clinical management asymptomatic liver mass
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CLINICAL MANAGEMENT
GASTROENTEROLOGY 2006;131:619-623
Loren Laine, Section Editor
AsymptomaticLiverMass
ROBERTS. BROWN, JrDepartment of Medicine and Department of Surgery. Columbia University College of Physicians and Surgeons, Center for Liver Disease andTransplantation. New York-Presbyterian Hospital, New York. New York
Clinical Case
A 52-year-old man with no prior medical prob-lems is referred after a virtual colonoscopy done for
colon cancer screening revealed a 3-cm solid liver
mass. The patient has no prior history of liver disease
and no risk factors for viral hepatitis. Physical exami-
nation by his internist was unremarkable, and com-
plete blood count and liver tests were normal.
Background
Solitary lesions of the liver can have a myriad of
eriologies. Borh cysric and solid lesions can have benign
or malignant neoplasric eriology, in addirion to infec-
rious causes. Sim pie cysrs are rhe mosr common liverlesions, followed by benign neoplasms. Malignant lesions
are usually secondary (ie, metastaric), and infectious eri-
ologies are rare. The 5 most common solid lesions aredescribed in Table 1.
Benign Solid Lesions
In asympromatic individuais wirhour preexisring
liver disease, benign lesions are rhe mosr freguent eriology
of a solirary, solid liver mass. Of these, cavernous heman-
gioma are rhe mosr common wirh a prevalence as high as
20% from auropsy series.! These lesions are benign, can be
multiple in 10% of cases, and reguire no furrher rreatmenr
or follow-up, excepr for giant hemangiomas (defined as >4cm), which may be ar risk of bleeding. There is arare
associarion wirh hemangiomas in alrernare sires including
rhe brain.1 They are more common in women and are
usually discovered in asympromaric individuais undergoingabdominal imaging for other indicarions.
The next mosr common lesion is focal nodular hyper-
plasia (FNH), which has an incidence between 2.5% and8%.2 FNH is usually found in young females bur is not
clearly linked ro oral contraceptives, pregnancy, or fe-male hormones. Thus, some of the female predominance
seen in epidemiologic stUdies may be due to a detection
bias with more women having radiologic imaging, either
52
related to abdominal pain or pregnancy. FNH is a benign
condition that has very few complications and does not
lead to malignant degeneration.
Hepatic adenomas have an incidence of 1 per million
women without a history of oral conrraceptive use and are
increased in prevalence >30-fold with long-term oral con-
traceptives. Adenomas are also associated with androgenicsteroid use in men and various metabolic disorders such as
glycogen storage diseases.' Sporadic adenomas are exceed-
ingly rare. Thus, most of these lesions are seen in youngwomen with a history of oral conrraceptive use.4 Adenomas
carry a risk of both bleeding and rupture, although both of
these complications are rare. The risk may have been over-
stated in the past because the prevalence (ie, the denomi-nator) was not known. Now, with increased early detection,
the prevalence is likely higher than previously believed and
the risk of complications lower. Adenomas do carry a small
risk of malignanr degeneration, estimated at ~ 1% lifetimerisk, bur the rarity of primary hepatocellular carcinoma
(HCC) in patienrs withour preexisting liver disease castsdoubt on that estimate
Malignant Lesions of the Liver
In the absence of pre-existing liver disease or roxic
exposures, secondary liver cancers are more common than
a primary malignant tUmor of the liver. Primary malig-nant disease of the liver is rare in the absence of under-
Iying hepatitis B or cirrhosis. In the presence of under-
Iying cirrhosis, primary HCC is the most common
diagnosis. HCC usually arises in the setting of chronic
hepatitis B (with or without cirrhosis) or cirrhosis sec-
ondary to hepatitis C or hereditary hemochromarosis.Other causes of cirrhosis are less commonly associated
with HCC. The incidence is 1%-5% per year in these
Abbreviations used in this paper: FNH, focal nodular hyperplasia;
HCC. hepatocellular carcinoma; PSC, primary sclerosing cholangitis.<D2006 by the American Gastroenterological Association Institute
0016-5085/06/$32.00
doi:10.1053/j.gastro.2006.06.020
620 ROBERT BROWN
Table 1. Most Common Solitary Lesions of the Liver
Lesion
HemangiomaFocal nodular hyperplasiaAdenomaMetastatic lesion
Hepatocellular carcinoma
GASTROENTEROLOGYVai. 131, No. 2
Male:female
predominanceMalignantpotential
NoNo
YesAli malignantAli malignant
Prevalence/annual incidence
3%-20%/unknown3%-8%/unknown<1%/1-34/million<1%/variable<1%/120-350/million
(1%-5% in patients with risk factors)
F> M (2-6:1)F > M (6-8:1)F» M
Depends on tumorM > F (2-3:1)
high-risk groupS.5 Prognosis is generally poor and re-
lated to the degree of liver impairment, although some
patients will have good results with surgi cal inrerven-
tion, resection, ablation, or transplanration.
