, Haifa 32000, Israel
Author contributions: The manuscript was written by Assy N,
Nasser G, Djibre A, Beniashvili Z; Elias S collected data and
designed the manuscript; Zidan J reviewed the manuscript prior
to submission.
Correspondence to: Nimer Assy, MD, Liver Unit, Ziv
Medical Center, Zefat 13100, Israel. [anonimizat]
Telephone: +972-4-6828441 Fax: +972-4-6828442
Received: May 4, 2009 Revised: June 8, 2009
Accepted: June 15, 2009
Published online: July 14, 2009
Abstract
Due to the widespread clinical use of imaging modalities
such as ultrasonography, computed tomography
and magnetic resonance imaging (MRI), previously
unsuspected liver masses are increasingly being found
in asymptomatic patients. This review discusses the
various characteristics of the most common solid
liver lesions and recommends a practical approach
for diagnostic workup. Likely diagnoses include
hepatocellular carcinoma (the most likely; a solid liver
lesion in a cirrhotic liver) and hemangioma (generally
presenting as a mass in a non-cirrhotic liver). Focal
nodular hyperplasia and hepatic adenoma should be
ruled out in young women. In 70% of cases, MRI
with gadolinium differentiates between these lesions.
Fine needle core biopsy or aspiration, or both, might
be required in doubtful cases. If uncertainty persists
as to the nature of the lesion, surgical resection is
recommended. If the patient is known to have a primary
malignancy and the lesion was found at tumor staging
or follow up, histology is required only when the nature
of the liver lesion is doubtful.
© 2009 The WJG Press and Baishideng. All rights reserved.Key words: Liver mass; Hepatic nodule; Tumor; Lesion;
Cirrhosis; Hepatocellular carcinoma; Magnetic resonance
imaging; Ultrasonography; Computed tomography; Fine
needle aspiration; Biopsy
Peer reviewers: Raffaele Pezzilli, MD, Department of Internal
Medicine and Gastroenterology, Sant’Orsola-Malpighi Hospital,
Via Massarenti, 9, Bologna 40138, Italy; Paul E Sijens, PhD,
Associate Professor, Radiology, UMCG, Hanzeplein 1, 9713GZ
Groningen, The Netherlands
Assy N, Nasser G, Djibre A, Beniashvili Z, Elias S, Zidan
J. Characteristics of common solid liver lesions and
recommendations for diagnostic workup. World J Gastroenterol
2009; 15(26): 3217-3227 Available from: URL: http://www.
wjgnet.com/1007-9327/15/3217.asp DOI: http://dx.doi.
org/10.3748/wjg.15.3217
INTRODUCTION
Liver masses are increasingly being identified due to
the widespread use of imaging modalities such as
ultrasonography (US), computed tomography (CT),
and magnetic resonance imaging. The majority of
these lesions are detected incidentally in asymptomatic
patients. An accurate history and physical examination
are essential to the diagnosis and treatment of solid liver
masses. For example, the use of oral contraceptives or
anabolic steroids might be related to hepatic adenoma
(HA)[1]; alcohol use and occupational exposure are
associated with angiosarcoma[2] and primary sclerosing
cholangitis, liver fluke, Caroli’s disease, and choledochal
cysts are associated with cholangiocarcinoma[3]. Physical
examination should look for liver tenderness, stigmata of
chronic liver disease, or general deterioration signs (fever,
weight loss). High alkaline phosphatase, high lactate
dehydrogenase (LDH), low albumin, high prothrombin
time, and iron overload are non-specific but might
suggest an underlying chronic hepatitis, cirrhosis or an
infiltrative process[4]. A history of hepatitis B, C or liver
cirrhosis might point to hepatocellular carcinoma (HCC).
A previous neoplasm or history of chemotherapy
increases the suspicion of metastatic liver disease.
CURRENT KNOWLEDGE
In the majority of patients, a proper diagnosis can be

www.wjgnet.commade based on the characteristics on imaging modalities
(Lesions size < 1.0 cm are usually benign). For diagnostic
purposes, liver masses should be divided into those
occurring with and without cirrhosis. A liver mass in a
cirrhotic liver should be viewed as HCC until proven
otherwise. Multiple liver masses in a cirrhotic liver indicate
diffuse HCC, high-grade dysplastic nodules or, on rare
occasions, hepatic lymphoma[5]. Benign liver lesions are
found in more than 20% of the general population[6],
including haemangioma (4%), focal nodular hyperplasia
(FNH, 0.4%) and hepatic adenomas (0.004%). Multiple
liver lesions in a normal liver usually indicate liver
metastasis (most commonly from adenocarcinoma of
the colon, stomach, lung or prostate), but could be cysts
or hemangiomas[7]. Liver metastasis is a rare finding in a
cirrhotic liver[8] (Table 1). Multiple liver lesions of a benign
nature such as hemangiomas or focal nodular hyperplasia
are not uncommon in a normal liver.
Calcifications have no diagnostic utility but
might suggest fibro-lamellar carcinoma or colorectal
adenocarcinoma, whereas hemorrhage within the lesion
suggests adenoma[9]. The initial strategy in cirrhosis
should be the measurement of α-fetoprotein (AFP)
followed by ultrasound, contrast CT or magnetic
resonance imaging (MRI)[10,11]. Fine needle core biopsy
(FNCB) might be required, but biopsy of potentially
operable lesions should be avoided. This review
discusses the various characteristics of the most
common solid liver lesions and recommends a practical
approach for diagnostic workup.
DIAGNOSTIC VALUE OF TUMOR
MARKERS
AFP, PIVKA 2 (< 0.1 U/mL), desgamma-carboxy
prothrombin and CA 19-9 (< 37 U/mL) are tumor
markers for HCC. AFP is the first choice when diagnosing
HCC and 10 ng/mL is the cut-off level. The formula (Ca
19-9 + CEA × 40) provides an index accuracy of 86% in diagnosis of cholangiocarcinoma[12]. AFP values >
400 ng/mL are indicative of HCC. 30% of patients with
HCC < 2 cm have normal AFP , 20% of HCCs produce
no AFP, and levels from 20-250 are frequently seen in
regenerating nodules or viral cirrhosis. An increase in
AFP over time is virtually diagnostic of HCC[13]. Globally,
the serum level of at least one of the tumor markers
was elevated in 88% of patients with proven malignancy.
Elevation was marked in 57%. No tumor marker
alterations were detected in patients with benign lesions.
Early lesions may have elevated tumor markers in fewer
than 30% of cases[12].
IMAGING TECHNIQUES (TABLE 2)
A single imaging modality might suffice in cases that
show interval development or progression, such as
metastasis. Hemangiomas are often diagnosed by a
single dynamic contrast enhanced imaging modality
(MDCT). When further imaging techniques are
necessary, CT angiography, MRI, and contrast enhanced-
CT are performed to plan a surgical strategy. If this is
not available on site, the patient and physician should
decide whether the patient should undergo a biopsy or
be referred for additional imaging. The key features of
imaging techniques in the diagnosis of liver mass are
shown in Table 3. Imaging tools for tumor assessment
include: (1) Angiogram, RBC scintigraphy, contrast-
enhanced CT, Porto-angiography CT, color Doppler
ultrasound, contrast ultrasound, and gadopentetate
dimeglumine-enhanced MRI; (2) MD-DPDP enhanced
MRI imaging, Gd-Bopta-enhanced MRI imaging,
EOB DTPA (to assess hepatocyte function and biliary
excretion); (3) Plain film, US, CT scan (to assess tumor
calcifications); and (4) US, contrast US, enhanced CT,
MRI (utilized to assess capsule formation). US and CT
are indicated for diagnosis of biliary obstruction or
gallbladder diseases and for differentiation of cysts from
solid liver lesions. Intraoperative ultrasound detects small
liver lesions (< 5 mm). Endoscopic US assesses the left Table 1 Clinical differential diagnosis of the most common liver masses
Cirrhotic liver Common lesions Non-cirrhotic liver Common lesions
Malignant mass Hepatocellular carcinoma a,d Metastasis a,b
Cholangiocarcinoma Well differentiated HCC
High grade dysplastic nodule Fibro lamellar HCC a,b,c,g
Lymphoma Cholangiocarcinoma
Metastasis (exceptional) Hemangio-Endothelioma g
Lymphoma
Melanoma
Neuroendocrine tumor a
Sarcoma (angiosarcoma,leiomyosarcoma) g
Benign mass Low grade dysplasia d Hemangioma b
Focal fatty liver Focal nodular hyperplasia (FNH) a,b
Hemangioma Hepatic adenoma (HA) a,b
Hepatic adenoma g Nodular regenerative hyperplasia b,f
Partial nodular transformation e,f
Focal fatty infiltration c,e
Bile duct adenoma
a: Hyper vascular liver tumor; b: Tumors that are extremely rare in cirrhosis but relatively frequent in healthy normal liver; c: Tumors frequent in the left
lobe; d: Mainly in cirrhosis; e: Equally found in cirrhotic and non cirrhotic; f: Clinically mimics cirrhosis; g: Extremely rare tumors.3218 ISSN 1007-9327 CN 14-1219/R World J Gastroenterol July 14, 2009 Volume 15 Number 26

www.wjgnet.comliver lobe and the gastrohepatic ligament lymph nodes,
and can help perform FNA. Doppler US evaluates blood vessels patency and portal hypertension[14].
