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1 Both authors: Department of Radiology, University of Washington, Harborview Medical Center, 325 Ninth Ave., Box 359728, Seattle, WA 98104-2499.
Received October 7, 2005;
accepted after revision December 19, 2005.
This Radiological Reasoning article is available for SAM credit and
CME credits when completed with the additional educational material provided
in "Imaging of Hepatocellular Carcinoma: Self-Assessment Module."
See page S431 for
details.
Abstract
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A 49-year-old woman presented to the emergency department after a fall in which she sustained a right subcapital hip fracture. During her hospital stay she developed abdominal pain, and a hypoechoic liver mass was found on sonography. Multiphase CT showed a hepatic mass with brisk arterial phase enhancement, rapid washout on the portal venous phase, and delayed phase hypodensity. The final pathology diagnosis was hepatocellular carcinoma.
Conclusion
Incidental lesions are frequently discovered during routine radiographic evaluations. Correlation with clinical history and additional confirmatory imaging is essential for appropriate diagnosis and management.
Keywords: cancer • CT • liver disease • sonography
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The most common benign causes include hemangioma, focal nodular hyperplasia, and hepatic adenoma. Hemangiomas are typically hyperechoic, which this lesion is not. Adenomas can have a variable appearance and nearly all occur in women. Additional clinical history regarding the use of oral contraception or hormone therapy in this 49-year-old woman would be useful. Focal nodular hyperplasia is also a possibility because these lesions are usually seen in young women as well. The sonographic appearance may be isoechoic to surrounding normal liver, given the presence of hepatocytes that are normal to hypoechoic in appearance.
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-fetoprotein (46.7 ng/mL) levels. The patient also revealed a history
of alcohol abuse. Multiphase CT was performed after sonography. |
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Expert Discussion (Dr. Bittle)
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-fetoprotein level
were provided, the hepatic mass found on sonography should be considered HCC
until proven otherwise. Multiphase CT confirms this top differential
diagnosis. Unenhanced images show the mass to be hypodense to the remaining
liver, but the attenuation is greater than expected for a simple cyst. The
arterial phase images show rapid enhancement and a heterogeneous mosaic
pattern. The mass enhances greater than the surrounding liver but not as great
as blood pool. Portal venous phase images show globular enhancement with rapid
washout relative to the surrounding liver. A subtle fibrous capsule is also
seen on portal venous phase images, which can be seen with HCC. On 10-min
delayed phase images, the lesion remains hypodense. Although the clinical history and imaging findings in this patient are typical of HCC, it is pertinent to review the imaging characteristics of other malignant and benign hepatic masses (Table 1). Malignant lesions to consider include metastases, fibrolamellar HCC, and intrahepatic cholangiocarcinoma. Common benign lesions include hemangioma, focal nodular hyperplasia, and adenoma. In addition, benign lesions seen in cirrhotic livers include regenerative nodules, transient hepatic attenuation differences, and focal confluent fibrosis.
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Metastases, particularly hypervascular metastases such as those from melanoma, renal cell carcinoma, sarcoma, carcinoid, islet cell tumors, and some breast cancers, are best seen on arterial phase images, similar to HCC. However, most metastases are hypovascular and best detected on portal venous phase images. Multiple enhancing hepatic lesions in a patient with known carcinoma obviously favors metastases, but solitary metastases also occur; therefore, a solitary metastasis should be considered in the differential diagnosis for this patient. Calcifications seen with metastases from mucinous primary tumors and ovarian, thyroid, renal, lung, and breast primary cancers are best detected on unenhanced images, but calcifications are not seen in this patient.
Fibrolamellar HCC is uncommon and occurs in younger patients with no preexisting liver disease. Alpha-fetoprotein levels are usually normal, and the prognosis is much better than for conventional HCC. These tumors are usually large, with a large central scar that often calcifies. In contrast to focal nodular hyperplasia, the central scar typically does not enhance. None of these features are present in this patient.
Intrahepatic cholangiocarcinoma is typically a hypovascular lesion with prolonged contrast enhancement on delayed images because of slow diffusion into the fibrous stroma interstitium, which is not present in this patient. Portal venous phase images often show mild peripheral enhancement.
Hemangiomas are common benign lesions with typical enhancement characteristics of discontinuous peripheral puddling of contrast material after blood pool enhancement, a finding that is not present in this patient. Fibrotic or necrotic areas may be present and will not enhance. The peripheral rim of hypoattenuation often seen with malignant lesions is also absent.
