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CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2011;9:547562

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, and Department of Surgery, Division of Transplantation, University of Pennsylvania, Philadelphia, Pennsylvania

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

The widespread use of imaging analyses, either routinely or to evaluate symptomatic patients, has increased the detection of liver lesions (tumors and cysts) in otherwise healthy individuals. Although some of these incidentally discovered masses are malignant, most are benign and must be included in the differential diagnosis. The management of benign hepatic tumors ranges from conservative to aggressive, depending on the nature of the lesions. New imaging modalities, increased experience of radiologists, improved denition of radiologic characteristics, and a better understanding of the clinical features of these lesions have increased the accuracy of diagnoses and reduced the need for invasive diagnostic tests. These advances have led to constant adjustments in management approaches to benign hepatic lesions. We review the biologic and clinical features of some common hepatic lesions, to guide diagnosis and management strategies. Keywords: Adenoma; Hepatocellular; Hyperplasia; Hemangioma; Polycystic Liver Disease; Cystadenoma.

Solid Lesions
he clinical features of several solid hepatic lesions are summarized in Table 1. The pathology and histology of the major lesions are discussed in the Supplementary Material.

right hepatic lobe (Table 1).3,4 Liver adenomatosis has been variably dened as having anywhere from 3 to 10 adenomas, and is generally considered a separate entity from a solitary 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 denitive.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 receptors 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 in tumor development. Along with OCP use, several metabolic conditions and therapeutic 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.15 Another 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 ultrasound; CK, cytokeratin; CRP, C-reactive protein; CT, computed tomography; 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, inammatory hepatocellular adenoma; IPCLD, isolated polycystic liver disease; KMS, Kasabach-Merritt Syndrome; LA, liver adenomatosis; L-FABP, liver fatty acid binding protein; MRI, magnetic resonance imaging; NCAM, neuronal cell adhesion molecule; NRH, nodular regenerative 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/$36.00 doi:10.1016/j.cgh.2011.03.007

Hepatocellular Adenoma
Hepatocellular adenoma (HCA) is a benign neoplasm that tends to develop in individuals with a hormonal or metabolic abnormality that can stimulate hepatocyte proliferation. A consecutive autopsy study found a frequency of these lesions at 12 per 100,0001 while an ultrasound (US) study found the incidence to be 7 per 100,0002; however, there was a marked increase in the incidence of these lesions after the introduction of oral contraceptive (OCP) therapy such that the estimated incidence in women not taking OCPs was 1 to 1.3 per million with an increase to 3.4 per 100,000 in women taking estrogen therapy3 suggesting a causal relationship between OCPs and hepatic adenomas. HCAs are found predominantly in women in their third and fourth decades and are most often solitary and located in the

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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 patients with GSD who develop HCA from a female predominance to a 1:2 male predominance, and the incidence of adenomas increases dramatically for patients with GSD over 25 years of age. Management of HCA in patients with GSD differs from conventional therapy. Continuous nocturnal feeding has been shown to result in a decrease in tumor size in some patients with GSD.17 Despite this, hepatocellular carcinoma (HCC) has been known to develop in the background of HCA,18,19 and while surgical resection is associated with higher morbidity in GSD patients, surgical intervention, whether resection or liver transplantation, appears to be the prudent course.20 Antiepileptic drugs21 and hepatic hemosiderosis have also been connected to HCA development.22 Notwithstanding these myriad risk factors for HCA, otherwise healthy patients both male and femalewith no history of OCP, anabolic androgenic steroids (AAS), or antiepileptic drug use, and no underlying metabolic conditions have been known to develop these lesions. HCA are often symptomatic, being discovered incidentally in just 12 to 25 percent of cases,3,23 although this may be changing given the increasing frequency of imaging studies and the greater likelihood of discovering them incidentally. Common presentations are summarized in Table 1. Imaging studies of HCA are difcult to analyze because of the heterogeneous nature of these lesions (Table 2). Within the past decade, HCAs have been broadly categorized into 4 subtypes based on genetic and pathological criteria: 36% 46% of patients have hepatocyte nuclear factor-1 (HNF1 ) inactivating mutations; 18% 44% have the inammatory subtype (IHCA); 5% present with a -catenin activating mutation, and an additional 7% have a -catenin mutation with IHCA features, making the prevalence of -catenin mutations 13%14% overall. Currently 9%23% cannot be phenotypically or genetically categorized.24 26 A more recent study found that when characterized pathologically, the various HCA subtypes are associated with specic magnetic resonance imaging (MRI) patterns;27 these typical MRI ndings may make it possible to noninvasively determine the subtype of HCA without resorting to biopsy. Enhancement with gadobenate dimeglumine on MRI has also been helpful to differentiate HCA from focal nodular hyperplasia (FNH).28 Triple phase computed tomography (CT) can be used to image these lesions,29 andalthough not yet clinically used in the United States while awaiting Food and Drug Administration (FDA) approvalEuropean studies in contrast-enhanced ultrasound (CEUS) demonstrate promising results for diagnosing HCA.30 A denitive diagnosis, however, is difcult to establish by imaging alone (Figure 1). Biopsy can be of risk in HCA because of the vascular nature of these lesions and their propensity to hemorrhage. Nevertheless, new genetic and molecular criteria have been established that can establish a denitive diagnosis, which can be benecial in the management of these tumors. While there is some benet in obtaining a biopsy, at this stage it should be reserved for select cases where genetic and molecular diagnostic tools are available and are deemed necessary in making treatment decisions. Table 3 summarizes pertinent information that can be obtained 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 for these lesions to hemorrhage and the slim but real possibility of

Table 1. Clinical Features of Solid Hepatic Lesions

Hepatic biochemical tests

1 10 6 1 10 6 to 1.2 10 4 0.33 to 1.2 10 4 1:815 1:815 1:9 or more 1:517 3040 3040 3040 3040 122 122 0.115 0.119 6080 6080 2040 7681 Yes (causally related) Yes (causally related) Yes Possibly Chronic RUQ or epigastric pain; Chronic RUQ or epigastric pain; Chronic RUQ or epigastric pain; Epigastric or abdominal palpable mass; sudden acute palpable mass; sudden acute palpable mass; sudden acute pain; palpable mass; pain; circulatory collapse; pain; circulatory collapse; pain; circulatory collapse; hepatomegaly; weight malaise; chronic iron anemia malaise malaise loss; asthenia; fever Elevated transaminase levels Elevated transaminase levels Generally normal Generally normal and AP and AP 1 10
6

HCA

LA

THCA

FNH

Possibly RUQ pain; tumor mass in epigastrium; severe pain, nausea, dyspepsia, early satiety; vomiting; weight gain; hepatomegaly Generally normal

Hemangioma

0.420 1:26 3050 1 to 30 7193

Incidence (%) Sex ratio (M:F) Mean age range (y) Size range (cm) Percent single (%) Estrogen sensitive Presenting symptoms

F, female; M, male.

