Ebook Gastrointestinal imaging: Part 2

(BQ) Part 2 book Gastrointestinal imaging presents the following contents: Focal liver disease, gallbladder, pancreas, bile ducts, spleen, multisystem disorders and syndromes, peritoneum, mesentery and abdominal wall.

Focal Liver Disease

Cystic Hepatic Tumors

Jin-Young Choi, Guilherme Moura da Cunha, Beatriz C Baranski Kaniak, and Claude B. Sirlin

A Simple Hepatic Cysts and Polycystic Liver Disease

Definition

Simple hepatic cysts are benign developmental epithelium-

lined lesions that contain serous fluid and do not

commu-nicate with the biliary system Autosomal dominant

polycystic liver disease is an inherited disorder characterized

by cyst formation in several organs, including the liver

Demographic and Clinical Features

Simple hepatic cysts are present in at least 2.5% of adults

and are more frequent in women They are usually detected

incidentally Hepatic cysts can be solitary or multiple Over

90% are asymptomatic; rarely symptoms may arise owing

to compression of bile ducts or other adjacent structures

Most hepatic cysts are sporadic, but can also occur in asso ciation with autosomal dominant (AD) polycystic hep-

atorenal disease About 40% of patients with AD polycystic

hepatorenal disease with renal involvement have hepatic

cysts; 15% of affected patients have multiple hepatic cysts but

no radiographically identifiable renal cysts AD polycystic

liver disease is usually asymptomatic Rarely advanced

disease manifests with painful hepatomegaly, abdominal

protuberance and discomfort, hepatic dysfunction,

compro mised pulmonary function from diaphragmatic

compression, and, as a result of vascular compression,

pre-sinusoidal portal hypertension or Budd-Chiari syndrome

Pathology

Histologically, hepatic cysts are lined with a single layer

of cuboidal epithelium, identical to that of bile ducts, and

a thin rim of fibrous stroma Although the pathogenesis

of hepatic cysts is not known, it is believed that they are

congenital/developmental in origin, resulting from

pro-gressive dilation of biliary microhamartomas that failed

to develop normal connections with the biliary tree AD

polycystic liver disease is part of the fibropolycystic liver

disease spectrum, which includes bile duct hamartoma,

Caroli disease, and congenital hepatic bfibrosis The diseases

in this spectrum all are caused by congenital bile duct

mal-formation In AD polycystic liver disease, innumerable

well-defined cysts are present, usually in both lobes of the liver These cysts are histologically identical to hepatic cysts and their pathogenesis is thought to be similar

Imaging Features

On all imaging modalities, cysts are sharply marginated, round or ovoid in shape, contain simple-appearing fluid, and show no or only a few thin (equal to or less than

2 mm) septations The presence of multiple, thick (equal to

or greater than 3 mm), irregular, or nodular septations or internal debris suggests a neoplastic or infectious process and warrants a more aggressive workup

On ultrasound, cysts are sonolucent with posterior acoustic enhancement and imperceptible walls (Figure 60-1)

At unenhanced CT, cysts are homogeneously ing; after intravenous administration of contrast, the cyst wall and its content do not enhance (Figure 60-2) At MRI, cysts are homogeneously hypointense onT1-wighted images and homogeneously and markedly hyperintense (“light bulb” appearance) on T2-weighted images (Figure 60-3)

hypoattenuat-Heavily T2-weighted images accentuate the apparent intensity of the cyst relative to the surrounding liver Owing

hyper-to T2 shine-through, cysts may be mildly hyperintense on

Figure 60-1 Longitudinal ultrasound image shows two hepatic cysts (arrows) in the liver One is 3.5 cm in diameter and the other is 1.8 cm Notice imperceptible walls, posterior acoustic enhancement, and absence of internal echoes

diffusion-weighted sequences (Figure 60-3) Enhancement

does not occur after administration of contrast agents

Hepatic cysts are rarely complicated by intracystic hemorrhage or inflammation; such cysts may have low-

level echoes at ultrasound, intermediate to high

attenu-ation at CT, and heterogeneous signal intensity at both

T1-and T2-weighted imaging Fluid-fluid levels may be

vis-ible when mixed blood products are present Complicated

cysts may also have septations, slightly thickened walls,

and mural calcifications Such cysts may be indistinguishable

at imaging from cystic neoplasms

The appearance of AD polycystic liver disease is tical to that of sporadic hepatic cysts except that the cysts

iden-in polycystic liver disease are much more numerous (Figure

60-4), are more likely to be hemorrhagic, and— depending

on their size, number, and location—may cause narrowing

of portal veins, hepatic veins, or inferior vena cava In cases complicated by venous obstruction, intrahepatic collateral vessels may be observed The liver drained by compressed hepatic veins may be congested and show a heterogeneous (“nutmeg”) enhancement pattern after the administration

of contrast

Differential Diagnosis

■ Hydatid cyst: History to exposure to dogs and sheep; patients typically come from endemic areas Cysts are encapsulated and frequently show “eggshell” peripheral calcifications; daughter cysts on the inside

of the main cyst are usually seen

■ Abscess: Encapsulated cystic mass with surrounding edema; patients typically have fever and an elevated white count.

■ Biliary cystadenoma: Encapsulated cystic mass with numerous septations typically diagnosed in a middle- aged woman

■ Cystic metastasis: Seen in the presence of a known malignancy; typically has an enhancing irregular rim of viable neoplastic tissue

Management/Clinical IssuesThe presence of thick, irregular, or nodular septations

or debris suggests a neoplastic or infectious process and warrants a more aggressive workup Cysts complicated

by hemorrhage or inflammation may be difficult to ferentiate from cystic neoplasms Intracystic hemorrhage

dif-is more frequently encountered in polycystic liver ddif-is-ease than in sporadic hepatic cysts Rarely patients with

dis-AD polycystic liver disease require surgical intervention

Figure 60-3 Hepatic cyst at MRI A 76-year-old woman with a 6.5-cm hepatic cyst Dynamic T1-weighted MR images at 3T were

acquired before (A) and after administration of gadobenate in the late hepatic arterial (B), portal venous (C), 3-minute delayed

hepatobiliary (D), and 60-minute delayed hepatobiliary (E) phases The cyst’s wall (white arrow) is imperceptible and does not

enhance on any of the postcontrast images Notice excretion of contrast material into the bile duct in the hepatobiliary phase

(black arrow in E); as cysts do not communicate with the biliary tree, there is no enhancement of the cyst’s lumen Relative to liver,

the cyst is hypointense on T1-weighted (F) and markedly hyperintense on T2-weighted (G) images It is markedly hyperintense on a

b = 0 s/mm 2 (H) image and, owing to T2 shine-through, minimally hyperintense on a moderately diffusion-weighted b = 500 s/mm 2

image (I) The cysts has a high apparent diffusion coefficient (J)

Figure 60-4 CT of autosomal dominant polycystic liver disease (A and B) shows cysts of the kidneys as well as the liver

(fenestration, marsupialization, resection, transplant) for

relief of symptoms; imaging helps in surgical planning

by demonstrating the size, extent, and distribution of the

cysts as well as their effects on vessels, ducts, and other

adjacent structures

Key Points

■ Hepatic cysts are common benign developmental lesions while AD polycystic liver disease is an inherited disorder involving several organs

■ A  simple hepatic cyst is characterized by a round

or ovoid lesion with no perceptible wall or, after the administration of contrast, enhancement

■ Hepatic cysts do not communicate with the biliary tree

■ The presence of thick, irregular, or nodular septations

or debris suggests a neoplastic or infectious process and warrants a more aggressive workup

Further Reading

Mortele KJ, Peters HE Multimodality imaging of common and

uncommon cystic focal liver lesions Semin Ultrasound CT

MR 2009;30:368–386.

Mortele KJ, Ros PR Cystic focal liver lesions in the

adult: dif-ferential CT and MR imaging features RadioGraphics 2001;

21:895–910.

Federle MP, Brancatelli G Imaging of benign hepatic masses

Semin Liver Dis 2001;21:237–249.

B Biliary Cystadenoma and Cystadenocarcinoma

Definition

Biliary cystadenoma and biliary cystadenocarcinoma are

rare multilocular cystic tumors of biliary origin Biliary

cystadenomas and cystadenocarcinomas only rarely

com-municate with the biliary tree

Demographic and Clinical Features

Biliary cystadenoma and biliary cystadenocarcinoma are

rare, account for less than 5% of all hepatic cystic

neo-plasms, and have an estimated prevalence of 1 in 20,000

to 100,000 and 1 in 10 million, respectively Biliary

cyst-adenoma shows a strong female predominance (90%

occur in women); however, biliary cystadenocarcinoma

does not appear to have a gender predilection Discovery

typically occurs in middle-aged adults Patients may be

asymptomatic or may complain of intermittent pain or

biliary obstruction Although these lesions are usually

intrahepatic (85%), extrahepatic locations have been

described

Biliary cystadenoma is considered premalignant; about 10% of lesions have dysplastic or borderline malignant histologic features Biliary cystadenocarcinoma is malig-nant but relatively unaggressive Local invasion or distant metastasis is uncommon, and long-term survival can be achieved after complete surgical resection

PathologyGrossly, biliary cystadenoma and biliary cystadenocarci-noma are globular and have smooth surfaces The tumors usually are large, ranging in size from 1.5 to 35 cm, and almost always multilocular The multilocularity is a key feature that differentiates them from hepatic cysts The loc-ules usually contain mucinous fluid Bloody fluid is unusual but may be observed in biliary cystadenoma undergoing malignant change A  well-defined, thick fibrous capsule lines the tumor This capsule may contain calcifications Mural nodules and papillary excrescences are seen in both biliary cystadenoma and biliary cystadenocarcinoma but are more common and tend to be larger in biliary cystadenocarcinoma

At microscopy, the tumor wall comprises three ers: an inner layer of biliary-type cuboidal or columnar nonciliated epithelium, a middle layer of moderately

lay-to densely cellular stroma, and a dense outer layer of lagenous connective tissue Biliary cystadenoma is classi-fied into two histologic subtypes depending on the type

col-of cellular stroma: cystadenoma with mesenchymal ovarian-like stroma and cystadenoma with hyaline stroma Carcinoma arising in cystadenoma with hyaline stroma

is more aggressive, and the presence of ovarian-like stroma is considered a favorable prognostic indicator About 10% of biliary cystadenomas have signs of dys-plasia or borderline malignancy Dysplastic changes include foci of epithelial atypia, loss of polarity, and mitotic activity Features of malignant transformation include severe architectural atypia, exophytic papilla, and cellular anaplasia and pleomorphism When malig-nant transformation occurs, it is usually of papillary or tubular-papillary type

Imaging Features

At ultrasound, both biliary cystadenoma and biliary adenocarcinoma are cyst-like multilocular, hypoechoic lesions with internal septa (Figure 60-5) Small nodules may stud the cyst wall At CT and MRI, they appear as solitary well-defined encapsulated cystic masses Internal septa, mural nodules, and, at CT, capsular calcifications may be evident Depending on hemorrhage and protein content, cystic fluid may have variable signal intensity on both T1- and T2-weighted images Polypoid, pedunculated projections are characteristic of biliary cystadenocarci-noma, but these excrescences can be seen in cystadenomas without malignant transformation Thus imaging does

cyst-not allow accurate differentiation between biliary

cystad-enoma and cystadenocarcinoma Moreover, the classic

imaging features described here may be subtle, and these

lesions may be mistaken for hepatic cysts at imaging (see

Figures 60-5; Figure 60-6)

Differential Diagnosis

■ Hemorrhagic cyst: The most challenging differential diagnosis of biliary cystadenoma is hemorrhagic hepatic cyst, in which imaging may depict internal clots as papillary excrescences and pseudonodules

Pseudonodules associated with hemorrhagic cysts usually do not enhance after the administration of contrast

■ Hepatocellular carcinoma: These may have necrotic components and appear cystic Hypervascularity of the solid components suggests the diagnosis of hepa-tocellular carcinoma

■ Cholangiocarcinoma:  A  variant of noma, intraductal papillary cholangiocarcinoma, may appear as a cystic mass with mural nodule

cholangiocarci-■ Undifferentiated embryonal cell carcinoma: Although embryonal cell carcinoma usually occurs in childhood, the tumor may present in adulthood

■ Cystic metastasis:  This is typically is not lated and a primary malignancy is typically known

encapsu-at the time of detection

Management/Clinical IssuesBiliary cystadenoma is a premalignant tumor and has a propensity for malignant degeneration Noninvasive imag-ing does not reliably differentiate biliary cystadenoma from cystadenocarcinoma Biopsy is relatively contraindicated owing to the risk of cyst content spillage and extrahe-patic seeding Moreover, because of variability in tumor sampling, fine-needle aspiration cannot reliably exclude malignancy and is not helpful in making the diagnosis For these reasons, lesions thought to represent biliary cystade-noma or biliary cystadenocarcinoma should be completely resected It is often difficult to distinguish biliary cystad-enoma from a complicated hepatic cyst Resection rather than imaging follow-up is generally curative and avoids the possibility of subsequent malignant degeneration

Key Points

■ Rare, multilocular cystic tumors of biliary origin

■ Characteristic imaging findings include a thick sule, mural nodules, and internal septations

cap-■ Noninvasive imaging does not reliably differentiate biliary cystadenoma from cystadenocarcinoma

■ Characteristic imaging features may be subtle, and these lesions may be mistaken for hepatic cysts

■ Need surgical resection

■ Most biliary cystadenomas occur in the middle-aged women

Figure 60-5 Ultrasound of a biliary cystadenoma arising in a 55-year-old woman (A, B, C, and D) show a 6-cm multiloculated

cystic mass with internal septa arising from left lobe of the liver In this case, no mural nodules are identified The mass was

misinterpreted as a complex cyst

Further Reading

Mortele KJ, Peters HE Multimodality imaging of common and

uncommon cystic focal liver lesions Semin Ultrasound CT

MR 2009;0:368–386.