Cholangiocarcinoma can arise either sporadically or in
patients with primary sclerosing cholangitis (PSC). Inthe former, patienrs are older, presenr with painless
jaundice, and commonly have lesions presenr at the
bifurcation of the right and left hepatic ducrs (Klatskin
tumors). In patients with PSC, the lesions can be any-
where but are frequently seen in extrahepatic dominanr
strictures. Patienrs typically are found in the first year
after diagnosis of PSC and are jaundiced. The incidence
af cholangiocarcinoma in PSC is < 1% per year and
usually is seen in patienrs with significanr hyperbiliru-
binemia.6 These tumors are slow growing with an ex-
tensive desmoplastic reaction. Diagnosis is based on
characteristic cholangiographic appearance in patienrs
without PSc. Diagnosis is more difficult in the presence
af diffuse strictures because brushing is neither sensitive
nor specific in the presence of chronic infIammation.
Prognosis is related to the degree ofliver impairmenr andwhether the lesion is resectable. Most lesions are not
discovered unril both lobes of the liver are involved,
making resection impossible, and treatment is then pal-
liative. Transplantation is not used widely for cholangio-
carcinoma because of high recurrence rates, although
some early encouraging data have been reported using
neoadjuvanr therapy.7,8 Other primary liver malignancies
are exceedingly rare and are usually vascular or stromal
tumors including epithelioid hemangioendothelioma
and angiosarcoma.
The most common malignanr lesions of the liver in
the general population are metastatic lesions to the liver,
particularly colorectal, lung, pancreas, breast, neuroen-
docrine, and urogenital. The epidemiology and outcomes
of these lesions refIect the primary tumor. Because all of
these lesions represenr stage IV metastatic disease, the
outcomes are generally poor, although resection of iso-
lated liver metastases has some success, particularly forcolon carcinoma.
Potential Management StrategiesThere are several approaches to diagnosis and
therapy when faced with a single hepatic lesion, which
vary in terms of diagnostic accuracy and invasiveness.
One could pursue (1) no further evaluation or follow-up,
(2) additionallaboratory studies, (3) further imaging and
follow-up with imaging studies, (4) percutaneous biopsy,(5) radio frequency or other percutaneous ablation tech-
niques, (6) laparoscopy with biopsy and possible resec-tion or ablation, or (7) laparotomy with resection/exci-
sional biopsy.
No Further Evaluation or Follow-up
In an asymptomatic patienr with normal liverfunction tests and no evidence of chronic liver disease, it
is overwhelmingly likely that the patienr has a benignliver lesion Thus, it would be cost-effective to halt the
workup until the patient has symptoms or develops other
abnormalities on routine health screening. This will also
prevent the stress on the patienr of worry, the cumulativeradiation of follow-up imaging, and the risks involved
with biopsy. Because a false-positive test is more likely
than a true positive test due to the low prevalence of
malignanr or premalignanr disease, this may prevenr
morbidity and mortality associated with biopsy, abla-tion, or resection. However, it has a small chance of
missing a significanr lesion, which will be more difficult
(or impossible) to treat at a later stage when it presenrs
symptomatically.