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Table 2. Imaging Studies


US HCA Heterogeneous; hyperechoic if steatotic but anechoic center if hemorrhage CEUS Arterial phase: hyperenhancement; hypoenhancement in portal phase and no enhancement in late phase CT Well demarcated with peripheral enhancement; homogenous more often then heterogeneous; hypodense if steatotic, hyperdense if hemorrhagic MRI HNF1 : signal lost on chemical shift; moderate arterial enhancement without persistent enhancement during delayed phase IHCA: markedly hyperintense on T2 with stronger signal peripherally; persistent enhancement in delayed phase -catenin: inammatory subtype has same appearance as IHCA; noninammatory is heterogeneous with no signal dropout on chemical shift, isointense of T1 and T2 with strong arterial enhancement and delayed washout T1: heterogeneous and well dened iso- to hyperintense mass Strongly hyperintense with persistent contrast enhancement in delayed phase

THCA

Variable appearance

FNH

Generally isoechoic

Subcapsular feeding arteries with mixed or centripetal lling; arterial phase shows hyperenhancement with hypoenhancement and no enhancement in the portal and late phases, respectively Arterial phase: hyperenhancement; portal and late phases: isoenhancement

Hypo- to isoattenuating

NRH

Isoechoic/hyperechoic

Isoenhancement during arterial, portal, and late phases Arterial phase: discontinuous peripheral nodular enhancement; progressive and centripetal ll in the portal and late phases No enhancement during arterial, portal, or late phases. Lack of enhancement because of avascularity

Hemangioma

Hyperechoic with welldened rim and with few intranodular vessels Homogeneous anechoic uid-lled space without clear walls and with posterior acoustic enhancement Anechoic with irregular walls and internal septations

SHC

Central scar. Arterial phase shows homogenous hyperdense lesion; returns to precontrast density during portal phase, which is hypo- or isodense Nonenhancing nodules, sometimes hypodense, with variable sizes (most sub-centimeter) Discontinuous peripheral nodular enhancement isoattenuating to aorta with progressive centripetal ll in Isodense to water (because of lack of vascularity); well demarcated

T1: isointense or slightly hypointense. Gadolinium produces early enhancement with central scar enhancement during delayed phase T2: slightly hyperintense or isointense T1: hyperintense T2: varied intensity (hypo/iso/hyperintense) T1: hypointense; discontinuous peripheral enhancement with centripetal ll in T2: hyperintense relative to spleen T1: hypointense (no enhancement with gadolinium) T2: hyperintense to spleen and isointense relative to simple uid BENIGN SOLID AND CYSTIC LESIONS OF THE LIVER

HBCA

Arterial phase: hyperenhancement of cystic wall, internal septations, and intracystic solid portion; enhancement washes out progressively; hypoenhancement during portal and late phases

Isodense lesion with well-dened thick wall, mural nodules, and internal septations

T1: multilocular mass with homogenous hypointensity

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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.

malignant transformation. Hemorrhage has been reported in 11 to 29 percent of HCA cases.36,37 Almost all cases of spontaneous rupture occur in lesions greater than 5 cm.7 Management of a hemorrhagic lesion varies depending on the severity of bleeding. To avoid the complications associated with emergency hepatectomy, conservative management using blood products with the hope of achieving hemodynamic stability has

been suggested as a temporary approach.38 However, such a strategy may not be successful in some cases because of ongoing hemorrhage. Other methods of management include controlling bleeding by packing the liver, emergency hepatectomy, embolization of the right or left hepatic artery, and urgent liver transplantation.38,39 Embolization using interventional radiology with later planned elective liver resection is a commonly

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


Lesion HCA HNF1 (36%46%) Pathological/histological characteristics Informative immunohistochemical staining Clonality Genetic associations

Inammatory (18%44%)

-catenin (13%14%)

THCA (subtype of inammatory HCA) FNH

Intratumoral steatosis, lobulated contours, microadenomas, association with additional benign tumors, without inammatory inltrate or cytological abnormalities Tumoral peliosis, steatosis in background liver, inammatory inltrate, sinusoidal dilation, dystrophic vessels, telangiectasias, ductular reaction, micro- and macroscopic hemorrhage more frequent, BMI 25, alcohol consumption Association with elevated risk for HCC, frequently found in male patients (38%), cytological abonormalities, acinar pattern (pseudoglandular formation) High BMI, elevated GGTP, inammatory inltrate Association with other vascular anomalies, classically show central scar

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

SAA, CRP, GS (peripheral hepatocytes Monoclonal eventually positive), CK-7, CK-19, NCAM, CD34

None known

Nuclear -catenin, GS (strong, diffuse staining), CK-7, CK-19, NCAM, CD34

Monoclonal

Mutations in CTNNB1, GLUL and GPR49 overexpressed

Elevated SAA and CRP, CK-7, CK-19, Monoclonal None known NCAM, CD34 GS (staining shows large areas stained in Polyclonal in Elevated Ang1/Ang2 a heterogeneous pattern, with particular 73% of ratio positivity surrounding hepatic veins), cases L-FABP positive, SAA and nuclear catenin negative, CK-7, CK-19, NCAM, CD34

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 presents primarily with bleeding. Approximately 5%10% of HCAs will transform into HCC25,36,40a much larger number than the mortality associated with partial hepatectomy. Malignant transformations 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 HCA progression should discontinue therapy as this may lead to regression of the tumor.9,41 It must be noted, however, that not all tumors regress, and some may even increase in size after cessation of therapy.42 In addition, subsequent HCC development has been reported even when tumors have been observed to regress.43,44 Lesions smaller than 5 cm can probably be managed conservatively as these tumors have rarely been noted to rupture or transform to malignancy,45 although opinions have varied and some believe that HCA should be treated aggressively in order to avoid potential serious complications. In the conservative approach, patients should have follow-up imaging 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, but alpha-fetoprotein is not a reliable marker of malignant transformation as levels are usually normal.46 Treatment options include radio frequency ablation (RFA),47 transcatheter arterial embolization (TAE),48 as well as hepatic resection.4,49

benign liver tumors.32,57 On imaging, THCA typically appears as a well-dened heterogeneous mass (Table 2).55,58 The molecular analysis of THCA in recent years has rmly established these lesions as a subtype of HCA (Table 3).56,57 In addition, the angiopoietin-1/angiopoietin-2 ribonucleic acid (RNA) ratio, as well as the protein cluster prole of THCA, are more similar to HCA.59 Ultimately, this reclassication assists in the management of these lesions because they must be dealt with as aggressively as HCA. THCA are likely to be symptomatic because they often hemorrhage and contain focal areas of necrosis.56,57 Because of the high probability for these lesions to hemorrhage, and because of their unknown potential to degenerate toward malignancy,57 surgery is recommended as the treatment of choice in the case of THCA.

