DOI:10.2214/AJR.07.3947
AJR 2009; 193:W7-W13
© American Roentgen Ray Society
Hepatocellular Carcinoma Variants: Radiologic-Pathologic Correlation
Yong Eun Chung1,
Mi-Suk Park1,2,3,
Young Nyun Park3,4,
Hye-Jeong Lee1,
Jae Yeon Seok4,
Jeong-Sik Yu1 and
Myeong-Jin Kim1,3
1 Department of Radiology, Research Institute of Radiological Science, Yonsei
University College of Medicine, Seoul, Korea.
2 Department of Diagnostic Radiology, Yonsei University Health System, Severance
Hospital, Seodaemun-ku, Shinchon-dong 134, Seoul 120-752, Korea.
3 Institute of Gastroenterology, Yonsei University College of Medicine, Seoul,
Korea.
4 Department of Pathology, Yonsei University College of Medicine, Seoul,
Korea.
Received March 5, 2008;
accepted after revision December 7, 2008.
Address correspondence to M. S. Park
(radpms{at}yuhs.ac).
WEB This is a Web exclusive article.
Abstract
OBJECTIVE. The purpose of this article is to show the imaging
findings of variant types of hepatocellular carcinoma (HCC) with pathologic
correlations.
CONCLUSION. The variant types of HCC may not share its typical
imaging characteristics. An understanding of the radiologic findings for
variant types of HCC can be helpful in the differential diagnosis of hepatic
tumors.
Keywords: CT • hepatic tumors • hepatocellular carcinoma • liver • MRI • oncologic imaging
Introduction
Hepatocellular carcinoma (HCC) is the most common form of primary
hepatic tumor and its incidence has increased in recent years. The risk
factors for HCC are well established and include viral hepatitis, alcoholic
liver cirrhosis, and exposure to hepatotoxins. The typical sonographic and
unenhanced CT findings of HCC show a well-circumscribed hypoechoic or
hypoattenuated mass with or without the hypoechoic rim of a tumor capsule. MRI
typically shows that HCC is hyperintense relative to the liver on T2-weighted
images and hypointense on T1-weighted images. On dynamic CT and MRI, HCC shows
early enhancement in the arterial phase and contrast medium washout in the
equilibrium phase. Equilibrium phase CT and MRI could show a thin
rim-enhancing tumor capsule with variable incidence, ranging from 10% to 80.7%
of the cases, depending on the series
[1].
Although the prevalence is variable depending on the series, hemorrhage or
calcification (
5%), central scar ( 3%), or gross fat ( 1.6%)
may be seen within the HCC tumor
[2]. HCC in noncirrhotic
patients usually manifests as either a large solitary mass or a dominant mass
with small satellite nodules that more frequently shows necrosis and central
scar formation than HCC in cirrhotic patients
[3].
Pathologically, there are several variant types of HCC: clear cell type
HCC, fibrolamellar HCC, sarcomatoid HCC, combined HCC-cholangiocarcinoma, and
sclerosing HCC [4]. Clinically,
sarcomatoid HCC and combined HCC-cholangiocarcinoma show poorer prognosis than
classic HCC, whereas fibrolamellar HCC shows better prognosis and sclerosing
HCC shows prognosis similar to classic HCC
[5-7].
Radiologically, these variants do not share imaging characteristics typical of
HCC.
The diagnosis of HCC larger than 2 cm can be made without biopsy if a mass
in a cirrhotic liver shows the typical features of HCC on contrast-enhanced CT
or MRI and the 
-fetoprotein level is greater than 200 ng/mL
[8]. In the case of HCC with
atypical imaging features, however, this guideline cannot be applied.
Therefore, recognizing these variants and their imaging features has clinical
consequences, even though a preoperative biopsy is still needed because these
variants cannot be completely differentiated from other tumors by imaging
only.
In this article, we collectively review and illustrate the radiologic
findings for variant types of HCC and correlate these findings with pathologic
analyses.
HCC, Predominantly Clear Cell Type
Cytoplasmic fat is frequently present in well-differentiated HCC and is
abundant in approximately 10% of cases. A large amount of cytoplasmic fat or
glycogen can cause the cytoplasm to appear white in routine pathologic
sections, producing a "clear cell" appearance. On microscopy,
19.6% of HCCs have been reported to have cytoplasmic fat. On imaging, however,
only 1.6% of cases have been reported to show a cytoplasmic fat component
[9]. HCCs with a clear cell
appearance frequently show increased echogenicity on sonography and decreased
attenuation on unenhanced CT without specificity
[10]. A signal drop on
opposed-phase T1-weighted MR images is diagnostic for the fat component within
an HCC (Figs. 1A,
1B,
1C,
1D,
1E, and
1F).