Additional Laboratory Studies and CancerScreening
The absence of clinical liver disease and normal
liver function tests do not exclude underlying liver dis-
ease. Screening tests for hepatitis B, hepatitis C, and
hereditary hemochromatosis could be obtained because
ali are associated with an increased risk of primary hep-atocellular carcinoma. Other tests for liver disease could
include anrinuclear antibody, anrimitochondrial anti-
body, smooth muscle anribodies, ceruloplasmin, and (X,-
antitrypsin levels or phenotype. Tumor markers could be
53
August 2006
sent, including a-fetoprotein (for HCC), carcinoembry-
onic antigen (CEA; for colon and cholangiocarcinoma),
CA 19-9 (for biliary or pancreatic cancer), prostate-
specific antigen (PSA) screening (for prostate), and CA
125 (for ovarian). This strategy has the primary advan-
tage of reducing the likelihood of missing a malignant
lesion, and, compared with the more invasive strategies,
it is less likely to lead to costly and low-yield follow-up
tests because in the absence of risk facrors or viral hep-
atitis the risk of primary malignancy is low. However,
although testing for viral hepatitis is both sensitive and
specific, both autoantibodies and tumor markers are
costly with a low yield anel have significant false-positive
and negative rates. This can lead to unnecessary testing
and follow-up in the former situation and a false sense ofreassurance in the latter situation.
Further Imaging and Follow-up WithImaging Studies
In this strategy, aelditional (anel more involved)
screening for malignancy and follow-up of the lesion to
assure stability of size is undertaken. In addition to the
laboratory testing in strategy 2, routine age-appropriatecancer screening should be performed (eg, colonoscopy;
mammography for women). More rigorous testing for ma-
lignancy is also done because biopsy wiIl not be undertaken.This can include chest x-ray, upper endoscopy in popula-
tions in which gastric cancer is endemic, and, in women,
pelvic ultrasound for gynecologic malignancy. FinaIly, con-
firmatory radiologic testing and then follow-up studies at
define<! intervals are used to try to define better the diag-
nosis and to assure stability of size.
On ultrasound, hemangiomas tend to be hyperechoic andare sometimes lobular, whereas other solid lesions tend to be
hypoechoic. Noncontrast computerized tomography (CT) is
rarely of assistance because the vascular enhancement is the
most diagnostic feature. Technetium-labeled red blooc\ ceIl
scans, or single-photon emission compured tomography(SPECT) imaging, can be used to look for hemangioma anddifferentiate between "hot" (FNH) and "colei" (adenomas
and malignancy) liver lesions, bur it is not very sensitive,
particularly for small lesions.
Triphasic contrast CT or gadolinium contrast-
enhanced magnetic resonance imaging (MRI) are the
most sensitive and specific imaging tests. These, in par-
ticular MRI, are usually diagnostic for hemangioma.FNH can be difficult to differentiate from adenoma or
even malignancy on imaging, although on triple-phaseCT or gadolinium-enhanced MRI a central scar, which is
characteristic of FNH, may be seen. In this strategy, we
go farther to exclude cancerous or precancerous lesions.
One can almost always exclude malignant lesions, but
54
ASYMPTOMATlC LlVER MASS 621
the possibility of both adenoma and FNH frequently
remains. In this case, follow-up scanning with further
work-up anel possible biopsy of lesions that grow is
frequently used. The downside to this strategy is that itinvolves numerous tests, and it often will not differen-
tiate between 2 of the most common causes of solitaryliver lesions, adenoma and FNH.