Focal Nodular Hyperplasia


For several years, FNH has been viewed as a hyperplastic, and not a neoplastic, response of hepatic parenchyma to a pre-existing vascular malformation arising during development. More recently, evidence has been published that supports and elucidates this etiological theory of FNH development; in most cases, FNH appears to be caused by a portal tract injury that results in the formation and enlargement of arterial to venous shunts.60 This causes local arterial hyperperfusion resulting in oxidative stress which then triggers a reaction from hepatic stellate cells to form the central scar that is typical of these lesions.61 FNH is the second most common benign hepatic lesion, with an incidence at necropsy ranging from 0.3 to 3 percent.1,62 Clinically relevant tumors, however, are far more rare with a frequency in US studies being just 0.03 percent.2 FNH can have a spectrum of demographic features but is noted predominantly in women in their third and fourth decades (Table 1).63,64 The higher prevalence in women along with evidence that FNH tends to be larger and develop earlier in females has led to the conclusion that female sex hormones play a large role in tumor development, and suggests that OCP use be discontinued in cases of FNH; however, OCP use has not led to changes in these lesions over time, and pregnancy has also not been associated with any observed changes in tumor size.65,66 In 2 case-controlled studies, a slight statistical correlation between OCP use and FNH has been observed,10,67 but, the changes observed are generally subclinical, and it does not appear that modern OCPs contribute in any signicant way to the progression of these tumors. Because of the controversy surrounding this issue, a conservative approach for women with a diagnosis of FNH who wish to continue OCP therapy is to have yearly US studies for 2 to 3 years to monitor any changes in the size of their lesions. By contrast, in non-OCP users follow-up imaging is not necessary for patients with a rm diagnosis of FNH. Most cases of FNH are discovered incidentally, but about 20 to 40 percent may present with symptoms.68,69 Symptoms are summarized in Table 1. FNH is often associated with other vascular anomalies: up to 20% of cases are associated with hepatic hemangioma,70 and other tumors such as HCA and HCC have also been observed in tandem with FNH71,72 observations that are in keeping with the notion that FNH develops in the background of vascular malformations. Imaging techniques designed to differentiate FNH from other hepatic lesions have improved signicantly over the past decade (Figure 2). The identication of classic FNH with its

Liver Adenomatosis
Liver adenomatosis refers to the patient with multiple adenomas, and has been variably dened as anywhere from 3 to 10 adenomas in the liver.5,6 Presentation of adenomatosis, as well as the histological and radiographic features is the same as HCA (Table 1). The optimal mode of management for adenomatosis is not well dened because cases hitherto have been infrequent and the diffuse nature of these lesions makes partial hepatic resection difcult, if not impossible. The various treatment options that have been reported include a conservative approach for patients with smaller lesions,50 resection of the largest symptomatic tumors (generally those 5 cm),51 transcatheter arterial embolization,48 transcatheter arterial chemoembolization (TACE),52 RFA,53 and orthotopic liver transplantation.49 The conservative approach for liver adenomatosis (LA) is the same as in HCA. Resection of larger peripheral lesions may be combined with another localized therapy, such as embolization for remaining lesions. Irrespective of the treatment method selected, patients must be followed closely because of the potential for these lesions to rupture or undergo malignant transformation.54

Telangiectatic Hepatocellular Adenoma


Telangiectatic hepatocellular adenoma (THCA), previously known as telangiectatic focal nodular hyperplasia, has recently been reclassied as a subcategory of IHCA. This shift in classication has been propelled by 2 facts: (1) THCA more closely resembles HCA at the molecular level when compared with FNH; and (2) like HCA, THCA is managed aggressively as opposed to FNH in which a conservative approach is advocated. This lesion is frequently associated with OCP use and/or hormonal therapy,5557 and anywhere from 15% 40% of patients present with another benign liver lesion55,57 (other characteristics are summarized in Table 1). Many patients with THCA are overweightan association that has not been noted with other

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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.

spoke-wheel central scar makes this lesion easy to characterize by imaging (Table 2). Differentiation of these lesions from HCA is crucial as the two are managed very differently. Consequently, cases that are even mildly ambiguous present a challenging problem and require a balance between the risks of surgery against an inconclusive diagnosis. Improvements in hepatobiliary contrast agents, particularly gadobenate dimeglumine, have improved the diagnostic accuracy of MRI.28,73 Recent reports on triphasic and multi-section spiral CT have shown that these imaging modalities can accurately diagnose FNH.74,75 Yet the most drastic improvements have been with the use of CEUS,76 and this has been shown to be at least as accurate as MRI or CT in identifying FNH. While biopsy is rarely required in the case of FNH, new histopathological characteristics have recently been identied that help differentiate these tumors from HCA and HCC (Table 3). It must be noted, however, that at this stage these markers are investigational and are not standard of care. When a rm diagnosis of FNH is established, management should be conservative. Most of these tumors are asymptomatic and remain stable over time.77 In those instances in which a change in size is noted, regression is usually observed rather than growth. Spontaneous rupture of FNH is rare with only a few scattered case reports over the past 2 decades.78,79 Another rare presentation is for HCC to develop within FNH.80 There have been no reports in the literature of overt transformation of FNH to a malignant growth and the debate over the malignant potential of FNH is ongoing. Genetic evidence has been used recently to establish the clonality of FNH operating under the notion that neoplastic growths should demonstrate monoclonality while hyperplastic lesions should be polyclonal. Studies on this issue have been conicting, with 27 percent of resected FNH lesions demonstrating monoclonality and the rest being polyclonal.33,34,81 Surgical intervention is required for severely symptomatic tumors and lesions in which a rm diagnosis of FNH cannot be established. Partial hepatic resection is the most common method of surgical treatment,82 but more recently embolization and RFA have been used.83,84 These interventional procedures are associated with fewer complications and a lower morbidity than surgery, but no large series have been published comparing the outcomes of these various interventions.