Focal nodular hyperplasia typically shows homogeneous arterial enhancement and enhancement of the central scar on delayed images. The mass is usually peripheral and may be pedunculated. Although the mass in this patient is peripheral and expansile, no central scar is seen and the enhancement is heterogeneous.
Hepatic adenomas occur predominantly in women of child-bearing age and are associated with oral contraceptive use or, in men, with steroid use. Adenomas are usually solitary, may be encapsulated, and have a tendency to hemorrhage. Their CT appearance is variable, but uncomplicated adenomas often show arterial and portal venous enhancement. Unfortunately, hepatic adenomas usually are not reliably differentiated from HCC on the basis of imaging alone; they are considered in this patient.
Nonmalignant lesions are also seen in cirrhotic livers. Regenerative nodules are typically isodense to liver and essentially indistinguishable unless they contain iron. Regenerative nodules containing iron are called siderotic nodules and are best seen as hyperdense nodules on unenhanced images. Transient hepatic attenuation differences are typically arterioportal shunts that may or may not be associated with tumors. Wedge-shaped hyperenhancement during arterial phase imaging that is isodense to normal liver in the portal venous phase is typically seen. Focal confluent fibrosis is usually a wedge-shaped lesion radiating from the porta hepatis with capsular retraction and associated parenchymal atrophy. None of the features described for nonmalignant cirrhotic liver lesions are present in this patient.
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1-antitrypsin
deficiency, excessive androgen and oral contraceptive use, hemochromatosis,
and exposure to aflatoxin or vinyl chloride
[2]. Cirrhosis results from the development of diffuse fibrosis and nodules from cellular necrosis. Microscopically, the nodules encountered progress sequentially from regenerative nodules to low- and high-grade dysplastic nodules to the "nodule within a nodule" appearance of a dysplastic nodule with a focus of HCC to frank HCC (small, < 2 cm; large, > 2 cm) [4]. Siderotic regenerative and dysplastic nodules accumulating iron are also seen. Tumor angiogenesis also occurs during this process, developing nontriadal arterial neovascularity in dysplastic nodules pathologically [1], which later aids the detection of HCC when multiphase imaging techniques are used. Macroscopically, Eggel has classified HCC as nodular, massive, and diffuse [5]. HCC may be solitary, multifocal, or diffuse.
Most high-risk patients are screened with hepatic sonography and serum
-fetoprotein tests, but no convincing evidence suggests that screening
improves survival [6]; however,
early detection does improve the long-term outcome. A recent study found
sonography to have a 4.3% false-negative rate in patients with known hepatitis
B and elevated -fetoprotein levels
[7]. Lesions smaller than 2 cm
are particularly difficult to detect with sonography
[8]. Contrast-enhanced Doppler
sonography has shown promise distinguishing cirrhotic nodules from early HCC
by detecting the intratumoral arterial blood flow that is present in HCC but
not seen in nonmalignant cirrhotic nodules
[2]. MDCT and MRI improve
detection of the changes of cirrhosis and the development of HCC; however, a
wide range of sensitivities of these techniques exists, and all have a low
sensitivity for detection of lesions smaller than 2 cm
[8]. Dynamic phase
contrast-enhanced imaging is essential for both CT and MRI evaluation of HCC.
MDCT of the liver includes three or four phases, including unenhanced,
arterial, and portal venous phases and an optional delayed equilibrium phase.
Sensitivities reported for detecting HCC are 59-68% for multiphase
contrast-enhanced CT [1] and
33-77% for multiphase contrast-enhanced MRI
[9]. Even with adequate
multiphase MDCT and MRI techniques, many small HCCs are not visualized because
their enhancement characteristics follow those of the liver parenchyma.
The CT appearance of regenerative and dysplastic nodules can be confusing. Both have predominantly a portal venous blood supply and thus often resemble the adjacent liver parenchyma. Regenerative nodules without iron deposition are isodense to liver on unenhanced CT but typically distort the liver contour. They remain isodense to liver in the arterial phase and enhance homogeneously in the portal venous phase, also after the liver parenchyma; therefore they are not directly detected. Also, siderotic regenerative nodules with iron deposition are hyperdense on unenhanced CT. The portal venous enhancement of the regenerative and dysplastic nodules parallels the enhancement of the fibrotic changes in the liver, making them often indistinguishable. Transient hepatic attenuation differences with wedge-shaped arterial enhancement that becomes isodense in the portal venous phase may be associated with regenerative and dysplastic nodules, HCC, and benign hepatic tumors such as hemangioma and focal nodular hyperplasia. Transient hepatic attenuation differences also occur without masses in cirrhotic livers because of hemodynamic alterations, arterioportal shunts, and aberrant blood supply [10].
