2011 07 lesiones solidas y quisticas de higado

8/4/2019 2011 07 Lesiones Solidas y Quisticas de Higado

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STATE OF THE ART

Biologic and Clinical Features of Benign Solid and Cystic Lesions

of the Liver

OREN SHAKED,* EVAN S. SIEGELMAN, KIM OLTHOFF, and K. RAJENDER REDDY*

*Division of Gastroenterology and Hepatology, Department of Radiology, andDepartment of Surgery, Division of Transplantation, University of Pennsylvania,

Philadelphia, Pennsylvania

This article has an accompanying continuing medical education activity on page e71. Learning ObjectivesAt theend of this activity, the learner will know the different types, the clinical features, and the diagnosis and treatmentoptions for patients with benign solid and cystic lesions of the liver.

The widespread use of imaging analyses, either routinely orto evaluate symptomatic patients, has increased the detec-tion of liver lesions (tumors and cysts) in otherwise healthyindividuals. Although some of these incidentally discoveredmasses are malignant, most are benign and must be in-cluded in the differential diagnosis. The management ofbenign hepatic tumors ranges from conservative to aggres-sive, depending on the nature of the lesions. New imagingmodalities, increased experience of radiologists, improveddefinition of radiologic characteristics, and a better under-standing of the clinical features of these lesions have in-creased the accuracy of diagnoses and reduced the need forinvasive diagnostic tests. These advances have led to con-

stant adjustments in management approaches to benignhepatic lesions. We review the biologic and clinical featuresof some common hepatic lesions, to guide diagnosis andmanagement strategies.

Keywords: Adenoma; Hepatocellular; Hyperplasia; Hemangioma;Polycystic Liver Disease; Cystadenoma.

Solid Lesions

The clinical features of several solid hepatic lesions aresummarized in Table 1. The pathology and histology ofthe major lesions are discussed in the Supplementary Material.

Hepatocellular AdenomaHepatocellular adenoma (HCA) is a benign neoplasm

that tends to develop in individuals with a hormonal or meta-bolic abnormality that can stimulate hepatocyte proliferation. Aconsecutive autopsy study found a frequency of these lesions at12 per 100,0001 while an ultrasound (US) study found theincidence to be 7 per 100,0002; however, there was a markedincrease in the incidence of these lesions after the introductionof oral contraceptive (OCP) therapy such that the estimatedincidence in women not taking OCPs was 1 to 1.3 per millionwith an increase to 3.4 per 100,000 in women taking estrogentherapy3 suggesting a causal relationship between OCPs andhepatic adenomas.

HCAs are found predominantly in women in their third andfourth decades and are most often solitary and located in the

right hepatic lobe (Table 1).3,4 Liver adenomatosis has been

variably defined as having anywhere from 3 to 10 adeno-

mas, and is generally considered a separate entity from a soli-

tary HCA.5,6 In addition to a higher prevalence, cases of HCA in

women taking OCPs tend to be more symptomatic.7 HCA has

a tendency to regress after discontinuation of OCP therapy,

making the connection between the 2 even more definitive.8,9

While a more recent study concluded that women taking later

generation OCPs were not at an increased risk for developing

HCA,10 another study found that estrogen and androgen recep-

tors were present on up to 1 third of HCAs, 11 and HCAs have

been known to enlarge during pregnancy,12 lending additional

support to the notion that female sex hormones play a role intumor development.

Along with OCP use, several metabolic conditions and ther-

apeutic drugs have been associated with HCA tumorigenesis.

The use of anabolic androgen steroids (AAS) can lead to the

development of HCA.13,14 Androgens do not only increase the

likelihood of developing HCA in males; individuals, male or

female, with high levels of endogenous androgens or estrogens

are also at risk for developing HCA.15Another major risk factor

Abbreviations used in this paper: AAS, anabolic androgenic steroids;

ADPKD, autosomal dominant polycystic kidney disease; AP, alkaline

phosphatase; BMI, body mass index; CA19-9, carbohydrate antigen

19-9; CEA, carcinoembryonic antigen; CEUS, contrast enhanced ultra-sound; CK, cytokeratin; CRP, C-reactive protein; CT, computed tomog-

raphy; FNH, focal nodular hyperplasia; GS, glutamine synthetase; GSD,

glycogen storage disease; HBCA, hepatobiliary cystadenoma; HBCAC,

hepatobiliary cystadenocarcinoma; HCA, hepatocellular adenoma;

HCC, hepatocellular carcinoma; HNF1, hepatocyte nuclear factor-1;

IHCA, inflammatory hepatocellular adenoma; IPCLD, isolated polycys-

tic liver disease; KMS, Kasabach-Merritt Syndrome; LA, liver adenoma-

tosis; L-FABP, liver fatty acid binding protein; MRI, magnetic resonance

imaging; NCAM, neuronal cell adhesion molecule; NRH, nodular regen-

erative hyperplasia; OCP, oral contraceptive; PCLD, polycystic liver

disease; RFA, radiofrequency ablation; RUQ, right upper quadrant;

SAA, serum amyloid A; SHC, simple hepatic cyst; THCA, telangiectatic

hepatocellular adenoma; US, ultrasound.

2011 by the AGA Institute

1542-3565/$36.00doi:10.1016/j.cgh.2011.03.007

CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2011;9:547562


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for HCA is glycogen storage disease (GSD) types Ia and III. 16

Interestingly, the female-to-male ratio is reversed in patientswith GSD who develop HCA from a female predominance to a1:2 male predominance, and the incidence of adenomas in-creases dramatically for patients with GSD over 25 years of age.Management of HCA in patients with GSD differs from con-

ventional therapy. Continuous nocturnal feeding has beenshown to result in a decrease in tumor size in some patients

with GSD.17 Despite this, hepatocellular carcinoma (HCC) hasbeen known to develop in the background of HCA,18,19 andwhile surgical resection is associated with higher morbidity inGSD patients, surgical intervention, whether resection or livertransplantation, appears to be the prudent course.20 Antiepi-leptic drugs21 and hepatic hemosiderosis have also been con-nected to HCA development.22 Notwithstanding these myriadrisk factors for HCA, otherwise healthy patientsboth male

and femalewith no history of OCP, anabolic androgenic ste-roids (AAS), or antiepileptic drug use, and no underlying met-abolic conditions have been known to develop these lesions.

HCA are often symptomatic, being discovered incidentally injust 12 to 25 percent of cases,3,23 although this may be changinggiven the increasing frequency of imaging studies and thegreater likelihood of discovering them incidentally. Commonpresentations are summarized in Table 1.

