cirrhosis-associated he pa to cellular nodules

8/6/2019 Cirrhosis-Associated He Pa to Cellular Nodules

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A diagnostic is a sentence.


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Cirrhosis-associated

Hepatocellular Nodules:

Correlation of Histopathologic and

MR Imaging Features

RadioGraphics 2008;28:747-769

Introduction


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Content

Introduction

Nodule Classification

Nodule Characterization Differential Diagnosis


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Introduction

Hepatocellular carcinoma (HCC) is the fifth most common tumor in the

world and is the third most common cause of cancer-related death, after

lung and stomach cancer.

Cirrhosis is the strongest predisposing factor for HCC, withapproximately 80% of cases of HCC developing in a cirrhotic liver.

The annual incidence of HCC is 2.0%6.6% in patients with cirrhosis

compared with 0.4% in patients without cirrhosis.


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Introduction

The incidence of HCC increased from 1.3 per 100 000 in 19811983 to 3.0

per 100 000 in 19961998 (US). In Vietnam

Age-standardized rate (per 100 000) of major cancers in Hanoi (1996) and Ho Chi Minh City (199596). Pham ThiHoang Anh and Nguyen Ba Duc. Japanese Journal of Clinical Oncology32:S92-S97 (2002)


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Liver cirrhosis: irreversible remodeling of the

hepatic architecture with bridging fibrosis and

a spectrum of hepatocellular nodules. Guidelines nodular hepatocellular lesions

(Canada 1995), there are two categories of

nodules:

(a) regenerative lesions and

(b) dysplastic or neoplastic lesions

Lesions in italics are described in this article


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There are four classes of lesions that characteristically are found in thecirrhotic liver: regenerative nodules, dysplastic foci, dysplastic nodules,and hepatocellular carcinomas. Term: cirrhosis-associated hepatocellularnodules.

Stepwise pathway of carcinogenesis for HCC in cirrhosis:- regenerative nodules may be monoacinar or multiacinar, surrounded by

fibrous septa, diameter up to 5cm but rare.

- dysplastic and neoplastic nodules: abnormal growth do not satisfy the

histologic criteria for malignancy or invasion .

- HCC are malignant neoplasms composed of dedifferentiated hepatocytes.


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Note:

The diagnostic differentiation of dysplastic nodules from other cirrhosis-associated hepatocellular nodules may be difficult even at histopathologicanalysis, and molecular geneticsbased techniques may be necessary.Although these nodules may transform over time into HCC, but relatively

slow.

Dysplastic nodules should not be treated or managed as cancers, andpatients with known or suspected dysplastic nodules should not bemonitored more aggressively than patients without such nodules (AmericanAssociation for the Study ofLiverDiseases).

Siderotic Nodules.- The term was coined by radiologists to describecirrhosis-associated nodules (regenerative or dysplastic) with high levels ofendogenous iron. Siderotic nodules rarely, if ever, are malignant


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Characteristics of Cirrhosis-associated Hepatocellular Nodules inComparison with Parenchyma


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Nodule Characterization

1. Size

As a general rule, lesions with a

diameter of less than 2 cm are

more likely to be benign than

malignant and, if malignant, are

usually well differentiated.

2. Importance of Clinical History

and Laboratory Testing (table)

The diagnostic value of imaging

is greatest when the images areinterpreted with consideration

given to the available clinical and

laboratory data.


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4. Hepatocellular FunctionRegenerative nodules generally have normal hepatocellular function andtherefore demonstrate avid uptake of hepatocellular contrast agents. Asdedifferentiation proceeds, the number of expressed organic ion transportersdecreases, with a resultant progressive reduction in the uptake ofhepatocellular agents.

5. Kupffer Cell Density

The density of Kupffer cells within regenerative lesions = surroundingnonneoplastic hepatic parenchyma. The cell density is visible at contrast-enhanced imaging because Kupffer cells avidly accumulate particulateagents through phagocytic mechanisms.

According to empirically derived values reported in the literature, dysplasticnodules and well-differentiated HCCs have variable Kupffer cell densities,ranging from diminished to elevated levels. Moderately and poorlydifferentiated HCCs tend to have a diminished Kupffer cell density.


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6. Usefulness of MR Imaging

A critical role is the depiction of early-stage HCC.