The gold standard for detection and location of
focal lesions is MRI or triple phase dynamic spiral
CT[15]. Conventionally, a triple phase CT scan includes
unenhanced, arterial and venous phases. The fourth phase
is a delayed venous scan quadruple phase MDCT[16]. This
is required only for small lesions thought to be HCC or
cysts and hemangiomas. CT portography is one of the
most sensitive imaging modalities for secondary lesions,
but it is an examination that is performed in highly
selected cases only, in few institutions and not for all types
of liver lesions[16,17]. FDG PET CT scan is not very useful
for HCC and therefore is not the best imaging modality
to distinguish benign from malignant lesions[18]. A nuclear
scan with Tc-99m-sulfur colloid shows increased uptake
in FNH. MIBG and octreotide scintigraphy detect
neuroendocrine tumors[19]. Hepatic Tc-99m red blood cell
scan diagnoses hemangiomas > 2.5 cm (most university
centers do not use this method and prefer contrast
enhanced US, CT, and MRI)[20]. Ultrasound contrast agents
and MRI using iron or gadolinium contrast better detect
smaller lesions, satellite lesions or distant metastasis[21-23]. Table 2 Accuracy and key features of imaging techniques in the diagnosis of most common liver masses
US-US doppler, contrast
ultrasoundTriphasic CT MRI PET SCAN CT-angiography
Hemangioma
(1-10 cm)++ +++ ++++ +++
Hyperechoic
Doppler: low flow, low index,
absence of spectral broadeningPeripheral puddles, fill in from
periphery, enhancement on
delayed scanPeripheral enhancement
centripetal progression
Hyperintense on T2, hypo
intense on T1
SS > 95%, SP 95%No uptake Cotton wool pooling
of contrast, normal
vessels without AV
shunt, persistent
enhancement
Focal fatty
liver+ ++ +++ Normal finding
Hyper echoic, no mass effect, no
vessel displacementSharp interface
Low density (< 40 u)No uptake
FNH (< 3 cm) + ++ ++++ +++
Homogenous iso, hypo, or hyper
echoic, central hyper echoic area
Central arterial signal
Doppler: high flow, spectral
broadeningHomogeneous enhance strongly
with hepatic arterial phase
Isodense with liver; Central low
density scarHyper vascular +Gd
Isodense T1
Hyper intense scar T2
SS > 95%; SP > 95%No uptake Hyper vascular 70%
centrifugal supply
Adenoma
(5-10 cm)+ ++ ++ ++
Heterogeneous
Hyper echoic
If haemorrhage: anechoic center
In doppler: variable flow, spectral
broadening Homogenous > Heterogeneous,
Peripheral feeders filling in
from periphery Capsule, Hyper intense in
T1 (intra lesional fat) No uptake
uptake if
degenera-tion
to HCCHyper vascular
Large peripheral
Vessel
Central scar if
haemorrhage
HCC + +++ +++ + ++++
Hypo or hyper echoic
Doppler: hyper vascular
Doppler: index and flow high,
spectral broadeningHyper vascular, often irregular
borders
Heterogeneous > Homogeneous
abnormal internal vessel
Hallmark is venous washout
SS 52%-54%Hyper vascular
Poor different: Hypo intense
T-1, Hyper intense T2
Well different: Hyper
intense T-1, Iso intense T-2
SS 53%-78%Increased
uptake, but
many HCCs
show no uptake
at PETHyper vascular
Av shunting
Angiogenesis
Cholangio-
carcinomaBile duct dilatation if major ducts
are involved. Intra-hepatic CCC:
no bile dilatationHypo dense lesion. Delayed
enhancementHypo intense T1
Hyper intense T2
MRCP is usefulUptake ++
SS 93%Hypervascular
Metastasis +1+++ +++ +++++ ++++
SS 40%-70% hypo to hyper
echoic; doppler; low index
and flow; presence of spectral
broadening SS 49%-74 % complete ring
enhancementSS 68%-90 %
Low intensity T-1
High intensity T-2SS 90%-100% SS 88%-95%
hyper vascular
1Intraoperative ultrasound, contrast ultrasound and EUS are highly sensitive to detect liver mass; +: Degree of accuracy; SS: Sensitivity; SP: Specificity; MRI:
Magnetic resonance imaging; CT: Computed tomography; HCC: Hepatocellular carcinoma.
Table 3 Immunohistochemical staining in the evaluation of
hepatic tumors
Tumor Recommended immunostaining
HCC Polyclonal CEA
Cytokeratin 8/18 pair (+/+ staining)
Cytokeratin 7/20 pair(-/- staining)
Hep Par 1, AFP
Cholangiocarcinoma Cytokeratin 7/19 pair (+/+ staining)
Cytokeratin 7/20 pair (+/- staining)
B-HCG, CEA, Mucin-1
Epithelioid
hemangioendotheliomaCD34
CD31
Factor Ⅷ
Angiomyolipoma HMB-45, smooth muscle actin
Metastatic carcinoma
Neuroendocrine Chromagin, synaptophysin, neural enolase
Pancreas Cytokeratin 7/20 pair (+/+ staining)
Colorectal Cytokeratin 7/20 pair( -/+ staining)
Breast Cytokeratin 7/20 pair (+/- staining)
Lung Cytokeratin 7/20 pair (+/- staining)Assy N et al. Diagnosis of solid liver mass 3219

www.wjgnet.comRadiographic characteristics favoring HCC include the
presence of a capsule bulging beyond the normal hepatic
contour or a lesion with different densities. Contrast
injection produces an immediate enhancement of most
hepatomas.
FINE NEEDLE ASPIRATION AND CORE
BIOPSY (FNAB)
FNAB is safe, accurate and cost effective. Its specificity
approaches 100% and its sensitivity is 67%-100%[24,16].
FNAB under CT or US in an appropriate location is
the method of choice. FNAB is superior to FNCB;
however, the methods are complementary, i.e. FNAB
and FNCB have an accuracies of 78% separately and
88% when considered in combination[25,26]. However,
many pathologists state that core biopsies are much
preferred over needle biopsies for diagnosis of hepatic
masses, because well differentiated HCCs cannot be
separated from normal liver. Complications (mostly
hemorrhages) are rare, with 0.5% minor complications
and 0.05% major complications[27-30]. Another concern
is the possible seeding of a tumor. Blind FNAB is
diagnostic in > 50% of cases[31], which increases to 65%
when performing a second pass. An additional 5%-10%
of tumors will be recognized if a cell block is obtained.
Cohn ’s cytological criteria help to distinguish HCC from
non-neoplastic lesions (81% of HCC show at least two
criteria)[32], e.g. increased nuclear/cytoplasmic ratio,
trabecular pattern, and atypical naked hepatocyte nuclei.
Some key features of immunohistochemical staining in
the evaluation of hepatic tumors are shown in Table 3.
GENERAL APPROACH TO LIVER
MASSES IN CIRRHOTIC LIVERS (TABLE 1,
FIGURE 1)
Mass > 2 cm
Enhancement in the arterial phase and washout in the
portal venous phase is essential for the diagnosis of a
liver lesion > 2 cm in a cirrhotic liver. More than 80%
of masses > 2 cm in a cirrhotic liver are HCC[33,34]. An
elevated AFP confirms the diagnosis. If AFP is normal,
further imaging will be diagnostic (triphasic CT, MRI)[13].
If there is still doubt, FNCB might be indicated (Figure 1).
Mass < 2 cm
Seventy-five percent of masses < 2 cm in a cirrhotic liver
are HCCs[35]. AFP levels and imaging might secure the
diagnosis. If still in doubt, repeated imaging that detects
enlargement of the lesion, or FNAB/FNCB might be
indicated. Due to the risk of tumor seeding, biopsy
should be avoided if surgical resection is possible[36].
A small nodule can be preneoplastic or benign. The
American Association for the Study of Liver Diseases
(AASLD) distinguishes lesions < 1 cm from those > 1
cm but < 2 cm. They suggest performing two imaging
techniques from among US, CT, and MRI with Ⅳ
contrast injection. If two techniques display typical imaging criteria, it is possible to diagnose HCC. Larger
nodules should be diagnosed and small lesions should
be surveyed every three months[37]. Caturelli showed that
69% of new nodules in a cirrhotic liver are malignant.
Moreover, liver cell dysplasia is found in 60% of
cirrhotic livers containing HCC and in only 10% of non-
cirrhotic livers[38].
AFP is increased without a liver mass
In this case, repeated dynamic CT or MRI every
three months is the rule[39]. An elevated AFP does not
necessarily diagnose HCC, especially in patients with
HCV who commonly have modest elevation of AFP
without HCC. A marked AFP is helpful, but modest
elevations would certainly not be an indication for OLT
in the absence of a liver mass.