Imaging studies of HCA are difficult to analyze because ofthe heterogeneous nature of these lesions (Table 2). Within thepast decade, HCAs have been broadly categorized into 4 sub-types based on genetic and pathological criteria: 36%46% ofpatients have hepatocyte nuclear factor-1 (HNF1) inacti-

vating mutations; 18%44% have the inflammatory subtype(IHCA); 5% present with a-catenin activating mutation, andan additional 7% have a -catenin mutation with IHCA fea-

tures, making the prevalence of-catenin mutations 13%14%overall. Currently 9%23% cannot be phenotypically or geneti-cally categorized.2426 A more recent study found that whencharacterized pathologically, the various HCA subtypes are as-sociated with specific magnetic resonance imaging (MRI) pat-terns;27 these typical MRI findings may make it possible tononinvasively determine the subtype of HCA without resortingto biopsy. Enhancement with gadobenate dimeglumine on MRIhas also been helpful to differentiate HCA from focal nodularhyperplasia (FNH).28 Triple phase computed tomography (CT)can be used to image these lesions,29 andalthough not yetclinically used in the United States while awaiting Food andDrug Administration (FDA) approvalEuropean studies incontrast-enhanced ultrasound (CEUS) demonstrate promising

results for diagnosing HCA.30A definitive diagnosis, however, isdifficult to establish by imaging alone (Figure 1).

Biopsy can be of risk in HCA because of the vascular natureof these lesions and their propensity to hemorrhage. Neverthe-

less, new genetic and molecular criteria have been establishedthat can establish a definitive diagnosis, which can be beneficialin the management of these tumors. While there is some benefitin obtaining a biopsy, at this stage it should be reserved forselect cases where genetic and molecular diagnostic tools areavailable and are deemed necessary in making treatment deci-sions. Table 3 summarizes pertinent information that can beobtained from a biopsy to assess a differential diagnosis.3135

The recommended management of HCA is more aggressive

than most other benign lesions because of the tendency forthese lesions to hemorrhage and the slim but real possibility ofT

ab

le

1.

ClinicalFeaturesofSolidHepat

icLesions

HCA

LA

THCA

FNH

Hemang

ioma

Incidence(%)

1

106

to1.2

104

1

106

1

106

to1.2

104

0.33

0.420

Sex

ratio(M:F)

1:815

1:815

1:9

ormore

1:517

1:26

Mea

nagerange(y)

3040

3040

3040

3040

3050

Size

range(cm)

122

122

0.115

0.119

1to30

Perc

entsingle(%)

6080

6080

2040

7681

7193

Estr

ogensensitive

Yes(causallyrelated)

Yes(causallyrelated)

Yes

Poss

ibly

Possibly

Pres

enting

symptoms

ChronicRUQ

orepigastricpain;

palpablemass;sudd

enacute

pain;circulatorycolla

pse;

malaise;chroniciron

anemia

ChronicRUQ

orepigastricpain;

palpablemass;suddenacute

pain;circulatorycollapse;

malaise

ChronicRUQ

orepigastricpain;

palpablemass;suddenacute

pain;circulatorycollapse;

malaise

Epiga

stricorabdominal

pa

in;palpablemass;

he

patomegaly;weight

los

s;asthenia;fever

RUQ

pain;tumormassinepigastrium;

severepain,nausea,dyspepsia,

earlysatiety;vomiting;weightgain;

hepatomegaly

Hep

aticbiochemical

te

sts

Elevatedtransaminase

levels

andAP

Elevatedtransaminaselevels

andAP

Generallynormal

Gene

rallynormal

Generallynormal

F,fe

male;M,male.

548 SHAKED ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 9, No. 7


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malignant transformation. Hemorrhage has been reported in11 to 29 percent of HCA cases.36,37 Almost all cases of sponta-neous rupture occur in lesions greater than 5 cm.7 Managementof a hemorrhagic lesion varies depending on the severity ofbleeding. To avoid the complications associated with emer-gency hepatectomy, conservative management using bloodproducts with the hope of achieving hemodynamic stability has

been suggested as a temporary approach.38 However, such astrategy may not be successful in some cases because of ongoinghemorrhage. Other methods of management include control-ling bleeding by packing the liver, emergency hepatectomy,embolization of the right or left hepatic artery, and urgent livertransplantation.38,39 Embolization using interventional radiol-ogy with later planned elective liver resection is a commonly

Figure 1. MR illustration of a lipid-containing hepatocellular adenoma in a 32-year-old woman with a history of oral contraceptive use. (A) Axial in

phase T1-weighted image does not show a mass. Given that the lesion is isointense to the surrounding liver suggests it is of hepatocellular origin.

(B) Axial opposed phase T1-weighted image shows loss of signal intensity within the lesion indicating the presence of lipid within the mass. Lipid is

more often present in adenomas compared with focal nodular hyperplasia. (C) Axial fat suppressed T2-weighted image shows heterogeneous signal

low, intermediate, and high signal intensity within the lesion. One would have expected focal steatosis to have been hypointense to isointense

compared with liver on this pulse sequence.

Table 3. Histologic, Immunohistochemical, and Genetic Aids in Differential Diagnosis

Lesion

Pathological/histological

characteristics Informative immunohistochemical staining Clonality Genetic associations

HCA

HNF1 (36%46%) Intratumoral steatosis, lobulated

contours, microadenomas,

association with additional

benign tumors, without

inflammatory infiltrate or

cytological abnormalities

SREBP-1, ChREBP, and L-FABP repressed,

GS (peripheral hepatocytes eventually

positive), CK-7, CK-19, NCAM, CD34

Monoclonal Mutations in TCF1,

FABP1 and UGT2B7

downregulated

Inflammatory

(18%44%)

Tumoral peliosis, steatosis in

background liver, inflammatory

infiltrate, sinusoidal dilation,

dystrophic vessels,

telangiectasias, ductular

reaction, micro- and

macroscopic hemorrhage more

frequent, BMI 25, alcoholconsumption

SAA, CRP, GS (peripheral hepatocytes

eventually positive), CK-7, CK-19, NCAM,

CD34

Monoclonal None known

-catenin (13%14%) Association with elevated risk for

HCC, frequently found in male

patients (38%), cytological

abonormalities, acinar pattern

(pseudoglandular formation)

Nuclear -catenin, GS (strong, diffuse

staining), CK-7, CK-19, NCAM, CD34

Monoclonal Mutations in CTNNB1,

GLUL and GPR49

overexpressed

THCA (subtype of

inflammatory HCA)

High BMI, elevated GGTP,

inflammatory infiltrate

Elevated SAA and CRP, CK-7, CK-19,

NCAM, CD34

Monoclonal None known

FNH Association with other vascular

anomalies, classically show

central scar

GS (staining shows large areas stained in

a heterogeneous pattern, with particular

positivity surrounding hepatic veins),

L-FABP positive, SAA and nuclear -

catenin negative, CK-7, CK-19, NCAM,

CD34

Polyclonal in

73% of

cases

Elevated Ang1/Ang2

ratio

Ang, angiopoeitin; ChREBP, carbohydrate regulatory element binding protein; SREBP, sterol regulatory element binding protein.