Mortele KJ, Ros PR Cystic focal liver lesions in the adult: differential

CT and MR imaging features RadioGraphics 2001; 21: 895–910.

Choi BI, Lim JH, Han MC, et al Biliary cystadenoma and

cystadenocar-cinoma: CT and sonographic findings Radiology 1989; 171:57–61.

C Von Meyenberg Complexes

Definition

Von Meyenberg complexes (VMCs), also known as biliary

hamartomas, are benign cystic lesions derived from

malformed bile ducts and surrounded by a variable amount of fibrous stroma They do not communicate with the biliary tree

Demographic and Clinical FeaturesThe prevalence of VMCs has been estimated at about 1%

to 5% in autopsy series VMCs are considered part of the congenital hepatic fibrocystic disease spectrum and may coexist with other manifestations of this spectrum, such as Caroli disease or congenital hepatic fibrosis Nevertheless they usually occur as isolated finings VMCs are usually asymptomatic and discovered incidentally at imaging Their clinical importance is that they can be misinter-preted at imaging as hepatic metastases

Figure 60-6 Contrast-enhanced CT images (same patient as in Figure 60-5) (A) show a 6-cm hypoattenuating mass arising from the liver Subtle mural thickening (arrow) was unnoticed and the mass was misinterpreted as a hepatic cyst CT performed for unrelated reasons 3 months (B) and 1 year (C) later show interval development of a small extramural nodule (arrow) at the site of mural thickening; this nodule was unnoticed Two years later, the patient presented with acute abdominal pain due to spontaneous intralesional hemorrhage CT now showed a 10-cm mass (D) The mural nodule (arrow) had grown slightly The perihepatic fat was stranded, presumably as a reaction to the hemorrhage The lesion was resected and confirmed to be a biliary cystadenoma

(A) (B)

Figure 60-7 Von Meyenberg complexes at contrast-enhanced CT in the portal venous (A) and 3-minute-delayed (B) phases are

seen as innumerable hypoattenuating nodules in the right lobe of the liver The lesions are of uniform size but some are slightly

irregular in shape

Pathology

VMCs are congenital bile duct malformations caused by

fail-ure of embryonic involution At gross pathology, the lesions

appear as multiple black or gray-white to gray- yellow

nod-ules scattered across the hepatic parenchyma They are well

defined, irregular in shape, and relatively uniform in size;

the majority measure less than 5  mm, although they may range up to 15 mm in diameter Microscopically, VMCs are malformed (dilated, tortuous, or branching) bile ducts lined

by a single layer of cuboidal epithelium and surrounded by fibrocollagenous stroma They do not communicate with the biliary tree

Figure 60-8 Von Meyenberg complexes at MRI Axial T2-weighted (A) and, in the hepatobiliary phase, a gadoxetate-enhanced

T1-weighted image (B) demonstrate innumerable lesions throughout the liver The vast majority are smaller than 5 mm; the largest

is 12 mm (arrow) Many are irregularly shaped The hepatobiliary-phase image demonstrates no communication with

the biliary tree

Imaging Features

On ultrasound, VMCs have a variable appearance; they

may be hypoechoic, hyperechoic, or heterogeneous The

variability in appearance is thought to reflect the lesions’

underlying structure, comprising malformed bile ducts

embedded in a fibrocollagenous stroma The presence of

multiple “comet-tail” echoes within a liver lesion is

consid-ered a unique ultrasound feature of VMCs These echoes

are attributed to sound-beam reverberation caused by

cholesterol crystals within the cystically dilated bile ducts

Unenhanced CT shows multiple hypoattenuating cystic hepatic nodules (Figure 60-7) At MRI, VMCs are

hypointense relative to liver parenchyma on T1-weighted

images and strongly hyperintense on T2-weighted images

(Figure 60-8) MR cholangiography shows no

communi-cation of the lesions with the biliary tree Although hepatic

cysts have a smooth contour, VMCs tend to have a more

irregular contour at both CT and MRI (see Figures 60-7

and 60-8) The lesions usually do not enhance in the

arte-rial phase after administration of contrast agents, although

smooth, uniform rim enhancement in the late venous

phases may be observed Mural nodular enhancement has

been reported but is atypical Hepatocyte-specific contrast

media, such as gadoxetate, do not accumulate within the

lesions (see Figure 60-8) Unlike cysts and cystic

metasta-ses, VMCs tend to be uniform in size, with the vast

major-ity of lesions measuring less than 15 mm

■ Peribiliary cysts: Typically seen in a patient with liver cirrhosis Cysts are periportal in distribution and typically centrally located in the liver

■ Caroli disease: Saccular or fusiform dilation of the intrahepatic bile ducts communicating with the biliary system A central dot sign is typically present

Management/Clinical IssuesVMCs are usually discovered incidentally at imaging For the radiologist, the key issue is to recognize the lesions as benign and not to mistake them for metastases Cho langiocarcinoma arising in VMCs has been reported, but this is rare; routine follow-up of patients with VMCs is not necessary

Key Points

■ Benign liver cystic malformations

■ May be misinterpreted at imaging as multiple hepatic metastases Features that suggest the correct diagnosis include relative size unifor-mity, slight contour irregularity, marked T2 sig-nal hyperintensity, and absence of arterial-phase enhancement

Further Reading

Hussain SM, Semelka RC Liver masses Magn Reson Imaging Clin North Am 2005;13:255–275.

Mortele KJ, Peters HE Multimodality imaging of common and

uncommon cystic focal liver lesions Semin Ultrasound CT

MR 2009;30:368–386.

Zheng RQ, Zhang B, Kudo M, Onda H, Inoue T Imaging

findings of biliary hamartomas World J Gastroenterol

2005;11:6354–6363.

Hemangioma is a common benign hepatic tumor

com-posed of blood-filled spaces lined with endothelium and

surrounded by a thin fibrous stroma

Demographic and Clinical Features

Hemangiomas are the most common benign hepatic

tumors, with a prevalence of up to 20% in autopsy series

They occur more frequently in women and are usually

asymptomatic, being discovered only incidentally at

imag-ing Most hemangiomas are of little clinical relevance

except that, at imaging, they may be mistaken for other

entities including malignant liver lesions, potentially

leading to unnecessary anxiety, workup, and intervention

Patients with giant hemangiomas may have abdominal

symptoms related to mass effect on the hepatic capsule or

adjacent abdominal structures Very rarely, giant

hem-angiomas may cause platelet sequestration and

thrombo-cytopenia (Kasabach-Merritt syndrome) Hemangiomas

often coexist with focal nodular hyperplasias The presence

of innumerable hemangiomas, often tiny, is called

hem-angiomatosis; this condition may be associated with

systemic vascular syndromes such as hereditary

hemor-rhagic telangiectasias and systemic hemangiomatosis

Hemangiomas do not undergo malignant transformation

and rarely hemorrhage or rupture spontaneously even if

massive; hemorrhage and rupture may occur after biopsy,

however

Pathology

Grossly, hemangiomas are well-circumscribed sponge-like

blood-filled mesenchymal tumors Microscopically

hem-angiomas consist of numerous vascular channels lined

with a single layer of flat endothelial cells and separated

by fibrous septa Very rarely hemangiomas contain coarse

calcification or phleboliths; these may be peripheral,

cen-tral, or patchy in distribution

There are several histologic and clinical variants

Capillary hemangiomas are characterized by a closely

packed aggregation of normal-caliber capillaries Cavernous

hemangiomas have large vascular spaces enclosed by a connective tissue framework Sclerosed hemangiomas contain hyalinized and fibroconnective tissue as a result

of degeneration Giant hemangiomas are those measuring larger than 6 or 10 cm These are typically heterogeneous

They may contain myxoid tissue within the lesion’s stroma

as well as areas of thrombosis; centrally there may be a cleft-like area of cystic degeneration

The pathogenesis of hemangioma is not well stood It is postulated that abnormalities in sex-linked genes and/or female sex hormones may contribute to the development of these lesions The role of sex hormones in causing enlargement during pregnancy is controversial

under-Cirrhosis may cause hemangiomas to undergo sclerosis

Imaging FeaturesMost hemangiomas are round or lobulated Sclerosed hemangiomas may have an irregular shape and, if located near the liver periphery, may cause inward retrac-tion of the liver surface On ultrasound, hemangiomas are usually are homogeneously hyperechoic owing to the multiple interfaces between the walls of the intra-lesional vascular channels and the blood within them (Figure 61-1) Posterior acoustic enhancement is charac-teristic Margins are well defined and there is no periph-eral halo Hemangiomas, especially those larger than

3  cm, may have atypical sonographic features and be heterogeneous or appear hypo- or isoechoic, reflecting intralesional thrombosis or fibrosis (see Figure 61-1) In fatty livers, hemangiomas may appear hypoechoic relative

to surrounding parenchyma

Hemangiomas usually have a nonspecific appearance

at unenhanced CT and appear hypodense By son, the findings at unenhanced MRI are often diagnostic

compari-Because most hemangiomas are composed almost entirely

of slow-flowing blood, they have prolonged T1 and T2 relaxation times and consequently appear, relative to liver,

as hypointense at T1-weighted imaging and markedly hyperintense at T2-weighted imaging (Figure 61-2) The marked T2 hyperintensity may approximate that of cysts and liquid-filled structures and is one of the most reliable findings in diagnosing hemangioma At diffusion-weighted imaging, hemangiomas are hyperintense, mainly reflecting T2 shine-through Giant hemangiomas frequently have

mildly complex signal intensity at T2-weighted imaging

due to the presence of cystic degeneration in the lesion

center and fibrous elements within the lesion stroma

Sclerosed hemangiomas lack the characteristic marked T2

hyperintensity and may appear only mildly or moderately

hyperintense at T2-weighted imaging relative to the liver

Three typical patterns of enhancement after the

administration of contrast have been described at CT and

MRI: (1) immediate uniform enhancement (type 1, small

capillary hemangiomas less than 1.5 cm in size, “rapidly

filling” or “flash filling” hemangiomas) (Figure 61-3); (2)

peripheral, discontinuous, globular, expanding ment with complete centripetal progression to uniform high enhance ment (type 2, the most common pattern,

enhance-“classic” hemangiomas) (Figure 61-4); and (3) peripheral, discontinuous, globular, expanding enhancement with incomplete centripetal progression and a persistent central area of nonenhancement representing cystic degeneration (type 3, typically in giant hemangiomas) (Figure 61-5) Although the central area of nonenhancement is composed

of cystic degeneration, it may have a stellate configuration that can be mistakenly called a “scar” at imaging

Figure 61-1 Hemangioma at ultrasound (A) A 3-cm hemangioma (electronic calipers on A) is sharply demarcated,

homogenous, and hyperechoic; there is posterior acoustic enhancement In a healthy patient with no underlying liver disease, a lesion with this sonographic appearance could be interpreted as a hemangioma (B) A 6-cm hemangioma in a different patient

is a heterogeneous mass and cannot be diagnosed as a hemangioma based on its ultrasound appearance

Figure 61-2 Hemangioma at MRI T1- and T2-weighted images at 3T show a 3.5-cm hemangioma (arrow) in segment 7. The hemangioma is hypointense relative to liver on a T1-weighted image (A) and markedly hyperintense on a T2-weighted image (B)

In addition to these typical patterns, atypical patterns

have also been described “Slow filling” hemangiomas may

appear as hypoattenuating lesions or have tiny enhancing

dots (“bright dot” sign) that do not progressively expand

to the classic globular enhancement Sclerosed

hemangio-mas may be slow in filling and may have continuous rather

than discontinuous peripheral rim enhancement

Delayed (more than 5 minutes) contrast-enhanced images

are helpful for differentiating small, rapidly filling

heman-giomas from hypervascular metastases Metastases

typi-cally manifest venous-phase hypoenhancement (“washout”

appearance), whereas hemangiomas manifest venous-phase hyperenhancement approximately in parallel with that of the aorta and other major blood vessels, reflecting the lesions’ large blood volume In addition, a transtumoral arterioportal shunt is often associated with hemangio-mas, especially the rapidly filling types, and manifests

as arterial-phase hyperenhancement of the perilesional liver parenchyma (often resembling a perilesional halo);

the hyperenhancing parenchyma fades to isoattenuation

or isointensity in the venous phases (see Figure 61-3) The presence of a perilesional perfusional halo around a small

Figure 61-3 Flash-filling hemangioma at CT Before (A) and after contrast administration, late arterial (B), portal venous (C),

and 5-minute delayed (D) images showing a 1-cm flash-filling hemangioma (arrow) It enhances diffusely; the degree of

enhancement approximately parallels that of the aorta on all phases Notice a halo of perilesional enhancement surrounding

the hemangioma, most noticeable in the arterial phase Flash-filling hemangiomas are high-flow lesions; they are frequently

associated with transtumoral shunting, which may manifest at dynamic imaging as a halo of arterial-phase perilesional

enhancement

arterial-phase hyperenhancing mass favors the diagnosis

of a rapidly filling hemangioma over other hypervascular

lesions

In general MRI depicts the dynamic enhancement features of hemangiomas to better advantage than CT; it

therefore often permits a confident diagnosis of

hemangi-oma even in cases where CT is equivocal or indeterminate

The enhancement of hemangioma during the rial phase is the same for gadoxetate as with extracellular

arte-contrast agents With gadoxetate, however, hemangiomas

appear hypointense to the liver in the hepatobiliary phase

(the lesions lack hepatocytes and hence do not retain the

contrast material in this phase; hepatocytes within

sur-rounding liver, by comparison, take up the agent avidly,

causing the liver to be hyperenhanced) (Figure 61-6)

