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,

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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.