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employed approach in the management of a lesion that pres-ents primarily with bleeding. Approximately 5%10% of HCAswill transform into HCC25,36,40a much larger number than themortality associated with partial hepatectomy. Malignant trans-formations appear to occur in the -catenin subset of HCAs.25

There are several approaches to the management of HCA.Patients using OCPs, AAS, or other drugs associated with HCAprogression should discontinue therapy as this may lead toregression of the tumor.9,41 It must be noted, however, that notall tumors regress, and some may even increase in size aftercessation of therapy.42 In addition, subsequent HCC develop-ment has been reported even when tumors have been observedto regress.43,44 Lesions smaller than 5 cm can probably bemanaged conservatively as these tumors have rarely been notedto rupture or transform to malignancy,45 although opinionshave varied and some believe that HCA should be treatedaggressively in order to avoid potential serious complications.In the conservative approach, patients should have follow-upimaging once every 6 months for a couple of years to establish

any growth patterns, and then annually. Alpha-fetoprotein(AFP) levels can be followed as well with similar frequency, butalpha-fetoprotein is not a reliable marker of malignant trans-formation as levels are usually normal.46 Treatment optionsinclude radio frequency ablation (RFA),47 transcatheter arterialembolization (TAE),48 as well as hepatic resection.4,49

Liver Adenomatosis

Liver adenomatosis refers to the patient with multipleadenomas, and has been variably defined as anywhere from 3to 10 adenomas in the liver.5,6 Presentation of adenomatosis,as well as the histological and radiographic features is the sameas HCA (Table 1). The optimal mode of management for ade-

nomatosis is not well defined because cases hitherto have beeninfrequent and the diffuse nature of these lesions makes partialhepatic resection difficult, if not impossible. The various treat-ment options that have been reported include a conservativeapproach for patients with smaller lesions,50 resection of thelargest symptomatic tumors (generally those 5 cm),51 trans-catheter arterial embolization,48 transcatheter arterial chemo-embolization (TACE),52 RFA,53 and orthotopic liver transplan-tation.49 The conservative approach for liver adenomatosis (LA)is the same as in HCA. Resection of larger peripheral lesionsmay be combined with another localized therapy, such as em-bolization for remaining lesions. Irrespective of the treatmentmethod selected, patients must be followed closely because ofthe potential for these lesions to rupture or undergo malignant

transformation.54

Telangiectatic Hepatocellular Adenoma

Telangiectatic hepatocellular adenoma (THCA), previ-ously known as telangiectatic focal nodular hyperplasia, hasrecently been reclassified as a subcategory of IHCA. This shift inclassification has been propelled by 2 facts: (1) THCA moreclosely resembles HCA at the molecular level when comparedwith FNH; and (2) like HCA, THCA is managed aggressively asopposed to FNH in which a conservative approach is advocated.This lesion is frequently associated with OCP use and/or hor-monal therapy,5557 and anywhere from 15%40% of patientspresent with another benign liver lesion55,57 (other characteris-

tics are summarized in Table 1). Many patients with THCA areoverweightan association that has not been noted with other

benign liver tumors.32,57 On imaging, THCA typically appears asa well-defined heterogeneous mass (Table 2).55,58

The molecular analysis of THCA in recent years has firmlyestablished these lesions as a subtype of HCA (Table 3).56,57 Inaddition, the angiopoietin-1/angiopoietin-2 ribonucleic acid(RNA) ratio, as well as the protein cluster profile of THCA, aremore similar to HCA.59 Ultimately, this reclassification assistsin the management of these lesions because they must be dealtwith as aggressively as HCA. THCA are likely to be symptomaticbecause they often hemorrhage and contain focal areas ofnecrosis.56,57 Because of the high probability for these lesions tohemorrhage, and because of their unknown potential to degen-erate toward malignancy,57 surgery is recommended as thetreatment of choice in the case of THCA.

Focal Nodular Hyperplasia

For several years, FNH has been viewed as a hyperplas-tic, and not a neoplastic, response of hepatic parenchyma to apre-existing vascular malformation arising during development.

More recently, evidence has been published that supports andelucidates this etiological theory of FNH development; in mostcases, FNH appears to be caused by a portal tract injury thatresults in the formation and enlargement of arterial to venousshunts.60 This causes local arterial hyperperfusion resulting inoxidative stress which then triggers a reaction from hepaticstellate cells to form the central scar that is typical of theselesions.61 FNH is the second most common benign hepaticlesion, with an incidence at necropsy ranging from 0.3 to 3percent.1,62 Clinically relevant tumors, however, are far morerare with a frequency in US studies being just 0.03 percent. 2

FNH can have a spectrum of demographic features but isnoted predominantly in women in their third and fourth de-

cades (Table 1).63,64

The higher prevalence in women along withevidence that FNH tends to be larger and develop earlier infemales has led to the conclusion that female sex hormonesplay a large role in tumor development, and suggests that OCPuse be discontinued in cases of FNH; however, OCP use has notled to changes in these lesions over time, and pregnancy hasalso not been associated with any observed changes in tumorsize.65,66 In 2 case-controlled studies, a slight statistical correla-tion between OCP use and FNH has been observed,10,67 but, thechanges observed are generally subclinical, and it does notappear that modern OCPs contribute in any significant way tothe progression of these tumors. Because of the controversysurrounding this issue, a conservative approach for women witha diagnosis of FNH who wish to continue OCP therapy is to

have yearly US studies for 2 to 3 years to monitor any changesin the size of their lesions. By contrast, in non-OCP usersfollow-up imaging is not necessary for patients with a firmdiagnosis of FNH.

Most cases of FNH are discovered incidentally, but about 20to 40 percent may present with symptoms.68,69 Symptoms aresummarized in Table 1. FNH is often associated with other

vascular anomalies: up to 20% of cases are associated withhepatic hemangioma,70 and other tumors such as HCA andHCC have also been observed in tandem with FNH71,72obser-

vations that are in keeping with the notion that FNH developsin the background of vascular malformations.