■ Adenocarcinoma metastases:  Hepatocellular noma in cirrhotic patients on ultrasound—underlying cirrhosis or known primary malignancy should trig-ger further differentiation with MRI

carci-■ Sclerosed hemangioma causing liver surface tion may mimic adenocarcinoma metastasis or peripheral mass-like cholangiocarcinoma

Figure 61-4 “Classic” hemangioma at CT Before (A) and after contrast administration, late arterial (B), portal venous (C), and 5-minute delayed (D) images show a 3.5-cm classic hemangioma (arrow) The hemangioma exhibits peripheral discontinuous globular expanding enhancement with complete centripetal progression to uniform high enhancement At each postcontrast time point, the enhancing components of the hemangioma approximately match the aorta in degree of enhancement

(A) (B) (C)

Figure 61-6 “Classic” hemangioma at 3T MRI with gadoxetate Fat-saturated dynamic T1-weighted images precontrast (A) and

after gadoxetate administration in the late arterial phase (B), the portal venous phase (C), at 3 minutes (D), at 5 minutes (E),

and in thehepatobiliary-phase (F) show peripheral discontinuous puddles of enhancement in the arterial phase The puddles

expand and coalesce to fill the entire hemangioma by 3 minutes At each postcontrast time point, the degree of enhancement

of the hemangioma approximately parallels that of the blood pool (compare the hemangioma with hepatic vessels); hence the

hemangioma is hypointense to liver at 5 minutes and in the hepatobiliary phase

Figure 61-5 Giant hemangioma at MRI with extracellular agent T1-weighted MR images acquired before (A) and after

administration of an extracellular gadolinium-based contrast agent in the late arterial (B), portal venous (C), 2-minute delayed

(D), 5-minute delayed (E), and 15-minute delayed (F) phases An 11-cm giant hemangioma exhibits peripheral discontinuous,

globular, expanding enhancement with incomplete centripetal progression The 15-minute delayed image shows a central area

of persistent nonenhancement (asterisk in F) This represents intralesional cystic degeneration

Management/Clinical Issues

Most hemangiomas are small, clinically inconsequential

(if correctly diagnosed), and need no treatment or further

follow-up Giant hemangiomas rarely cause symptoms

due to mass effect and may require surgical inter - vention

A small hyperechoic nodule typical of hemangioma discovered incidentally at ultrasound does not necessarily

require further confirmation However, metastasis from

a colon primary or a neuroendocrine tumor and small

hepatocellular carcinoma may show homogeneous

hyper-echogenicity, mimicking a hemangioma Therefore in

a patient with a known malignancy or with a risk factor

for hepatocellular carcinoma, further characterization

with contrast-enhanced imaging is recommended Biopsy

is rarely needed to establish the diagnosis and should be

avoided owing to bleeding risk Hemangiomas may grow;

interval growth of lesions with features diagnostic of

hem-angioma should not alter the diagnosis or raise concern

for malignant transformation MRI may permit more

confident diagnosis of rapidly filling, slowly filling, and

sclerosed hemangiomas than CT, and MRI may be

ben-eficial for the further characterization of lesions thought

to represent hemangiomas that cannot be diagnosed

unequivocally at CT

Key Points

■ The most common benign liver neoplasm

■ Hemangiomas may be mistaken for hypervascular malignant tumors

■ There are three typical enhancement patterns

■ Atypical enhancement patterns include slow filling and continuous ring enhancement

■ MRI depicts the enhancement pattern with greater clarity than CT

Further Reading

Federle MP, Brancatelli G Imaging of benign hepatic masses

Semin Liver Dis 2001;21:237–249.

Jang HJ, Yu H, Kim TK Imaging of focal liver lesions Semin

Roentgenol 2009;44:266–282.

Vilgrain V, Boulos L, Vullierme MP, Denys A, Terris B, Menu Y

Imaging of atypical hemangiomas of the liver with

patho-logic correlation RadioGraphics 2000;20:379–397.

B Focal Nodular Hyperplasia

Definition

Focal nodular hyperplasia (FNH) is a benign tumor

thought to arise as a hyperplastic response of the hepatic

parenchyma to regionally elevated hepatic arterial

perfu-sion, most commonly due to a preexisting microscopic

arterial malformation

Demographic and Clinical Features

FNH is the second most common benign liver tumor after

hemangioma It is more frequent in women of reproductive

age but can also occur in men, children, and older adults

FNHs are solitary in 80% to 95% of patients Multiple

FNHs may occur in association with other hypervascular hepatic lesions, such as hemangiomas and hepatocellular adenomas, or with systemic vascular syndromes, such as hereditary hemorrhagic telangiectasia FNH-like lesions morphologically and immunohistochemically simi-lar to classic FNH may also occur in the cirrhotic liver, presumably in response to cirrhosis-associated vascular alterations

FNH is usually asymptomatic, discovered tally, and of little clinical relevance except that it may be mistaken at imaging for other entities including malignant liver lesions, potentially leading to unnecessary anxiety, workup, and intervention Rarely, FNH can be symptom-atic owing to distention of the liver capsule or mass effect

inciden-on adjacent organs Irrespective of size, these lesiinciden-ons do not undergo malignant degeneration; spontaneous hem-orrhage or rupture is exceedingly uncommon

PathologyGrossly, FNH is lobulated, well circumscribed, and unen-capsulated The pathognomonic macroscopic feature

is the presence of a central scar with radiating septa Histologically the central scar contains myxoid fibrous connective tissue, bile ductular proliferation with sur-rounding inflammatory infiltrates, and malformed vascu-lar structures including tortuous arteries with thickened walls, capillaries, and veins Complete or incomplete fibrous septa traverse the lesion and carve it into nodules of hyperplastic parenchyma consisting of well-differentiated hepatocytes FNHs that have all these features are con-sidered “typical.” “Atypical” FNHs lack the central scar

or one of the other classic features Such lesions may resemble hepatocellular adenomas at gross pathology Histologically, a consistent feature of all FNHs is bile duct-ular proliferation Atypical FNH may also show cytologic atypia as well as mixed hyperplastic and adenomatous ele-ments Most FNHs contain Kupffer cells, but the density of Kupffer cells is variable

FNH is thought to arise as a polyclonal, hyperplastic response of the hepatic parenchyma to regionally elevated hepatic arterial perfusion, with disorganized nonneoplastic growth of hepatocytes and bile ducts The underlying cause of the elevated arterial perfusion may be a micro-scopic arterial malformation or arterioportal shunt The background liver typically is normal, although FNH‒like lesions also occur in conditions associated with arteriopor-tal shunting, such as cirrhosis, Budd-Chiari, and heredi-tary hemorrhagic telangiectasia As a result of arterial hyperperfusion, vascular endothelial and somatic growth factors are overexpressed, promoting hepatocellular hyperplasia and regeneration, and hepatic stellate cells are activated, leading to the formation of the central scar and fibrous septa

Although multiple FNHs may occur in the setting of hereditary hemorrhagic telangiectasia or in association

with other hypervascular lesions such as hemangiomas or

hepatocellular adenomas, the mechanism responsible for

this association has not been elucidated Although they are

more common in women, FNHs are hormonally

indepen-dent and unaffected by oral contraceptives or pregnancy

Imaging Features

At ultrasound, FNHs are usually isoechoic, making them

difficult to detect (“stealth lesions”), but they may have

variable echogenicity Some FNHs are surrounded by a

hypoechoic halo The central scar may be visible as a

linear or stellate hypo- or hyperechoic area Color and

power Doppler ultrasound may show evidence of

hyper-vascularity (Figure 61-7) Contrast-enhanced ultrasound

is usually diagnostic Two virtually pathognomonic

fea-tures at contrast-enhanced ultrasound are arterial-phase

centrifugal filling and stellate vascularity

On unenhanced CT, FNHs are either hypoattenuating

or isoattenuating to surrounding liver The central scar, if

seen on unenhanced images, is usually more

hypoattenu-ating than the rest of the lesion In the arterial phase, the

lesions show strong homogeneous enhancement except

for the central scar, which does not enhance early In the

portal venous and later phases, the lesions fade toward

isoattenuating relative to liver The central scar

charac-teristically enhances late to become iso- or

hyperattenu-ating relative to the rest of the lesion on delayed images

(Figure 61-8)

MRI has higher sensitivity (70%) and specificity (98%) for FNH than unenhanced ultrasound or contrast-enhanced

CT Typically FNH is iso- or hypointense on T1-weighted

imaging (94% to 100%) and slightly hyper- or isointense

on T2-weighted imaging (94% to 100%) The central scar, if visible on unenhanced images, is T1 hypointense and T2 hyperintense (84%), reflecting the presence of blood vessels, bile ductules, and edema within the mixed fibrous tissue (Figure 61-9) FNH shows marked homo-geneous enhancement in the arterial phase and then fades to become isointense or slightly hyperintense in the portal venous and later phases The central scar usually shows delayed enhancement and appears hyperintense

on delayed images (see Figure 61-9) FNH does not have

a tumor capsule, although a pseudocapsule, representing

a rim of compressed liver parenchyma, may be visible

Such pseudocapsules enhance in the delayed phases, but compared with true capsules, pseudocapsules tend to be thinner and, on unenhanced images, less prominent On diffusion-weighted images, FNHs are generally isointense

or slightly hyperintense relative to adjacent liver chyma (see Figure 61-9)

paren-Hepatobiliary contrast agents such as gadobenate (Gd-BOPTA) or gadoxetate (Gd-EOB-DTPA) are useful for differentiating FNH from hepatocellular adenoma Except for the hypointense central scar, FNH is usually diffusely hyper- or isointense in the hepatobiliary-specific phase (typically 1 to 3 hours’ delay for gadobenate and

a 20-minute delay for gadoxetate), whereas lular adenoma is usually hypointense (Figure 61-10) Uncommonly, FNHs show peripheral rather than diffuse hyperenhancement in the hepatobiliary phase

hepatocel-FNHs almost never show evidence of central necrosis, hemorrhage, calcification, or intralesional fat accumulation disproportionately greater than that of the surrounding

Figure 61-7 Focal nodular hyperplasia at ultrasound Gray-scale image (A) shows a well-circumscribed, mildly hypoechoic mass

in the left lobe of the liver The mass is homogeneous except for a hyperechoic central area (arrow) suggestive of a central scar

Color Doppler image (B) shows hypervascularity The ultrasound findings are suggestive but not diagnostic of focal nodular

hyperplasia A follow-up MRI (not shown) confirmed focal nodular hyperplasia

liver Such features are highly atypical and warrant further

evaluation

Differential Diagnosis

■ Hepatocellular adenoma: The presence of a capsule, abundant fatty change, washout on delayed imaging, and the “atoll” sign are features not seen in FNH

Only rarely will adenomas show retention of specific MRI contrast agents

hepato-■ Hepatocellular carcinoma: Most frequently arises in the setting of underlying chronic liver disease; rarely has a central stellate scar and typically does not retain hepatospecific MRI contrast agents

■ Hemangioma: Is T2-hyperintense, shows peripheral nodular enhancement, and does not retain hepato-specific MRI contrast agents

■ Hypervascular metastasis: Does not retain cific MRI contrast agents In general does not display

hepatospe-a T2-hyperintense schepatospe-ar

Management/Clinical IssuesDistinction between FNH and other hypervascular hepatic lesions such as hepatocellular adenoma, HCC, and hypervascular metastases is crucial Contrast-enhanced

CT or MRI performed with an extracellular gadolinium- based agent permits reliable noninvasive diagnosis if

Figure 61-8 Focal nodular hyperplasia at CT Before (A) and in the late arterial (B), portal venous (C), and 3-minute delayed (D) phases after contrast administration The images depict a 6.7-cm mass in the right lobe and a 2.4-cm mass in the left lobe (arrows) The larger mass contains a visible central scar (*), which is hypoattenuating precontrast It hypoenhances in the

arterial and portal venous phases but becomes isoenhanced in the delayed phase Except for the central scar, both masses are isoattenuating to liver precontrast; they enhance homogeneously in the arterial phase and fade to isoattenuation in subsequent phases Both masses were confirmed as focal nodular hyperplasia on follow-up MRI (not shown)

typical features of FNH are encountered Lesions with

atypical features require additional workup that may

include MRI with a hepatocyte-specific agent or

contrast-enhanced ultrasound Percutaneous needle

biopsy may be necessary occasionally but should be

avoided if possible, as the histologic diagnosis based on

core biopsy can be difficult and the risk of serious

bleed-ing or other complication after biopsy of a hypervascular

lesion is not negligible

Figure 61-9 Focal nodular hyperplasia at MRI with gadobenate MR images at 3T before (A) and, after administration of gadobenate, in the late arterial (B), portal venous (C), 5-minute delayed (D), and 2-hour delayed hepatobiliary (E) phases Also shown are T1-weighted in-phase (F) and out-of-phase (G) T2-weighted (H), and diffusion-weighted images The diffusion-weighted images were acquired with

b values of 0 (I) and 500 (J) s/mm 2 The focal nodular hyperplasia has a lobulated “popcorn” morphology It contains a central scar

from which radiates a network of fibrous septa that carve the mass into smaller nodules Except for the scar and fibrous septa, the mass enhances homogeneously and strongly in the arterial phase and then fades to isointensity Isointensity in the hepatobiliary phase of

the lesion’s nodular components confirms the presence of functioning hepatocytes The central scar is hyperenhanced at 5-minutes

(owing to extracellular pooling of the agent) and hypoenhanced in the hepatobiliary phase (the scar does not contain hepatocytes)

The nodular components of the mass are isointense to liver on T1-weighted images and mildly hyperintense on the T2-weighted image The mass contains no fat Because of its high water content, the scar is hyperintense on the T2-weighted image and on the b = 0 s/mm 2

image (arrows); it has relatively unrestricted diffusion and is isointense to the rest of the mass at b = 500 s/mm 2

Figure 61-10 Focal nodular hyperplasia at MRI with gadoxetate MR images at 3T before (A) and after administration of gadoxetate

in the early arterial (B), late arterial (C), portal venous (D), 3-minute transitional (D), and 20-minute delayed hepatobiliary

(F) phases The mass hyperenhances diffusely in the arterial phase, fades to isointensity in the portal venous phase, and

progressively enhances to hyperintensity in the hepatobiliary phase In this case, the central scar did not enhance in the vascular

phases, which is considered atypical for focal nodular hyperplasia Nevertheless a diagnosis of focal nodular hyperplasia can be

made with confidence in this case based on the lesion’s characteristic architecture and uptake of the hepatocyte-specific agent

Key Points

■ Common benign liver tumor

■ Hypervascular tumor containing central scar and radiating fibrous septa

■ A  lesion with typical features of FNH does not require biopsy or surgery

■ Lesions with atypical features of FNH require further evaluation, such as close follow-up or

additional imaging Biopsy may occasionally be necessary.