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Fig. 1B —59-year-old man with hepatocellular carcinoma (HCC) of
predominantly clear cell type. On fat-suppressed T2-weighted image, mass shows
heterogeneous high signal intensity relative to surrounding liver.
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Fig. 1C —59-year-old man with hepatocellular carcinoma (HCC) of
predominantly clear cell type. T1-weighted in-phase MR image shows lobulated
lesion (arrow) with low signal intensity in right lobe of liver.
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Fig. 1D —59-year-old man with hepatocellular carcinoma (HCC) of
predominantly clear cell type. T1-weighted opposed-phase MR image shows marked
signal drop within mass (arrow), suggesting high lipid content. Liver
parenchyma also shows signal drop, suggesting diffuse steatosis.
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Fig. 1E —59-year-old man with hepatocellular carcinoma (HCC) of
predominantly clear cell type. Photograph of gross section of resected
specimen shows well-demarcated, lobulated, whitish-tan, firm mass possessing
"clear cell" appearance.
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Fig. 1F —59-year-old man with hepatocellular carcinoma (HCC) of
predominantly clear cell type. Photomicrograph of microscopic specimen shows
HCC tumor cells with vacuolated appearance due to cytoplasmic accumulation of
large amounts of glycogen and lipid. (H and E; original magnification,
x200)
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The differential diagnosis of a hepatic tumor with cytoplasmic fat includes
hepatic adenoma, angiomyolipoma, and fat-containing metastasis. Hepatic
adenoma occurs frequently in young women and is associated with oral
contraceptive use and glycogen storage diseases. Imaging studies of hepatic
adenoma usually reveal heterogeneous lesions because of the high frequency of
hemorrhage. Angiomyolipoma is composed of smooth muscle, fat, and blood
vessels in various combinations. When its fat content is low, angiomyolipoma
can be difficult to differentiate from HCC. Although fat-containing metastases
are extremely rare, they can originate in a desmoid tumor, liposarcoma, Wilms
tumor, or clear cell-type renal cell carcinoma. Clinical history correlation,
evaluation of the extrahepatic primary tumor, and biopsy with
immunohistochemical staining may all be helpful in narrowing the differential
diagnosis [9].
Fibrolamellar HCC
Fibrolamellar HCC is a distinctive HCC variant that is not associated with
hepatitis or cirrhosis. This tumor occurs in young adults (second or third
decade of life) without sex predominance
[11,
12]. Pathologically,
fibrolamellar HCC usually presents as a single, large, well-demarcated, but
nonencapsulated tumor with a fibrous band infiltrating throughout. On
microscopic examination, the tumor is composed of well-differentiated
polygonal cells that grow in nests or cords and are separated by parallel
lamellae of dense collagen bundles. The fibrotic tissue coalesces to form a
central scar, which is reported in 20-60% of cases
[12].
Fibrolamellar HCC usually appears on ultrasound as a solitary,
well-defined, lobulated mass with variable echotexture
[12]. On unenhanced CT, the
tumor is low-attenuating compared with the surrounding liver, whereas on
dynamic contrast-enhanced CT it has predominant heterogeneous enhancement
[11]. Intratumoral
calcification (68%), a central scar (71%), and pseudocapsule (35%) are visible
on CT [11,
12].
On MRI, fibrolamellar HCC appears hypointense on T1-weighted images and
hyperintense on T2-weighted images relative to the surrounding liver. In
addition, fibrolamellar HCC displays heterogeneous enhancement on
gadolinium-enhanced MRI (Figs.
2A,
2B,
2C,
2D,
2E,
2F,
2G,
2H,
2I, and
2J). The fibrous central scar
and radial septa usually show delay enhancement on dynamic CT and MRI and
hypointense signal on all unenhanced MR images
[11,
12]. The hypointensity on
T2-weighted MRI of the central scar of fibrolamellar HCC has been used to
differentiate HCC from focal nodular hyperplasia, which shows a hyperintense
signal on T2-weighted MRI. If the fibrolamellar HCC scar has increased
vascularity or necrosis, however, it could appear hyperintense on T2-weighted
images [12].