Imaging techniques designed to differentiate FNH from

other hepatic lesions have improved significantly over the pastdecade (Figure 2). The identification of classic FNH with its

July 2011 BENIGN SOLID AND CYSTIC LESIONS OF THE LIVER 551


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spoke-wheel central scar makes this lesion easy to characterizeby imaging (Table 2). Differentiation of these lesions from HCAis crucial as the two are managed very differently. Consequently,cases that are even mildly ambiguous present a challengingproblem and require a balance between the risks of surgeryagainst an inconclusive diagnosis. Improvements in hepatobi-liary contrast agents, particularly gadobenate dimeglumine,have improved the diagnostic accuracy of MRI.28,73 Recent re-ports on triphasic and multi-section spiral CT have shown thatthese imaging modalities can accurately diagnose FNH.74,75Yetthe most drastic improvements have been with the use ofCEUS,76 and this has been shown to be at least as accurate asMRI or CT in identifying FNH. While biopsy is rarely required

in the case of FNH, new histopathological characteristics haverecently been identified that help differentiate these tumorsfrom HCA and HCC (Table 3). It must be noted, however, thatat this stage these markers are investigational and are notstandard of care.

When a firm diagnosis of FNH is established, managementshould be conservative. Most of these tumors are asymptomaticand remain stable over time.77 In those instances in which achange in size is noted, regression is usually observed ratherthan growth. Spontaneous rupture of FNH is rare with only afew scattered case reports over the past 2 decades.78,79 Anotherrare presentation is for HCC to develop within FNH. 80 Therehave been no reports in the literature of overt transformation ofFNH to a malignant growth and the debate over the malignant

potential of FNH is ongoing. Genetic evidence has been usedrecently to establish the clonality of FNH operating under thenotion that neoplastic growths should demonstrate monoclo-nality while hyperplastic lesions should be polyclonal. Studieson this issue have been conflicting, with 27 percent of resectedFNH lesions demonstrating monoclonality and the rest beingpolyclonal.33,34,81

Surgical intervention is required for severely symptomatictumors and lesions in which a firm diagnosis of FNH cannot beestablished. Partial hepatic resection is the most commonmethod of surgical treatment,82 but more recently embolizationand RFA have been used.83,84 These interventional proceduresare associated with fewer complications and a lower morbidity

than surgery, but no large series have been published compar-ing the outcomes of these various interventions.

Hepatic HemangiomaCavernous hepatic hemangiomas are benign vascular

lesions of the liver of unclear etiology. They are thought to arise

from congenital hamartomas that increase in size because of

progressive ectasia rather than hyperplasia or hypertrophy. Al-

ternatively, they may result from dilation of existing blood

vessels in normally developed tissue. Hemangiomas are the

most common benign hepatic tumors with an incidence in

autopsy studies ranging from 0.4% to 20%1,62; however, the

higher incidence rate reflects the inclusion of tiny lesions with

no clinical significance. Ultrasound studies have placed the

frequency at 0.7% to 1.5%,85,86 which more likely reflects the

actual incidence of clinically relevant hemangiomas in the gen-

eral population.Hemangiomas can be found in all age groups but are most

commonly discovered between the third and fifth decades of

life. Clinical features are summarized in Table 1. Lesions larger

than 4 cm have been dubbed Giant hemangiomas. 87

Hemangiomas in women tend to be discovered earlier, are

often larger, and are more likely to manifest clinically.88 These

data suggest that female sex hormones may play some role in

the pathogenesis of hepatic hemangioma. There have been

reports of these lesions growing in size during pregnancy89 and

in women taking OCPs.90 In addition, estrogen receptors have

been identified on some hemangiomas,91 and estrogen treat-

ment in vitro can cause the proliferation of hemangioma vas-

cular endothelial cells.92 By contrast, a case-controlled studyfound no causal link between OCP use and hepatic hemangio-

mas.93 It is clear that the relationship between hormonal in-

volvement and hemangioma development is tenuous at best,

and it is not a precondition for tumor development as heman-

giomas can present in men, women with no history of OCP use,

and postmenopausal women.

Hemangiomas are most often asymptomatic and are discov-

ered incidentally during imaging studies for unrelated issues.

Symptomatic hemangiomas occur in about 11 to 14 percent of

cases,94,95 although the frequency of symptoms increases when

only massive lesions are considered. Symptoms arising from

hepatic hemangiomas are most likely secondary to pressure or

displacement of adjacent anatomical structures by the lesion.The most common presentations are upper right quadrant pain

Figure 2. MR depiction of FNH incidentally found in a 33-year-old woman. (A) Axial fat suppressed T2-weighted image shows a right lobe liver FNH

that is minimally hyperintense relative to liver with a higher signal intensity central scar. (B ) Axial arterial phase gadolinium enhanced T1-weighted

image shows enhancement of the FNH but not the central scar. (C ) Delayed phase gadolinium enhanced T1-weighted image shows reversal of

contrast with washout of the FNH and delayed scar enhancement.



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or a mass felt in the epigastrium.96 Other common symptomsinclude severe pain, nausea, dyspepsia, early satiety, vomiting,weight gain, and hepatomegaly may be appreciated. The factthat these symptoms sometimes remain after a hemangioma

has been surgically excised suggests that these lesions may notalways be responsible for the discomfort. Rarely, large heman-giomas can result in consumptive coagulopathy manifesting asthrombocytopenia, disseminated intravascular coagulation,and systemic bleedinga condition known as KasabachMerrittsyndrome (KMS).97

Hepatic biochemical tests are unrevealing in hemangioma asthese lesions do not generally affect liver function except incases of obstructive jaundice or KMS. Imaging studies aresufficient to establish a diagnosis noninvasively (Figure 3). CTor MRI are used to determine the nature of the tumor, andconventional US can diagnose it as well. Dynamic CT is suffi-cient in most cases, but MRI should be used when the lesions

are less than 3 cm, close to the heart, or close to intrahepaticvessels. The use of contrast agents in US, when available, hassignificantly increased both the sensitivity and specificity of thisimaging modality and can be used to diagnose hepatic heman-giomas.98

Invasive diagnostic procedures are not necessary for detect-ing hemangiomas. Angiography can be helpful in identifyingthese lesions as the slow blood flow characteristic of hemangi-omas gives it a cotton-wool-like appearance,99 but it is cur-rently not used given the very high specificity of noninvasiveimaging studies in diagnosing this lesion. Biopsy should beavoided because of the high risk of bleeding involved. As a rulethere is no need for follow-up imaging studies unless there wasuncertainty in the diagnosis or if patients develop symptoms.