■ Contrast-enhanced ultrasound and MRI with hepatocyte-specific agents have high sensitivity and specificity for diagnosing FNH and may be useful for noninvasive workup of atypical lesions

Further Reading

Grazioli L, Morana G, Federle MP, et al Focal nodular

hyper-plasia: morphologic and functional information from MR

imaging with gadobenate dimeglumine Radiology 2001;

221:731–739.

Hussain SM, Terkivatan T, Zondervan PE, et al Focal nodular

hyperplasia:  findings at state-of-the-art MR imaging, US,

CT, and pathologic analysis Radiographics 2004;24:3–17;

Hepatocellular adenomas (formerly known as hepatic

ade-nomas) are a diverse group of rare monoclonal tumors of

hepatocellular origin with a variable propensity to

hemor-rhage or undergo malignant transformation; they are usually

found in young or middle-aged women with a long history of

oral contraceptive use Based on phenotypic and genotypic

characteristics, hepatocellular adenomas have recently been

categorized into four distinct pathomolecular subtypes:

■ Hepatocyte nuclear factor (HNF)1α-inactivated type (H-hepatocellular adenoma) H-hepatocellular ade-nomas are caused by biallelic inactivating mutations

of the HNF1A gene.

■ β-catenin-mutated type (β-hepatocellular adenoma)

β-hepatocellular adenomas are caused by mutations that result in sustained activation of β-catenin

■ Inflammatory type (I-hepatocellular adenoma)

I-hepatocellular adenomas are caused by sustained and inappropriate activation of a proinflammatory and proproliferative signaling pathway— the Janus kinase–signal transducer and activator of transcription (JAK-STAT pathway) About 10% of I-hepatocellular adenomas also have mutations of the β-catenin gene;

owing to the presence of inflammatory changes, these are categorized as I-hepatocellular adenomas rather than β-hepatocellular adenomas Historically I-hepatocellular adenomas were misclassified as telangiectatic focal nodular hyperplasia, a term no longer in use

■ Nonmutated, noninflammatory type These cellular adenomas are noninflammatory and do not

hepato-harbor mutations in HNF1A, β-catenin, or genes associated with the JAK-STAT pathway This sub-type is sometimes referred to as “miscellaneous” or

“unclassified.” The clinical features, demographics, pathologic features, molecular mechanisms, biologic behavior, and imaging findings of this subtype are not yet understood Hence this hepatocellular ade-noma subtype is not discussed further in this section

Hepatic adenomatosis refers to the presence of multiple

(arbitrarily defined as equal to or greater than cellular adenomas in a single individual In patients with hepatic adenomatosis, the lesions may be of any of the pathomolecular subtypes In contrast to previous views, hepatic adenomatosis is no longer thought to be a distinct clinical entity but simply a manifestation of hepatocellular adenoma characterized by a large number of lesions.Demographic and Clinical Features

10) hepato-Hepatocellular Adenomas

As a group, hepatocellular adenomas are uncommon mary liver tumors occurring predominantly in young and middle-aged adult women taking oral contracep-tives These lesions are 10 times less common in men than women They are rare in children and elderly women The estimated annual incidence is 1 per million in women with

pri-no history of oral contraceptive use and 30 to 40 per million

in those with prolonged use Because of reduced estradiol

in the formulation of oral contraceptives, the incidence of hepatocellular adenomas has declined since the 1980s The exact incidence is unknown, however, as widespread use

of CT and MRI is increasing the detection of incidental lesions that previously would have been undiscovered In addition to oral contraceptives, other risk factors include the use of androgens and other offending drugs (barbi-turates, clomiphene), obesity, alcohol overconsumption, hepatic steatosis, maturity-onset diabetes of the young (MODY, a familial form of diabetes), familial polyposis coli, and glycogen storage disease Hepatocellular adeno-mas are rare in patients with cirrhosis regardless of patient age, gender, or other risk factors

Most hepatocellular adenomas are asymptomatic and discovered incidentally Large hepatocellular adenomas may cause symptoms such as right-upper-quadrant dis-comfort due to mass effect or may present as a palpable mass Up to 30% of hepatocellular adenomas may present with intratumoral hemorrhage or rupture and intraperi-toneal hemorrhage; these cause hemodynamic instability and can be life-threatening Malignant transformation to hepatocellular carcinoma is uncommon but may occur in 5% to 10% of hepatocellular adenomas Risk factors for rupture include pregnancy, tumor diameter greater than

5  cm, subcapsular location, and I-hepatocellular noma subtype Risk factors for malignant transformation

ade-include male gender (10 times greater risk than women),

underlying glycogen storage disease, androgen usage,

tumor diameter greater than 5 cm, and β-hepatocellular

adenoma subtype Hepatocellular adenomas may regress

after cessation of oral contraceptives, androgens, and

other offending drugs

Pathomolecular Subtypes

Specific demographic and clinical features depend on the

pathomolecular subtype

H-Hepatocellular Adenoma Subtype

This subtype accounts for 35% to 40% of all

hepatocel-lular adenomas and occurs almost exclusively in women

Over 90% of patients have a history of oral contraceptive

use Rarely, H-hepatocellular adenomas occur in women

or in men in the setting of MODY-type 3 and

famil-ial hepatic adenomatosis; in these rare situations, the

H-hepatocellular adenomas harbor germline mutations

in the HNF1A gene Overall about 50% of patients with

H-hepatocellular adenomas have solitary and 50% have

multiple lesions Most H-hepatocellular adenomas are

asymptomatic and discovered incidentally at imaging

Among the various hepatocellular adenoma subtypes,

H-hepatocellular adenomas are the least aggressive

bio-logically Tumors less than 5 cm in size pose minimal risk

of hemorrhage or rupture and virtually no risk of

malig-nant transformation

β-Hepatocellular Adenoma

This subtype accounts for about 10% of all

hepatocellu-lar adenomas, may occur in men as well as women, and

is associated with androgenic hormone administration,

glycogen storage disease, and familial polyposis

syn-drome Among the various hepatocellular adenoma

sub-types, β-hepatocellular adenomas are the most likely to

undergo malignant transformation These lesions may also

hemorrhage, although the exact frequency of bleeding is

unknown

I-Hepatocellular Adenoma

This subtype accounts for over 50% of all

hepatocellu-lar adenoma Whereas I-hepatocelluhepatocellu-lar adenomas occur

most frequently in women with history of oral

contra-ceptive usage, they may also occur in men In addition to

oral contraceptives, risk factors include obesity, hepatic

steatosis, and alcohol consumption Lesions in men are

almost always solitary; those in women may be multiple

Patients with I-hepatocellular adenomas may present

with anemia, abnormal serum liver chemistries, and

signs of systemic inflammation, including fever,

leuko-cytosis, and elevated serum levels of C-reactive protein

Among the various hepatocellular adenoma subtypes,

I-hepatocellular adenomas have the highest risk of

bleed-ing, which has been reported to occur in about 30% of

these lesions The subset of I-hepatocellular adenomas with

concomitant β-catenin‒activating mutations may progress

PathophysiologyHepatocellular adenomas are monoclonal proliferations

of hepatocytes The specific pathogenesis depends on the pathomolecular subtype

H-Hepatocellular Adenoma

H-hepatocellular adenomas are caused by biallelic

inacti-vating mutations of the HNF1A gene These mutations lead

to loss of function of the HNF1α protein encoded by the gene Since the protein normally helps to regulate hepatic differentiation and lipid metabolism, its inactivation leads

to dysregulated hepatocyte proliferation, accumulation of lipid within hepatocytes, and formation of diffusely stea-totic hepatocellular adenomas with absent expression of liver fatty acid‒binding protein (LFABP), a transcriptional target of HNF1 In 90% of H-hepatocellular adenomas, both

inactivating mutations of the HNF1A gene are somatic; in

10%, one of the mutations is somatic and the other is line As discussed previously, hepatocellular adenomas with germline mutations are associated with MODY3 and familial hepatic adenomatosis The contribution of oral contraceptive use to the development of these hepatocellu-lar adenomas is incompletely understood One hypothesis

germ-is that estrogens play a primary role in the pathogenesgerm-is

by exerting genotoxic effects that induce mutations in the

HNF1A gene Another hypothesis is that mutations in the

gene play the primary role by causing estrogen metabolites

to accumulate within hepatocytes and that the metabolites then stimulate hepatocellular proliferation

β-Hepatocellular Adenoma

These adenomas are caused by mutations that result in the sustained activation of β-catenin, a gene involved in the development, differentiation, and proliferation of hepa-tocytes Sustained activation of this gene may result from mutations in the β-catenin gene itself (these mutations make the protein encoded by the gene resistant to degrada-tion) or to mutations in the cytoplasmic complex respon-sible for the protein’s degradation Regardless of the cause, the sustained activation promotes hepatocellular prolif-eration and the development of hepatocellular adenomas with histologic features at the borderline between benign hepatocellular tumors and hepatocellular carcinomas

I-Hepatocellular Adenoma

These adenomas are caused by sustained and

inappropri-ate activation of the proinflammatory and proproliferative

JAK-STAT signaling pathway The resulting hepatocellular

adenomas are characterized by inflammatory cellular

infiltrates, overexpression of acute-phase reactants, dilated

sinusoids, blood-filled cavities (peliosis), abnormal vessels,

and a propensity for hemorrhage The cause of the tumoral

peliosis has not yet been delineated

Pathology

General Pathologic Features

At gross pathology, hepatocellular adenomas are usually

well circumscribed, spherical, and pale yellow to tan, with

a soft or friable consistency They may have an incomplete

fibrous capsule Areas of necrosis, hemorrhage, or

scar-ring may be evident They range in size from microscopic

(microadenomas) to huge masses over 20 cm in diameter

Histologically, hepatocellular adenomas are composed

of sheets mature-appearing, normal-sized to slightly

enlarged hepatocytes arranged in cords that are only

mildly thickened or disorganized and are separated by

sinusoids The cytoplasm may be normal or may contain

variable amounts of glycogen and lipid Isolated

arteri-oles unaccompanied by bile ducts (“naked” or “unpaired”

arteries) feed the tumor These arteries lack a fibrous

sheath and are surrounded by hepatocytes Some

por-tal venules may be present but normal porpor-tal tracts are

absent Although normal bile ducts are missing, bile may

be evident as plugs in canaliculi or as droplets within

hepatocytes Veins are dilated and thin-walled; they may

contain thrombi Kupffer cells are present in variable

numbers Hepatocellular adenomas lack a central scar and

radiating fibrous septa—a key histologic feature that helps

to distinguish these lesions from focal nodular

hyper-plasia Calcifications are present in 5% to 15% of lesions

Depending on the subtype, other histologic findings may

include enlarged tortuous arteries, telangiectasias,

sinu-soidal dilatation and congestion, peliosis, hemorrhage,

necrosis, fibrosis, edema, and intra- and extracellular fat

Pathomolecular Subtypes

The various pathomolecular subtypes differ in histologic

features, as discussed further on The histologic features

may overlap among the subtypes, however, and

defini-tive pathomolecular classification requires

immunohisto-chemical staining, which is not yet routinely available at

most institutions

H-Hepatocellular Adenoma

H-hepatocellular adenomas are characterized by diffuse

and marked steatosis, lack of inflammation, and absence

of cytologic or nuclear atypia Artery walls are thin The

diagnosis is verified by immunohistochemical staining for

LFABP, a transcriptional target for HNF1, which is pletely absent in H-hepatocellular adenomas This stain sharply delineates the tumor border and often reveals, in the peritumoral hepatic parenchyma, microscopic satel-lites of H-hepatocellular adenoma

com-β-Hepatocellular Adenoma

These adenomas are characterized histologically by logic abnormalities (nuclear atypia) and pseudoglandular formation Steatosis is rare These lesions may be difficult

cyto-to differentiate hiscyto-tologically from well-differentiated hepatocellular carcinoma (HCC) Malignant transforma-tion into overt HCC may manifest with the development

of either macroscopic (greater than or equal to 1 cm) HCC nodules or multiple microscopic foci of HCC The diagno-sis of β-hepatocellular adenoma is verified by immunohis-tochemical staining for either β-catenin itself (the mutant protein accumulates in the nucleus; the wild-type protein does not) or glutamine synthetase (which is diffusely over-expressed in these lesions)