Hepatic Hemangioma
Cavernous 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. Alternatively, 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 reects the inclusion of tiny lesions with no clinical signicance. Ultrasound studies have placed the frequency at 0.7% to 1.5%,85,86 which more likely reects the actual incidence of clinically relevant hemangiomas in the general population. Hemangiomas can be found in all age groups but are most commonly discovered between the third and fth 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 identied on some hemangiomas,91 and estrogen treatment in vitro can cause the proliferation of hemangioma vascular endothelial cells.92 By contrast, a case-controlled study found no causal link between OCP use and hepatic hemangiomas.93 It is clear that the relationship between hormonal involvement and hemangioma development is tenuous at best, and it is not a precondition for tumor development as hemangiomas can present in men, women with no history of OCP use, and postmenopausal women. Hemangiomas are most often asymptomatic and are discovered 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

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Figure 3. CT illustration of the characteristic enhancement features of liver hemangioma. Axial (A) arterial and coronal (B) portal phase enhanced CT images show progressive discontinuous peripheral nodular enhancement.

or a mass felt in the epigastrium.96 Other common symptoms include severe pain, nausea, dyspepsia, early satiety, vomiting, weight gain, and hepatomegaly may be appreciated. The fact that these symptoms sometimes remain after a hemangioma has been surgically excised suggests that these lesions may not always be responsible for the discomfort. Rarely, large hemangiomas can result in consumptive coagulopathy manifesting as thrombocytopenia, disseminated intravascular coagulation, and systemic bleedinga condition known as KasabachMerritt syndrome (KMS).97 Hepatic biochemical tests are unrevealing in hemangioma as these lesions do not generally affect liver function except in cases of obstructive jaundice or KMS. Imaging studies are sufcient to establish a diagnosis noninvasively (Figure 3). CT or MRI are used to determine the nature of the tumor, and conventional US can diagnose it as well. Dynamic CT is sufcient in most cases, but MRI should be used when the lesions are less than 3 cm, close to the heart, or close to intrahepatic vessels. The use of contrast agents in US, when available, has signicantly increased both the sensitivity and specicity of this imaging modality and can be used to diagnose hepatic hemangiomas.98 Invasive diagnostic procedures are not necessary for detecting hemangiomas. Angiography can be helpful in identifying these lesions as the slow blood ow characteristic of hemangiomas gives it a cotton-wool-like appearance,99 but it is currently not used given the very high specicity of noninvasive imaging studies in diagnosing this lesion. Biopsy should be avoided because of the high risk of bleeding involved. As a rule there is no need for follow-up imaging studies unless there was uncertainty in the diagnosis or if patients develop symptoms. Hemangiomas can occasionally change in size thus deviating from the norm.100 A conservative approach is recommended for the management of hepatic hemangiomas. Most hemangiomas remain asymptomatic and stable over time and surgical treatment for the prevention of rare complications is not justied.101 There is some suggestion that very large lesions present an added risk for spontaneous rupture or rupture because of trauma, but reports in the literature of such events are sparse.102 Surgical intervention is rarely required, and should only be recommended if hemangiomas are shown to be very symptomatic and the relative risks of surgery are well discussed. Enucleation may be a safer option than resection, but much depends on location and size.103 Radiofrequency ablation104 and cryoablation105 have also demonstrated some success in treating hemangiomas. Liver

transplantation is rarely indicated for these lesions, and the few cases that have been reported are associated with KMS.106 Extracorporeal hepatic resection is a very radical approach that has been proposed as an alternative mode of dealing with anatomically challenging hemangiomas.107

Nodular Regenerative Hyperplasia


Nodular regenerative hyperplasia (NRH) is a benign hepatic condition in which normal hepatic parenchyma is transformed into small regenerative nodules. Most investigators consider NRH to be a secondary consequence of altered blood ow: according to this model, obstructive portal venopathy either thrombosis or phlebitis causes ischemia, which in turn leads to hyperplasia of hepatic acini with adequate blood ow in order to compensate for atrophied hepatocytes. These hyperproliferative responses form nodules separated by atrophic areas with little to no brosis. NRH has a prevalence of 2.1 to 2.6 percent in the general population,108,109 and is often associated with other diseases, leading to the increased frequency of 5.3% in individuals over 80 years old.109 NRH most commonly presents in middle-aged and older patients reecting the connection between NRH and its associated diseases.108 NRH has been associated with various conditions that include immunological and hematological disorders, cardiac and pulmonary disorders, several drugs and toxins, neoplasias, and organ transplantation (Table 4). There is no apparent relationship between NRH and gender.108,109 Grossly, NRH does share common features with micronodular cirrhosis; however, using 3 histological criterianodules of regenerative hepatocytes separated by atrophic parenchyma, an absence of brous septa between nodules, and curvilinear compression of the central lobuleNRH can be distinguished from cirrhosis.110 112 NRH is rarely symptomatic. In most cases, the disease is discovered incidentally during work-up of an associated disorder. When clinical symptoms of NRH do manifest they most often present with hepatomegaly and features of portal hypertension, ascites, splenomegaly, or esophageal varices.108,109,113 Changes in hepatic biochemical tests are not generally observed, but when present they are nonspecic and therefore are unhelpful in establishing a diagnosis.109,113 Imaging studies are unable to establish a denitive diagnosis for NRH as the lesions are often too small to distinguish radiographically, and when observed they are difcult to differentiate from the regenerating nodules of cirrhosis.114 Biopsy remains the denitive method for establishing a conclusive diagnosis.