HCC: HCC is a common malignancy with an incidence
of 1%-6% among cirrhotic patients[13,40-42]. Risk factors
include cirrhosis, alcohol, HBV, HCV, metabolic liver
diseases, environmental carcinogens, hormonal treatments
and smoking[43,44]. Ninety to ninety five percent of HCCs
arise in cirrhotic livers. Autopsy studies indicate that
20%-40% of patients with cirrhosis have HCC. Tumor
size and severity of liver disease influence the survival
rate. Patients with tumors < 5 cm have a survival of 80%
at one year and 20% at three years. New abdominal pain,
recent hepatomegaly, hemoperitoneum, persistent fever or
weight loss in a cirrhotic patient should raise suspicion of
HCC. Laboratory results that characterize HCC include
a sudden increase in alkaline phosphatases, an increased
ratio AST/ALT, an erythrocytosis, persistent leukocytosis, HCC/or other
malignancyNot diagnostic (10%)
Benign lesion (15%
DN, RN)
Resection liver
transplantationUS/CT guided FNCB after excluding
cyst or hemangioma by contrast
enhanced CT/MRI
(seeding 0.003%, accuracy: 90%)If nodule > 2 cm ± AFP levels
> 400: need one imaging
technique to diagnose HCC
If nodules < 2 cm: two
conditions:
(1) Nodule > 1 cm: follow-up
every 3 mo
(2) Nodule between 1-2 cm:
two coincident imaging
techniques showing typical
findings.
If imaging appearance is
atypical, proceed for FNCB
If no nodule: Triphasic CT or
enhanced MRI over time Repeat FNCB or
second imaging study
Negative for HCC
Differentials: DN, RN,
focal fatty liverPositive for HCC
Assess for surgery/OLT: size, location,
number of lesions, CP-score, vascular
invasion, metastasisIncreased
(> 10 mg/mL)Normal
(< 10 mg/mL)AFP
Figure 1 Algorithm for the investigation of a liver mass in a cirrhotic liver.
Some hepatologists consider biopsy to be unnecessary for a mass in a cirrhotic
liver even if the α-fetoprotein (AFP) < 10; FNCB: Fine needle core biopsy; MRI:
Magnetic resonance imaging.3220 ISSN 1007-9327 CN 14-1219/R World J Gastroenterol July 14, 2009 Volume 15 Number 26

www.wjgnet.comrecurrent hypoglycemia, hypercholesterolemia and
hypercalcemia. The last four findings are paraneoplastic
manifestations[45] together with ectopic hormonal
syndrome, hypertrophic osteoarthropathy and porphyria
cutana tarda[46]. Complications of HCC include obstructive
jaundice[47], and rupture of HCC (60%-90% mortality).
Screening for HCC includes US + AFP levels every
six months. The AASLD guidelines recommend US only.
AFP is of little additional value. Lesions > 2 cm need just
one imaging technique showing typical findings (arterial
hypervascularization) or one imaging technique and AFP
levels > 400 in order to make a non-invasive diagnosis
of HCC[13]. Lesions < 2 cm are divided into larger and
smaller than 1 cm. Nodules > 1 cm but < 2 cm (1-2 cm)
need diagnostic workup with two coincident or serial
imaging techniques, rather than just proceeding with a
biopsy. Nodules < 1 cm need screening follow up every
three months. Nine to thirty seven percent of HCC are
resectable at diagnosis[48]. Contraindications to resection
include decompensated cirrhosis, extra-hepatic metastases,
involvement of hepatic nodes or inferior vena cava
(IVC), or bilobar extension[45]. The histological variants
in cirrhotic livers include trabecular (65%), mixed (15%),
compact (12%), pseudo glandular (5%) fibro lamellar
(1.5%), and scirrhous 0.5%[49].
Regenerative nodules: Dysplatic nodules often occur
within regenerative cirrhotic nodules. They can show low-
or high-grade dysplasia. A progression from regenerative
nodule with low-grade dysplasia to high-grade dysplasia,
in well differentiated and poorly differentiated HCC, is
possible[50-51]. MRI best differentiates this iso-or hypo-
intense lesion from hyper intense HCC. In difficult
cases, histology is required after liver resection or liver
transplant. If HCC cannot be confirmed, the investigation
must be repeated later. Over time, high-grade dysplastic
nodules can become malignant, suggesting preventive
ablation by ethanol[7].
GENERAL APPROACH TO LIVER MASSES
IN NON-CIRRHOTIC LIVERS (TABLE 1,
FIGURE 2)
Liver masses present with fever, pain, abdominal
discomfort, or accidentally without overt symptomology.
Benign masses include hemangioma, FNH, nodular
regenerative hyperplasia (NRH), and HA. The most
frequent malignancy is gastrointestinal, urogenital, lung
or breast carcinoma metastasis. Liver primary malignancy
includes fibrolamellar carcinoma, cholangiocarcinoma,
hepatic lymphoma and angiosarcoma[52,53].
Elevated AFP diagnoses HCC[54], otherwise, further
imaging is required. US or CT classifies cysts, metastases
and hemangioma. MRI identifies focal fatty liver, FNH,
HA and hemangioma[55]. When the diagnosis remains
uncertain, FNAB or follow up imaging is considered.
Resection is indicated for large (> 5 cm) or growing
adenomas. Benign lesions
Hemangiomas: Hemangiomas are found in 20% of
the general population, more commonly in women[56,57].
The majority are asymptomatic. Giant hemangiomas
(> 4 cm) are symptomatic in 40% of cases. Symptoms
are rare and can include abdominal pain, early satiety,
anorexia, and nausea[58]. Tc-99m labelled RBC Spect is
the best and least expensive modality (specificity 100%)
for lesions > 2.5 cm and MRI for lesions < 2 cm[59,60].
University centers rarely require RBC Spect for diagnosis
of hemangiomas due to the use of cross sectional
imaging. Histology of liver hemangiomas is blood-filled
vascular sinusoids separated by connective tissue septa
(peliosis lacks endothelial layer and fibrous trabeculae)[61].
The risk of rupture is minimal and does not justify
resection. Other complications include thrombosis,
sclerosis, and calcification. Liver hemangiomas can grow
during pregnancy or oral contraception. Kasabach-
Merritt syndrome (consumption coagulopathy) and
Bornman-Terblanche-Blumgart syndrome (fever and
abdominal pain) constitute uncommon complications[61].
FNH: Focal nodular hyperplasia is found more often in
women 20-50 years of age (80%). The pathogenesis is
unknown, but includes vascular injury. The lesion is usually
< 3 cm, asymptomatic and discovered accidentally. The
main difficulty for the physician is differentiating FNH
from adenoma or fibrolamellar carcinoma by imaging
techniques. However, fibrolamellar carcinomas enhance
heterogeneously, wash out, and have central calcifications
and enlarged lymph nodes. These features are very rarely Liver mass in healthy young adult liver
Evidence of liver disease (history, viral serology,
neoplastic markers); AFP elevated?
NoYes
Exclude HCC & CCC: Enhanced CT, MRI or
FNAB
Differential: Hemangioma, FNH, adenoma,
fibrolamellar CA, hemangioendothelioma
MASS < 2 cm MASS > 2 cm
Enhanced MRI
or triphasic CT1RBC scintigraphy
(if available)
Negative for
hemangioma
enhanced MRI Positive for
hemangioma:
stop
investigation
Adenoma vs HCC: difficult Hemangioma/FNH/fatty liver:
stop investigation-observation
servationNot diagnostic (10%)
Tru-cut needle liver biopsy (FNCB)
2nd attempt: 10%, laparoscopy or
resection if histological diagnosis
is unclear
Figure 2 Algorithm for the management of a liver mass in a non-cirrhotic
liver. 1Most centers do not use RBC scintigraphy to diagnose hemangioma
due to their use of cross sectional imaging such as contrast enhanced
ultrasonography (US)/CT/MRI.Assy N et al. Diagnosis of solid liver mass 3221

www.wjgnet.comfound in FNH. Lack of symptoms, normal liver enzymes
and no use of oral contraceptives argue in favour of
FNH. Recent literature suggests that MRI has 70%
sensitivity and 98% specificity for FNH (homogeneous
hypervascular lesion with central scar)[62,63]. If radiology is
unequivocal, most hepatologists advocate a “wait and see ”
attitude. Otherwise, image guided percutaneous biopsies
are performed, one in the tumoral tissue and the other in
the normal liver tissue. The histology resembles inactive
cirrhosis with proliferating hepatocytes around a normal
prominent central artery with a central fibrous scar[62].
The natural history of FNH is variable (stable, regressive
or progressive over time), but resection is not necessary
because it does not progress to malignancy. Complications
are rare and include hepatic vein thrombosis or Kasabach-
Merritt syndrome[63,64].
HA: Adenoma occurs in women with oral contraception
use > 5 years[65] or in diabetic patients. Multiple adenomas
are associated with glycogen storage disease type Ⅰ and
type Ⅲ[66]. Adenomatosis (> 10 adenomas) is observed
with anabolic or androgenic steroids consumption[67].