I-Hepatocellular Adenoma

These adenomas are characterized by inflammatory lar infiltrates, sinusoidal dilatation and congestion, peliosis, marked telangiectasia, thickened and tortuous (dystrophic) arterioles, and prominent ductular reaction Hemorrhage

cellu-is common Steatoscellu-is may be evident but, unlike the diffuse steatosis that characterizes H-hepatocellular adenomas, the steatosis in I-hepatocellular adenomas is usually distrib-uted nonuniformly In patients with multiple I-hepatocellular adenomas, the degree of steatosis in individual lesions varies The diagnosis is verified by immunohistochemi-cal staining for serum amyloid A and C-reactive protein, acute-phase reactants overexpressed by these tumors.Imaging Features

General Imaging Features

Hepatocellular adenomas have highly variable imaging appearances depending on their pathomolecular subtype and histologic features Nevertheless some imaging features are common to all subtypes Hepatocellular adenomas usually manifest as well-circumscribed, smoothly mar-ginated, round or oval expansile masses (Figures 61-11 and 61-12, although hemorrhage, necrosis, or scarring may cause some hepatocellular adenomas to be irregularly shaped (Figure 61-13) Hepatocellular adenomas typically hyperenhance in the arterial phase at CT or MRI, but the degree of hyperenhancement is variable Importantly, the arterial-phase enhancement tends to be diffuse (see Figures 61-12 and 61-13)—an important differentiating feature from hypervascular metastases, which, if larger than 3  cm, usually show peripheral rather than diffuse arterial-phase enhancement Although diffuse, the arte-rial phase hyperenhancement of hepatocellular adenomas

tends to be heterogeneous, in distinction to the

homoge-neous enhancement observed in focal nodular hyperplasia

Also unlike focal nodular hyperplasia, hepatocellular

adenomas generally do not have a sharply demarcated

T2-hyperintense delayed enhancing central scar and

radi-ating septa Areas of necrosis or hemorrhage within

hepa-tocellular adenomas, if any, do not enhance and appear

dark in all phases Hepatocellular adenomas may appear

encapsulated A tumor capsule, if present, enhances slowly

but progressively to appear hyperattenuating/intense on

delayed-phase images

In the hepatobiliary phase after gadobenate (Gd-BOPTA)

or gadoxetate (Gd-EOB-DTPA) administration there is

usu-ally little or no retention of contrast material and the lesion

is hypointense to the surrounding liver parenchyma (see

Figure 61-13) Hypointensity in the hepatobiliary phase

helps differentiate hepatocellular adenomas from focal

nodular hyperplasia, which, except for the central scar and

radiating septa, is usually iso- or hyperintense in this phase

The relative lack of intracellular retention of hepatobiliary

contrast agents by hepatocellular adenomas is thought to

be due to downregulation of the OATP membrane receptors

that normally transport these agents from the extracellular

space into the hepatocytes

Contrast-enhanced ultrasound may be helpful in ferentiating hepatocellular adenomas from focal nodular

dif-hyperplasia in difficult cases Hepatocellular adenomas

show peripheral enhancement initially with rapid

centrip-etal fill-in (outside-to-inside temporal pattern), reflecting

their blood supply from peripheral feeding vessels By

comparison, focal nodular hyperplasias are fed by central

feeding vessels and show a centrifugal (inside to outside) pattern of enhancement

Hepatobiliary-phase MRI and contrast-enhanced ultrasound are less helpful in differentiating hepatocellu-lar adenoma from HCC since the large majority of HCCs also demonstrate hepatobiliary-phase hypointensity and

a centripetal (outside to inside) temporal enhancement pattern on the respective modalities

The interpretation of imaging examinations depends not only on the imaging features but also the clinical con-text and presentation In a young or middle-aged woman

on oral contraceptives and without underlying cirrhosis, an arterial-phase diffusely hyperenhancing mass containing fat or blood products should be regarded as a hepatocellular adenoma until proven otherwise In men and individuals with cirrhosis, a mass with the same appearance is likely

to represent HCC; in postmenopausal women, such a mass should be considered indeterminate and warrants further evaluation

The appearance of the various subtypes in the tobiliary phase of MR images acquired with hepatocyte- specific agents has not yet been described in the literature and so is not discussed

Figure 61-11 Diffusely steatotic hepatocellular adenoma at 1.5T MRI in a patient with a long history of oral contraceptive use

A 10-cm oval, well-circumscribed, smoothly marginated expansile mass (arrow) arises exophytically from the right lobe of the liver

The mass shows uniform signal loss on a coronal out-of-phase T1-weighted gradient-echo MR image at 1.5T (A) compared with

an in-phase image (B), indicating diffuse intralesional steatosis The mass has imaging features characteristic of H-hepatocellular

adenoma

H-Hepatocellular Adenoma

H-hepatocellular adenomas characteristically manifest

as homogeneous masses with diffuse intralesional fat

Accordingly H-hepatocellular adenomas typically appear

homogeneously hyperechoic at gray-scale ultrasound imaging and homogeneously hypoattenuating at unen-hanced CT The sensitivity and specificity of ultrasound and conventional CT for the identification of intralesional

Figure 61-12 Diffusely hyperenhancing hepatocellular adenoma with focal areas of intralesional fat at 3T MRI in the setting

of hepatic steatosis Top row: T1-weighted fat-suppressed MR images at 3T before (A) and after injection of an extracellular

gadolinium-based contrast in the (B) arterial, (C) portal venous, and (D) 5-minute delayed phases Bottom row: T1-weighted out-of-phase (E) and in-phase (F) images, a proton-density fat-fraction map (G), and a T2-weighted single-shot fast spin-echo image (H) A 10-cm oval, well-circumscribed, smoothly marginated expansile mass (large arrow) arises from the right lobe of the liver The mass enhances diffusely but heterogeneously in the arterial phase (B) Contrast enhancement persists into the portal venous (C) and delayed (D) phases The mass contains focal areas of intralesional fat, as shown by patchy signal loss on out-of- phase (small arrows in E) compared with the in-phase image (F) and confirmed on the proton-density fat-fraction map (small arrows in G) The mass is mildly hyperintense on a T2-weighted image (H) Notice that the background liver is fatty The mass has imaging features suggestive but not diagnostic of I-hepatocellular adenoma

Figure 61-13 Diffusely hyperenhancing, irregularly shaped hepatocellular adenoma with hepatobiliary phase hypointensity at 3T gadoxetate-enhanced MRI in a woman with a long history of oral contraceptive use T1-weighted fat-suppressed MR images at 3T before (A) and after injection of a gadoxetate in the (B) arterial, (C) portal venous, (D) 5-minute transitional, and (E) 20-minute hepatobiliary phases A 4-cm well-circumscribed mass (arrow) arises from the right lobe of the liver The mass has an irregular shape due to central scarring from a prior intralesional hemorrhage The mass diffusely hyperenhances in the arterial phase (B) Notice mild heterogeneity due to central scarring The mass fades to isoenhancement relative to liver in the portal venous phase (C) and subsequently becomes mildly hypointense in the transitional phase (D) and moderately hypointense in the hepatobiliary phase (E) The hepatobiliary-phase hypointensity is typical of most hepatocellular adenomas

fat is low, however, as many factors other than fat may

affect the ultrasound echotexture and CT attenuation

Because of its ability to exploit differences in resonance

frequency between fat and water protons, MRI

identi-fies intralesional fat more reliably than ultrasound or

CT For this reason, MRI is recommended for the

evalu-ation of lesions that may represent hepatocellular

adeno-mas H-hepatocellular adenomas are characteristically

mildly and homogeneously hyperintense on unenhanced

T1-weighted in-phase MR images and show diffuse signal

loss on T1-weighted out-of-phase images (see Figure 61-11)

On T2-weighted images the lesions are usually are

homo-geneous; they may be hypo-, iso-, or slightly hyperintense

relative to the liver (see Figure 61-11) The background

liver may also be steatotic, especially in cases associated

with MODY type 3.  Rarely H-hepatocellular adenomas

may be heterogeneous owing to the presence of

macro-scopic deposits of fat, hemorrhage, necrosis, or a

combi-nation of these At dynamic CT or MRI performed with

extracellular agents, H-hepatocellular adenomas typically

hyperenhance mildly or moderately in the arterial phase

and then fade to isoenhancement in the portal venous and

delayed phases Contrast-enhanced ultrasound reveals

mild to moderate arterial hypervascularity with mixed

arterial-phase filling; the lesions are isoechoic relative to

the liver in the blood-pool phase

β-Hepatocellular Adenoma

β-hepatocellular adenomas may be homo- or heterogeneous

on all imaging modalities, depending on the presence of

hemorrhage, necrosis, and fibrosis At dynamic CT or MRI

performed with extracellular agents, H-hepatocellular

adenomas typically hyperenhance intensely and

hetero-geneously in the arterial phase The enhancement may

persist into the portal venous or delayed phases, or the

lesions may appear to wash out to become hypoenhanced

relative to the liver Those with a washout appearance may

be impossible to differentiate from carcinomas at imaging

I-Hepatocellular Adenoma

Specific sonographic findings have not yet been reported

for I-hepatocellular adenomas At unenhanced CT,

I-hepatocellular adenomas may be heterogeneously

hyper-attenuating The lesions are isointense or mildly

hyperin-tense at T1-weighted imaging and moderately hyperinhyperin-tense

at T2-weighted imaging (see Figure 61-12) Sometimes the

lesions are isointense to background liver at T2-weighted

imaging except for a peripheral rim of hyperintensity (the

“atoll” sign) T1 and T2 hyperintensity have been

attrib-uted to sinusoidal dilatation and peliosis I-hepatocellular

adenomas show either no signal loss or patchy signal loss

on out-of-phase compared with in phase T1-weighted

images, reflecting either the absence of fat or the

nonuni-form distribution of fat, respectively, in these lesions (see

Figure 61-12) Although the lesions themselves usually

contain no or little fat, the background liver is often fatty,

as this hepatocellular adenoma subtype is associated with hepatic steatosis (see Figure 61-12) At dynamic CT or MRI performed with extracellular agents, H-hepatocellular adenomas typically hyperenhance intensely in the arterial phase; characteristically the enhancement persists into the portal venous an delayed phases, probably because

of pooling of the contrast material within the lesion’s interstitial spaces, dilated sinusoids, and peliotic cavi-ties (see Figure 61-12) At contrast-enhanced ultrasound, I-hepatocellular adenomas hyperenhance diffusely in the arterial phase with centripetal filling A peripheral rim of sustained enhancement is observed in the portal venous and delayed phases but, unlike the sustained central enhancement observed after administration of extracel-lular agents at CT or MRI, the lesion’s center washes out

to become hypoechoic because the microbubbles do not diffuse into the interstitium

Differential Diagnosis

■ Focal nodular hyperplasia: Typically homogenous in appearance on all phases, fades out on delayed images, and has a T2-hyperintense scar that shows delayed enhancement

■ HCC, including the fibrolamellar type:  Typically arises in patients with chronic liver diseases and shows washout on delayed imaging, not infrequently with the presence of a pseudocapsule May be indistinguishable from some subtypes of hepatocellular adenoma

■ Hypervascular metastasis: Typically seen in patients with known underlying malignancy Lesions are typically hyperintense on T2-weighted images with washoutout on delayed imaging Metastases are not encapsulated

■ Hemangioma:  T2-hyperintense with characteristic peripheral nodular incomplete enhancement on early arterial imaging, with progressive fill in on delayed scans

■ Angiomyolipoma:  More frequently see in patients with tuberous sclerosis angiomyolipoma may be hypervascular and contain minimal amount of fat

Lack of underlying chronic liver disease may suggest angiomyolipoma

■ Focal steatosis: Nonspherical areas of signal dropout

on out-of-phase T1-weighted GRE sequences as pared with in-phase T1-weighted GRE sequences Typically detected in specific locations and without vascular or biliary distortion

The management of hepatocellular adenomas is

evolv-ing owevolv-ing to continuevolv-ing advances in the understandevolv-ing

of the pathomolecular underpinnings and natural

his-tory of these lesions In the appropriate clinical context

(see “Demographic and Clinical Features”), imaging-

detected lesions that show diffuse arterial- phase

hyper-enhancement but do not meet imaging criteria for focal

nodular hyperplasia are suggestive of hepatocellular

adenoma A proposed management algorithm for such

Imaging suggests HCA

Male Female

Symptomatic a Asymptomatic

Discontinue oral contraceptives, androgens, and other offending drug b

Figure 61-14 Proposed management algorithm for lesions thought to represent hepatocellular adenoma by imaging Notice that management depends on patient gender and symptoms, response of lesion to discontinuation of offending drugs, and imaging appearance a Symptoms for which treatment is indicated include intolerable pain, bleeding, and life-threatening hemorrhage

b In addition to oral contraceptives and androgens, other offending drugs include steroids, clomiphene, and barbiturates

c Most asymptomatic stable, smaller than 5 cm, diffusely steatotic hepatocellular adenomas can be managed conservatively,

as they are highly likely to be of the H-hepatocellular adenoma pathomolecular subtype The management is debated,

however, for diffusely steatotic hepatocellular adenomas in women who are trying to become pregnant; in such women,

some authors advocate treatment while others advocate conservative management d Nondiffusely steatotic hepatocellular adenomas are likely to be of the I-, β-, or unclassified hepatocellular adenoma subtypes, possibly with malignant transformation

to hepatocellular carcinoma Those that do not regress after cessation of oral contraceptives, androgens, and other offending drugs should either be biopsied (at appropriate institutions) or treated e The role of biopsy is controversial and evolving In centers with access to advanced immunohistochemical techniques, biopsy may be useful for guiding management of stable, smaller than 5 cm, nondiffusely steatotic lesions thought to represent hepatocellular adenomas Lesions confirmed as β-hepatocellular adenoma and lesions with malignant changes should be treated; those classified as H- or I-subtypes and those that are

unclassifiable can usually be managed conservatively f Clinical and imaging surveillance is recommended until menopause

g Treatment options include surgical resection, radiofrequency ablation, and transarterial chemoembolization Surgical resection

is generally the favored treatment, with other treatments reserved for patients who are not surgical candidates or do not wish

to undergo surgery Hepatic arterial embolization may be necessary prior to definitive treatment in patients who present with hemodynamic instability due to hepatocellular adenoma rupture

lesions is shown in Figure 61-14 As shown in the figure, the management is complex and depends on patient gender, symptomatology, response to cessation of oral contraceptives, size, imaging appearance, and institu-tional access to the advanced immunohistochemical staining techniques required for pathomolecular classi-fication Management may require an interdisciplinary group approach with input from hepatologists, sur-geons, interventionalists, diagnostic radiologists, and pathologists