Other roles: staging of HCC, differentiation of neoplastic lesions fromregenerative lesions, planning and guidance of therapy, and assessing theresponse to therapy.

Unenhanced Acquisitions.

The pulse sequences most commonly used: T1, T2, and T2* weighting.

Chemical fat-saturation sequences and gradient-recalled echo (GRE)sequences with out-of-phase and in-phase image acquisitions arehelpful for assessing hepatic or intralesional steatosis.

Diffusion-weighted sequences are used at some institutions to evaluatehepatocellular nodules.

Contrast-enhanced Acquisitions.

Three classes of MR contrast agents: gadolinium chelates with lowmolecular weight, hepatocellular agents, and superparamagnetic iron oxide(SPIO) particles.


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6. Usefulness of MR Imaging: Contrast-enhanced Acquisitions (cont).

Low-molecular-weight gadolinium chelates: extracellular agents generate T1shortening, provide information about tissue vascularity.

T1W, volumetric (3D) fat-saturated spoiled GRE sequences are well suitedfor this purpose.

The hepatic arterial phase is critical: acquisition of the center of k-spacecoincides with the peak arterial perfusion of hepatic nodules.

Portal venous phase: 2030 seconds after gadolinium administration.Recently, acquiring delayed venous phase and equilibrium phase images180240 seconds after contrast agent injection, to better assess venouswashout.

The disadvantages of gadolinium: precise timing and patient cooperation are

critical because gadolinium-related enhancement is transient.Well-differentiated HCCs and some dysplastic nodules may be portallyperfused and hypoenhanced or isoenhanced during the arterial phase, thusevading detection.

Benign cirrhotic tissue may be hyperenhanced because of alteredhemodynamics and may obscure underlying HCCs. In addition, benign

arteriovenous shunts and active inflammation may cause earlyenhancement mimicking that in HCC


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6. Usefulness of MR Imaging: Contrast-enhanced Acquisitions

(cont).

Calculating the Delay for Hepatic Arterial Phase Imaging

with a Test Bolus. Note: AT = acquisition time, IT = injection

time, TTP = time to peak aortic enhancement.


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Mixed extracellular and hepatocellular agents: a specific subcategory of

gadolinium chelates.

They are useful not only for evaluating lesion vascularity, but also for

assessing hepatocellular function on images acquired with an appropriate

delay. Two such agents have been manufactured commercially: gadobenate

dimeglumine (Gd-BOPTA) and gadoxetic acid disodium (Gd-EOB-DTPA).

Up to 5% of the dose of gadobenate is selectively taken up by functioning

hepatocytes and excreted into the bile. Although initial biliary excretion of the

agent is noticeable on delayed T1W images at 5 minutes after injection,

reliable characterization of hepatocellular function in the cirrhotic liverusually requires delays of 30120 minutes. Thus, although a single injection

of gadobenate permits assessment of lesion vascularity and hepatocellular

function, two imaging sessions are typically required if both types of data are

desired.


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SPIO particles (mean diameter of 25250 nm), are phagocytosed by Kupffer

cells in the liver and spleen.

At MR imaging, SPIO particles cause shortening of T2* and, to a lesser

degree, T2. In the cirrhotic liver, they accumulate in tissues that contain

Kupffer cells (eg, in regenerative nodules, some dysplastic nodules, and

regions of surrounding liver parenchyma), causing signal loss in those

regions on T2W images and T2*W images.

Most HCCs lack Kupffer cells, do not accumulate SPIO particles, and

therefore appear hyperintense relative to the liver parenchyma on T2W

images and T2*-weighted images obtained after the administration of SPIO


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SPIO particles may be used alone or in combination with gadolinium.

Contrast-enhanced MR imaging with the use of SPIO particles should beperformed with T2- or T2*W sequences. However, this technique hasimportant intrinsic disadvantages. First, lesion characterization is limitedbecause most lesions do not exhibit SPIO uptake and thus appear

hyperintense on T2W images. Second, well-differentiated HCC mayaccumulate SPIO particles and thus appear invisible against the normal liverbackground.