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Fig. 2C —32-year-old man with fibrolamellar hepatocellular carcinoma
(HCC). On portal venous phase CT scan, peripheral portion of tumor shows
isoattenuation (arrowhead) relative to surrounding liver. Central
portion of tumor shows low attenuation.
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Fig. 2D —32-year-old man with fibrolamellar hepatocellular carcinoma
(HCC). On fat-suppressed T2-weighted MR image, central portion of tumor
(arrowhead) shows low signal intensity relative to adjacent liver.
Innermost portion of central scar (arrow) shows high signal
intensity, which correlates to necrosis on microscopic specimen.
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Fig. 2F —32-year-old man with fibrolamellar hepatocellular carcinoma
(HCC). Gadolinium-enhanced arterial phase (F) and portal venous phase
(G) T1-weighted MR images show peripheral enhancement of mass.
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Fig. 2G —32-year-old man with fibrolamellar hepatocellular carcinoma
(HCC). Gadolinium-enhanced arterial phase (F) and portal venous phase
(G) T1-weighted MR images show peripheral enhancement of mass.
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Fig. 2I —32-year-old man with fibrolamellar hepatocellular carcinoma
(HCC). Photograph of gross specimen reveals well-defined yellow-to-greenish
mass with central scar (long arrows). Necrosis is noted within
central scar (short arrow).
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Fig. 2J —32-year-old man with fibrolamellar hepatocellular carcinoma
(HCC). Photomicrograph of microscopic specimen shows well-differentiated
polygonal cells that grow in nests or cords and are separated by parallel
lamellae of dense collagen bundles. (H and E; original magnification,
x100)
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Sarcomatoid HCC
Sarcomatous HCC is an aggressive variant of HCC with an incidence of
3.9-9.4%, with either a sarcomatous change in part of the HCC or coexistence
of a sarcoma and HCC [13].
Histologically, sarcomatoid HCC consists of very poorly differentiated cells
that grow rapidly, resulting in central necrosis or hemorrhage due to
inadequate blood supply. No capsule, intratumoral fat, or central scar is
present. On cross-sectional images, sarcomatoid HCC shows peripheral
enhancement with an unenhanced central portion that correlates to viable
cancerous tissue with fibrous stroma in the periphery and central necrosis of
the tumor, respectively [13]
(Figs. 3A,
3B,
3C,
3D,
3E, and
3F). The enhancement of the
solid portion has been reported to be variable
[14].
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Fig. 3B —63-year-old man with sarcomatoid hepatocellular carcinoma
(HCC). Equilibrium phase CT image shows hypoattenuated peripheral portion of
mass relative to surrounding liver; additionally, attenuation value (in
Hounsfield units) is lower than that of arterial phase, suggesting contrast
medium washout. Central portion of mass shows no enhancement during dynamic
CT, which reflects necrosis.
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Fig. 3D —63-year-old man with sarcomatoid hepatocellular carcinoma
(HCC). T2-weighted MR image shows hyperintense mass with multiple small
intratumoral cystic lesions. At posterolateral aspect of tumor, there is
crescent-shaped lesion that shows high signal intensity on T1-weighted image
(C) and fluid-fluid level on T2-weighted image (arrow), which
could be hemorrhage.
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Fig. 3E —63-year-old man with sarcomatoid hepatocellular carcinoma
(HCC). Photograph shows gross specimen of sarcomatoid HCC. Section reveals
well-defined pinkish-yellow solid mass. Tumor shows focal central necrosis
(arrows).
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Fig. 3F —63-year-old man with sarcomatoid hepatocellular carcinoma
(HCC). Microscopic specimen shows HCC (arrowheads) with marked atypia
and malignant cartilage component (asterisk) consistent with
sarcomatoid HCC. (H and E; original magnification, x100)
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Combined HCC-Cholangiocarcinoma
Combined HCC-cholangiocarcinoma is composed of elements from both entities
[15]. The characteristics of
these tumors, as visualized by contrast-enhanced dynamic imaging, depend on
the proportions of tumor components. On contrast-enhanced CT and MRI, the
HCC-dominant tumor is well enhanced in the early phase and washed out in the
late phase, and the cholangiocarcinoma-dominant tumor shows peripheral and
delayed enhancement [15,
16]. Sometimes, these mixed
tumors appear heterogeneously enhanced because the HCC component appears
hyperenhanced, whereas the cholangiocarcinoma component appears hypoenhanced
relative to the surrounding liver
[16] (Figs.
