Dr. Mannelli is in the Department of Radiology, University of Washington, Seattle, WA, and Dr. Rosenkrantz is in the Department of Radiology, New York University Langone Medical Center, New York, NY.
The cirrhotic liver provides a challenging background for the detection of hepatocellular carcinoma (HCC).1,2
Although MRI is the most accurate imaging method for the detection and
characterization of HCC, all imaging techniques may fail to detect small
HCCs.3 There is now broad agreement that in cirrhosis, there
is a stepwise progression from regenerative nodules (RN) to HCCs along
the following pathway: RN, low-grade dysplastic nodule (DN), high-grade
dysplastic nodule (DN), and HCC.4,5 An important caveat in
this pathway is that most RNs do not progress to DNs and, although DNs
are considered premalignant lesions, they may remain stable or even
regress without evolving into HCCs.
Along this pathway, functional changes occur within the lesion that affect its imaging characteristics:
- Progressive loss of hepatocellular function, leading to the lesion’s
inability to metabolize and accumulate hepatospecific contrast agents;
- Loss of the normal Kupffer cells population, leading to the lesion’s inability to take up ferromagnetic contrast agents;
- Progressive change in the lesion’s blood supply, with a
corresponding increase in its arterial supply relative to its portal
supply. This arterial neovascularization underlies the early arterial
phase enhancement and portal venous phase washout pattern characteristic
In addition, benign lesions may be present, confounding imaging interpretation.
Current guidelines recommend that cirrhotic patients undergo ultrasound screening every 6 months.6,7
Small HCCs have a wide range of appearances on ultrasound and can
demonstrate increased or decreased echogenicity in relation to the
adjacent liver parenchyma (Figures 1 and 2). Large HCCs may show
internal heterogeneity due to hemorrhage, necrosis, or fat. Ultrasound
usually cannot confidently establish the diagnosis of HCC. Thus, new
hepatic nodules detected during ultrasound screening warrant further
evaluation, which is based on the lesion’s size:
Nodules < 1 cm may be followed-up by ultrasound every 3 to 4 months, for 2 years.8-10
ranging from 1 to 2 cm should be further characterized at time of
detection using contrast-enhanced CT or MRI, or biopsy.8-10
biopsies (and some ablation procedures) are preferably performed under
ultrasound guidance. For this reason, it is essential to determine if
the nodule is detectable at ultrasound.11
CT and MRI
Noncontrast imaging is valuable for
assessing diffuse hepatic changes, such as fat infiltration and iron
deposition, and focal changes such as subtle calcification and
hemorrhage.9 However, CT and MRI allow multiphasic
postintravenous (IV) contrast imaging, which facilitates detection and
characterization of focal liver lesions and is widely used for this
purpose. Multiple phases may be obtained during contrast enhancement;
these may include early and late arterial phases, as well as portal and
equilibrium phases. Protocol optimization and optimal timing of the post
contrast phases maximizes the lesion-to-liver contrast. The minimum
requirement for liver imaging is an arterial phase (20–40 sec
postcontrast injection) and a portal venous phase (60–80 sec
postcontrast injection).1,2,12 Many systems allow direct
triggering of the acquisition by observing contrast medium arrival in
the aorta; this approach provides more consistent
MRI has a wider range of contrast mechanisms than CT. A
broad range of liver MRI protocols is possible due to the numerous
combinations of field strength, pulse sequence implementation, and
interdependent sequence parameters available.13-17
Comprehensive liver imaging using MRI now includes T2- and in- and
opposed-phase T1-weighted imaging, in addition to dynamic post-contrast
nodules (RN) are present throughout the background liver parenchyma of
cirrhotic livers (Figure 3). In RNs, all the normal cellular components
of liver parenchyma are present: hepatocytes, Kupffer cells, and biliary
ducts.4,5 Most RNs are indistinguishable from liver
parenchyma on imaging, although some demonstrate iron, glycogen, and
copper accumulation, which may allow for their detection on imaging.4,18
At CT, these may appear slightly hypo- or hyperdense compared to the
surrounding parenchyma. On T2W images, the accumulation of iron in RNs
typically appears as low SI compared to the surrounding liver
parenchyma. In addition, fibrous septa surrounding RNs often have
increased SI on T2W images. On T1W images, RNs vary in appearance and
can demonstrate hypo-, iso-, or hyper-intensity relative to the
surrounding liver. Hepatic artery and portal vein blood supply, as well
as hepatic venous drainage, are not altered in RNs. Thus, following
contrast administration RNs show enhancement similar to the normal liver
parenchyma on all phases.4 Finally, RNs are usually smaller than 2 cm.3,4
may appear identical to RNs and HCCs on MRI and CT imaging (Figure 4).