To overcome these limitations, some institutions advocate double contrast-enhanced MR imaging in which both SPIO particles and a gadolinium are

administered sequentially. A shortcoming of double contrast-enhancedimaging is that it is logistically more difficult than contrast-enhanced imagingwith the use of a single agent. It also exposes the patient to two drugs and,thus, to a greater risk of adverse effects. A potential technical limitation ofSPIO is that, in addition to shortening the T2* of liver tissue, it shortens T1and therefore reduces the effectiveness of the subsequent gadolinium

injection at dynamic T1W imaging.


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Differential Diagnosis

Table: MR Imaging basedDifferential Diagnosis

Cirrhosis-associated

Hepatocellular Nodules

Note.Most HCCs detected at

surveillance imaging are smalland show no evidence of

intralesional fat, a tumor capsule,

or aggressive behavior. Thus, the

absence of these features does

not necessarily imply benignity.


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1. Regenerative Nodules

Gross Pathologic and Histologic Features

Although most d < 2 cm, regenerative nodules with d > 2 cm have been

observed in patients with long-standing Budd-Chiari syndrome and in

patients with cirrhosis due to autoimmune hepatitis. The largest nodulesare usually located near major vessels.

Regenerative nodules characteristically are surrounded by regions of

bridging fibrosis (Fig 1). In the early stages of cirrhosis, the liver may

contain nonregenerative nodules of hepatocellular tissue carved out by

bridging fibrosis. Such nodules may resemble regenerative nodules atgross pathologic evaluation; however, because they lack regenerative

features, they are not classified as regenerative.


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Differential Diagnosis1. Regenerative Nodules

Gross Pathologic and Histologic Features

Figure 1. a 54 y/o/m with HCV-induced cirrhosis. (ac) Axial 2D T2*W spoiled GRE

images obtained at 3 T with a TE of 5.8 msec. (a) Unenhanced image shows minimal

heterogeneity of the liver parenchyma, with faintly visible nodules of various sizes

(arrows). (b) Image obtained after SPIO administration shows a marked loss of signal

intensity because of the phagocytic uptake of SPIO particles in the nodules (arrows),which appear dark and sharply circumscribed.


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1. Regenerative NodulesGross Pathologic and Histologic Features

Figure 1. (c) Double contrast-enhanced image obtained after the intravenous

administration of a gadolinium-based contrast agent shows fibrotic reticuli with high

signal intensity due to extracellular accumulation of the low-molecular-weight agent.

The enhancement of fibrotic tissue further increases the visibility of the innumerable

nodules (arrows). (d) Photograph of explanted liver from a 67-year-old woman withHCV-induced cirrhosis shows an outer surface studded with regenerative nodules of


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Unenhanced MR Imaging Features.

Regenerative nodules are usually innumerable, but they may be difficult

to see on radiologic images, depending on the imaging technique used.

When they are visible, regenerative nodules appear sharplycircumscribed within the liver parenchyma.

- On unenhanced T2- and T2*W images, the nodules typically display

low signal intensity; their signal intensity on T1-weighted images is

variable.

- Lipid-containing regenerative nodules display signal loss on out-of-phase GRE images and unenhanced asymmetric spin-echo images in

comparison with in-phase images. Steatotic regenerative nodules tend to

occur in multiples (Fig 2). A single fatty nodule is suggestive of a

dysplastic or malignant process (Fig 3).


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Figure 2. Steatotic regenerative nodules in a 54 y/o/w with cirrhosis secondary to fatty

liver disease. (a, b) Comparison of axial unenhanced 2D spoiled GRE out-of-phase (TE,

2.3 msec) (a) and in-phase (TE, 4.6 msec) (b) images obtained at 1.5 T shows a diffuse

signal intensity loss in the liverin a because of phase interferenceinduced fat and water

signal cancellation (chemical shift of the second kind), a finding indicative of diffuse

steatosis. Superimposed on the steatotic background are multiple steatotic nodules

(arrows) with a signal intensity that is markedly lower than that of background in a and


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Figure 3. Steatotic HCC in a 48 y/o/m with HCV-induced cirrhosis. (ac) Axial SPIO-

enhanced 2D spoiled GRE images obtained at 1.5 T with TEs of 2.6 msec (a), 4.8 msec

(b), and 6.6 msec (c) show a 15-mm nodule in liver segment VIII (arrow). A loss of signal

intensity in the nodule periphery on the out-of-phase images (a, c) in comparison with

that on the in-phase image (b) is indicative of intralesional fat.