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Table 4. Diseases Associated With NRHa


Immunological Autoimmune Polyarteritis nodosa Rheumatoid arthritis Feltys syndrome Systemic lupus erythematosus Progressive systemic sclerosis Antiphospholipid syndrome Primary biliary cirrhosis Celiac disease CREST syndrome Primary Sjgrens syndrome Polymyalgia rheumatica Lymphocytic thyroiditis Schnitzler syndrome Immunodeciency Hypogammaglobulinemia Common Variable Immunodeciency Hyper IgM syndrome Bruton syndrome HIV patients Acquired protein S deciency Thrombophilia Hematological Drugs and toxins Cardiac and pulmonary disorders Other

Myeloproliferative neoplasms Chemotherapeutic agents Chronic myelogenous leukemia 6-Thioguanine Primary myelobrosis (myeloid metaplasia) Busulfan and 6-thioguanine Polycythemia vera Doxyrubicin Essential thrombocytosis Cyclophosphamide Chlorambucil Lymphoproliferative neoplasms Cytosine arabinoside Chronic lymphocytic leukemia Bleomycin Hodgkins lymphoma Carmustine Non-Hodgkins lymphoma Oxaliplatin Waldenstrms macroglobulinemia Azathioprine Other Thrombotic thrombocytopenic purpura Sickle cell anemia Mastocytosis Aplastic anemia HIV drugs Nevirapine Didanosine IL-2 therapy Other Toxic oil syndrome Anabolic androgenic steroids 6-Mercaptopurine

Cardiac Neoplasia Congenital heart disease Massive hepatic metastasis Congestive heart failure Hepatocellular carcinoma Myocardial infarction Carcinoid syndrome Endocardial cushion defect Infections, endocarditis Organ transplantation Bone marrow transplantation Pulmonary Renal transplantation Pulmonary emphysema Liver transplantation Bronchial asthma Interstitial pneumonia Miscellaneous Pulmonary hypertension Portal vein agenesis Tuberculosis Diabetes mellitus BuddChiari syndrome Age greater than 80 y Amyloidosis Visceral leishmaniasis Familial idiopathic pulmonary brosis Chronic renal disease

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HIV, human immunodeciency 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 the underlying etiological condition (see Table 4). In cases of NRH complicated by portal hypertension, treatment options include beta-blocker prophylaxis and/or endoscopic therapy for esophageal varices, pharmacologic therapy of ascites, and surgical shunting procedures or transjugular intrahepatic portosystemic shunts (TIPS).115 NRH leading to liver failure can also be treated by liver transplantation, although the requirement for this procedure is extremely rare.116

Cystic Lesions of the Liver Simple Hepatic Cyst


Simple hepatic cysts (SHC) are though to be congenitally derived hepatic lesions that are being discovered incidentally at greater frequencies during abdominal imaging studies. Defects of intrahepatic bile duct formation in utero likely give rise to ductules that lack a connection to the rest of the biliary system; these aberrant ductules eventually dilate to form SHC. Evidence has been found of bile duct epithelium in the cystic lining of SHC, giving credence to the hypothesis of its congenital biliary etiology.117 Autopsy and laparotomy series put the incidence of these lesions in the general population at 0.2% to 1%.117,118 Ultrasound studies have found that the actual frequency of these lesions is far greater, being anywhere from 2.5 to 10.5 percent in the general population.119,120 The number of clinically relevant cysts, however, remains low. SHC are found most often in older patients, with the incidence of these lesions increasing dramatically in individuals over 60.119 Table 5 summarizes the common clinical features of the cystic hepatic lesions discussed. When only larger, symptomatic cysts are considered, the female/male ratio shifts considerably with women more often being affected.121 This suggests some role for female sex hormones in the development of these tumors, but there are no denitive studies to support or refute this supposition. Less than 4% of SHC are symptomatic,120 but larger cysts, especially those greater than 5 cm, have a higher association with symptomatic manifestation.122 Upper right quadrant or epigastric pain is the most common symptom (see Table 5 for others). Patients can present with jaundice, portal hypertension, and hepatomegaly.123 Most symptoms associated with SHC seem 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 using US, which is both highly sensitive and specic for these lesions.124 Hemorrhage into an SHC can complicate a clear diagnosis because of the similar appearance of hemorrhagic cysts to biliary cystadenomas and cystadenocarcinomas.123 A recent report has suggested that contrast-enhanced US can be used to differentiate between SHC and other cystic lesions.125 Hepatic biochemical tests are generally unrevealing; however, serum levels of carbohydrate antigen 19-9 (CA19-9) are usually normal or slightly elevated in SHC when compared with biliary cystadenoma or cystadenocarcinoma where higher levels of serum CA19-9 are observed.126 In most cases, the expense of CT or MRI, along with the accuracy of US, make these imaging studies unnecessary in establishing a differential diagnosis for SHC. Diffusion-weighted MRI, however, can differentiate SHC from hydatid cysts if the diagnosis is unclear.127 Treatment of SHC should be conservative because of their generally benign nature. Complications that merit medical intervention include hemorrhage,123 rupture,128 and infection,120,121 although such cases are rare. When complications do present or symptoms become unmanageable, treatment options for SHC include percutaneous aspiration,129 alcoholic sclerotherapy,121 open or laparoscopic deroong,130 cystojejunostomy,131 cystectomy, and partial hepatic resection.121,132 Surgical intervention has been shown to be effective in reducing or eliminating symptoms.133 Aspiration therapy is generally associated with very high rates of recurrence, and is therefore not recommended for long-term treatment of SHC.121 Laparoscopic fenestration appears to achieve the best results when morbidity, mortality, recurrence, and additional surgical procedures are all considered.131,132 Partial resection is rarely needed and should be reserved for cases in which laparoscopy is anatomically unfeasible.

Polycystic Liver Disease


Polycystic liver disease (PCLD), like SHC, is thought to arise from aberrant formation of fetal bile ducts that have no connection with the biliary system. It is possible that biliary microhamartomas (von Meyenburgs complexes) evolve into the larger cysts that are observed in PCLD patients; the number of biliary microhamartomas in adjacent hepatic parenchyma is

Table 5. Clinical Features of Cystic Hepatic Lesions


SHC Incidence (%) 0.210.5 Sex ratio (M:F) 1:1.56 Mean age range (y) 5070 Size range (cm) 1 to 30 Percent single 6875 Dominantly affected lobe Right Estrogen sensitive Unknown Presenting symptoms RUQ or epigastric pain; abdominal distension; abdominal mass; nausea; vomiting; fatigue; dyspnea; fever; early satiety Serum tumor markers CA19-9 may be elevated F, female; M, male. PCLD 0.131 1:2.514.5 4050 325 HBCA

3.54.6 of primary biliary tumors 1:9 or more 4060 2.545 None 8090 Bilateral distribution None Possibly Possibly Abdominal pain; nausea; vomiting; RUQ or epigastric pain; abdominal mass; early satiety; fatigue; dyspnea; dyspepsia; anorexia; nausea; hepatomegaly; palpable mass occasional vomiting; fever CA19-9 generally elevated CA19-9 and CEA may be elevated