Abdominal discomfort is common[68]. The lesion is
hypo- to hyper- echoic on US and hypo- to hyper- dense
on CT. MRI is not specific[69,70]. The lesions are often <
8 cm but can be > 15 cm microscopically; they appear
as monotonous sheets of normal or small hepatocytes
with no bile duct, portal tract or central vein. Five
percent of hepatic adenomas transform to HCC[71].
β-catenin immunostaining might be useful for diagnosis.
Spontaneous rupture and hemoperitoneum occur in 10%
of cases, especially during menstruation, pregnancy or
post partum. Most hepatologists advocate resection and
discontinuation of oral contraception[72,73].
NRH and partial nodular transformation (PNT):
NRH (large regenerative nodule) is associated with
Behcet’s disease, rheumatic diseases, myeloproliferative
disorders, chronic venous congestion, metastatic
neuroendocrine tumors, Budd-Chiari syndrome, and
various drugs (steroids, contraceptives, antineoplastics,
anticonvulsives, and immunosuppressives)[74]. Some
lesions present with portal hypertension and cholestasis.
A diagnostic open liver biopsy is rarely required[75].
NRH shows diffuse hyperplastic nodules with thickened
liver cell plates without fibrosis. Reticulin changes are
characteristic. Portal vein thrombosis could lead to NRH
by parenchymal atrophy and compensatory hyperplasia.
Portal vein thrombosis has also been invoked in the
pathogenesis of PNT[76].
Focal fatty infiltration of the liver: In 10% of patients
with fatty liver, fat accumulates focally or shows focal
sparing, usually in the anteromedial segment of the left
lobe. These patients usually have diabetes, hyperlipidemia,
obesity, drink alcohol or take steroids[77]. On US, fat is hyper
echoic. On CT, it has low attenuation. Focal fatty liver does
not displace intrahepatic vessels. The gold standard imaging
technique is MRI with increased signal on T1 sequence[78].
Fat suppression techniques are also very promising. Other rare benign tumors
Hepatobiliary cyst adenoma: This lesion is rare,
occurs predominantly in middle-aged women and causes
abdominal pain. It differs from benign cyst by having
thick septated wall. Up to 25% become malignant
(cystadenocarcinoma), therefore surgical excision is
indicated[79].
Bile duct adenoma (cholangioma): Bile duct adenomas
are solitary sub capsular nodules measuring 1-20 mm
described in patients with α-1-antitrypsin deficiency. The
bile ducts are smaller and do not contain bile.
Biliary papillomatosis: Only 50 cases have been
described worldwide[80]. It is a tumor of middle age,
leading to biliary obstruction by tumor shedding, mucus
and lithiasis, cholangitis and hemobilia. Diagnosis is made
by endoscopic retrograde cholangiopancreatography
(ERCP), which shows typical mucinous discharge from
a dilated ampulla, multiple filling defects and stenosis.
Hepatectomy can effect a cure.
Mesenchymal and neural tumors: This category
includes lipomas, myolipomas, angiomyolipomas,
schwannomas, neurofibromas and chondromas.
Inflammatory pseudotumor: This is a rare, benign
inflammatory condition of middle-aged men. Patients
might present fever, weight loss, leukocytosis and
elevated ESR. If the diagnosis can be made on biopsy,
there should be no need for resection; rather the primary
source should be treated[81].
Pseudo-lesions: A pseudo-lesion is a non-diseased
area of different signal intensity, attributable to
focal alteration in hemodynamics or parenchymal
metabolism[82]. Pseudo-lesions seen in cirrhotic and non-
cirrhotic livers include arterio-portal shunts, regenerating
nodules, confluent fibrosis, and abnormal blood inflow.
Malignant lesions
Liver metastasis: The liver is the most common site
of metastasis from the gastrointestinal tract, pancreas,
breast, and lung[41]. Multiple defects in the liver imaging
suggest a metastatic process. Only 20% of liver
metastases present as solitary lesions. Generally, both
hepatic lobes are involved. On CT-scan, colorectal
metastases appear as low attenuation lesions, often with
irregular margins and necrotic centres[14]. During the
early vascular phase of dynamic CT, metastasis appears
with increased enhancement. The sensitivity of CT
(85%) can be augmented by CT arterial portography[83].
Intraoperative US has excellent sensitivity and specificity
for colorectal adenocarcinoma metastasis[84]. The most
promising imaging modality is PET CT with FDG that
accumulates in cells with hypermetabolism. Colon, lung
and breast cancers can be staged with PET CT with
sensitivity of 92%-100% and specificity of 85%-100%[85].
The hypervascularity of neuroendocrine tumors is
often evident on dynamic CT[86]. Somatostatin receptor 3222 ISSN 1007-9327 CN 14-1219/R World J Gastroenterol July 14, 2009 Volume 15 Number 26

www.wjgnet.comscintigraphy can localize 90% of neuroendocrine tumors
(gastrinoma)[87].
In metastatic colorectal carcinoma, the prognosis is
improved following surgical resection. Contraindications
to resection include: N > 4 liver metastases, extrahepatic
spread and involvement of hepatic lymph nodes.
Metastatic liver tumors that might calcify include colon,
leiomyosarcoma, osteogenic sarcoma, rhabdomyosarcoma,
chondrosarcoma, ovarian cystadenocarcinoma, melanoma,
pleural mesothelioma, neuroblastoma, and testis tumors.
Calcified metastases from stomach, pancreas, lung and
breast to the liver are extremely rare. Guided FNA will
help identify the primary lesion[88].
HCC (see previous section on HCC): Almost all
patients with HCV related HCC have cirrhosis, whereas
patients with HCC related to HBV are less likely to have
cirrhosis. The absence of cirrhosis makes this tumor
more amenable to surgical resection[34].
Fibrolamellar carcinoma: The fibrolamellar variant
is a distinctive subtype of HCC but is not associated
with classic risk factors for HCC. It occurs at a mean
age of 26 years, presenting as a large, solitary painful
mass usually located in the left lobe. The AFP level is
normal[89]. The term “fibrolamellar ” characterizes the
microscopic appearance of the lesion: thin layers of
fibrosis separate the neoplastic hepatocytes[90]. A fibrous
central scar may be seen on imaging studies[91]. 50% of
lesions are resectable at the time of diagnosis[90].
Intrahepatic cholangiocarcinoma: Cholangio –
carcinoma accounts for 20% of primary liver tumors
and arises as adenocarcinoma or papillary or mucinous
carcinomas[92]. Risk factors include cirrhosis, primary
sclerosing cholangitis (PSC, 10%), bile duct adenoma,
choledochal cysts, biliary papillomatosis, Caroli’s disease,
and liver fluke[93-95]. Jaundice is the most common clinical
presentation[96], and rapidly increasing bilirubin associated
with weight loss predicts cholangiocarcinoma. Tumor
markers CEA, CA-19-9 or AFP might be elevated. CA
19-9 level > 100 has 89% sensitivity and 86% specificity[97].
There are three anatomic subtypes: Peripheral intrahepatic
15%, perihilar central (Klatskin tumor) 60%, and distal
common bile duct 25%. Peripheral cholangiocarcinoma
resembles HCC without cirrhosis. The central hilar
and distal types are associated to sclerosing cholangitis,
inflammatory bowel disease, or other chronic biliary
disease. US and CT show marked intrahepatic duct
dilatation[98]. An abrupt change in the calibre of the bile
duct suggests malignancy[99]. Digital image analysis and
fluorescent in situ hybridization are more sensitive than
routine standard brush cytology in the diagnosis of
cholangiocarcinoma. ERCP, percutaneous transhepatic
cholangiography (PTC) and magnetic resonance
cholangiopancreatography (MRCP) assess the resectability
of the tumor.
PET CT stages these tumors with a sensitivity of
93%. The suggested screening includes US, CEA and CA
19-9 every six months, ERCP and brush cytology if there is biliary stenosis. Combined HCC-cholangiocarcinoma
shows features of both hepatocellular and biliary epithelial
differentiation[100].
Epithelioid hemangioendothelioma: This low-grade
malignancy affects individuals between 20-80 years of
age. It is associated with oral contraception and exposure
to polyvinyl[101]. Epithelioid hemangioendothelioma
presents with abdominal pain, hepatomegaly, low fever
and normal liver enzymes. Endothelial cells stain for
CD34, CD31 and factor Ⅷ. The prognosis is good with
surgical resection or liver transplantation[102,103].
Cystadenocarcinoma: Usually in the right lobe,
cystadenocarcinoma is multicystic and contains bile-
stained material. It presents as abdominal pain with
weight loss[104] and prognosis is good[105].
Lymphomas and leukemia: Liver involvement is
common in Hodgkin’s disease including lymphoma
infiltration (diffuse small nodules or large masses), drugs,
viral hepatitis, and sepsis. Cholestasis is uncommon and
vanishing bile duct syndrome has been described[106].
The differential diagnosis includes reactive infiltrate and
T-cell lymphomas.
Primary hepatic lymphoma is rare and can present
as solitary or multiple masses, as a diffuse hepatic
involvement with hepatomegaly, or as hepatic failure
with elevated LDH[107]. Peripheral gamma delta T cell
lymphomas with massive hepatic sinusoidal infiltration
and splenic involvement have also been described[108].