Hemangiomas can occasionally change in size thus deviatingfrom the norm.100

A conservative approach is recommended for the manage-ment of hepatic hemangiomas. Most hemangiomas remainasymptomatic and stable over time and surgical treatment forthe prevention of rare complications is not justified.101 There issome suggestion that very large lesions present an added riskfor spontaneous rupture or rupture because of trauma, butreports in the literature of such events are sparse.102 Surgicalintervention is rarely required, and should only be recom-mended if hemangiomas are shown to be very symptomatic andthe relative risks of surgery are well discussed. Enucleation maybe a safer option than resection, but much depends on location

and size.103

Radiofrequency ablation104

and cryoablation105

havealso demonstrated some success in treating hemangiomas. Liver

transplantation is rarely indicated for these lesions, and the fewcases that have been reported are associated with KMS. 106 Ex-tracorporeal hepatic resection is a very radical approach thathas been proposed as an alternative mode of dealing with

anatomically challenging hemangiomas.107

Nodular Regenerative Hyperplasia

Nodular regenerative hyperplasia (NRH) is a benignhepatic condition in which normal hepatic parenchyma istransformed into small regenerative nodules. Most investiga-tors consider NRH to be a secondary consequence of alteredblood flow: according to this model, obstructive portal venopa-thyeither thrombosis or phlebitiscauses ischemia, which inturn leads to hyperplasia of hepatic acini with adequate bloodflow in order to compensate for atrophied hepatocytes. Thesehyperproliferative responses form nodules separated by atro-phic areas with little to no fibrosis. NRH has a prevalence of 2.1

to 2.6 percent in the general population,108,109

and is oftenassociated with other diseases, leading to the increased fre-quency of 5.3% in individuals over 80 years old.109

NRH most commonly presents in middle-aged and olderpatients reflecting the connection between NRH and its asso-ciated diseases.108 NRH has been associated with various con-ditions that include immunological and hematological disor-ders, cardiac and pulmonary disorders, several drugs and toxins,neoplasias, and organ transplantation (Table 4). There is noapparent relationship between NRH and gender.108,109

Grossly, NRH does share common features with micronodu-lar cirrhosis; however, using 3 histological criterianodules ofregenerative hepatocytes separated by atrophic parenchyma, anabsence of fibrous septa between nodules, and curvilinear com-

pression of the central lobuleNRH can be distinguished fromcirrhosis.110112

NRH is rarely symptomatic. In most cases, the disease isdiscovered incidentally during work-up of an associated disor-der. When clinical symptoms of NRH do manifest they mostoften present with hepatomegaly and features of portal hyper-tension, ascites, splenomegaly, or esophageal varices.108,109,113

Changes in hepatic biochemical tests are not generally observed,but when present they are nonspecific and therefore are unhelp-ful in establishing a diagnosis.109,113 Imaging studies are unableto establish a definitive diagnosis for NRH as the lesions areoften too small to distinguish radiographically, and when ob-served they are difficult to differentiate from the regenerating

nodules of cirrhosis.114

Biopsy remains the definitive methodfor establishing a conclusive diagnosis.

Figure 3. CT illustration of the char-

acteristic enhancement features of

liver hemangioma. Axial (A ) arterial

and coronal (B ) portal phase en-

hanced CT images show progressive

discontinuous peripheral nodular en-

hancement.



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Table 4. Diseases Associated With NRHa

Immunological Hematological Drugs and toxins

Cardiac and pulmonary

disorders

Autoimmune Myeloproliferative neoplasms Chemotherapeutic agents Cardiac N

Polyarteritis nodosa Chronic myelogenous leukemia 6-Thioguanine Congenital heart disease

Rheumatoid arthritis Primary myelofibrosis (myeloid metaplasia) Busulfan and 6-thioguanine Congestive heart failure

Feltys syndrome Polycythemia vera Doxyrubicin Myocardial infarction

Systemic lupus erythematosus Essential thrombocytosis Cyclophosphamide Endocardial cushion defect

Progressive systemic sclerosis Chlorambucil Infections, endocarditis O

Antiphospholipid syndrome Lymphoproliferative neoplasms Cytosine arabinoside

Primary biliary cirrhosis Chronic lymphocytic leukemia Bleomycin Pulmonary

Celiac disease Hodgkins lymphoma Carmustine Pulmonary emphysema

CREST syndrome Non-Hodgkins lymphoma Oxaliplatin Bronchial asthma

Primary Sjgrens syndrome Waldenstrms macroglobulinemia Azathioprine Interstitial pneumonia Polymyalgia rheumatica Pulmonary hypertension

Lymphocytic thyroiditis Other HIV drugs Tuberculosis

Schnitzler syndrome Thrombotic thrombocytopenic purpura Nevirapine

Sickle cell anemia Didanosine

Immunodeficiency Mastocytosis IL-2 therapy

Hypogammaglobulinemia Aplastic anemia

Common Variable Immunodeficiency Other

Hyper IgM syndrome Toxic oil syndrome

Bruton syndrome Anabolic androgenic steroids

HIV patients 6-Mercaptopurine

Acquired protein S deficiency

Thrombophilia

HIV, human immunodeficiency virus; IL, interleukin.

aThis table has been reproduced in the supplementary material along with its complete references (Supplementary Table 1).


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Treatment of NRH is geared toward management of theunderlying etiological condition (see Table 4). In cases of NRHcomplicated by portal hypertension, treatment options includebeta-blocker prophylaxis and/or endoscopic therapy for esoph-ageal varices, pharmacologic therapy of ascites, and surgicalshunting procedures or transjugular intrahepatic portosystemicshunts (TIPS).115 NRH leading to liver failure can also betreated by liver transplantation, although the requirement forthis procedure is extremely rare.116

Cystic Lesions of the Liver

Simple Hepatic Cyst

Simple hepatic cysts (SHC) are though to be congeni-tally derived hepatic lesions that are being discovered inciden-tally at greater frequencies during abdominal imaging studies.Defects of intrahepatic bile duct formation in utero likely giverise to ductules that lack a connection to the rest of the biliarysystem; these aberrant ductules eventually dilate to form SHC.

Evidence has been found of bile duct epithelium in the cysticlining of SHC, giving credence to the hypothesis of its congen-ital biliary etiology.117 Autopsy and laparotomy series put theincidence of these lesions in the general population at 0.2% to1%.117,118 Ultrasound studies have found that the actual fre-quency of these lesions is far greater, being anywhere from 2.5to 10.5 percent in the general population.119,120 The number ofclinically relevant cysts, however, remains low.