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Figure 3c. d) Axial gadolinium-enhanced 3D fat-saturated T1-weighted spoiled GRE

image shows heterogeneous enhancement of the nodule. (e) Photograph of a section of

the liver, which was explanted 45 days after MR imaging, shows a yellowish nodule

(arrows) in an anatomic location corresponding to that of the nodule in ad. Histologic

analysis showed it to be a moderately differentiated steatotic HCC.


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Contrast-enhanced MR Imaging Features.

- Contrast-enhanced imaging features are diagnostically more specific than

findings at unenhanced imaging.

- After the injection of gadolinium, most regenerative nodules enhance to the

same degree as the adjacent liver or show slightly less enhancement.- Uptake and excretion of gadobenate dimeglumine by these nodules is usually

preserved. Consequently, on images acquired during the hepatocellularphase

after an injection of gadobenate dimeglumine, virtually all regenerative nodules

have a similar signal intensity, which gives the liver a homogeneous appearance

(Fig 4).

- Occasionally, regenerative nodules may have sufficient hepatocellular

function to take up the hepatocellularagent but not to excrete it; such nodules

show hyperintense signal.

- Finally, because most regenerative nodules have a preserved phagocytic

function, they are SPIO avid and appear hypointense on SPIO-enhanced T2-

and T2*W images (Fig 1).


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Figure 4. Regenerative nodules and HCC in a 57 y/o/m with cirrhosis. (a) Axial

SPIO-enhanced 2D T2*W (TE, 5.8 msec) spoiled GRE image shows a small

hepatocellular carcinoma (arrow), which has higher signal intensity than the

regenerative nodules surrounding it, because of its lesser phagocytic uptake ofSPIO articles.


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Figure 4. (b - f) Axial 3D fat-saturated T1W spoiled GRE images acquired at 3 T

one week later, before (b) and in three phases after (c - f) an injection of a

gadoliniumt. The unenhanced image (b) does not show the small HCC, but the

hepatic arterial phase image (c) shows increased signal intensity in the carcinoma

(arrow).


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Figure 4. (d, e) Portal venous (d) and equilibrium (e) phase images show washout

in the lesion center, which has lower signal intensity than that of the liver

parenchyma, while contrast material retained in the lesion rim results in

hyperintense signal suggestive of a capsule or pseudocapsule. The innumerable

regenerative nodules have signal intensity that is varied in b, isointense to that ofthe parenchyma in c, and slightly less intense than that of the parenchyma in e.


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Figure 4. (f) Hepatocellular phase image obtained 90 minutes after the injection

shows slightly lower signal intensity in the carcinoma because of less active

hepatocellular function than in background liver. Because most of the regenerative

nodules have taken up some gadolinium, the cirrhotic parenchyma appears more

homogeneous than in e. However, the regenerative nodules and fibrous reticuli aremost visible in a, the SPIO-enhanced image.


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2. Siderotic NodulesBecause of their high iron content, siderotic nodules have low signal

intensity on T1- and T2*-weighted unenhanced MR images. These

lesions may be either regenerative or dysplastic, and no

unenhanced imaging feature (size, number, distribution) permits

reliable differentiation between the two.To our knowledge, no studies have yet been performed to assess

whether contrast-enhanced imaging helps distinguish regenerative

siderotic nodules from dysplastic ones.


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Differential Diagnosis3. Dysplastic Nodules

Histologic Features.Dysplastic nodules are characterized histologically by progressive

architectural derangement, nuclear crowding, atypia, and a variable number of

unpaired arterioles or capillaries.

-Low-grade dysplastic nodules closely resemble regenerative nodules

histologically. They have a preserved hepatic architecture, as well as normalvascular profile, hepatocellular function, and Kupffer cell density. They have

low malignant potential with slow, infrequent progression to HCC.

-High-grade dysplastic nodules show some architectural distortion with

sinusoidal "capillarization" and an increased density of unpaired arteries (Fig

5). The Kupffer cell density is variable; it may be increased, normal, ordiminished. High-grade dysplastic nodules progress to HCC more frequently

than low-grade dysplastic nodules. The high-grade nodules closely resemble

well-differentiated HCC and are difficult to distinguish histologically,

particularly those that are small.