The liver might be diffusely or locally infiltrated by
multiple myelomas or leukemia (chronic lymphoid
leukemia, hairy cell leukemia)[109-113].
Neuroendocrine tumors: Neuroendocrine tumors
originating in the gastrointestinal tract frequently
metastasize to the liver[114]. Liver metastases can be
resected[115]. Traditional chemotherapy is not effective.
α-interferon has been associated with tumor response. The
use of somatostatin analogs in the carcinoid syndrome
improves symptoms. Liver transplant remains an option[116].
Angiosarcoma: Angiosarcoma is associated with
exposure to vinyl chloride[117]. Most patients are not
amenable to surgery. Usually both hepatic lobes
are involved and rapid tumor growth and tendency
to metastasize contribute to its dismal prognosis.
Chemotherapy and radiotherapy have no role, and ligation
of the hepatic artery might permit palliation.
Undifferentiated sarcoma of the liver: This rare
tumor mainly affects children. The clinical features are
fever and a liver mass with recurrent hypoglycemia. The
median survival is two months. Imaging shows a solid
and cystic lesion with multiple loculi[118].
Other mesenchymal cell malignancies: Rhabdomyo-
sarcoma is the most common tumor of the biliary tree
in young children. The tumor can mimic a choledocal Assy N et al. Diagnosis of solid liver mass 3223

www.wjgnet.comcyst[119].
Fibrosarcoma presents as a hepatic mass with
recurrent hypoglycemia that will resolve after resection.
Serum IGF-2 is elevated[120] and Leiomyosarcoma
presents with general deterioration and right upper
quadrant pain. Angiograms or CT-angiography show a
hypervascular tumor. Liver transplantation is possible[121].
LIVER BIOPSY VERSUS LIVER MASS
RESECTION
Before hepatic resection, lesions should be measured,
counted and localized to the Couinaud segments.
Their relationship to major anatomical structures
(portal vein, hepatic artery, inferior vena cava, and
hepatic vein) should be detailed[122-125]. If malignancy is
obvious, biopsy should be avoided because of possible
dissemination[30,44,126]. Liver histology by true cut needle
biopsy is much more profitable than fine needle aspiration
and cytological examination but has several disadvantages.
If the tumor is small (< 3 cm), a second attempt should
be made in 20% of cases[127], bleeding is mild in 1% and
severe in 0.1%. In 10% of cases, a firm diagnosis is not
established and resection should be performed.
The Child Pugh score helps select which patients
should undergo hepatic resection[128]. Survival depends
on the regenerative potential and the presence of
cirrhosis[129]. Traditionally, cirrhosis is a contraindication
to hepatic resection because of the high mortality rate
(20%). A dilemma arises when patients with cirrhosis
require a hepatic resection. The problem is that
10%-20% of patients with cirrhosis have primary hepatic
malignancy. Moreover, 80%-90% of patients with HCC
and 10%-20% of patients with cholangiocarcinoma have
cirrhosis. The operative mortality of extensive hepatic
resection in patients without cirrhosis is 10%[130].
Treatment modalities include radiofrequency ablation
(RFA), percutaneous ethanol injection, cryoablation,
hepatic arterial chemoembolisation (TACE), and
laparoscopic liver resection. Patients with compensated
cirrhosis might benefit from liver resection, RFA or
TACE, but patients with decompensated cirrhosis would
probably experience no survival benefit[131]. In highly
selected patients with incidental, central or multifocal
tumors, hepatic transplantation might be more beneficial.
CONCLUSION
In the diagnostic strategy of liver masses, two scenarios are
examined: (1) incidentally discovered solid lesions or masses
in a cirrhotic patient. The most likely diagnosis is HCC,
followed by high and low-grade dysplastic nodule. Lesions >
2 cm are diagnosed by imaging techniques, lesions of 1-2 cm
require histology if imaging modalities are atypical, and
lesions < 1 cm require US follow-up every three months;
(2) incidentally discovered solid lesions or masses in a non
cirrhotic patient. The most prevalent lesion is hemangioma.
FNH and adenoma should be ruled out in young women
with contraceptive treatment. If the lesion is found at staging or follow up of a known primary malignancy,
histology is required when the lesion is doubtful. The most
common liver metastases are from adenocarcinoma of
colon, stomach, lung, prostate, or breast.
REFERENCES
1 Giannitrapani L , Soresi M, La Spada E, Cervello M,
D'Alessandro N, Montalto G. Sex hormones and risk of liver
tumor. Ann N Y Acad Sci 2006; 1089 : 228-236
2 Dogliotti E . Molecular mechanisms of carcinogenesis by
vinyl chloride. Ann Ist Super Sanita 2006; 42: 163-169
3 Shaib Y , El-Serag HB. The epidemiology of cholangio –
carcinoma. Semin Liver Dis 2004; 24: 115-125
4 Borentain P , Gérolami R, Dodero F, Chrestian MA,
Quillichini F, Ardissone J, Perrimond H, Chamlian A,
Gérolami A. [High serum alkaline phosphatase level
revealing a liver adenoma] Gastroenterol Clin Biol 2006; 30:
304-306
5 Coakley FV , Schwartz LH. Imaging of hepatocellular
carcinoma: a practical approach. Semin Oncol 2001; 28:
460-473
6 Karhunen PJ , Penttilä A, Liesto K, Männikkö A, Möttönen
MM. Occurrence of benign hepatocellular tumors in
alcoholic men. Acta Pathol Microbiol Immunol Scand A 1986;
94: 141-147
7 Hussain SM , Semelka RC. Liver masses. Magn Reson
Imaging Clin N Am 2005; 13: 255-275
8 Seitz G . [Why are metastases in cirrhotic livers so rare?]
Ultraschall Med 1989; 10: 123-126
9 Hussain SM , Terkivatan T, Zondervan PE, Lanjouw
E, de Rave S, Ijzermans JN, de Man RA. Focal nodular
hyperplasia: findings at state-of-the-art MR imaging, US,
CT, and pathologic analysis. Radiographics 2004; 24: 3-17;
discussion 18-19
10 Okuda K . Early recognition of hepatocellular carcinoma.
Hepatology 1986; 6: 729-738
11 Sherman M . Alphafetoprotein: an obituary. J Hepatol 2001;
34: 603-605
12 R a m a g e J K , D o n a g h y A , F a r r a n t J M , I o r n s R ,
Williams R. Serum tumor markers for the diagnosis of
cholangiocarcinoma in primary sclerosing cholangitis.
Gastroenterology 1995; 108: 865-869
13 Caturelli E , Solmi L, Anti M, Fusilli S, Roselli P, Andriulli
A, Fornari F, Del Vecchio Blanco C, de Sio I. Ultrasound
guided fine needle biopsy of early hepatocellular carcinoma
complicating liver cirrhosis: a multicentre study. Gut 2004;
53: 1356-1362
14 Tsao JI , DeSanctis J, Rossi RL, Oberfield RA. Hepatic
malignancies. Surg Clin North Am 2000; 80: 603-632
15 Balci NC , Befeler AS, Leiva P, Pilgram TK, Havlioglu N.
Imaging of liver disease: comparison between quadruple-
phase multidetector computed tomography and magnetic
resonance imaging. J Gastroenterol Hepatol 2008; 23:
1520-1527
16 Murakami T , Oi H, Hori M, Kim T, Takahashi S, Tomoda
K, Narumi Y, Nakamura H. Helical CT during arterial
portography and hepatic arteriography for detecting
hypervascular hepatocellular carcinoma. AJR Am J
Roentgenol 1997; 169: 131-135
17 Hori M , Murakami T, Kim T, Takahashi S, Oi H, Tomoda
K, Narumi Y, Nakamura H. Sensitivity of double-phase
helical CT during arterial portography for detection of
hypervascular hepatocellular carcinoma. J Comput Assist
Tomogr 1998; 22: 861-867
18 van Kouwen MC , Oyen WJ, Nagengast FM, Jansen
JB, Drenth JP. FDG-PET scanning in the diagnosis of
gastrointestinal cancers. Scand J Gastroenterol Suppl 2004; 85-92
19 Kinnard MF , Alavi A, Rubin RA, Lichtenstein GR. Nuclear
imaging of solid hepatic masses. Semin Roentgenol 1995; 30:
375-3953224 ISSN 1007-9327 CN 14-1219/R World J Gastroenterol July 14, 2009 Volume 15 Number 26

www.wjgnet.com20 Martínez-Lázaro R , Domínguez P, Pascau J, Bittini
A, Lafuente J, Desco M. Usefulness of Tc-99m RBC
SPECT/MRI fusion imaging in small suspected hepatic
hemangiomas. Clin Nucl Med 2004; 29: 844-845
21 Kanematsu M , Hoshi H, Yamada T, Murakami T, Kim
T, Kato M, Yokoyama R, Nakamura H. Small hepatic
nodules in cirrhosis: ultrasonographic, CT, and MR imaging
findings. Abdom Imaging 1999; 24: 47-55
22 Gandhi SN , Brown MA, Wong JG, Aguirre DA, Sirlin CB.
MR contrast agents for liver imaging: what, when, how.