4A,
4B,
4C,
4D,
4E,
4F, and
4G).
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Fig. 4A —52-year-old man with combined hepatocellular carcinoma (HCC)
and cholangiocarcinoma. On axial arterial phase CT scan, tumor shows strong
enhancement (arrowheads), whereas portion of tumor shows low
attenuation without enhancement (arrow). Thin hyperenhancing capsule
around mass is seen.
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Fig. 4B —52-year-old man with combined hepatocellular carcinoma (HCC)
and cholangiocarcinoma. On portal venous phase CT scan, mass shows low
attenuation relative to surrounding liver due to washout of contrast
medium.
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Fig. 4C —52-year-old man with combined hepatocellular carcinoma (HCC)
and cholangiocarcinoma. On T2-weighted MR image, mass shows high signal
intensity (arrowheads). Small portion of tumor shows isointense to
slightly low signal intensity (arrow).
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Fig. 4E —52-year-old man with combined hepatocellular carcinoma (HCC)
and cholangiocarcinoma. On contrast-enhanced arterial phase T1-weighted MR
image, portion of tumor that showed high signal intensity on T2-weighted image
shows strong enhancement (arrowheads), whereas portion that showed
isointense or slightly low signal intensity on T2-weighted image shows no
enhancement (arrow). Strongly enhanced portion was confirmed to be
HCC component, whereas unenhanced portion was correlated to cholangiocarcinoma
component.
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Fig. 4F —52-year-old man with combined hepatocellular carcinoma (HCC)
and cholangiocarcinoma. On equilibrium phase MR image, mass shows low signal
intensity compared with surrounding liver, suggesting contrast medium washout.
Peripheral thin enhancing capsule is also well depicted around mass in this
image.
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Fig. 4G —52-year-old man with combined hepatocellular carcinoma (HCC)
and cholangiocarcinoma. Photomicrograph of microscopic specimen shows
cholangiocarcinoma component (asterisk) and HCC component
(arrowheads) consistent with combined HCC and cholangiocarcinoma. (H
and E; original magnification, x40)
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On T1- and T2-weighted MR images, these tumors are hypointense and
heterogeneously hyperintense, respectively.
Sclerosing HCC
Sclerosing or scirrhous HCC is a rare hepatic tumor characterized by
intense fibrosis. Sclerosing HCC is frequently associated with hypercalcemia
and hypophosphatemia, which may be related to the parathyroid hormone-related
protein produced by the tumor
[17]. This tumor type appears
as a heterogeneous echoic mass on ultrasound. On dynamic contrast-enhanced CT
and MRI, sclerosing HCC shows hypervascularity and remarkable progressive and
prolonged enhancement [7,
18] (Figs.
5A,
5B,
5C, and
5D). In large tumors,
progressive central enhancement can be seen on delayed phase CT
[7,
18]. These tumors appear
hypointense on T1-weighted MR images and hyperintense on T2-weighted MR images
[18]. The adjacent liver
capsule may retract, especially in highly fibrotic tumors.
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Fig. 5A —52-year-old woman with sclerosing hepatocellular carcinoma
(HCC). Arterial (A), portal venous (B), and delayed phase
(C) CT scans show heterogeneous, progressively enhancing mass in right
lobe of liver.
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Fig. 5B —52-year-old woman with sclerosing hepatocellular carcinoma
(HCC). Arterial (A), portal venous (B), and delayed phase
(C) CT scans show heterogeneous, progressively enhancing mass in right
lobe of liver.
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Fig. 5C —52-year-old woman with sclerosing hepatocellular carcinoma
(HCC). Arterial (A), portal venous (B), and delayed phase
(C) CT scans show heterogeneous, progressively enhancing mass in right
lobe of liver.
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Fig. 5D —52-year-old woman with sclerosing hepatocellular carcinoma
(HCC). Photomicrograph of microscopic specimen shows hepatocellular
differentiation with intense fibrosis (asterisk) compatible with
sclerosing HCC. (H and E; original magnification, x200)
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Summary
Variant types of HCC may not share the imaging characteristics typical of
classic HCC. Familiarity with the disease entity and the radiologic findings
of variant types of HCC can be helpful in the differential diagnosis of
HCC.
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Abstract
Introduction