In DNs, all of the usual cellular components of normal liver parenchyma
(hepatocytes, Kupffer cells, and biliary ducts) are still found.4 DNs may be divided into low-, moderate-, and high-grade DNs.4
A feature that distinguishes them from RNs is early arterial
neovascularization, most prominent in the high-grade nodules. Although
DNs may have any signal intensity on T1-weighted images, fat
accumulation can be present and can be detected using in- and
opposed-phase T1-weighted images.19,20 On T2W images, DNs are
usually iso- or hypointense compared to the liver parenchyma. Because
of some degree of neovascularization, DNs may show early homogeneous
arterial enhancement similar to HCC following IV contrast
administration, although they generally do not show washout in the
delayed phases.19,20 Like RNs, DNs are usually smaller than 2 cm.
carcinomas may exhibit a spectrum of CT and MR imaging characteristics,
in part related to their variable degree of differentiation.
Well-differentiated HCCs still exhibit some cellular similarity to
hepatocytes, and thus retain some degree of hepatocellular function,
whereas in poorly differentiated HCC, hepatocellular function is lost.1-5,9,19,21
In addition, areas of hemorrhage or focal fat can be present within
HCCs, leading to variable imaging features (Figure 5). At noncontrast CT
imaging, HCCs can be hypo-, iso- or hyperdense compared to liver
parenchyma. HCCs are usually hypointense on T1W images, but they can be
iso- or hyperintense. Fat is rarely present in HCCs, but like
fat-containing benign lesions, it can be demonstrated using in- and
opposed-phase T1W images. HCCs typically show mild increased SI on T2W
images because of inflammation, edema and necrosis within the lesion
(Figure 6). Despite this hyperintensity, differentiation from the
surrounding liver parenchyma on T2W imaging can still be difficult,
given the possibility of motion and other artifacts, as well as possibly
altered T2 signal within the liver parenchyma itself. Furthermore, HCCs
with low signal on T2W imaging have been described.
variable imaging features of HCC on noncontrast CT and MRI, postcontrast
imaging is critical to accurately detecting HCC with these modalities.
Typically, following IV contrast medium administration, HCCs show
heterogeneous early arterial enhancement and washout in the delayed
phase, reflecting the predominant blood supply from arterial
neovascularization (Figure 7). However, in small HCCs, the enhancement
pattern can be homogeneous, and the washout may be minimal.1-5,9,19,21
Furthermore, in well-differentiated HCCs, the hepatic artery and portal
venous blood supply may still be present in a proportion that makes
these lesions difficult to characterize even after contrast
administration. At MR imaging, subtraction imaging can help detect both
the arterial enhancement and the washout,
especially in HCCs that have high SI on pre-contrast, T1W images. A
pseudocapsule, presenting as an enhancing peripheral rim, may also be
present in the delayed postcontrast phases, both at CT and MRI,1-5,9,19,21
and can be an additional helpful diagnostic feature.