Percutaneous Biopsy
Biopsy should give an immediate answer to the
question of etiology and allow appropriate therapy and
follow-up. Fine needle aspiration is adequate for diagnosis of
a metastatic malignant tumor of the liver. To differentiate
FNH, adenoma, and weIl-elifferentiated HCC, core biopsy
is required because the hepatic architecture is the primary
distinguishing feature in most cases. The aelvantage of this
strategy is that most malignancies can be accurately diag-
nosed and FNH and adenoma elifferentiated in the majority
of cases. However, percutaneous biopsy entails risks of
bleeding, pneumothorax, and tumor spread along the nee-
dle tract. In addition, specimens may be nondiagnostic or
negative for malignancy, leading to a false sense of securiry.
Finally, many practitioners wiIl continue to follow the
lesion radiologically, regarelless of a benign biopsy result,
thus incurring the risk of the procedure without influencing
management, which would make the biopsy irrelevant in
that case. Therefore, in a low-prevalence population with
nonsuspicious imaging and anciIlary testing, the risk ofbiopsy may not be balanced by benefit because it wiIl not
influence treatment, outcome, or follow-up plans.
Radio Frequency or Other Percutaneous
Ablation Techniques
In this approach, the lesion is treated with ther-
mal energy (radio frequency), a chemical agent (ethanol
or acetic acid), or cooling (cryoablation) to destroy the
lesion. These treatments can be performed percutane-
ously with radiologic guidance, laparoscopically, or at
open laparotomy. Core biopsy of the lesion can be per-
formed at the same time. The advantage of this approach
is that it may be both diagnostic and therapeutic. For
adenomas and other benign lesions, it is likely curative.
Ir can be performed in a minimally invasive manner anel
is effective at local destruction without extensive damageto the remainder of the liver. The disadvantages are that,
if the biopsy is nondiagnostic, which often cannot be
determined on frozen section, no diagnosis will be made.
It is more invasive and riskier than the prior strategies,
which may not be warranted when greater than 50% of
lesions do not require therapy. It cannot be applied safely
and effectively to larger lesions (above 4-5 cm) or in
622 ROBERTBROWN
cerrain paresof rhe liver (eg, high in rhe dome). Finally,ir doesnor avoiel rhe neeel for follow-up imaging.
LaparoscopyWith Biopsyand PossibleResectionor Ablation .This srraregy is similar ro the use of ablarion
rechniques,excepr ir can be used in larger lesions, rhosein proximiryto major blood vessels, or rhose elifficulr toaccesspercuraneously.Ir shares ali the limitarions ofpercutaneousablarion and is more invasive.
Laparotomy With ResectionjExcisional
Biopsy
This straregy will allow access ro the largesrlesions anel rhe most elifficult areas ro access in rhe
liver, bur involves laparoromy, a 4- or 5-elay hospitalsray on average, somewhar higher risk, anel a more
prolongeel recovery.
Recommended ManagementStrategy
In our parienr, I would employ a straregy ofaddirional laboratory testing and further imaging. Inapproachinga solitary asymptomatic liver mass, rhe crir-icaldiagnostic issue is to decide wherher rhis is a benignlesion,which ir is in most cases, as opposed ro a malig-nant lesion. For benign lesions, one has ro dererminewhether ir requires follow-up or therapy (eg, aelenomas)or nor (mosr parienrs wirh FNH or hemangioma). In rhecaseof malignant lesions, one has to determine whetherrhe cancer is primary to the liver or metastaric. To do
rhis, I rry ro answer 4 essential questions:
1. Is ir solielor cysric?2. Are rhere risk factors for or any evidence of chronic
underlying liver disease?3. What are rhe clinical and demographic fearures of rhe
patient: in particular, gender, age, comorbidiries, anelrisk facrors for orher malignancies?
4. Are rhere any systemic signs suggesrive of infecrion orcancer?
In this case, even a noncontrast CT can exclude cysticlesions;rhus, ali of rhe cysric lesions of the liver are elimi-nared,most of which are simple benign cysrs. Simple cysrsof rhe liver do not require any furrher workup, and cysricneoplasmsof rhe liver are usually complex on imaging andare quire uncommon. Thus, for most cases in which asimple cyst is seen in the liver in rhe presence of normalliver function tesrs, no furrher workup is neeeled.