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Figure 4. Coronal T2-weighted image shows multiple liver and renal cysts in a 43-year-old woman with autosomal polycystic liver and kidney disease.

directly proportional to the size of the cysts, suggesting that these microhamartomas are the pathological forerunners of the cystic lesions. A major distinction between SHC and PCLD is that the latter has a strong genetic component resulting in the formation of multiple cysts within the liver. Using phenotypic data, Gigot et al dened 3 types of the disease depending on the number of hepatic cysts and the amount of normal parenchyma remaining.134 From both a genetic and a clinical perspective, however, what presents as PCLD is in fact 2 distinct diseases that give rise to polycystic liver disease. Most patients with PCLD have concomitant polycystic kidneys, and the underlying genetic mutation is in either PKD1 or PKD2.135 These mutations are inherited in an autosomal dominant manner, so patients with this condition actually have autosomal dominant polycystic kidney disease (ADPKD) with associated polycystic liver (Figure 4). Isolated PCLD (IPCLD), by contrast, can be brought about by at least 2 mutations distinct from those of ADPKD. Mutations in PRKCSH136 and SEC63,137 encoding hepatocystin and Sec63p, respectively, have been strongly associated as etiological factors in IPCLD. These 2 proteins are associated with the endoplasmic reticulum, and are involved in carbohydrate processing, folding, and the translocation of newly synthesized glycoproteins, although the exact mechanisms by which these proteins give rise to multiple hepatic cysts are unknown. PCLD has a reported frequency in the general population ranging from 0.13% in autopsy series to 0.9% in US studies.120,138 Most patients have ADPKD, with the remainder having IPCLD.132,138 It is possible that other, as yet unidentied mutations, are also etiologic sources of the disease. There appears to be a strong predilection for this disease among females (Table 5). This gender imbalance has led investigators to believe that estrogen concentrations are involved in disease pathogenesis, and evidence to support this includes the presence of estrogen receptors on cholangiocytes where normally they are not expressed.139

Symptoms of PCLD are summarized in Table 5. Rupture or hemorrhage into a cyst can present as an acute abdomen. Other complications include infection, portal hypertension, biliary obstruction, and rarely, cholangiocarcinoma.140 In 1 series, a signicant number (84%) of patients with this disease were reported to be symptomatic.141 Hepatic synthesis is usually preserved in PCLD. CA19-9 levels, which are generally indicative of malignant growth, are signicantly higher in patients with PCLD as compared to those with SHC.142 While this does not assist in the diagnosis of PCLD, cystadenoma and cystadenocarcinoma must be excluded in order to determine the most appropriate mode of treatment. CA19-9 serum levels can be used to assess the efcacy of treatment. Asymptomatic cysts are not clinically relevant and should be managed conservatively. The interventional armamentarium for symptomatic cysts includes aspiration with sclerotherapy, open or laparoscopic fenestration, partial resection, or liver transplantation (with or without simultaneous kidney transplant).131,132,143 Sclerotherapy using ethanolamine oleate has had promising results as compared with other sclerosing agents.144 Combination therapies of resection and fenestration have also been used to good effect.143 Laparoscopic deroong is associated with lower morbidity and higher success rates than laparotomy procedures132; however, unroong of some cysts is usually followed by growth of other cysts. The appropriate treatment modality can be very challenging to determine, and should be based on the size and distribution of symptomatic cysts, hepatic vascular anatomy, and hepatic reserve. When multiple cysts are present, it is quite difcult to determine which cyst(s) might be responsible for the symptoms. A preliminary report has demonstrated that liver volume can be reduced with the use of lanreotide,145 although its use is currently considered investigational. Liver transplantation can be considered in very severe cases where there is associated portal hypertension, muscle wasting, and massive hepatomegaly.143

Hepatobiliary Cystadenoma
Hepatobiliary cystadenomas (HBCAs) are primary cystic neoplasms of the biliary tree whose denitive etiology remains unclear. Some investigators speculate that HBCAs are derivatives of intrahepatic ovarian heterotopia or ectopic intrahepatic gallbladder rests, while others consider these tumors the products of aberrantly-formed bile ducts. There is a general consensus that these cysts are congenitally derived. HBCAs can be divided into a few subtypes: HBCAs can be either mucinous or serous, with the mucinous type being far more common; further, HBCAs can be categorized based on the presence or absence of an ovarian-like mesenchymal stroma between the inner epithelial lining and the outer brous capsule.146 The incidence of these lesions in the general population is small, as HBCA make up only 3.5 to 4.6 of the total number of intrahepatic cysts of bile-duct origin.147,148 In practice, however, these are the most commonly encountered primary cystic neoplasms of the liver, comprising up to 10% of all cysts greater than 4 cm in size.121 HBCAs are found predominantly in middle-aged individuals, and have a much higher prevalence among females. The clinical features of HBCA are summarized in Table 5.146,148 Tumors tend to be large compared with other hepatic lesions; in the largest series, tumor size averaged greater than 10 cm.146 Most HBCAs are multiloculated with internal septations. Other com-

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Table 6. Management Strategies for Benign Solid and Cystic Hepatic Tumors
Associated complications (rate if known) HCA Hemorrhage and spontaneous rupture (11%29%) Malignant potential (rate if known) Yes (5%10%), almost exclusively of -catenin subtype OCP use Discontinue Pregnancy Biopsy (yes or no) Follow-up Conrm diagnosis and monitor if treatment is conservative Management Conservative treatment if 5 cm and asymptomatic for HNF1 , and IHCA subtypes. Resect if symptomatic and/or 5 cm, or if -catenin subtype Variable; resection of largest lesions combined with RFA is suggested when possible Resect or ablate tumor

LA

Hemorrhage and rupture

Yes

Discontinue

THCA

Hemorrhage and rupture

Unknown

Discontinue

FNH

Association with other vascular anomalies; spontaneous rupture is extremely rare

Rare if any

Not absolutely contraindicated

Generally contraindicated, Generally no. In select but can be cases if diagnosis is individualized if carefully uncertain and managed histologic, genetic, and molecular markers to be used Generally contraindicated, Same as for HCA but can be individualized if carefully managed Generally contraindicated, Same as for HCA but can be individualized if carefully managed Not contraindicated No