Hepatocyte-specific, gadolinium-based MR contrast agents and
ferromagnetic MRI contrast agents have also been used to characterize
HCC based on the lack of normal biliary metabolism and Kupffer cells
within HCC, respectively; however, diagnosis can remain difficult even
using these agents, given that well-differentiated HCC tumor cells may
still be able to metabolize and accumulate hepatocyte-specific
gadolinium-based contrast agents or retain Kupffer cells, thus showing
uptake using ferromagnetic contrast agents.1-5,9,19,21
detecting and characterizing a lesion as HCC can be challenging,
particularly in the cirrhotic patient, where artifacts due to ascites
and difficulties in breath holding are common. Comparison and
correlation with previous imaging is essential; in a complex case,
changes in size on serial examinations may be the most helpful
observation for lesion characterization.1-5,9,19,21 In
addition, when encountering an indeterminate liver lesion, correlation
with an elevated serum alpha-fetoprotein level may be helpful. However,
this laboratory test has a limited negative predictive value, especially
in the setting of hepatitis C-related cirrhosis, and a normal level
does not exclude HCC.22 Finally, diffusion weighted imaging
(DWI) is a functional MRI technique that recently has been introduced in
liver MR imaging protocol. While this sequence may help detect small
lesions within the liver parenchyma (Figure 8), DWI does not currently
allow for definitive lesion characterization in the cirrhotic liver. 23-26
term nodule-in-nodule is used to describe the appearance of a small HCC
arising within a DN (Figure 9). In this case, the lesion will exhibit
the previously described imaging characteristics of HCC, while being
located within a larger nodule having the characteristics of a DN.4,5
Unidentified bright objects (UBO)
bright objects (UBO) describe those lesions that show arterial phase
enhancement on CT or MR imaging following IV contrast medium
administration but do not fulfill the criteria to be characterized as
lesions measure under 20 mm in size, and are often irregularly shaped
and peripherally located. On MRI, UBOs show no signal changes on T1- or
T2-weighted images. UBOs are too small to be characterized by a single
imaging study or to undergo targeted biopsy. These lesions are common
and probably represent variants of regenerative nodules or arteriovenous
shunts (Figures 10 and 11). They may resolve spontaneously and usually
require serial imaging to monitor for potential progression.10,27
resection and transplantation represent the only curative treatments
for HCC. Forms of ablative treatments, which are not curative, include
trans-arterial chemo-embolization (TACE), trans-arterial embolization
(TAE), radiofrequency ablation (RFA), cryoablation, and Yttrium-90
radio-embolization. These ablative techniques induce tumor necrosis. 28,29
CT and MRI may be used to assess therapy success by discerning between
viable and necrotic HCC. Because the treatment targets HCC
vascularization, a successfully treated necrotic HCC will not enhance
following IV contrast administration.28,29 At MRI, to assess
the presence of post-contrast enhancement, subtraction images can be
useful, given the possibility of increased signal in the lesion on
precontrast T1W sequences related to the therapy (Figure 12). In
addition, apparent diffusion coefficient (ADC) maps calculated from DWI,
can be useful to quantify changes in HCCs following treatment.21,30
For instance, in one study, HCC that responded to chemo-embolization
demonstrated an increase in ADC values following treatment.31
It is important to be aware of factors that can confound assessment for
treatment response. Following ablation, especially within the first 30
days, an enhancing rim consisting of granulation tissue can surround an
HCC that is in fact completely necrotic.28,29 In addition,
benign reactive areas of abnormal arterial enhancement can be present in
the treated lobe following treatment; such regions may be recognized by
the lack of washout in the delayed phase. CT has also occupied a
particular role following selective hepatic arterial injection using
Lipiodol; this agent is usually cleared from normal liver parenchyma
within 7 to 10 days, upon which CT may be performed to assess for any
lesions retaining the agent, which would indicate areas of tumor.
Finally, follow-up of HCC treated using pharmacological therapy with
sorafenib is performed via size criteria.
CT, and ultrasound imaging represent an essential tool in the detection
and characterization of liver
lesions in cirrhotic patients. Despite the different imaging modalities
and novel contrast media making it possible to do a multiparametric
evaluation of liver lesions, a confident characterization may still
represent a challenge even for an expert liver imager and, in some
cases, a biopsy is still required to reach a final diagnosis. Hybrid
imaging with PET/CT and PET/MR may lead to new answers with the
potential to determine liver lesion choline and glucose metabolism; but
whether this will have a clinical impact on patient management is yet to
- Furlan A, Marin D, Agnello F, et al. Hepatocellular carcinoma
presenting at contrast-enhanced multi-detector-row computed tomography
or gadolinium-enhanced magnetic resonance imaging as a small (</=2
cm), indeterminate nodule: Growth rate and optimal time for imaging
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- Addley HC, Griffin N, Shaw AS, et al. Accuracy of hepatocellular
carcinoma detection on multidetector CT in a transplant liver population
with explant liver correlation. Clin Radiol. 2011;66:349-356.
- Anis M, Irshad A. Imaging of hepatocellular carcinoma: Practical guide to differential diagnosis. Clin Liver Dis. 2011;15:335-352, vii-x.
- Matsui O. Imaging of multistep human hepatocarcinogenesis by CT during intra-arterial contrast injection. Intervirology. 2004;47:271-276.