This patient has no evielence of clinical liver diseaseand has normal liver function rests. It is important,
GASTROENTEROLOGYVaI. 131, No.2
however, ro check rhe serum a-feroprotein levei as wellas screening tests for hepariris B, hepatiris C, and hered-irary hemochromatosis because rhese are all associaredwith an increased risk of primary HCC. In the absence ofmarkers for hepatitis B and C and presence of normalliver funcrion rests and presumably normal contour ofthe liver on imaging wirh no evidence of occulr cirrhosis,rhe likelihood of HCC is exceedingly small. In thisinstance, rhe mosr likely diagnosis would be a benignhepatic hemangioma.
I would firsr oreler a contrast-enhanced MRI ro assess
for hemangioma. The CT obrained with a virrualcolonoscopy will nor provide the vascular detail to eval-uare for hemangioma, which requires a contrasr-enhanced MRI or triple-phase CT. In my experience,MRI is able to diagnose hemangioma in almosr all cases.If the MRI is equivocal, which only happens in smalllesions, I have nor found nuclear medicine scans helpful.If the parient has an asympromaric lesion wirh an MRI ortriple-phase spiral CT with contrast that is diagnosric ofhemangioma, no further evaluarion is required. Biopsy israrely necessary, alrhough rhe fear ofbleeding complica-rions from biopsy is probably overrared.
In the absence of hemangioma, the mosr commondiagnosric dilemma is distinguishing FNH from ade-noma, particularly in young women. Ir is important todistinguish rhese 2 diseases because adenoma has borh ahigher rate of bleeding and some malignant porential,particularly as rhese lesions increase in size.
FNH is rhe mosr likely diagnosis because rhe patientis male. Small FNH would require no further follow-upor therapy. In a low-risk parienr such as rhis, who isunlikely ro have an adenoma, the presence of a centralscar would clinch rhe diagnosis of FNH. However, inyoung women wirh risk facrors, a single imaging resrwould nor lead me ro a definitive diagnosis of hepaticadenoma. In this serring, observation ro assess regressionoff oral conrraceptives wirh serial imaging or percutane-ous ultrasound or CT-guided biopsy is warranted. In rheabsence of biopsy confirmarion, I may choose to obrainrepeat imaging, even wirh presumed FNH to ensure rharthe size of the lesion remains srable ro be certain rhar I
have nor missed a malignancy.In a patienr with imaging tests not diagnostic of
hemangioma or FNH, my subsequent management isbased on the size of the lesion and rhe pretest probabilityof adenoma or malignancy, including evidence of chronicliver disease. Thus, for small «2 cm) likely benignlesions, my approach is usually serial follow-up imagingif rhe MRI is nondiagnostic. I may also choose ro performmore rigorous resring for malignancy, especially if abiopsy will not be performed. In addition to rourine
55
August 2006
Solid lesion on Ultrasound or non-contrast CT
MRI ar Triple phase CT with contrast
IrDiagnostic of hemangioma
No further workup
ASYMPTOMATIC LlVER MASS 623
1Solid lesion, not hemangioma
.LPresence of liver disease
]No risk factors for liver disease or
other malignancy1
Exclude HCC or
cholangiocarcinoma
rRisk factors or
imaging suspicious of adenoma
I
1No risk factors or
imaging suspicious of adenoma
ITrial off oral contraceptives
or percutaneous biopsy
Probable FNH
No follow-up or seria I reimaging
Figure 1. Suggested diagnostic strategy for an incidental asymptomatic solid liver lesion.
age-appropriate cancer screening (eg, prostate), I usually
obtain a carcinoembcyonic amigen (CEA) test and obtaina chest x-ray. If the lesion is greater than 2 cm and there
is a histocy ar evidence of chronic liver disease, these
lesions are presumed to be HCC unless proven otherwise.