As a general rule, definitive treatment is recommended for hepatocellular adenomas with intolerable or life-

threatening symptoms and asymptomatic hepatocellular

adenomas at high risk for future complications such as

hemorrhage or malignant transformation; this latter

group includes hepatocellular adenomas in men,

hepato-cellular adenomas that grow during follow-up,

hepatocel-lular adenomas equal to or greater than 5 cm that fail to

regress after cessation of offending drugs,

immunohisto-chemically confirmed β-hepatocellular adenomas,

hepa-tocellular adenomas with histologically demonstrated

malignant changes, and non‒diffusely steatotic

hepatocel-lular adenomas (as these may represent β-hepatocelhepatocel-lular

adenomas) The location of the hepatocellular adenoma

also is contributory, with more aggressive management

directed toward subcapsular lesions

Treatment options include surgical resection, radiofrequency ablation, and transarterial chemoem-

bolization Surgical resection is generally the favored

treatment, with other treatments reserved for patients

who are not surgical candidates or who do not wish to

undergo surgery Hepatic arterial embolization may be

necessary prior to definitive treatment in patients who

present with hemodynamic instability due to

hepatocel-lular adenoma rupture In contrast, small stable

asymp-tomatic lesions in young or middle-aged women that are

either diffusely steatotic at imaging (highly likely to be

H-hepatocellular adenomas) or thought to be at low risk

for malignant transformation based on

immunohisto-chemical subtyping (e.g., H-hepatocellular adenoma,

I-hepatocellular adenoma, or unclassified) can usually

be followed conservatively with periodic clinical and

imaging surveillance until menopause The management

is debated, however, for small hepatocellular adenomas

in women who are trying to become pregnant, as

preg-nancy may promote lesion growth and hemorrhage; in

such women, some authors advocate treatment while

others advocate conservative management The

manage-ment of adenomas in patients with hepatic adenomatosis

is similar to that in those with isolated hepatocellular

adenomas

The role of biopsy is controversial and evolving In centers with access to advanced immunohistochemical

techniques, biopsy may be useful for guiding

manage-ment of stable, small (less than 5  cm), non‒diffusely

steatotic lesions Lesions confirmed as β-hepatocellular

adenoma and those with malignant changes should be

treated; those classified as H- or I-subtypes and those

that are unclassifiable can usually be managed

conser-vatively In centers without access to advanced

immu-nohistochemical techniques, liver biopsy should be

avoided if possible; the histologic diagnosis based on

routine histochemical staining of core biopsy specimens

is difficult and the risk of serious bleeding or other

complications after biopsy of a hypervascular lesion

is not negligible

In addition to treatment of hepatocellular adenomas, patient management should also be directed at any under-lying liver condition or other predisposing factor, such as glycogen storage disease, MODY, hepatic steatosis, obesity, and excess alcohol consumption

MRI is recommended in the workup and follow-up

of most lesions thought to represent hepatocellular nomas As shown in the algorithm, the identification of diffuse intralesional fat may help to guide patient manage-ment, as it provides strong noninvasive evidence favoring the H subtype, and MRI is currently the most definitive modality for the identification of intralesional fat MRI also is more reliable than unenhanced ultrasound or dynamic CT for identifying other features of hepatocel-lular adenoma (e.g., intralesional blood products) and for differentiating it from focal nodular hyperplasia Finally,

ade-in patients beade-ing treated conservatively, MRI permits imaging surveillance without exposing patients to ion-izing radiation

Key Points

■ Diverse group of rare monoclonal tumors of cellular origin

hepato-■ Usually found in young or middle-aged women with

a long history of oral contraceptive use

■ Recently categorized into four distinct pathomolecular subtypes

■ Variable clinical presentation, imaging, and pathologic appearance, pathogenesis, and natural history depending pathomolecular subtype

■ H-hepatocellular adenomas are the least aggressive, I-hepatocellular adenomas the most likely to hem-orrhage, and β-hepatocellular adenomas the most likely to undergo malignant transformation

■ Imaging interpretation depends not only on the imaging features but also the clinical context and presentation

■ Hepatobiliary phase MRI after the administration of hepatocyte-specific agents and contrast-enhanced ultrasound after the administration of microbub-bles help in the differentiation of hepatocellular adenoma from focal nodular hyperplasia but not

in the differentiation of hepatocellular adenoma from HCCs

■ With the exception of diffusely steatotic tocellular adenomas (highly likely to be of the H-hepatocellular adenoma subtype), imaging fea-tures may overlap among the subtypes and imaging usually does not provide reliable pathomolecular classification

hepa-■ Hepatic adenomatosis is no longer thought to be a distinct clinical entity but simply a manifestation

of hepatocellular adenoma characterized by a large number of lesions

Further Reading

Bioulac-Sage P, Balabaud C, Zucman-Rossi J Subtype

clas-sification of hepatocellular adenoma Dig Surg 2010;27(1):

39–45.

Bioulac-Sage P, Laumonier H, Couchy G, et al Hepatocellular

adenoma management and phenotypic classification:  the

Bordeaux experience Hepatology 2009;50(2):481–489.

Grazioli L, Bondioni MP, Haradome H, et  al Hepatocellular

adenoma and focal nodular hyperplasia:  value of etic acid-enhanced MR imaging in differential diagnosis

gadox-Radiology 2012;262(2):520–529.

Grazioli L, Federle MP, Brancatelli G, Ichikawa T, Olivetti L,

Blachar A Hepatic adenomas: imaging and pathologic

find-ings RadioGraphics 2001;21:877–892; discussion, 892–874.

Hussain SM, van den Bos IC, Dwarkasing RS, Kuiper JW, den

Hollander J Hepatocellular adenoma:  findings at the-art magnetic resonance imaging, ultrasound, computed

state-of-tomography and pathologic analysis Eur Radiol 2006; 16:

1873–1886.

Katabathina VS, Menias CO, Shanbhogue AK, Jagirdar J, Paspulati

RM, Prasad SR Genetics and imaging of hepatocellular

adeno-mas: 2011 update RadioGraphics 2011; 31(6):1529–1543.

Shanbhogue A, Shah SN, Zaheer A, Prasad SR, Takahashi N, Vikram R Hepatocellular adenomas:  current update on

genetics, taxonomy, and management J Comput Assist Tomogr 2011;35(2):159–166.

Shanbhogue AK, Prasad SR, Takahashi N, Vikram R, Sahani DV Recent advances in cytogenetics and molecular biology of adult hepatocellular tumors:  implications for imaging and

management Radiology 2011;258(3):673–693.

van Aalten SM, Thomeer MG, Terkivatan T, et al Hepatocellular adenomas: correlation of MR imaging findings with patho-

logic subtype classification Radiology 2011;261(1):172–181.

Van den Bos IC, Hussain SM, de Man RA, Zondervan PE, Ijzermans JN, Krestin GP Primary hepatocellular lesions: imaging findings on state-of-the-art magnetic resonance

imaging, with pathologic correlation Curr Probl Diagn Radiol 2008;37:104–114.

Hepatocellular Carcinoma

and Precursors

Jin-Young Choi, Guilherme Moura da Cunha, Beatriz C Baranski Kaniak, and Claude B. Sirlin

A Benign and Premalignant Liver Nodules in the Cirrhotic Liver

Definition

Cirrhosis-associated nodules comprise a histologic

spec-trum ranging from benign to malignant Although this

spectrum is continuous, the nodules are classified based

on histologic features as regenerative nodules (RNs, also

known as cirrhotic nodules), low-grade dysplastic nodules

(LGDNs), high-grade-dysplastic nodules (HGDNs), focal

nodular hyperplasia (FNH)‒like lesions, and

hepatocel-lular carcinomas (HCCs) This section discusses RNs,

LGDNs, HGDNs, and FNH-like lesions

Demographic and Clinical Features

In the cirrhotic liver, most HCCs are thought to develop

via multistep hepatocarcinogenesis, a histologic sequence

of progressively more dedifferentiated nodules:  RN to

LGDN to HGDN to HCC RNs are the most common

cirrhosis-associated nodules and are considered benign,

since they lack cellular atypia or other histologic features

of malignancy Whereas LGDNs are further along the

hepatocarcinogenesis pathway than RNs, most LGDNs

probably do not progress to overt HCC or progress very

slowly; from a clinical perspective, therefore, LGDNs may

also be considered benign HGDNs have a substantially

higher risk of malignant transformation and so are

consid-ered premalignant FNH-like lesions in cirrhosis have only

recently been described These lesions are probably benign

rather than premalignant; their main clinical significance

is that they can be confused with hypervascular HCC

Pathophysiology

RNs result from localized proliferation of hepatocytes

and their supporting stroma in response to repetitive liver

injury These nodules are round, sharply circumscribed,

and distributed diffusely throughout the cirrhotic liver

They have an intact reticulin framework, preserved portal

tracts, and sustained hepatocellular and phagocytic

functions The hepatocytes in RNs resemble those in mal livers Most RNs have a diameter of less than 1 cm

nor-LGDNs closely resemble RNs histologically Cellular atypia is mild and hepatocytes are only minimally abnormal Portal tracts are intact These nodules are predominantly supplied by portal veins HGDNs show architectural distortion and more advanced cytologic atypia As dedifferentiation progresses within dysplastic nodules, angiogenic pathways are activated, which mani-fests as an increased density of unpaired arteries (arteries without accompanying portal veins) LGDNs and HGDNs tend to be larger than RNs but rarely exceed 2  cm in diameter

RNs, LGDNs, and HGDNs are surrounded by mixed fibrous tissue, but true tumor capsules are absent The nodules may contain iron deposits Intralesional steatosis

is rare unless the background liver is steatotic

Although most FNHs occur in noncirrhotic livers, FNH-like lesions can arise in cirrhosis, presumably in response to arterioportal shunting and other blood flow alterations in this condition FNH-like lesions arising in cirrhotic livers have pathologic features similar to those

of FNHs arising in the noncirrhotic liver except that they may be surrounded by mixed fibrous tissue and appear to

be encapsulated These features include enlarged cytes as well as fibrous septa containing unpaired arteries accompanied by bile duct proliferation

hepato-Imaging FeaturesWhereas RNs are innumerable and distributed diffusely throughout the cirrhotic liver, they may or may not be visible at imaging, depending on imaging modality and technique At ultrasound and CT, the cirrhotic liver parenchyma characteristically appears coarse and hetero-geneous, but individual regenerative or dysplastic nodules are rarely discerned (Figure 62-1)

Regenerative and dysplastic nodules are depicted to better advantage at MRI The signal intensity character-istics of these nodules overlap with each other and with well-differentiated HCCs; however, MRI does not usually permit a specific histologic diagnosis Typical imaging

features are emphasized below RNs usually are iso- or

mildly hypointense on T2- and T2*-weighted images and

isointense on diffusion-weighted images On T2-weighted

images, LGDNs tend to have slightly lower signal intensity

than adjacent liver, while HGDNs may be hypo- or

isoin-tense Regardless of grade, dysplastic nodules are rarely

hyperintense on T2- or diffusion-weighted images; T2

or diffusion-weighted hyperintensity favors HCC

Regenerative and dysplastic nodules have variable

sig-nal intensity on T1-weighted images; sigsig-nal intensity on

T1-weighted images usually does not help in the

differen-tial diagnosis between RN, LGDN, HGDN, and HCC

Regenerative and dysplastic nodules may have a

similar degree of steatosis as background liver, but

intra-lesional steatosis greater than that of background liver is

unusual Hemorrhage and necrosis are exceedingly rare

Tumor capsules are absent The presence of any of these

imaging features (intralesional steatosis, hemorrhage, necrosis, tumor capsule) suggests HCC

On contrast-enhanced CT and MRI, RNs and LGDNs typically isoenhance relative to liver Owing to the activa-tion of angiogenic pathways and recruitment of neovas-cualrity, HGDNs may hyperenhance in the arterial phase and resemble hypervascular HCC Late venous-phase imaging helps in the differential diagnosis of nodules with arterial-phase hyperenhancement:  dysplastic nod-ules are usually isoenhancing in the late venous phase owing to preserved portal venous flow, whereas HCCs are more likely to be hypoenhancing (washout) due to loss

of portal venous flow Some regenerative and dysplastic nodules are hypovascular These hypovascular nodules lack arterial-phase hyperenhancement after administra-tion of extracellular agents and are hypoenhancing in the portal venous or delayed phases; they may resemble hypovascular HCCs