Radiographics 2006; 26: 1621-1636
23 Solbiati L , Tonolini M, Cova L, Goldberg SN. The role of
contrast-enhanced ultrasound in the detection of focal liver
leasions. Eur Radiol 2001; 11 Suppl 3: E15-E26
24 Torzilli G , Makuuchi M, Ferrero A, Takayama T, Hui AM,
Abe H, Inoue K, Nakahara K. Accuracy of the preoperative
determination of tumor markers in the differentiation of
liver mass lesions in surgical patients. Hepatogastroenterology
2002; 49: 740-745
25 França AV , Valério HM, Trevisan M, Escanhoela C, Sevá-
Pereira T, Zucoloto S, Martinelli A, Soares EC. Fine needle
aspiration biopsy for improving the diagnostic accuracy of
cut needle biopsy of focal liver lesions. Acta Cytol 2003; 47:
332-336
26 Borzio M , Borzio F, Macchi R, Croce AM, Bruno S, Ferrari A,
Servida E. The evaluation of fine-needle procedures for the
diagnosis of focal liver lesions in cirrhosis. J Hepatol 1994; 20:
117-121
27 Buscarini L , Fornari F, Bolondi L, Colombo P, Livraghi T,
Magnolfi F, Rapaccini GL, Salmi A. Ultrasound-guided fine-
needle biopsy of focal liver lesions: techniques, diagnostic
accuracy and complications. A retrospective study on 2091
biopsies. J Hepatol 1990; 11: 344-348
28 Chawla YK , Ramesh GN, Kaur U, Bambery P, Dilawari JB.
Percutaneous liver biopsy: a safe outpatient procedure. J
Gastroenterol Hepatol 1990; 5: 94-95
29 Fornari F , Civardi G, Cavanna L, Di Stasi M, Rossi S, Sbolli
G, Buscarini L. Complications of ultrasonically guided fine-
needle abdominal biopsy. Results of a multicenter Italian
study and review of the literature. The Cooperative Italian
Study Group. Scand J Gastroenterol 1989; 24: 949-955
30 Smith EH . Complications of percutaneous abdominal fine-
needle biopsy. Review. Radiology 1991; 178: 253-258
31 Edoute Y , Malberger E, Tibon-Fishe O, Assy N. Non-
imaging-guided fine-needle aspiration of liver lesions: a
retrospective study of 279 patients. World J Gastroenterol
1999; 5: 98-102
32 Cohen MB , Haber MM, Holly EA, Ahn DK, Bottles K,
Stoloff AC. Cytologic criteria to distinguish hepatocellular
carcinoma from nonneoplastic liver. Am J Clin Pathol 1991;
95: 125-130
33 Durand F , Regimbeau JM, Belghiti J, Sauvanet A, Vilgrain
V, Terris B, Moutardier V, Farges O, Valla D. Assessment of
the benefits and risks of percutaneous biopsy before surgical
resection of hepatocellular carcinoma. J Hepatol 2001; 35:
254-258
34 Ryder SD . Guidelines for the diagnosis and treatment of
hepatocellular carcinoma (HCC) in adults. Gut 2003; 52
Suppl 3: iii1-iii8
35 Caturelli E , Biasini E, Bartolucci F, Facciorusso D,
Decembrino F, Attino V, Bisceglia M. Diagnosis of
hepatocellular carcinoma complicating liver cirrhosis: utility
of repeat ultrasound-guided biopsy after unsuccessful first
sampling. Cardiovasc Intervent Radiol 2002; 25: 295-299
36 Torzilli G , Minagawa M, Takayama T, Inoue K, Hui AM,
Kubota K, Ohtomo K, Makuuchi M. Accurate preoperative
evaluation of liver mass lesions without fine-needle biopsy.
Hepatology 1999; 30: 889-893
37 Bruix J , Sherman M, Llovet JM, Beaugrand M, Lencioni
R, Burroughs AK, Christensen E, Pagliaro L, Colombo M,
Rodés J. Clinical management of hepatocellular carcinoma.
Conclusions of the Barcelona-2000 EASL conference. European Association for the Study of the Liver. J Hepatol
2001; 35: 421-430
38 Rapaccini GL , Pompili M, Caturelli E, Anti M, Aliotta
A, Cedrone A, Amadei E, Grattagliano A, Squillante
MM, Rabitti C. Focal ultrasound lesions in liver cirrhosis
diagnosed as regenerating nodules by fine-needle biopsy.
Follow-up of 12 cases. Dig Dis Sci 1990; 35: 422-427
39 Cedrone A , Covino M, Caturelli E, Pompili M, Lorenzelli G,
Villani MR, Valle D, Sperandeo M, Rapaccini GL, Gasbarrini
G. Utility of alpha-fetoprotein (AFP) in the screening of
patients with virus-related chronic liver disease: does
different viral etiology influence AFP levels in HCC? A
study in 350 western patients. Hepatogastroenterology 2000;
47: 1654-1658
40 Sherman M . Screening for hepatocellular carcinoma.
Hepatol Res 2007; 37 Suppl 2: S152-S165
41 El-Serag HB , Mason AC. Rising incidence of hepatocellular
carcinoma in the United States. N Engl J Med 1999; 340:
745-750
42 Barbara L , Benzi G, Gaiani S, Fusconi F, Zironi G, Siringo S,
Rigamonti A, Barbara C, Grigioni W, Mazziotti A. Natural
history of small untreated hepatocellular carcinoma in
cirrhosis: a multivariate analysis of prognostic factors of
tumor growth rate and patient survival. Hepatology 1992; 16:
132-137
43 Simonetti RG , Cammà C, Fiorello F, Politi F, D'Amico
G, Pagliaro L. Hepatocellular carcinoma. A worldwide
problem and the major risk factors. Dig Dis Sci 1991; 36:
962-972
44 Souto E , Gores GJ. When should a liver mass suspected of
being a hepatocellular carcinoma be biopsied? Liver Transpl
2000; 6: 73-75
45 Mor E , Kaspa RT, Sheiner P, Schwartz M. Treatment of
hepatocellular carcinoma associated with cirrhosis in the era
of liver transplantation. Ann Intern Med 1998; 129: 643-653
46 Reddy KR , Schiff ER. Approach to a liver mass. Semin Liver
Dis 1993; 13: 423-435
47 Bolondi L , Sofia S, Siringo S, Gaiani S, Casali A, Zironi
G, Piscaglia F, Gramantieri L, Zanetti M, Sherman M.
Surveillance programme of cirrhotic patients for early
diagnosis and treatment of hepatocellular carcinoma: a cost
effectiveness analysis. Gut 2001; 48: 251-259
48 Peng YC , Chan CS, Chen GH. The effectiveness of serum
alpha-fetoprotein level in anti-HCV positive patients for
screening hepatocellular carcinoma. Hepatogastroenterology
1999; 46: 3208-3211
49 Nakashima T , Kojiro M. Pathologic characteristics of
hepatocellular carcinoma. Semin Liver Dis 1986; 6: 259-266
50 Terminology of nodular hepatocellular lesions. International
Working Party. Hepatology 1995; 22: 983-993
51 Hussain SM , Zondervan PE, IJzermans JN, Schalm SW,
de Man RA, Krestin GP. Benign versus malignant hepatic
nodules: MR imaging findings with pathologic correlation.
Radiographics 2002; 22: 1023-1036; discussion 1037-1039
52 Craig JR . Fibrolamellar carcinoma: Clinical and pathologic
features. In: Okuda K, Tabor E, eds. Liver Cancer. New
York: Churchill Livingstone, 1997: 255-262
53 Melato M , Laurino L, Mucli E, Valente M, Okuda K.
Relationship between cirrhosis, liver cancer, and hepatic
metastases. An autopsy study. Cancer 1989; 64: 455-459
54 Johnson PJ . Role of alpha-fetoprotein in the diagnosis and
management of hepatocellular carcinoma. J Gastroenterol
Hepatol 1999; 14 Suppl: S32-S36
55 Wilson SR . Imaging of benign hepatic lesions. In: Freeny
PC, ed. Radiology of the liver, biliary tree and pancreas.
Reston: American Roentgen Ray Society, 1996: 17-25
56 Takagi H . Diagnosis and management of cavernous
hemangioma of the liver. Semin Surg Oncol 1985; 1: 12-22
57 Cherqui D , Rahmouni A, Charlotte F, Boulahdour H,
Métreau JM, Meignan M, Fagniez PL, Zafrani ES, Mathieu
D, Dhumeaux D. Management of focal nodular hyperplasia
and hepatocellular adenoma in young women: a series Assy N et al. Diagnosis of solid liver mass 3225

www.wjgnet.comof 41 patients with clinical, radiological, and pathological
correlations. Hepatology 1995; 22: 1674-1681
58 Trastek VF , van Heerden JA, Sheedy PF 2nd, Adson MA.
Cavernous hemangiomas of the liver: resect or observe? Am
J Surg 1983; 145: 49-53
59 Stark DD , Felder RC, Wittenberg J, Saini S, Butch RJ, White
ME, Edelman RR, Mueller PR, Simeone JF, Cohen AM.