Monitor

Investigate treatment options

Classic features requires no follow-up; atypical lesions should be monitored

NRH Hemangioma SHC

PCLD

Portal hypertension; ascites; esophageal varices Rare: obstructive jaundice; consumptive coagulopathy Rare: obstructive jaundice; portal hypertension; hemorrhage; rupture; infection Hemorrhage; rupture; infection; portal hypertension; biliary obstruction Obstructive jaundice, chronic cholecystitis, and cholelithiasis (1/3 of clinically relevant cases)

No No No

Not contraindicated Not absolutely contraindicated Not contraindicated

Not contraindicated Not contraindicated Not contraindicated

Yes No No

Determine underlying disease Classic features require no follow-up Monitor

Conservative. Surgical intervention required for severely symptomatic tumors, or tumors without a rm diagnosis Treat underlying condition and manage portal hypertension Conservative Conservative

BENIGN SOLID AND CYSTIC LESIONS OF THE LIVER

Rare

Not contraindicated

Not contraindicated

No

Monitor closely with imaging

HBCA

Yes (as high as 26%)

Not contraindicated

Not contraindicated

No

Investigate surgical options

Conservative management of asymptomatic cysts. Symptomatic cysts can be managed surgically Complete resection of the tumor whenever possible

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mon features are focal calcication, nodularity, and septal thickening. Approximately 90% of HBCAs are intrahepatic and the remaining 10% arise in the extrahepatic biliary tree.147,148 The much higher incidence in women suggests an involvement of female sex hormones in mediating tumor development, and studies have demonstrated the presence of estrogen and progesterone receptors within the mesenchymal stroma of most HBCAs.149 Cytoplasmic analysis of these lesions has revealed positivity to CK7, CK8, CK18, and CK19 in the inner epithelial layer, which are the typical ndings of biliary epithelium.149 Reports have been inconsistent regarding the levels of CA19-9 and carcinoembryonic antigen (CEA) in the cystic uid and serum of affected patients with some indicating increased levels150 while others note normal levels of these tumor markers.151 The absence of CA19-9 or CEA cannot rule out HBCA, but its presence should alert physicians to the possibility of a biliary cystadenoma or cystadenocarcinoma. The symptoms associated with HBCA are likely a result of mass effect (Table 5). Complications of HBCA are obstructive jaundice, chronic cholecystitis, and cholelithiasis.147 Jaundice can be present in up to one-third of clinically relevant cases.152 Diagnosis of HBCA is dependent on imaging studies, although the features that are characteristic of HBCA can also be observed in other lesions, and it is often difcult to distinguish HBCA from other lesions such as hydatid cysts and hepatobiliary cystadenocarcinomas.153 The features that characterize HBCA include a multiloculated lesion with internal septations, thickened or irregular walls, calcications, papillary projections, mural nodules, and a surrounding brous capsule.151,154 MRI using gadoxetic acida liver-specic contrast agent that is eliminated by the biliary systemmay prove useful in diagnosing HBCA.155 Fine needle aspiration is not sensitive or specic enough to aid in the diagnosis, making histological examination the only denitive means of differentiation HBCA from other possible lesions.153 There is much evidence to suggest that HBCA can undergo malignant transformation and become a hepatobiliary cystadenocarcinoma (HBCAC). Areas of benign HBCA epithelium are detected in a large number of HBCACs.146 148 In addition, the average age of individuals with HBCAC is at least a decade older than patients with HBCA, which supports the notion that cystadenomas naturally progress toward a carcinogenic state.146 148 If all HBCACs arise from HBCA precursors, the rate of malignant transformation may be estimated at 26 percent based on the largest series in the literature.146 The threat of malignant development, coupled with the difculties in accurately differentiating HBCAs from their malignant counterparts, dictates that conservative management is not appropriate when HBCA is included in a differential diagnosis. Aspiration has been associated with a 100% recurrence rate, and subtotal resection does not resolve symptoms in the majority of cases.121,146 Complete resection of these lesions is recommended in cases of HBCA.121,154

lesions may be secondary to bacterial, parasitic, fungal, and granulomatous liver disease, which can lead to pyogenic and amebic liver abscess formation, echinococcal and hydatid cysts, and hepatic grandulomas. The etiologies of these various lesions are many and their prompt and accurate diagnosis depends on a high degree of clinical suspicion and a thorough patient history. Furthermore, although outside the scope of this review, the consideration of HCC must always remain at the forefront of the physicians mind when characterizing a newly discovered hepatic lesion, particularly in the case of patients with hepatitis B or C infection.

Summary
Incidentally discovered liver masses are an increasing phenomenon associated with the widespread use of imaging studies for diagnostic work-up. A signicant number of these incidentalomas are benign and require no intervention on the part of the physician. One of the greatest obstacles faced is the accurate diagnosis of such lesions, both to provide a measure of psychological comfort for patients as well as to insure that a conservative approach is appropriate. The use of biopsy in diagnosing these tumors has been largely mitigated by the increased sensitivity and specicity of an assortment of imaging modalities (Table 2). New biomolecular and genetic criteria have allowed physicians to subclassify many benign lesions in order to tailor patient care more appropriately (Table 3); however, these markers are investigational and have not yet achieved the status of standard of care. Ultimately, the simple fact is that most individuals live and die with a benign liver tumor rather than from them, and minimizing unnecessary intervention is critical in providing the best possible care. The differential diagnosis for an incidental hepatic mass must incorporate multifarious factors ranging from patient characteristics, history of hormonal and other drug therapies, comorbidities, and radiographic ndings. The role of immunohistochemical and genetic markers needs to be explored further. Taken together, these data provide valuable clues that can help establish a denitive diagnosis and help guide patient management. It is prudent to employ follow-up imaging before having the knee-jerk response of taking a biopsy of all lesions, due in part to the risk of bleeding and other complications associated with this procedure, as well as the challenges of obtaining a reliable histologic diagnosis. Further, the vascular nature of many hepatic lesions, along with the fact that focal biopsies may not detect areas of malignancy in heterogeneous lesions, argue against the routine use of a biopsy. Recent observations have redened the classication of several lesions and have concomitantly led to distinct recommendations for their care. Table 6 summarizes recommended management strategies for the lesions covered in this review. Benign lesions should be managed conservatively whenever possible. Indications for surgical intervention include unmanageable symptoms, a high probability of complications such as hemorrhage and rupture, and the threat of malignant transformation. The treatment options outlined and the recommendations herein given provide a general outline for dealing with benign hepatic tumors; however, in appropriately selecting a mode of therapy, the individual needs of the patient, and the availability of the local expertise, must always be considered as the overarching guide to successful patient care.