In the hepatobiliary phase after administration of hepatocyte-specific contrast, most regenerative and dys-plastic nodules are isointense to background liver Some LGDNs appear hyperintense in the hepatobiliary phase, presumably reflecting overexpression of the organic anion-transporter protein (OATP) membrane transport-ers responsible for hepatocellular uptake of the contrast agent or underexpression of the multidrug-resistance protein canalicular transporters responsible for its biliary excretion By comparison, HGDNs may appear hypoin-tense in the hepatobiliary phase, which has been attributed

to underexpression of the OATP A  cirrhosis-associated nodule that is hypointense in the hepatobiliary phase after administration of hepatocyte-specific contrast is likely a HGDN or a HCC (Figure 62-2)

FNH-like lesions hyperenhance in the arterial phase and fade to isointensity in the portal venous and later phases; they typically are iso- or hyperintense in the hepatobiliary phase after the administration of hepatocyte-specific agents

Figure 62-1 Cirrhotic liver imaged at ultrasound in the

transverse plane shows diffusely heterogeneous and coarse

liver parenchyma but does not delineate individual nodules

(Figure 62-3) Hypointensity in the venous or hepatobiliary

phases favors the diagnosis of HCC

Siderotic nodules are associated with cirrhosis; they have high levels of iron deposition relative to background

liver The nodules appear hyperdense at unenhanced

CT and moderately to markedly hypointense at T2- and

T2*-weighted MRI They are indistinguishable from

nonsiderotic nodules at ultrasound, since ultrasound is not

sensitive to iron deposition Histologically siderotic nodules

may be regenerative or dysplastic; no imaging findings

dif-ferentiate between the two types Homogeneous siderotic

nodules are rarely malignant The development of an

iron-poor component within a preexisting siderotic nodule

raises concern for malignant transformation

Regardless of imaging features, cirrhosis-associated nodules with a diameter of more than 2 cm are more likely

to be malignant than benign

Differential Diagnosis

Hypervascular HCC:  The presence of any intralesional

steatosis, hemorrhage, necrosis, and/or tumor capsule

suggests HCC

■ Hemangiomas: T2-hyperintense with characteristic peripheral nodular incomplete enhancement on early arterial imaging with progressive fill-in on delayed scans

■ Hypovascular HCC: Typically slightly intense and identified on diffusion-weighted images;

T2-hyper-is also hypointense on delayed postcontrast T1- weighted images following hepatospecific contrast administration

Management

Cirrhosis-associated nodules represent a histologic

spec-trum ranging from benign to malignant, but the vast

majority of such nodules are benign and may be

moni-tored safely with routine follow-up imaging (e.g., at 6 to 12

months) Cirrhosis-associated nodules larger than 2 cm or

with any of the following imaging features may represent HCC and warrant additional workup:  interval growth;

arterial-phase hyperenhancement; venous-phase hancement; absent or, compared with background liver, diminished uptake of hepatocyte-specific agents in the hepatobiliary phase; T2 hyperintensity; diffusion-weighted hyperintensity; intralesional steatosis; hemorrhage; necro-sis; tumor capsule; or presence within a siderotic nodule

hypoen-of a discrete iron-poor component For such lesions, tional workup may include close follow-up imaging (e.g.,

addi-at 2 to 4  months), additional imaging, correladdi-ation with serum biomarkers of HCC, or biopsy

dif-■ Regenerative and dysplastic nodules are depicted to better advantage at MRI than ultrasound or CT

■ The signal intensity characteristics of RNs, LGDNs, and HGDNs overlap with each other and with well-differentiated HCCs; MRI does not usually per-mit a specific histologic diagnosis

■ The vast majority of cirrhosis-associated nodules are benign and may be monitored safely with routine follow-up imaging

■ Cirrhosis-associated nodules with any of the follow- ing features may represent HCC and warrant addi-tional workup: size equal to or greater than 20 mm;

arterial-phase hyperenhancement; venous- phase hypo - enhance ment; absent or, compared with background liver, diminished uptake of hepatocyte-specific agents

in the hepatobiliary phase; T2 hyperintensity; diffusion-weighted hyperintensity; intralesional steato-sis; hemorrhage; necrosis; tumor capsule; or development within a siderotic nodule of an iron- poor component

Figure 62-3 Probable focal nodular hyperplasia‒like lesion MR images at 3T were acquired before (A) and after gadoxetate

administration in the early hepatic arterial (B), late hepatic arterial (C), portal venous (D), transitional (E), and hepatobiliary

(F) phases A 20-mm nodule (arrow) hyperenhances in the arterial phase and fades to isointensity in the transitional and portal

venous phases Except for a central scar, the nodule is hyperintense in the hepatobiliary phase

Further Reading

Krinsky GA, Lee VS MR imaging of cirrhotic nodules Abdom

Imaging 2000;25:471–482.

Hanna RF, Aguirre DA, Kased N, Emery SC, Peterson MR, Sirlin

CB Cirrhosis-associated hepatocellular nodules: correlation

of histopathologic and MR imaging features RadioGraphics

2008;28:747–769.

van den Bos IC, Hussain SM, de Man RA, Zondervan PE, Ijzermans

JN, Krestin GP Primary hepatocellular lesions: imaging findings on state-of-the-art magnetic resonance imaging,

with pathologic correlation Curr Probl Diagn Radiol 2008;

37:104–114.

B Hepatocellular Carcinoma: Diagnosis

Definition

Hepatocellular carcinoma (HCC) is the most common

malignant primary neoplasm of the liver; it is composed

of cells with hepatocellular differentiation

Demographic and Clinical Features

HCC is the fifth most common tumor worldwide and the

third common cause of cancer-related death Most HCCs

occur in individuals with cirrhosis, in whom the annual

incidence of HCC ranges from 1% to 10%, depending on

the etiology or coetiologies of cirrhosis as well as other

factors HCCs can develop in individuals without

cir-rhosis, most commonly in those with chronic hepatitis B

infection Other risk factors for HCC development in

the absence of cirrhosis include chronic hepatitis C viral

infection, exposure to aflatoxins, nonalcoholic

steato-hepatitis, diabetes, and the presence of certain types

of hepatocellular adenomas HCC is more common in

middle-aged and elderly adults and affects men more

fre-quently than women

HCC is usually asymptomatic until it has progressed

to an advanced stage The prognosis of symptomatic HCC

is dismal; such tumors are usually incurable and affected

patients have less than 10% 1-year survival Surveillance

of at-risk patients with imaging tests permits diagnosis

of HCC in its early stages, allows for timely intervention,

and prolongs survival For this reason, current clinical

practice guidelines recommend that at-risk patients

(those with cirrhosis or chronic hepatitis B viral

infec-tion) undergo imaging surveillance for HCC Although

these guidelines recommend that surveillance be done

with ultrasound, ultrasound has low per-patient

sensi-tivity for the detection of HCC, and many institutions

use CT or MRI instead for the surveillance of at-risk

is seen in half of large HCCs Capsule formation is rare in small HCCs less than 2 cm

The stepwise development of HCC from regenerative nodule through low-grade dysplastic nodule and high- grade dysplastic nodule is well established During hepa-tocarcinogenesis, sequential changes occur in the vessels supplying the nodules As the high-grade dysplastic nod-ule evolves toward malignancy, abnormal neoplastic arte-rial supply increases and normal arterial and portal supply decreases The density of abnormal neoplastic arteries is markedly increased in moderately and poorly differen-tiated HCCs; normal portal tracts are almost absent Well-differentiated HCCs, by comparison, have variable degrees of arterial and portal venous supply and their histologic features overlap with those of high-grade dys-plastic nodules

Organic anion-transporting polypeptides (OATPs), expressed at the basolateral membrane of hepatocytes, mediate the hepatocellular uptake of hepatocyte-specific

MR contrast agents such as gadoxetate (Gd-EOB-DTPA) and gadobenate (Gd-BOPTA), whereas multidrug resis-tance‒associated protein 2 (MRP2), expressed on the canalicular surface, mediates the excretion of these agents from hepatocytes According to recent studies, OATP expression usually (about 95% of HCCs) is reduced while MRP2 expression is usually maintained or even increased

in HCC

Imaging FeaturesMass-like HCCs are well demarcated, round or ovoid, and frequently encapsulated Infiltrative HCCs have irregular, indistinct margins with frequent invasion of the portal

or hepatic veins A  mixed pattern, in which mass-like and infiltrative HCCs are present simultaneously, is also common Classifying HCC according to pathologic mac-roscopic classification by imaging can be difficult The massive type consists of a large tumor with an unclear or irregular boundary The diffuse type is characterized by the diffuse proliferation of numerous small tumor nod-ules throughout the parenchyma, sometimes involving an entire liver lobe or even the whole organ

Large mass-like HCCs often have a nodule-in-nodule

or mosaic architecture (Figure 62-4), representing the presence of confluent nodules separated by fibrous septa and areas of necrosis within the lesion The distribution of

these components (nodules, septa, necrotic areas) usually

appears random A tumor capsule may be evident (Figure

62-5) HCCs may occasionally contain hemorrhage or

intracellular fat A  dominant hemorrhagic or fatty

nod-ule in a cirrhotic liver should be regarded with suspicion

(Figure 62-6) HCCs are rarely siderotic; in a diffusely

iron-overloaded liver, an iron-sparing nodule should raise

concern for malignancy

Portal or hepatic vein invasion is an important feature

of HCC Malignant venous thrombosis is characterized by the presence of enhancing soft tissue within the vein’s lumen;

additional findings that are often present include sion of the vein, intraluminal neovascularity, and contigu-ity or direct contact with parenchymal tumor Malignant venous thrombosis can also be observed with cholangio-cellular carcinoma but rarely if ever with metastases from

Figure 62-4 Hepatocellular carcinoma, mosaic architecture Coronal (A) and sagittal (B) reformatted CT images in the portal

venous phase show a 7.6-cm heterogeneous well-circumscribed mass (arrows) in a 56-year-old man with cirrhosis The mass

contains internal compartments in a seemingly random distribution

Figure 62-5 Hepatocellular carcinoma, tumor capsule 3T MR images acquired in the arterial (A) and 5-minute delayed

(B) phases shows a 3-cm mass (arrows) in the left lobe of the liver in a man with cirrhosis The mass hyperenhanced diffusely in

the arterial phase A smooth peripheral rim of enhancement surrounds the mass in the delayed phase This rim of enhancement

is consistent with a pseudocapsule

outside the liver; hence the presence of malignant venous

thrombosis virtually excludes metastatic disease from the

differential diagnosis Less commonly, HCCs invade bile

ducts Extrahepatic metastases occur in advanced HCC but

are rare in small nodular HCC Intraperitoneal metastases

are uncommon; these may develop after rupture of a HCC,

percutaneous biopsy, or surgery

Figure 62-6 Steatotic hepatocellular carcinoma T1-weighted 3T MR images show a 4-cm mass (arrows) in the left lobe of the liver in a woman with cirrhosis Intralesional fat is evidenced by signal loss on the out-of-phase (A) compared with the in-phase (B) image In a patient with cirrhosis, the presence of intralesional fat disproportionately greater to that in background liver is highly suspicious for hepatocellular carcinoma

Figure 62-7 Small hepatocellular carcinoma Ultrasound

image in a 57-year-old man with cirrhosis depicts a 1.4-cm

hypoechoic nodule This finding is suggestive but not

diagnostic for hepatocellular carcinoma and further

evaluation with contrast-enhanced CT or MRI is warranted

At ultrasound, HCCs may appear as a solitary or tiple discrete nodules or ill-defined infiltrative masses Small tumors without fatty metamorphosis are usually hypoechoic (Figure 62-7) Large mass-like HCCs tend to

mul-be heterogeneous and may have a hypoechoic rim sponding to a fibrous capsule

corre-At unenhanced CT, HCCs usually are hypo- or isodense The signal intensity of HCCs on T1-weighted imaging varies with tumor growth and biochemical com-position; most HCCs are hypo- or isointense relative to liver; but owing to the presence of copper, glycogen, and other paramagnetic materials, they may be hyperintense Intracellular fat, if present, appears as signal loss on out-of-phase versus in-phase gradient-echo images (see Figure 62-6) Mild hyperintensity of a nodule in a cirrhotic liver on T2-weighted imaging is highly suggestive of malignancy The fibrous tumor capsule is seen as an intact hypointense rim on both T1- and T2-weighted imaging Disruption

of the capsule suggests that the tumor may have spread outside the capsule to infiltrate the surrounding paren-chyma The appearance of HCCs on diffusion-weighted imaging is variable Although restricted diffusion favors the diagnosis of HCC over benign lesions, many HCCs are not associated with restricted diffusion; hence the absence

of diffusion restriction does not exclude the diagnosis

of HCC

Multiphasic CT and MRI are the standard imaging techniques for diagnosing and staging HCC (Figures 62-8 and 62-9) Owing to their abnormal neoplastic arterial blood supply, most HCCs are hypervascular

in the arterial phase Hence arterial-phase imaging is important to characterize lesions based on vascularity and to detect hypervascular HCC Owing to reduced or

absent portal venous flow, HCCs characteristically have

reduced enhancement compared to liver in the portal

venous and delayed phases Hence portal venous and

delayed-phase imaging is important for lesion

char-acterization and helps differentiate HCC from benign

lesions:  lesions that wash out to hypoenhancement

in the late venous phase compared with background

liver are more likely to be HCC, whereas lesions that

fade to isoenhancement compared with liver

paren-chyma are more likely to be benign Portal venous and

delayed-phase imaging is also useful for identifying a

tumor capsule:  capsules usually enhance progressively

from the arterial to the late venous phases and show

delayed-phase hyperenhancement (see Figure 62-5) This is clinically relevant because the presence of a tumor capsule strongly favors the diagnosis of HCC in patients with cirrhosis The portal venous and delayed phases are also important for assessing portal and hepatic venous patency as well as extrahepatic findings