- Choi BI. Hepatocarcinogenesis in liver cirrhosis: Imaging diagnosis. J Korean Med Sci. 1998;13:103-116.
- European Association for the Study of the Liver et al. Clinical Practice Guidelines: Management of hepatitis C virus infection. J Hepatol. 2011;55:245-264.
- Tan CH, Low SC, Thng CH. APASL and AASLD Consensus guidelines on imaging diagnosis of hepatocellular carcinoma: A Review. Int J Hepatol. 2011; article ID 519783.
- Ayuso C, Rimola J, Garcia-Criado A. Imaging of HCC. Abdom Imaging. 2012;37:215-30.
- Kim TK, Lee KH, Khalili K, Jang HJ. Hepatocellular nodules in liver cirrhosis: Contrast-enhanced ultrasound. Abdom Imaging. 2011;36:244-263.
- Khalili K, Kim TK, Jang HJ, et al. Indeterminate 1-2-cm nodules
found on hepatocellular carcinoma surveillance: Biopsy for all, some, or
none? Hepatology. 2011;54:2048-2054.
- Serste T, Barrau V, Ozenne V, et al. Accuracy and disagreement of CT
and MRI for the diagnosis of small hepatocellular carcinoma and
dysplastic nodules: Role of biopsy. Hepatology. 2012;55:800-806.
- Lomas DJ, Mannelli L. Hepatobiliary MRI. In: Harris RK, Wasylishen
R, eds. Encyclopedia of magnetic resonance. New York, NY: Wiley
- Mannelli L, Godfrey E, Graves MJ, et al. Magnetic resonance
elastography: Feasibility of liver stiffness measurements in healthy
volunteers at 3T. Clin Radiol. 2012;67:258-262.
- Rosenkrantz AB, Mannelli L, Mossa D, Babb JS. Breath-hold
T2-weighted MRI of the liver at 3T using the BLADE technique: Impact
upon image quality and lesion detection. Clin Radiol. 2011;66:426-433.
- Mannelli L, Godfrey E, Joubert I, et al. MR elastography: Spleen
stiffness measurements in healthy volunteers—preliminary experience. AJR Am J Roentgenol. 2010;195:387-392.
- Chung S, Breton E, Mannelli L, Axel L. Liver stiffness assessment by tagged MRI of cardiac-induced liver motion. Magn Reson Med. 2011;65:949-955.
- Rosenkrantz AB, Mannelli L, Kim S, Babb JS. Gadolinium-enhanced
liver magnetic resonance imaging using a 2-point Dixon fat-water
separation technique: Impact upon image quality and lesion detection. J Comput Assist Tomogr. 2011;35:96-101.
- Lee JM, Choi BI. Hepatocellular nodules in liver cirrhosis: MR evaluation. Abdom Imaging. 2011;36:282-289.
- Lee JM. Imaging of hepatocellular carcinoma. Cancer Imaging. 2011;11:S72.
- Lee JM, Trevisani F, Vilgrain V, Wald C. Imaging diagnosis and staging of hepatocellular carcinoma. Liver Transpl. 2011;17 Suppl 2:S34-S43.
- Kim S, Mannelli L, Hajdu CH, et al. Hepatocellular carcinoma:
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- El-Serag HB, Kramer JR, Chen GJ, et al. Effectiveness of AFP and
ultrasound tests on hepatocellular carcinoma mortality in HCV-infected
patients in the USA. Gut. 2011;60:
- Colagrande S, Belli G, Politi LS, et al. The influence of diffusion-
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- Hardie AD, Naik M, Hecht EM, et al. Diagnosis of liver metastases:
Value of diffusion-weighted MRI compared with gadolinium-enhanced MRI. Eur Radiol. 2010;20:1431-1441.
- Taouli B, Thakur RK, Mannelli L, et al. Renal lesions:
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- Willatt JM, Hussain HK, Adusumilli S, Marrero JA. MR Imaging of
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- Lencioni R, Crocetti L. Local-regional treatment of hepatocellular carcinoma. Radiology. 2012;262:43-58.
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- Mannelli L, Patterson AJ, Zahra M, et al. Evaluation of nonenhancing
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a predictor of decrease in tumor volume in response to
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- Mannelli L, Kim S, Hajdu CH, et al. Assessment of tumor necrosis of
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