Magnetic resonance imaging of cavernous hemangioma
of the liver: tissue-specific characterization. AJR Am J
Roentgenol 1985; 145: 213-222
60 Sigal R , Lanir A, Atlan H, Naschitz JE, Simon JS, Enat R,
Front D, Israel O, Chisin R, Krausz Y. Nuclear magnetic
resonance imaging of liver hemangiomas. J Nucl Med 1985;
26: 1117-1122
61 Sewell JH , Weiss K. Spontaneous rupture of hemangioma
of the liver. A review of the literature and presentation of
illustrative case. Arch Surg 1961; 83: 729-733
62 Yamamoto M , Ariizumi S, Yoshitoshi K, Saito A, Nakano
M, Takasaki K. Hepatocellular carcinoma with a central scar
and a scalloped tumor margin resembling focal nodular
hyperplasia in macroscopic appearance. J Surg Oncol 2006;
94: 587-591
63 Lizardi-Cervera J , Cuéllar-Gamboa L, Motola-Kuba D.
Focal nodular hyperplasia and hepatic adenoma: a review.
Ann Hepatol 2006; 5: 206-211
64 Rogers JV , Mack LA, Freeny PC, Johnson ML, Sones PJ.
Hepatic focal nodular hyperplasia: angiography, CT,
sonography, and scintigraphy. AJR Am J Roentgenol 1981;
137: 983-990
65 Rabe T , Feldmann K, Grunwald K, Runnebaum B. Liver
tumours in women on oral contraceptives. Lancet 1994; 344:
1568-1569
66 Labrune P , Trioche P, Duvaltier I, Chevalier P, Odièvre M.
Hepatocellular adenomas in glycogen storage disease type I
and III: a series of 43 patients and review of the literature. J
Pediatr Gastroenterol Nutr 1997; 24: 276-279
67 Grazioli L , Federle MP, Brancatelli G, Ichikawa T, Olivetti
L, Blachar A. Hepatic adenomas: imaging and pathologic
findings. Radiographics 2001; 21: 877-892; discussion 892-894
68 Erdogan D , Busch OR, van Delden OM, Ten Kate FJ,
Gouma DJ, van Gulik TM. Management of spontaneous
haemorrhage and rupture of hepatocellular adenomas. A
single centre experience. Liver Int 2006; 26: 433-438
69 Mathieu D , Bruneton JN, Drouillard J, Pointreau CC,
Vasile N. Hepatic adenomas and focal nodular hyperplasia:
dynamic CT study. Radiology 1986; 160: 53-58
70 Kume N , Suga K, Nishigauchi K, Shimizu K, Matsunaga
N. Characterization of hepatic adenoma with atypical
appearance on CT and MRI by radionuclide imaging. Clin
Nucl Med 1997; 22: 825-831
71 Colli A , Fraquelli M, Massironi S, Colucci A, Paggi S, Conte
D. Elective surgery for benign liver tumours. Cochrane
Database Syst Rev 2007; CD005164
72 Kerlin P , Davis GL, McGill DB, Weiland LH, Adson
MA, Sheedy PF 2nd. Hepatic adenoma and focal nodular
hyperplasia: clinical, pathologic, and radiologic features.
Gastroenterology 1983; 84: 994-1002
73 D e m a r c o M P , S h e n P , B r a d l e y R F , L e v i n e E A .
Intraperitoneal hemorrhage in a patient with hepatic focal
nodular hyperplasia. Am Surg 2006; 72: 555-559
74 Al-Mukhaizeem KA , Rosenberg A, Sherker AH. Nodular
regenerative hyperplasia of the liver: an under-recognized
cause of portal hypertension in hematological disorders. Am
J Hematol 2004; 75: 225-230
75 Trenschel GM , Schubert A, Dries V, Benz-Bohm G.
Nodular regenerative hyperplasia of the liver: case report of
a 13-year-old girl and review of the literature. Pediatr Radiol
2000; 30: 64-68
76 Tanaka M , Wanless IR. Pathology of the liver in Budd-
Chiari syndrome: portal vein thrombosis and the
histogenesis of veno-centric cirrhosis, veno-portal cirrhosis,
and large regenerative nodules. Hepatology 1998; 27: 488-49677 Perlemuter G , Bigorgne A, Cassard-Doulcier AM, Naveau
S. Nonalcoholic fatty liver disease: from pathogenesis to
patient care. Nat Clin Pract Endocrinol Metab 2007; 3: 458-469
78 Karcaaltincaba M , Akhan O. Imaging of hepatic steatosis
and fatty sparing. Eur J Radiol 2007; 61: 33-43
79 Wheeler DA , Edmondson HA. Cystadenoma with
mesenchymal stroma (CMS) in the liver and bile ducts.
A clinicopathologic study of 17 cases, 4 with malignant
change. Cancer 1985; 56: 1434-1445
80 L a m C M , Y u e n S T , Y u e n W K , F a n S T . B i l i a r y
papillomatosis. Br J Surg 1996; 83: 1715-1716
81 C o f f i n C M , W a t t e r s o n J , P r i e s t J R , D e h n e r L P .
Extrapulmonary inflammatory myofibroblastic tumor
(inflammatory pseudotumor). A clinicopathologic and
immunohistochemical study of 84 cases. Am J Surg Pathol
1995; 19: 859-872
82 Tamura S , Kihara Y, Yuki Y, Sugimura H, Shimizu T, Adjei
ON, Watanabe K. Pseudo lesions on CTAP secondary to
arterio-portal shunts. Clin Imaging 1997; 21: 359-365
83 Schwartz L , Brody L, Brown K, Covey A, Tuorto S,
Mazumdar M, Riedel E, Jarnagin W, Getrajdman G, Fong
Y. Prospective, blinded comparison of helical CT and CT
arterial portography in the assessment of hepatic metastasis
from colorectal carcinoma. World J Surg 2006; 30: 1892-1899;
discussion 1900-1901
84 Leen E , Ceccotti P, Moug SJ, Glen P, MacQuarrie J,
Angerson WJ, Albrecht T, Hohmann J, Oldenburg A,
Ritz JP, Horgan PG. Potential value of contrast-enhanced
intraoperative ultrasonography during partial hepatectomy
for metastases: an essential investigation before resection?
Ann Surg 2006; 243: 236-240
85 Nagaoka S , Itano S, Ishibashi M, Torimura T, Baba K,
Akiyoshi J, Kurogi J, Matsugaki S, Inoue K, Tajiri N, Takada
A, Ando E, Kuromatsu R, Kaida H, Kurogi M, Koga H,
Kumashiro R, Hayabuchi N, Kojiro M, Sata M. Value of
fusing PET plus CT images in hepatocellular carcinoma and
combined hepatocellular and cholangiocarcinoma patients
with extrahepatic metastases: preliminary findings. Liver Int
2006; 26: 781-788
86 Schillaci O . Somatostatin receptor imaging in patients with
neuroendocrine tumors: not only SPECT? J Nucl Med 2007;