Alpha-fetoprotein testing may be of assistance but is
neither sensitive nor specific. An elevated <x-fetoprotein
level will be seen in only approximately 45% of HCC.5
Small tumors will often not produce a diagnostic levei of
<x-fetoprotein, and many patiems with abnormal <x-feto-
protein will not have cancer. Alpha-fetoprotein is gen-
erally not useful unless the level is over 500 ng/dL. Our
approach to biopsy of possible HCC is related to trans-
piam candidacy. In patiems with lesions that are be-tween 2 and 5 cm, who have other independem indica-
tions for transplamation, we generally presume these
lesions are HCC and do not biopsy. In patiems such as
this gentleman, who has no other indication for trans-
plantation other than possible HCC, a biopsy is war-
ramed. Concerns about needle tract spread of the tumor
are small relative to the morbidity of a transplam that
might not otherwise be needed.
If the patiem has no evidence of chronic liver disease,
the differential diagnosis is principally between focal
nodular hyperplasia and adenoma. In a patiem such asthis one with a low risk for adenoma but a higher risk for
other malignancies, a biopsy may be warranted, partic-
ularly if the lesion is large, ie, greater than 3 to 4 cm. If
the lesion is small and ali other tests are negative, afollow-up scan in 3 to 6 months to assess for growth may
be ali that is required, particularly if a cemral scar is seen
on MRI that is compatible with FNH. My approach to
solitacy lesions is summarized in Figure 1.Further therapy is based on the diagnosis established
by imaging, biopsy, and/or laboratocy testing. Patients
with FNH and hemangiomas require no further therapy.For adenomas, particularly if they are large ar occur in amale, local excision might be recommended, and, forother tumors, a comprehensive tumor treatmem strategywould be developed.
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Dis 2001;5:17-42.
2. Kerlin P, Davis GL, McGiII DB, Weiland LH, Adson MA, Sheedy PF11.
Hepatic adenoma and focal nodular hyperplasia: clinical, pathologic,and radiologic features. Gastroenterology 1983;84:994-1002.
3. Labrune P, Trioche P, Duvaltier I, Chevalier P, Odievre M. Hepato-
celiular adenomas in glycogen storage disease type I and 11I:aseries of 43 patients and review of the literature. J Pediatr Gas-troenterol Nutr 1997;24:276-279.
4. Rooks JB, Ory HW, Ishak KG, Strauss LT, Greenspan JR, Hili AP,
Tyler CW Jr. Epidemiology of hepatoceliular adenoma. The role oforal contraceptive use. JAMA 1979;242:644-648.
5. Brown RSJr, Scharshmidt BF. Screening for hepatoceliular carc~
noma. In: Kramer BS, Gohagen JK, Prorok PC, eds. In a guide to
cancer screening-theory and practice. New York: Marcel Dekker,1999:299-326.
6. Lazaridis KN, Gores GJ. Primary sclerosing cholangitis and cholan-giocarcinoma. Semin Liver Dis 2006;26:42-51.
7. Rea DJ, Heimbach JK, Rosen CB, Haddock MG, Alberts SR, Kre-
mers WK, Gores GJ, Nagorney DM. Liver transplantationwithneoadjuvant chemoradiation is more effective than resection for
hilar cholangiocarcinoma. Ann Surg 2005;242:451-461.8. Heimbach JK, Haddock MG, Alberts SR, Nyberg SL, Ishitani MB,
Rosen CB, Gores GJ. Transplantation for hilar cholangiocarcinoma.Liver Transpl 2004;10:S65-S68.
Address requests for reprints to: Robert S. Brown, Jr, MD, MPH,
Assoclate Professor of Medlcine and Surgery, Columbia University
Coliege of Physiclans and Surgeons, Center for Llver Disease and
Transplantation, New York-Presbyterlan Hospital, 622 W. 168thStreet, PH 14 Center, New York, New York 10032-3784. e-mail:
rb464@columbla.edu; fax: (212) 305-4343.
56Reprinted trom Gastroenterology (2006 Aug) 131(2):61-623, RSBrown, Jr.,Asymptomatic Liver Mass, Copyright@2006,with permissiontrom Elsevier.
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