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Unenhanced MR Imaging Features.- As expected on the basis of their histopathologic characteristics, dysplastic

nodules have variable appearances on MR images, and their signal intensity

characteristics overlap with those of regenerative nodules and well-

differentiated HCCs.

-On T2W images, low-grade dysplastic nodules tend to have low signal

intensity relative to adjacent liver, whereas high-grade dysplastic nodules tendto have slightly higher signal intensity.

-T1W images are not helpful because both low- and high-grade dysplastic

nodules display variable (low, intermediate, or high) signal intensity.

Contrast-enhanced MR Imaging Features.- On gadolinium- and SPIO-enhanced images, low-grade dysplastic nodules

typically are indistinguishable from regenerative nodules, whereas high-grade

dysplastic nodules are indistinguishable from well-differentiated HCC (Fig 5).

- It is not yet clear whether gadobenate dimeglumineenhanced imaging

permits the characterization of dysplastic nodules.


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Figure 5. Dysplastic nodule in a 45 y/o/w with alcoholic cirrhosis. (a) Axial SPIO-

enhanced 2D T2*W (TE, 6.6 msec) spoiled GRE image obtained at 1.5 T shows a 10-

mm nodule in liver segment V (arrow) that has a higher signal intensity than the

surrounding parenchyma because of less intranodular uptake of SPIO. (b) Axial

gadolinium-enhanced 3D fat-saturated T1W spoiled GRE image obtained during thearterial phase shows nodular enhancement (arrow).


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Figure 5. (c) Photograph of a gross pathologic section of the liver, which was explanted

2 months later, shows a well-defined 12-mm nodule (arrows) in a location corresponding

to that in a and b. (d) Photomicrograph (original magnification, x100; H-E stain) shows a

well-defined transition between the liver parenchyma (arrowheads) and nodule (arrows).

Increased cellular and capillary density, a higher nuclear-cytoplasmic ratio, and

moderate architectural distortion in the nodule are indicative of high-grade dysplasia.


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4. Hepatocellular Carcinomas

Unenhanced MR Imaging Features.- The signal intensity characteristics of HCCs depend on their size, grade,

and biologic features. On T1W images, small HCCs may have variable

signal intensity; on T2W images, signal intensity usually is slightly

increased. Some well-differentiated HCCs may appear isointense or even

hypointense.- Large HCCs have signal intensity alterations caused by intralesional fat,

hemorrhage, and necrosis than is seen in smaller lesions.

- Steatotic HCCs: a signal intensity decrease on out-of-phase images in

comparison with in-phase images (Fig 3), and they are easily identified by

comparing fat-saturated images with nonfat-saturated ones.

- Hemorrhagic HCCs may have marked high signal intensity on T1W imagesand low signal intensity on T2- and T2*W images.

- Intralesional necrosis typically manifests as one or more areas of low

signal intensity on T1W images and high signal intensity on T2W images.


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Differential Diagnosis4. Hepatocellular Carcinomas

Contrast-enhanced MR Imaging Features.-Approximately 80%90% of HCCs are hypervascular: intensely enhanced

during the arterial phase after a bolus injection of a gadolinium (Fig 4). In

delayed imaging phases, hypervascular HCCs undergo washout and typically

have low signal intensity ; however, some may appear isointense to the liver

parenchyma and therefore may be difficult to see on images obtained during

the portal venous phase and later phases.

-About 10%20% of HCCs are hypovascular and show contrast enhancement

slightly less than that in the surrounding liver on arterial phase images.

Typically, hypovascular HCCs are small, well-differentiated tumors. However,

poorly differentiated and diffusely infiltrating hypovascular HCCs also may

occur. Such lesions may be difficult to detect on gadolinium-enhanced MR

images despite their large size and aggressive behavior, but they are usually

visible on SPIO-enhanced images.- Because of their diminished uptake of gadolinium, HCCs appear as unenhanced foci

of low signal intensity on hepatocellularphase images (Fig 4).


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Moderately and poorly differentiated HCCs characteristically accumulate less

SPIO than the surrounding liver parenchyma and have relatively high signal

intensity on T2- and T2*W SPIO-enhanced images. Well-differentiated HCCs

may accumulate SPIO and tend to be iso- or hypointense compared with the

background liver. Thus, the degree of SPIO uptake may be used as anoninvasive means of grading HCCs. Large HCCs may have nonuniform

Kupffer cell density and show heterogeneous accumulation of SPIO particles.