The CT appearance of HCC is reflective of the size of the lesion. Smaller HCCs (< 2 cm) are typically hypodense on unenhanced images, show diffuse enhancement in the arterial phase, and are hypodense relative to the remaining liver on portal venous phase images. Larger HCCs often show heterogeneous arterial enhancement, necrosis, and occasionally a tumor capsule. In addition, peripheral exophytic HCCs have an increased risk of spontaneous rupture resulting in hemoperitoneum and are seen in approximately 10% of HCCs [11]. Faster acquisition times and an increased rate of contrast injection with MDCT allow more consistent arterial phase imaging when compared with single-detector CT [12]. Using MDCT, Lee et al. [12] found the most common enhancement pattern of HCC to be hypervascularity in the arterial phase and a heterogeneous mosaic pattern in both the arterial and portal venous phases. Abnormal internal vessels were also frequently seen during arterial phase imaging, also likely because of the rapid MDCT acquisition and injection rate. Additional findings of HCC include satellite nodules, vascular invasion, extrahepatic spread to lymph nodes, and metastatic dissemination. Venous invasion is most often seen with HCC and is rare in other hepatic neoplasms.
Continued advances in MRI techniques, such as faster imaging to decrease respiratory and motion artifacts, have improved the MRI detection of regenerative and dysplastic nodules in the cirrhotic liver and HCC. Regenerative nodules have a variable T1 appearance related to the presence of siderotic nodules and iron deposition. Siderotic nodules typically show low T1 signal because of the increased susceptibility effects of iron. Nonsiderotic nodules are typically best seen on T2-weighted and gradient-echo imaging as low-signal nodules. Regenerative nodules do not enhance after the administration of gadolinium and remain isointense relative to the liver parenchyma. Dysplastic nodules also have a variable imaging appearance as they progress from low- to high-grade. They are typically hyperintense on T1-weighted and hypointense on T2-weighted images [5]. As the dysplastic nodule becomes higher-grade, the hepatic arterial supply increases and arterial enhancement after gadolinium administration may be seen, but the T2 signal on unenhanced images will help differentiate the dysplastic nodule from HCC. The nodule-within-a-nodule sign of HCC developing within a dysplastic nodule is seen as a focus of increased T2 signal in the low-T2-signal dysplastic nodule. The focus of HCC will also show arterial enhancement.
The MRI appearance of HCC can be quite variable and is often related to the degree of differentiation. The T1 appearance is variable, with 40% showing low signal and 35% having high signal [5]; 90% show increased T2 signal [5]. The increased T1 signal may be related to a variable amount of fat, copper, or glycoproteins [1]. Dynamic phase gadolinium enhancement is an essential sequence to detect HCC. As on CT, small HCCs show homogeneous arterial enhancement. Large HCCs typically show heterogeneous enhancement with necrosis and fatty metamorphosis. A tumor capsule may also be seen. A mosaic pattern is often seen, reflecting a confluence of multiple small tumor nodules with thin septa and areas of necrosis [4]. Vascular invasion of the portal vein is seen as a flow void on T1 gradient-refocused echo images [4]. The tumor thrombus may also enhance during the arterial phase after gadolinium administration.
In summary, despite the rising incidence of HCC worldwide, early detection,
particularly of small lesions, which have a better prognosis, remains
difficult. Screening with serial sonography and serum -fetoprotein
levels is common, but sonography may be falsely negative. Progressive
advancements in MDCT and MRI continue to improve the detection of small
resectable lesions, but the survival rates remain low, with 23% 1-year and 5%
5-year survival rates [2].
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  C.-H. Liu, D. C. Rivard, A. C. Silva, K. J. Burkholz, and S. D. Beaty Imaging of Focal Hepatic Lesions: Self-Assessment Module Am. J. Roentgenol., June 1, 2008; 190(6_Supplement): S65 - S68. [Abstract] [Full Text] [PDF]
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M. M. Bittle and F. S. Chew Imaging of Hepatocellular Carcinoma: Self-Assessment Module Am. J. Roentgenol., June 1, 2006; 186(6_Supplement_1): S431 - S433. [Abstract] [Full Text] [PDF]
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