SHC are found most often in older patients, with the inci-dence of these lesions increasing dramatically in individualsover 60.119 Table 5 summarizes the common clinical features ofthe cystic hepatic lesions discussed. When only larger, symp-tomatic cysts are considered, the female/male ratio shifts con-siderably with women more often being affected.121 This sug-gests some role for female sex hormones in the development ofthese tumors, but there are no definitive studies to support orrefute this supposition.

Less than 4% of SHC are symptomatic,120 but larger cysts,especially those greater than 5 cm, have a higher associationwith symptomatic manifestation.122 Upper right quadrant orepigastric pain is the most common symptom (see Table 5 forothers). Patients can present with jaundice, portal hypertension,and hepatomegaly.123 Most symptoms associated with SHCseem to be related to the obstructive effect these lesions have

within the liver and on adjacent viscera. Hemorrhage, rupture,and infection are other potential causes of symptoms.

Diagnosis of SHC can be accomplished in most cases usingUS, which is both highly sensitive and specific for these le-sions.124 Hemorrhage into an SHC can complicate a clear diag-nosis because of the similar appearance of hemorrhagic cysts tobiliary cystadenomas and cystadenocarcinomas.123 A recent re-port has suggested that contrast-enhanced US can be used todifferentiate between SHC and other cystic lesions.125 Hepaticbiochemical tests are generally unrevealing; however, serumlevels of carbohydrate antigen 19-9 (CA19-9) are usually normalor slightly elevated in SHC when compared with biliary cysta-denoma or cystadenocarcinoma where higher levels of serumCA19-9 are observed.126 In most cases, the expense of CT orMRI, along with the accuracy of US, make these imaging stud-ies unnecessary in establishing a differential diagnosis for SHC.Diffusion-weighted MRI, however, can differentiate SHC fromhydatid cysts if the diagnosis is unclear.127

Treatment of SHC should be conservative because of their

generally benign nature. Complications that merit medicalintervention include hemorrhage,123 rupture,128 and infec-tion,120,121 although such cases are rare. When complications dopresent or symptoms become unmanageable, treatment optionsfor SHC include percutaneous aspiration,129 alcoholic sclero-therapy,121 open or laparoscopic deroofing,130 cystojejunos-tomy,131 cystectomy, and partial hepatic resection.121,132 Surgi-cal intervention has been shown to be effective in reducing oreliminating symptoms.133 Aspiration therapy is generally asso-ciated with very high rates of recurrence, and is therefore notrecommended for long-term treatment of SHC.121 Laparoscopicfenestration appears to achieve the best results when morbidity,mortality, recurrence, and additional surgical procedures are allconsidered.131,132 Partial resection is rarely needed and shouldbe reserved for cases in which laparoscopy is anatomicallyunfeasible.

Polycystic Liver Disease

Polycystic liver disease (PCLD), like SHC, is thought toarise from aberrant formation of fetal bile ducts that have noconnection with the biliary system. It is possible that biliarymicrohamartomas (von Meyenburgs complexes) evolve into thelarger cysts that are observed in PCLD patients; the number ofbiliary microhamartomas in adjacent hepatic parenchyma is

Table 5.Clinical Features of Cystic Hepatic Lesions

SHC PCLD HBCA

Incidence (%) 0.210.5 0.131 3.54.6 of primary biliary tumors

Sex ratio (M:F) 1:1.56 1:2.514.5 1:9 or more

Mean age range (y) 5070 4050 4060

Size range (cm) 1 to 30 325 2.545

Percent single 6875 None 8090

Dominantly affected lobe Right Bilateral distribution None

Estrogen sensitive Unknown Possibly Possibly

Presenting symptoms RUQ or epigastric pain; abdominal

distension; abdominal mass;

nausea; vomiting; fatigue;

dyspnea; fever; early satiety

Abdominal pain; nausea; vomiting;

early satiety; fatigue; dyspnea;

hepatomegaly; palpable mass

RUQ or epigastric pain; abdominal mass;

dyspepsia; anorexia; nausea;

occasional vomiting; fever

Serum tumor markers CA19-9 may be elevated CA19-9 generally elevated CA19-9 and CEA may be elevated

F, female; M, male.



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directly proportional to the size of the cysts, suggesting thatthese microhamartomas are the pathological forerunners of thecystic lesions. A major distinction between SHC and PCLD isthat the latter has a strong genetic component resulting in theformation of multiple cysts within the liver. Using phenotypicdata, Gigot et al defined 3 types of the disease depending on the

number of hepatic cysts and the amount of normal parenchymaremaining.134 From both a genetic and a clinical perspective,however, what presents as PCLD is in fact 2 distinct diseasesthat give rise to polycystic liver disease. Most patients withPCLD have concomitant polycystic kidneys, and the underlyinggenetic mutation is in either PKD1 or PKD2.135 These mutationsare inherited in an autosomal dominant manner, so patientswith this condition actually have autosomal dominant polycys-tic kidney disease (ADPKD) with associated polycystic liver(Figure 4). Isolated PCLD (IPCLD), by contrast, can be broughtabout by at least 2 mutations distinct from those of ADPKD.Mutations in PRKCSH136 and SEC63,137 encoding hepatocystinand Sec63p, respectively, have been strongly associated as etio-logical factors in IPCLD. These 2 proteins are associated with

the endoplasmic reticulum, and are involved in carbohydrateprocessing, folding, and the translocation of newly synthesizedglycoproteins, although the exact mechanisms by which theseproteins give rise to multiple hepatic cysts are unknown.

PCLD has a reported frequency in the general populationranging from 0.13% in autopsy series to 0.9% in US stud-ies.120,138 Most patients have ADPKD, with the remainder hav-ing IPCLD.132,138 It is possible that other, as yet unidentifiedmutations, are also etiologic sources of the disease. There ap-pears to be a strong predilection for this disease among females(Table 5). This gender imbalance has led investigators to believethat estrogen concentrations are involved in disease pathogen-esis, and evidence to support this includes the presence of

estrogen receptors on cholangiocytes where normally they arenot expressed.139

Symptoms of PCLD are summarized in Table 5. Rupture orhemorrhage into a cyst can present as an acute abdomen. Othercomplications include infection, portal hypertension, biliaryobstruction, and rarely, cholangiocarcinoma.140 In 1 series, asignificant number (84%) of patients with this disease werereported to be symptomatic.141 Hepatic synthesis is usuallypreserved in PCLD. CA19-9 levels, which are generally indicativeof malignant growth, are significantly higher in patients withPCLD as compared to those with SHC.142 While this does notassist in the diagnosis of PCLD, cystadenoma and cystadeno-carcinoma must be excluded in order to determine the mostappropriate mode of treatment. CA19-9 serum levels can beused to assess the efficacy of treatment.