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Structural Variation of Large Hepatocellular Carcinomas.

Small HCCs tend to be homogeneous, round or oval, and well defined. By

contrast, large HCCs may exhibit a broad spectrum of morphologic features,

including a mosaic pattern, a tumor capsule, an intratumoral nodule ("nodule-

in-nodule" appearance), and extracapsular extension with the formation of

satellite nodules.

-The mosaic pattern reflects underlying mosaic pathologic features and is

defined by the presence of multiple compartments of variable signal intensity

at unenhanced T1-, T2-, and T2*W imaging. The compartments are distributed

within the mass in a seemingly random manner and enhance to variable

degrees after the administration of contrast material (Fig 9).


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Figure 9c. HCC with a mosaic pattern of enhancement in a 62 y/o/m with HCV-

induced cirrhosis. (a) Axial unenhanced 3D fat-saturated T1W spoiled GRE image

obtained at 3 T shows a well-circumscribed mass (arrow) at the junction of liver

segments VII and VIII with signal isointense to that of the liver parenchyma but with

a lower-signal-intensity periphery (arrowheads) that represents a capsule. (b) Axial

gadolinium-enhanced images during the hepatic arterial phase show heterogeneousenhancement of the mass.


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- A characteristic but uncommon finding is the nodule-in-nodule appearance,

which generally represents a HCC within a larger dysplastic or regenerative

nodule.

- On arterial phase images obtained after gadolinium administration, the

carcinomatous nodule typically appears enhanced, while the surroundingregenerative or dysplastic nodule does not enhance and has lower signal

intensity.

- On SPIO-enhanced T2- and T2*-weighted images, signal in the carcinoma

usually appears hyperintense, while that in the regenerative nodule or

dysplastic nodule is hypointense (Fig 5).

- At dynamic gadolinium-enhanced imaging, necrotic HCCs that contain

nodules of viable tumor tissue also may have a nodule-in-nodule appearance

(Fig 11).


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Figure 11. Nodule-in-nodule appearance of HCC in a 56 y/o/w with HCV-inducedcirrhosis. (a, b) Axial SPIO-enhanced 2D T2*-weighted spoiled GRE (TE, 6.6 msec)

(a) and T2-weighted echo-train spin-echo (TE, 90 msec) (b) images obtained at 1.5

T show a 35-mm heterogeneously hyperintense mass in the right liver lobe (arrows).


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Figure 11. (c) Axial gadolinium-enhanced 3D fat-saturated T1W spoiled GRE image

obtained during the hepatic arterial phase shows a markedly enhanced mural nodule

(arrowheads) within the largely nonenhanced mass. The lack of enhancement in the

mass is suggestive of necrosis. (d) Photograph of a section from the liver, which was

explanted 10 weeks after MR imaging, shows two mural nodules (arrows) within the

mass. At histologic analysis, the nodules proved to be viable HCC; the rest of the mass

consisted of necrotic tissue. Note the multiple regenerative nodules (*) in the


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IMAGINGTECHNIQUE

The sequences used can vary according to vendor and personalpreferences (117), but certain guidelines should be followed:

- First, sequences should be performed during suspendedrespiration or should be respiratory averaged (some T2-weightedsequences).

- Second, GRE sequences have replaced spin-echo sequences forT1-weighted imaging.

- Third, three-dimensional gadolinium-enhanced GRE sequencesare preferred to two-dimensional GRE sequences.

- Fourth, contrast agent bolus timing is strongly recommended.


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Spoiled Gradient Echo

Incoherent or Spoiled Gradient Echo

FLASH (fast low-angle shot): Siemens Medical Solutions

SPGR (spoiled gradient echo): GE Medical Systems

Background: Spoiled gradient-echo sequences destroy or

"spoil" any residual transverse magnetization remaining atthe end of each TR. In that way, every RF flip applied in a

sequence acts solely on longitudinal magnetization.

Features: Used in fast T1-weighted imaging. The short TRs

allow 3D and breath-hold 2D acquisitions.


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Sensitivity of various imaging tests for

detecting hepatocellular carcinoma

cirrhosis-associated he pa to cellular nodules

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