Over 20% of HCCs appear hypovascular at CT or MRI and show contrast enhancement slightly less than that in the surrounding liver on arterial-phase images (see Figure 62-10), either owing to true hypovascularity or to mistim-ing of the arterial phase Hypovascular HCCs are difficult

to differentiate at conventional imaging from lar regenerative and dysplastic nodules

Figure 62-8 Hypervascular hepatocellular carcinoma CT images acquired before (A) and in the late arterial (B), portal venous

(C), and 3-minute delayed (D) phases after contrast administration in a man with cirrhosis show a 2.3-cm mass in the right lobe of

the liver, which hyperenhances diffusely in the arterial phase and washes out to hypoattenuation relative to the liver in the portal

venous and 3-minute delayed phases In a patient with cirrhosis, a mass greater than or equal to 2 cm mass with arterial-phase

hyperenhancement and portal venous or delayed-phase washout is diagnostic of hepatocellular carcinoma

In general the most important imaging features

favor-ing HCC in a patient with cirrhosis include size larger

than 2  cm, arterial-phase hyperenhancement, delayed-

phase hypoenhancement (washout), rapid interval

growth, and (if present) malignant venous thrombosis

Characteristic morphologic features include tumor

cap-sule, nodule-in-nodule or mosaic architecture, and (for

large hypervascular HCCs) prominent intralesional

arter-ies The presence of mild hyperintensity at T2-weighting

favors the diagnosis of HCC over regenerative nodules

or dysplastic nodules, but this finding is neither

sensi-tive nor specific and the diagnosis of HCC should not be

made solely on the basis of this finding Less common but suggestive features of HCC include restricted diffu-sion, intralesional hemorrhage, fat deposition dispro-portionate to the rest of the liver, and iron sparing in an iron-overloaded liver

Emerging evidence suggests that hepatocyte-specific agents may improve sensitivity for HCC After admin-istration of these agents, the enhancement pattern of most HCCs in the dynamic phases is similar to that with extracellular gadolinium-based contrast agents except that washout may appear more rapid with gadoxetate because the background liver parenchyma progressively

Figure 62-9 Hypervascular hepatocellular carcinoma at MRI with extracellular contrast MR images at 3T were acquired before (A) and in the late arterial (B), portal venous (C), and 3-minute delayed (D) phases after extracellular contrast administration in a man with cirrhosis An 8-mm nodule in the right lobe vividly hyperenhances in the arterial phase and washes out to hypointensity relative to the liver in the portal venous and 3-minute delayed phases Despite its small size, this nodule is highly suspicious for hepatocellular carcinoma

enhances (Figure 62-11) In the hepatobiliary phase,

most (about 95%) HCCs are well delineated as areas of

hypointensity relative to the background liver owing to

their reduced OATP expression, as discussed earlier (see

Figure 62-11) By comparison, regenerative and dysplastic

nodules characteristically are iso- or even

hyperin-tense in the hepatobiliary phase Hence the presence of

hepatobiliary-phase hypointensity favors the

diagno-sis of HCC, and the use of hepatocyte-specific agents

with hepatobiliary imaging helps to diagnose HCCs

that cannot be characterized confidently based on

imaging characteristics in the dynamic phases (e.g., HCCs without portal or delayed-phase washout; hypovascular HCCs)

About 5% of HCCs show paradoxical uptake of gadoxetate in the hepatobiliary phase, appearing as iso- or hyperintense lesions relative to surrounding liver paren-chyma; this has been attributed in part to the expression

of elevated OATP in these atypical lesions The percentage

of HCCs that show paradoxical uptake of the other hepatocyte-specific agent, gadobenate, in the hepatobiliary phase is unknown

Figure 62-10 Hypovascular hepatocellular carcinoma CT images acquired before (A) and in the late arterial (B), portal venous

(C), and 3-minute delayed (D) phases after contrast administration in a man with cirrhosis show a 3.5-cm mass in segment 4;

it is isoattenuating to liver precontrast and in the arterial phase The mass enhances less than liver in the portal venous and

delayed phases A smooth continuous rim of enhancement in the portal venous and delayed phases suggests the presence of a

tumor capsule Because this mass lacked arterial phase hyperenhancement, it did not meet imaging criteria for hepatocellular

carcinoma A biopsy confirmed a final histologic diagnosis of hepatocellular carcinoma

Differential Diagnosis

■ Transient arterial enhancement due to ous arterioportal shunts: Transient area of hyperen-hancement in the arterial phase without correlate on any other sequence Fades out on more delayed post-contrast sequences

nontumor-■ Confluent hepatic fibrosis:  Typically nonspherical

in appearance without arterial hyperenhancement

or washout; seen in anterior segments of the right hepatic lobe or medial segments the left hepatic lobe

Most common in patients with primary sclerosing cholangitis‒induced liver cirrhosis

■ High-grade dysplastic nodules:  May be guishable from HCC In a patient with cirrhosis, fea-tures that suggest HCC include size larger than 2 cm, arterial-phase hyperenhancement, delayed-phase hypoenhancement (washout), rapid interval growth, and (if present) malignant venous thrombosis

indistin-■ Hemangioma:  Rarely seen in cirrhotic livers

T2-hyperintense with characteristic peripheral ular incomplete enhancement on early arterial imag-ing with progressive fill-in on delayed scans

nod-■ FNH: Rarely seen in cirrhotic livers Homogeneous enhancement without washout T2-hyperintense scar that shows delayed enhancement Appears iso-

or hyperintense on delayed imaging following the administration hepatospecific contrast material

■ Intrahepatic cholangiocellular carcinoma; Typically T2 hypointense centrally owing to stromal fibrosis

Associated bile duct dilation and capsular retraction

Early peripheral rim-like enhancement with eral washout but central progressive enhancement

periph-Variant

Fibrolamellar HCC occurs in noncirrhotic livers, most

fre-quently in adolescents or young adults without risk factors

for HCC As risk factors for HCC are absent, the lesions are not discovered in the asymptomatic phase during sur-veillance; rather, they typically present with symptoms and are large at diagnosis Nevertheless the prognosis for fibrolamellar HCC is more favorable than that for usual HCCs, at least in part because patients with fibrolamellar HCC do not have underlying liver disease contributing to morbidity and mortality At imaging, fibrolamellar HCCs characteristically have intralesional fibrous septa as well as central areas of necrosis These fibrous bands and necrotic areas may be mistaken for the stellate central scar of FNH, potentially causing diagnostic confusion Nevertheless fibrolamellar HCCs can usually be differentiated from FNHs at noninvasive imaging Compared with FNHs, fibrolamellar HCCs tend to be more heterogeneous on both unenhanced and contrast-enhanced images; also, the necrotic areas within fibrolamellar HCCs do not enhance,

in distinction to the delayed enhancement characteristic of the FNH stellate scar (Figure 62-12) Hepatobiliary agents such as gadoxetate may be helpful in difficult cases; FNHs characteristically show hepatobiliary-phase enhancement while fibrolamellar HCCs do not

ManagementSmall arterially enhancing lesions are common in the cir-rhotic liver: the large majority of such lesions are benign while only a smallminority are HCCs The identification of small HCCs is important, because treatment of small HCCs

is more efficacious that that of large HCCs The diagnosis of small HCCs depends on lesion size and other imaging fea-tures In 2011, the American College of Radiology released

a standardized system for interpreting liver lesions on CT and MRI surveillance examinations for HCC This sys-tem is called LI-RADS (Liver Imaging‒Reporting And Data System) and can be reviewed at http://www.acr.org/LI-RADS Lesions that meet the criteria for definite HCC

Figure 62-11 Hepatocellular carcinoma at MRI with gadoxetate MR images at 3T were acquired before (A) and in the

early arterial (B), late arterial (C), portal venous (D), and hepatobiliary (E) phases after gadoxetate administration in a

man with cirrhosis A 2.8-cm mass in right lobe exhibits characteristic gadoxetate-enhanced MRI features of hepatocellular carcinoma: arterial phase hypervascularity, rapid apparent washout relative to the liver, and hepatobiliary phase hypointensity

can be treated as HCCs without biopsy Lesions that do

not meet the criteria for definite HCC may require close

follow-up, additional imaging, or biopsy Emerging

evi-dence suggests that MRI with hepatocyte-specific agents

may improve the sensitivity for HCC diagnosis, especially

for lesions that do not meet the criteria for definite HCC

when imaged with the use of conventional agents The

treatment of HCC depends on multiple factors

includ-ing the extent (stage) of tumor as well as the presence and

degree of cirrhosis and portal hypertension For patients

with cirrhosis and portal hypertension, liver

transplanta-tion is the only potentially curative optransplanta-tion for HCC Liver

transplantation is not performed for patients with portal

or hepatic venous tumor invasion owing to unacceptably

high recurrence rates Liver transplantation is usually

reserved for patients with one HCC nodule smaller than

5 cm or with two or three HCC nodules each smaller than

3 cm Although HCC is by far the most common nancy associated with cirrhosis, patients with cirrhosis also have an elevated risk for the development of cholan-giocellular carcinoma The differentiation between HCC and intrahepatic cholangiocellular carcinoma is critical, since patients with intrahepatic cholangiocellular carci-noma should not undergo liver transplantation owing to unacceptably high post‒liver transplantation recurrence rates Imaging features at multiphasic CT or MRI with extracellular agents that suggest the diagnosis of cholan-giocellular carcinoma over HCC include peripheral rather than diffuse hyperenhancement in the arterial phase and sustained central enhancement rather than washout in the delayed phase In a patient being considered for liver transplantation, a mass with such imaging features should

(C)

Figure 62-12 Fibrolamellar hepatocellular carcinoma MRI shows a left lobe mass that is lobulated and heterogeneous in

signal intensity on the T2-weighted sequence (A) Following intravenous contrast administration, the mass show heterogeneous

enhancement in the arterial phase (B) The central fibrous scar (arrows) shows low T2 signal intensity and does not enhance in the

arterial or the delayed phases (C)

be biopsied to help determine the patient’s eligibility for

transplantation

Key Points

■ Usually occurs in patients with cirrhosis

■ Classic enhancement features include arterial-phase hyperenhancement and venous- and delayed-phase hypoenhancement

■ Characteristic morphologic features include tumor capsule and mosaic or nodule-in-nodule archi - tecture

■ Moderate hyperintensity at T2-weighted imaging is

a common and characteristic signal-intensity feature

of HCC

■ Uncommon but suggestive features of HCC include restricted diffusion, intralesional hemorrhage, intracellular fat, and iron sparing in an iron- overloaded liver

■ HCC has a tendency to invade portal and hepatic veins; less commonly, it invades bile ducts

Further Reading

ACR LIRADS website: http://www.acr.org/LI-RADS

Baron RL, Brancatelli G Computed tomographic imaging

of hepatocellular carcinoma Gastroenterology 2004;127:

S133–143.

Kojiro M Histopathology of liver cancers Best Pract Res Clin

Gastroenterol 2005;19:39–62.

Willatt JM, Hussain HK, Adusumilli S, Marrero JA MR imaging

of hepatocellular carcinoma in the cirrhotic liver: challenges

and controversies Radiology 2008;247:311–330.

chemo-■ Transcatheter arterial chemoembolization: Typi cally involves the injection of chemotherapeutic agents, with or without iodized oil and embolic agents, into the branch of the hepatic artery that feeds the tumor

■ Transcatheter arterial (chemotherapy-eluting) bead embolization This is a variant of the transarterial chemoembolization technique that uses drug-eluting beads to gradually release chemotherapy, thereby prolonging the exposure of the cancer cells to the chemotherapeutic agent and reducing damage to the hepatic microcirculation

■ Percutaneous ethanol injection:  Refers to injection

of pure alcohol into the tumor, inducing protein denaturation, cellular dehydration, and local tumor necrosis

■ Radiofrequency ablation: Uses high-frequency nating current via electrodes placed within the tis-sue to induce thermal energy and cause coagulative necrosis

alter-■ Microwave ablation: Uses microwaves generated by needles placed within tissue to induce coagulative necrosis

■ Cryoablation:  Uses extreme cold to destroy tissue around needles placed in tumors

This discussion focuses on transcatheter arterial embolization and radiofrequency ablation

chemo-Demographic and Clinical FeaturesThe only curative treatments for hepatocellular carcinoma (HCC) are surgical procedures such as hepatic resec-tion and liver transplantation However, less than 20%

of patients with HCC are candidates for surgery ety of interventional procedures—including transarterial chemoembolization and radiofrequency ablation—are utilized for local control of HCC These techniques are most commonly used for patients who are not candidates for surgery, as a bridge to transplant for patients who are

A vari-on the waitlist for deceased-dA vari-onor liver transplantatiA vari-on, and as a pretransplant downstaging procedure for patients with advanced HCC who otherwise would be considered ineligible for liver transplantation

The assessment of tumor response to ablation or moembolization is important, since early detection of residual or locally recurrent tumor after intervention can improve the efficacy of retreatment Currently the most widely used modalities for follow-up after ablation or chemoembolization are contrast-enhanced CT and MRI Contrast-enhanced ultrasound can also be used

che-Pathophysiology

In transarterial chemoembolization, arterial embolization interrupts tumor blood supply and postpones growth until replaced by neovascularity Also, local administration of chemotherapy allows higher doses within the tumor tis-sue while simultaneously reducing systemic exposure In radiofrequency ablation, heat is locally generated around

an electrode shaft inserted in the tumor tissue, causing coagulative necrosis

At pathology, the transarterial chemoembolization‒treated area shows partial or complete necrosis, depend-ing on the degree of devascularization The treated zone

of radiofrequency ablation demonstrates the classic manifestations of coagulative necrosis The marginal area shows a hemorrhagic rim with degenerated hepatocytes,