48: 498-500
87 Seemann MD , Meisetschlaeger G, Gaa J, Rummeny EJ.
Assessment of the extent of metastases of gastrointestinal
carcinoid tumors using whole-body PET, CT, MRI, PET/CT
and PET/MRI. Eur J Med Res 2006; 11: 58-65
88 Wee A . Fine needle aspiration biopsy of the liver:
Algorithmic approach and current issues in the diagnosis of
hepatocellular carcinoma. Cytojournal 2005; 2: 7
89 Soreide O , Czerniak A, Bradpiece H, Bloom S, Blumgart L.
Characteristics of fibrolamellar hepatocellular carcinoma. A
study of nine cases and a review of the literature. Am J Surg
1986; 151: 518-523
90 C r a i g J R , P e t e r s R L , E d m o n d s o n H A , O m a t a M .
Fibrolamellar carcinoma of the liver: a tumor of adolescents
and young adults with distinctive clinico-pathologic
features. Cancer 1980; 46: 372-379
91 Brandt DJ , Johnson CD, Stephens DH, Weiland LH.
Imaging of fibrolamellar hepatocellular carcinoma. AJR Am
J Roentgenol 1988; 151: 295-299
92 Landis SH , Murray T, Bolden S, Wingo PA. Cancer
statistics, 1998. CA Cancer J Clin 1998; 48: 6-29
93 Callea F , Sergi C, Fabbretti G, Brisigotti M, Cozzutto C,
Medicina D. Precancerous lesions of the biliary tree. J Surg
Oncol Suppl 1993; 3: 131-133
94 Watanapa P . Cholangiocarcinoma in patients with
opisthorchiasis. Br J Surg 1996; 83: 1062-1064
95 Shin HR , Lee CU, Park HJ, Seol SY, Chung JM, Choi HC,
Ahn YO, Shigemastu T. Hepatitis B and C virus, Clonorchis
sinensis for the risk of liver cancer: a case-control study in
Pusan, Korea. Int J Epidemiol 1996; 25: 933-940
96 Suzuki M , Takahashi T, Ouchi K, Matsuno S. The 3226 ISSN 1007-9327 CN 14-1219/R World J Gastroenterol July 14, 2009 Volume 15 Number 26

www.wjgnet.comdevelopment and extension of hepatohilar bile duct
carcinoma. A three-dimensional tumor mapping in the
intrahepatic biliary tree visualized with the aid of a graphics
computer system. Cancer 1989; 64: 658-666
97 Nichols JC , Gores GJ, LaRusso NF, Wiesner RH, Nagorney
DM, Ritts RE Jr. Diagnostic role of serum CA 19-9 for
cholangiocarcinoma in patients with primary sclerosing
cholangitis. Mayo Clin Proc 1993; 68: 874-879
98 Nesbit GM , Johnson CD, James EM, MacCarty RL,
Nagorney DM, Bender CE. Cholangiocarcinoma: diagnosis
and evaluation of resectability by CT and sonography as
procedures complementary to cholangiography. AJR Am J
Roentgenol 1988; 151: 933-938
99 Tillich M , Mischinger HJ, Preisegger KH, Rabl H, Szolar
DH. Multiphasic helical CT in diagnosis and staging of hilar
cholangiocarcinoma. AJR Am J Roentgenol 1998; 171: 651-658
100 Dunk AA , Spiliadis H, Sherlock S, Fowler MJ, Monjardino
JP, Scheuer PJ, Thomas HC. Hepatocellular carcinoma:
clinical, aetiological and pathological features in British
patients. Int J Cancer 1988; 41: 17-23
101 Dean PJ , Haggitt RC, O'Hara CJ. Malignant epithelioid
hemangioendothelioma of the liver in young women.
Relationship to oral contraceptive use. Am J Surg Pathol
1985; 9: 695-704
102 Ashraf S , Ashraf HM, Mamoon N, Luqman M. Epithelioid
hemangioendothelioma of the liver. J Coll Physicians Surg
Pak 2007; 17: 280-282
103 Bufton S , Haydon G, Neil D. Liver transplantation for
hepatic epithelioid hemangioendothelioma: a case series.
Prog Transplant 2007; 17: 70-72
104 Teoh AY , Ng SS, Lee KF, Lai PB. Biliary cystadenoma and
other complicated cystic lesions of the liver: diagnostic and
therapeutic challenges. World J Surg 2006; 30: 1560-1566
105 Hai S , Hirohashi K, Uenishi T, Yamamoto T, Shuto
T, Tanaka H, Kubo S, Tanaka S, Kinoshita H. Surgical
management of cystic hepatic neoplasms. J Gastroenterol
2003; 38: 759-764
106 Schmitt A , Gilden DJ, Saint S, Moseley RH. Clinical
problem-solving. Empirically incorrect. N Engl J Med 2006;
354: 509-514
107 Zornoza J , Ginaldi S. Computed tomography in hepatic
lymphoma. Radiology 1981; 138: 405-410
108 Belhadj K , Reyes F, Farcet JP, Tilly H, Bastard C, Angonin R,
Deconinck E, Charlotte F, Leblond V, Labouyrie E, Lederlin
P, Emile JF, Delmas-Marsalet B, Arnulf B, Zafrani ES,
Gaulard P. Hepatosplenic gammadelta T-cell lymphoma is
a rare clinicopathologic entity with poor outcome: report on
a series of 21 patients. Blood 2003; 102: 4261-4269
109 Kuroda N , Mizobuchi M, Shimamura Y, Daibata M,
Miyoshi I, Ohara M, Hirouchi T, Mizuno K, Lee GH.
Bridging necrosis and reticulin bridging fibrosis induced by
intrahepatic involvement of acute biphenotypic leukemia.
APMIS 2006; 114: 908-911
110 Dellon ES , Morris SR, Tang W, Dunphy CH, Russo MW.
Acute liver failure due to natural killer-like T-cell leukemia/
lymphoma: a case report and review of the literature. World
J Gastroenterol 2006; 12: 4089-4092
111 Powell N , Rusli F, Hubscher SG, Karanth M, Mutimer D.
Adult T-cell leukemia presenting with acute liver failure.
Leuk Res 2006; 30: 1315-1317
112 Ando K , Miyazawa K, Kuriyama Y, Kimura Y, Mukai K,
Ohyashiki K. Hemophagocytic syndrome associated with
CD8 positive T-cell chronic lymphocytic leukemia. Leuk
Lymphoma 2004; 45: 193-198
113 Kraut EH . Clinical manifestations and infectious complications of hairy-cell leukaemia. Best Pract Res Clin
Haematol 2003; 16: 33-40
114 Shah NA , Urusova IA, D'Agnolo A, Colquhoun SD,
Rosenbloom BE, Vener SL, Geller SA, Younes M, Lechago J,
Heaney AP. Primary hepatic carcinoid tumor presenting as
Cushing's syndrome. J Endocrinol Invest 2007; 30: 327-333
115 Garrot C , Stuart K. Liver-directed therapies for metastatic
neuroendocrine tumors. Hematol Oncol Clin North Am 2007;
21: 545-560; ix-x
116 Kulke M . Advances in the treatment of neuroendocrine
tumors. Curr Treat Options Oncol 2005; 6: 397-409
117 Locker GY , Doroshow JH, Zwelling LA, Chabner BA.
The clinical features of hepatic angiosarcoma: a report of
four cases and a review of the English literature. Medicine
(Baltimore) 1979; 58: 48-64
118 Lao XM , Chen DY, Zhang YQ, Xiang J, Guo RP, Lin XJ, Li
JQ. Primary carcinosarcoma of the liver: clinicopathologic
features of 5 cases and a review of the literature. Am J Surg
Pathol 2007; 31: 817-826
119 Zampieri N , Camoglio F, Corroppolo M, Cecchetto M,
Ornis S, Ottolenghi A. Botryoid rhabdomyosarcoma of the
biliary tract in children: a unique case report. Eur J Cancer
Care (Engl) 2006; 15: 463-466
120 Chan G , Horton PJ, Thyssen S, Lamarche M, Nahal A,
Hill DJ, Marliss EB, Metrakos P. Malignant transformation
of a solitary fibrous tumor of the liver and intractable
hypoglycemia. J Hepatobiliary Pancreat Surg 2007; 14: 595-599
121 Saint-Paul MC , Gugenheim J, Hofman P, Arpurt JP,
Fabiani P, Michiels JF, Fujita N, Goubeaux B, Loubière R,
Delmont J. [Leiomyosarcoma of the liver: a case treated by
transplantation] Gastroenterol Clin Biol 1993; 17: 218-222
122 Heiken JP . Liver. In: Lee JKT, Sagel SS, Stanley RJ,
Heiken JP, eds. Computed Body Tomography with MRI
Correlation. Philadelphia: Lippincott-Raven, 1998: 701-779
123 Harned RK 2nd , Chezmar JL, Nelson RC. Imaging of
patients with potentially resectable hepatic neoplasms. AJR
Am J Roentgenol 1992; 159: 1191-1194
124 Small WC , Mehard WB, Langmo LS, Dagher AP, Fishman
EK, Heiken JP, Bernardino ME. Preoperative determination
of the resectability of hepatic tumors: efficacy of CT during
arterial portography. AJR Am J Roentgenol 1993; 161: 319-322
125 Heyneman LE , Nelson RC. Modality for imaging liver
tumors. In: Clavien PA, ed. Malignant Liver Tumors:
Current and Emerging Therapies. Malden: Blackwell
Science, 1999: 46-62
126 Takamori R , Wong LL, Dang C, Wong L. Needle-tract
implantation from hepatocellular cancer: is needle biopsy of
the liver always necessary? Liver Transpl 2000; 6: 67-72
127 Francque SM , De Pauw FF, Van den Steen GH, Van Marck
EA, Pelckmans PA, Michielsen PP. Biopsy of focal liver
lesions: guidelines, comparison of techniques and cost-
analysis. Acta Gastroenterol Belg 2003; 66: 160-165
128 Assy N , Pruzansky Y, Gaitini D, Shen Orr Z, Hochberg Z,
Baruch Y. Growth hormone-stimulated IGF-1 generation in
cirrhosis reflects hepatocellular dysfunction. J Hepatol 2008;
49: 34-42
129 Assy N , Hochberg Z, Amit T, Shen-Orr Z, Enat R, Baruch Y.
Growth hormone-stimulated insulin-like growth factor (IGF)
I and IGF-binding protein-3 in liver cirrhosis. J Hepatol 1997;
27: 796-802
130 Bouwman DL , Walt AJ. Current status of resection for
hepatic neoplasms. Semin Liver Dis 1983; 3: 193-202
131 Frezza EE . Therapeutic management algorithm in cirrhotic
and noncirrhotic patients in primary or secondary liver
masses. Dig Dis Sci 2004; 49: 866-871
S- Editor Tian L L- Editor Stewart GJ E- Editor Lin YPAssy N et al. Diagnosis of solid liver mass 3227