Asymptomatic cysts are not clinically relevant and should bemanaged conservatively. The interventional armamentariumfor symptomatic cysts includes aspiration with sclerotherapy,open or laparoscopic fenestration, partial resection, or livertransplantation (with or without simultaneous kidney trans-plant).131,132,143 Sclerotherapy using ethanolamine oleate has

had promising results as compared with other sclerosingagents.144 Combination therapies of resection and fenestrationhave also been used to good effect.143 Laparoscopic deroofing isassociated with lower morbidity and higher success rates thanlaparotomy procedures132; however, unroofing of some cysts isusually followed by growth of other cysts. The appropriatetreatment modality can be very challenging to determine, andshould be based on the size and distribution of symptomaticcysts, hepatic vascular anatomy, and hepatic reserve. Whenmultiple cysts are present, it is quite difficult to determinewhich cyst(s) might be responsible for the symptoms. A prelim-inary report has demonstrated that liver volume can be reducedwith the use of lanreotide,145 although its use is currentlyconsidered investigational. Liver transplantation can be consid-ered in very severe cases where there is associated portal hyper-tension, muscle wasting, and massive hepatomegaly.143

Hepatobiliary Cystadenoma

Hepatobiliary cystadenomas (HBCAs) are primary cysticneoplasms of the biliary tree whose definitive etiology remainsunclear. Some investigators speculate that HBCAs are deriva-tives of intrahepatic ovarian heterotopia or ectopic intrahepaticgallbladder rests, while others consider these tumors the prod-ucts of aberrantly-formed bile ducts. There is a general consen-sus that these cysts are congenitally derived. HBCAs can bedivided into a few subtypes: HBCAs can be either mucinous orserous, with the mucinous type being far more common; fur-

ther, HBCAs can be categorized based on the presence or ab-sence of an ovarian-like mesenchymal stroma between theinner epithelial lining and the outer fibrous capsule.146 Theincidence of these lesions in the general population is small, asHBCA make up only 3.5 to 4.6 of the total number of intrahe-patic cysts of bile-duct origin.147,148 In practice, however, theseare the most commonly encountered primary cystic neoplasmsof the liver, comprising up to 10% of all cysts greater than 4 cmin size.121

HBCAs are found predominantly in middle-aged individuals,and have a much higher prevalence among females. The clinicalfeatures of HBCA are summarized in Table 5.146,148 Tumorstend to be large compared with other hepatic lesions; in the

largest series, tumor size averaged greater than 10 cm.146

MostHBCAs are multiloculated with internal septations. Other com-

Figure 4. Coronal T2-weighted image shows multiple liver and renal

cysts in a 43-year-old woman with autosomal polycystic liver and kid-

ney disease.



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Table 6. Management Strategies for Benign Solid and Cystic Hepatic Tumors

Associated complications

(rate if known)

Malignant potential

(rate if known) OCP use Pregnancy Biopsy (yes or no) Follow-up

HCA Hemo rrhag e a nd s po ntane ous

rupture (11%29%)

Yes (5%10%), almost

exclusively of

-catenin subtype

Discontinue Generally contraindicated,

but can be

individualized if carefully

managed

Generally no. In select

cases if diagnosis is

uncertain and

histologic, genetic,

and molecular

markers to be used

Confirm diagnosis and

if treatment is conse

LA Hemorrhage and rupture Yes Discontinue Generally contraindicated,

but can be


managed

Same as for HCA Monitor

THCA Hemorrhage and rupture Unknown Discontinue Generally contraindicated,

but can be


managed

Same as for HCA Investigate treatment o

FNH A ss oci atio n with o the r va sc ula ranomalies; spontaneous

rupture is extremely rare

Rare if any Not absolutelycontraindicated

Not contraindicated No Classic features requirefollow-up; atypical les

should be monitored

NRH P orta l hype rtens io n; a sc ites ;

esophageal varices

No Not

contraindicated

N ot contraindicated Yes Determine underlying d

Hemangioma Rare: obstructive jaundice;

consumptive coagulopathy

No Not absolutely

contraindicated

Not contraindicated No Classic features require

follow-up

SHC Rare: o bs tructive ja un di ce;

portal hypertension;

hemorrhage; rupture;

infection

No Not

contraindicated

Not contraindicated No Monitor

PCLD Hemorrhage; rupture; infection;

portal hypertension; biliary

obstruction

Rare Not

contraindicated

Not contraindicated No Monitor closely with im

HBCA Obstructive jaundice, chronic

cholecystitis, and

cholelithiasis (1/3 of

clinically relevant cases)

Yes (as high as 26%) Not

contraindicated

Not contraindicated No Investigate surgical opt


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mon features are focal calcification, nodularity, and septalthickening. Approximately 90% of HBCAs are intrahepatic andthe remaining 10% arise in the extrahepatic biliary tree. 147,148

The much higher incidence in women suggests an involvementof female sex hormones in mediating tumor development, andstudies have demonstrated the presence of estrogen and pro-gesterone receptors within the mesenchymal stroma of mostHBCAs.149

Cytoplasmic analysis of these lesions has revealed positivityto CK7, CK8, CK18, and CK19 in the inner epithelial layer,which are the typical findings of biliary epithelium.149 Reportshave been inconsistent regarding the levels of CA19-9 andcarcinoembryonic antigen (CEA) in the cystic fluid and serumof affected patients with some indicating increased levels150

while others note normal levels of these tumor markers.151 Theabsence of CA19-9 or CEA cannot rule out HBCA, but itspresence should alert physicians to the possibility of a biliarycystadenoma or cystadenocarcinoma.