Miscellaneous Lesions
There are many other benign hepatic tumors and cysts that also deserve mention. These include mesenchymal hamartomas, hemangioendotheliomas, angiomyolipomas, focal fatty inltrates, inammatory pseudotumors, macroregenerative nodules, Carolis disease, and traumatic cysts. In addition, liver

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Supplementary Material
Note: To access the supplementary material accompanying this article, visit the online version of Clinical Gastroenterology and Hepatology at www.cghjournal.org, and at doi:10.1016/ j.cgh.2011.03.007. References
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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: Rajender.reddy@uphs.upenn.edu; fax: (215) 615-1601. Conicts of interest The authors disclose no conicts.

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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 vessels running across the surface, but can also be intrahepatic. The tumors are well demarcated from the surrounding liver but lack a true brous capsule, which makes diffuse hemorrhage throughout the liver and peritoneum more likely. On microscopic analysis the tumors are composed of benign hepatocytes arranged in sheets and cords with thin-walled vascular channels scattered throughout the tumor. Bile ducts are generally absent from these lesions. THCA. THCA has typical features that differentiate it from 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 in larger lesions. The abnormal vessels that make up THCA drain directly into the adjacent sinusoids, which can be variably dilated, and a few brous septa can be found as well. In comparison with HCA, THCA can be lobulated with dystrophic arteries and a ductular reaction. FNH. In the classic form of FNH, observed in about 80 percent of cases, the lesion is characterized by hyperplasia with a central stellate scar radiating into distinct nodules. Ductular differentiation and malformed vessels associated with nodular hepatic parenchyma are also commonly observed features of FNH. Very rarely are these lesions encapsulated or pedunculated, nor is it common for calcication to be present in FNH. Hemangioma. Histologically, hemangiomas are composed of large vascular spaces lined by a single layer of epithelium and separated by brous septa. They are usually discrete, well-circumscribed masses that appear dark purple upon gross examination. Normally, the lesions collapse when blood is removed and demonstrate a honeycombed surface. Older hemangiomas may have areas of scarring or calcication. Grossly, when brosis occurs, it usually begins centrally and can cause the lesion to appear rm and white. NRH. Histologically, NRH converts normal hepatic parenchyma into diffuse nodules, generally 1 to 3 mm in size, although they can be as large as 1 cm. Between nodules are atrophic areas of ischemic hepatocytes, but there is generally no evidence of brosis. The nodules themselves are composed of hepatocytes usually arranged in double cell plates around a central blood vessel. Curvilinear compression of the central lobule secondary to the regenerating nodules can sometimes be seen. SHC. Histologically, SHCs are comprised of a thin layer of cuboidal epithelium surrounded by an outer layer of dense brous tissue and lled with serous uid. The uid is usually clear or yellowish, but can be yellowish brown to brown. The adjacent hepatic parenchyma often shows evidence of fatty change or periportal inammation. HBCA. The gross appearance of HBCA is that of a multiloculated cystic mass containing mucinous, or more rarely serous, uid. Histologic examination typically reveals an inner layer of cuboidal-to-columnar epithelium containing mucussecreting cells and often showing papillary projections, a layer of dense mesenchymal stroma containing spindled cells that has a similar appearance to ovarian stromal tissue, and an outer dense hyalinized brous capsule that creates a pseudocapsule

separating the tumor from adjacent hepatic parenchyma. While the ovarian-like stroma is present in the vast majority of HBCAs, this subtype has only been documented in women. References for Supplementary Table 1
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Supplementary Table 1. Diseases Associated With NRH


Immunological Autoimmune Polyarteritis nodosa14 Rheumatoid arthritis4,1315 Feltys syndrome4,15,23,24 Systemic lupus erythematosus1,4,2729 Progressive systemic sclerosis1,4,29 Antiphospholipid syndrome29,31,32 Primary biliary cirrhosis3638 Celiac disease41,42 CREST syndrome46 Primary Sjgrens syndrome49 Polymyalgia rheumatica4 Lymphocytic thyroiditis4 Schnitzler syndrome60 Hematological Myeloproliferative neoplasms Chronic myelogenous leukemia5 Primary myelobrosis (myeloid metaplasia)4,16,17 Polycythemia vera16,17 Essential thrombocytosis16 Lymphoproliferative neoplasms Chronic lymphocytic leukemia4 Hodgkins lymphoma4,43 Non-Hodgkins lymphoma4,21 Waldenstrms macroglobulinemia4,50 Drugs and toxins Chemotherapeutic agents 6-Thioguanine610 Busulfan and 6thioguanine5,18 Doxyrubicin25 Cyclophosphamide30 Chlorambucil25 Cytosine arabinoside33 Bleomycin25 Carmustine25 Oxaliplatin47,48 Azathioprine5154 Cardiac and pulmonary disorders Cardiac Congenital heart disease11,12 Congestive heart failure19,20 Myocardial infarction2 Endocardial cushion defect2 Infections endocarditis19 Other Neoplasia Massive hepatic metastasis4 Hepatocellular carcinoma4,21,22 Carcinoid syndrome26 Organ transplantation Bone marrow transplantation34,35 Renal transplantation39,40 Liver transplantation44,45

Immunodeciency Hypogammaglobulinemia Common Variable Immunodeciency7274 Hyper IgM syndrome72 Bruton syndrome72 HIV patients Acquired protein S deciency61 Thrombophilia79

Other Thrombotic thrombocytopenic purpura2,16 Sickle cell anemia65 Mastocytosis67 Aplastic anemia70

HIV drugs Nevirapine61,62 Didanosine61,66 IL-2 therapy68

Pulmonary Pulmonary emphysema2 Bronchial asthma2 Interstitial pneumonia2 Pulmonary hypertension2,28,55 Tuberculosis20,58

Miscellaneous Portal vein agenesis56,57 Diabetes mellitus2,59 BuddChiari syndrome63,64 Age greater than 80 y4 Amyloidosis2,69 Visceral leishmaniasis71 Familial idiopathic pulmonary brosis75 Chronic renal disease77

Other Toxic oil syndrome76 Anabolic androgenic steroids78 6-Mercaptopurine54

HIV, human immunodeciency virus; IL, interleukin.

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