The symptoms associated with HBCA are likely a result of

mass effect (Table 5). Complications of HBCA are obstructivejaundice, chronic cholecystitis, and cholelithiasis.147 Jaundicecan be present in up to one-third of clinically relevant cases.152

Diagnosis of HBCA is dependent on imaging studies, althoughthe features that are characteristic of HBCA can also be ob-served in other lesions, and it is often difficult to distinguishHBCA from other lesions such as hydatid cysts and hepatobi-liary cystadenocarcinomas.153 The features that characterizeHBCA include a multiloculated lesion with internal septations,thickened or irregular walls, calcifications, papillary projections,mural nodules, and a surrounding fibrous capsule.151,154 MRIusing gadoxetic acida liver-specific contrast agent that is elim-inated by the biliary systemmay prove useful in diagnosingHBCA.155 Fine needle aspiration is not sensitive or specificenough to aid in the diagnosis, making histological examina-tion the only definitive means of differentiation HBCA fromother possible lesions.153

There is much evidence to suggest that HBCA can undergomalignant transformation and become a hepatobiliary cystade-nocarcinoma (HBCAC). Areas of benign HBCA epithelium aredetected in a large number of HBCACs.146148 In addition, theaverage age of individuals with HBCAC is at least a decadeolder than patients with HBCA, which supports the notionthat cystadenomas naturally progress toward a carcinogenicstate.146148 If all HBCACs arise from HBCA precursors, the rateof malignant transformation may be estimated at 26 percentbased on the largest series in the literature. 146 The threat of

malignant development, coupled with the difficulties in accu-rately differentiating HBCAs from their malignant counter-parts, dictates that conservative management is not appropriatewhen HBCA is included in a differential diagnosis. Aspirationhas been associated with a 100% recurrence rate, and subtotalresection does not resolve symptoms in the majority ofcases.121,146 Complete resection of these lesions is recommendedin cases of HBCA.121,154

Miscellaneous Lesions

There are many other benign hepatic tumors and cyststhat also deserve mention. These include mesenchymal hamar-tomas, hemangioendotheliomas, angiomyolipomas, focal fatty

infiltrates, inflammatory pseudotumors, macroregenerativenodules, Carolis disease, and traumatic cysts. In addition, liver

lesions may be secondary to bacterial, parasitic, fungal, andgranulomatous liver disease, which can lead to pyogenic andamebic liver abscess formation, echinococcal and hydatid cysts,and hepatic grandulomas. The etiologies of these various le-sions are many and their prompt and accurate diagnosis de-pends on a high degree of clinical suspicion and a thoroughpatient history. Furthermore, although outside the scope of thisreview, the consideration of HCC must always remain at theforefront of the physicians mind when characterizing a newlydiscovered hepatic lesion, particularly in the case of patientswith hepatitis B or C infection.

Summary

Incidentally discovered liver masses are an increasingphenomenon associated with the widespread use of imagingstudies for diagnostic work-up. A significant number of theseincidentalomas are benign and require no intervention on thepart of the physician. One of the greatest obstacles faced is the

accurate diagnosis of such lesions, both to provide a measure ofpsychological comfort for patients as well as to insure that aconservative approach is appropriate. The use of biopsy indiagnosing these tumors has been largely mitigated by theincreased sensitivity and specificity of an assortment of imagingmodalities (Table 2). New biomolecular and genetic criteriahave allowed physicians to subclassify many benign lesions inorder to tailor patient care more appropriately (Table 3); how-ever, these markers are investigational and have not yet achievedthe status of standard of care. Ultimately, the simple fact is thatmost individuals live and die with a benign liver tumor ratherthan from them, and minimizing unnecessary intervention iscritical in providing the best possible care.

The differential diagnosis for an incidental hepatic massmust incorporate multifarious factors ranging from patientcharacteristics, history of hormonal and other drug therapies,comorbidities, and radiographic findings. The role of immuno-histochemical and genetic markers needs to be explored further.Taken together, these data provide valuable clues that can helpestablish a definitive diagnosis and help guide patient manage-ment. It is prudent to employ follow-up imaging before havingthe knee-jerk response of taking a biopsy of all lesions, due inpart to the risk of bleeding and other complications associatedwith this procedure, as well as the challenges of obtaining areliable histologic diagnosis. Further, the vascular nature ofmany hepatic lesions, along with the fact that focal biopsiesmay not detect areas of malignancy in heterogeneous lesions,

argue against the routine use of a biopsy.Recent observations have redefined the classification of sev-

eral lesions and have concomitantly led to distinct recommen-dations for their care. Table 6 summarizes recommended man-agement strategies for the lesions covered in this review. Benignlesions should be managed conservatively whenever possible.Indications for surgical intervention include unmanageablesymptoms, a high probability of complications such as hemor-rhage and rupture, and the threat of malignant transformation.The treatment options outlined and the recommendationsherein given provide a general outline for dealing with benignhepatic tumors; however, in appropriately selecting a mode oftherapy, the individual needs of the patient, and the availability

of the local expertise, must always be considered as the overar-ching guide to successful patient care.



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Supplementary Material

Note: To access the supplementary material accompa-nying this article, visit the online version of Clinical Gastroenter-ology and Hepatology at www.cghjournal.org, and at doi:10.1016/

j.cgh.2011.03.007.

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Reprint requests

Address requests for reprints to: K. Rajender Reddy, MD, University

of Pennsylvania, 2 Dulles, 3400 Spruce Street HUP, Philadelphia,

Pennsylvania 19104. e-mail: [email protected]; fax:

(215) 615-1601.

Conflicts of interest

The authors disclose no conflicts.

mailto:[email protected]:[email protected]:[email protected]


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Supplementary Material

Tumor Pathology

HCA. HCAs are hypervascular lesions that tend to

bulge from the surface of the liver and have large blood vesselsrunning across the surface, but can also be intrahepatic. The

tumors are well demarcated from the surrounding liver but lacka true fibrous capsule, which makes diffuse hemorrhagethroughout the liver and peritoneum more likely. On micro-scopic analysis the tumors are composed of benign hepatocytes

arranged in sheets and cords with thin-walled vascular channelsscattered throughout the tumor. Bile ducts are generally absentfrom these lesions.

THCA. THCA has typical features that differentiate itfrom both classical focal nodular hyperplasia (FNH) and HCA.Grossly these lesions can resemble HCA, although they appear

tan to pale brown with congested red areas being present inlarger lesions. The abnormal vessels that make up THCA draindirectly into the adjacent sinusoids, which can be variably

dilated, and a few fibrous septa can be found as well. In com-parison with HCA, THCA can be lobulated with dystrophicarteries and a ductular reaction.

FNH. In the classic form of FNH, observed in about 80

percent of cases, the lesion is characterized by hyperplasia witha central stellate scar radiating into distinct nodules. Ductulardifferentiation and malformed vessels associated with nodular

hepatic parenchyma are also commonly observed features ofFNH. Very rarely are these lesions encapsulated or peduncu-lated, nor is it common for calcification to be present in FNH.

Hemangioma. Histologically, hemangiomas are com-posed of large vascular spaces lined by a single layer of epithe-lium and separated by fibrous septa. They are usually discrete,

well-circumscribed masses that appear dark purple upon grossexamination. Normally, the lesions collapse when blood is re-moved and demonstrate a honeycombed surface. Older hem-

angiomas may have areas of scarring or calcification. Grossly,when fibrosis occurs, it usually begins centrally and can causethe lesion to appear firm and white.

NRH. Histologically, NRH converts normal hepaticparenchyma into dif

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