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Gastrointestinal Imaging |
1 From the Departments of Radiology (R.I., F.P., V.V.), Pathology (V.P.), Surgery (J.B.), and Hepatology (F.D.), Hôpital Beaujon, Clichy, France; Department of Radiology, Università Cattolica del Sacro Cuore, Policlinico A. Gemelli, Rome, Italy (F.P.); Department of Radiological Sciences, University of Rome-La Sapienza, Policlinico Umberto I, Rome, Italy (R.I., R.P.); and Departments of Radiology (T.M., M.H., T.K., H.N.), Pathology (K.W.), and Surgery (M.M.), Osaka University Graduate School of Medicine, Osaka, Japan. Received July 25, 2005; revision requested September 28; final revision received June 16, 2006; final version accepted September 12. Address correspondence to R.I., Via Arturo Graf, 40, 00137 Rome, Italy (e-mail: r_iannaccone{at}yahoo.it).
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONADVANCES IN KNOWLEDGEReferences |
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Materials and Methods: Institutional review board approval was obtained for this study; the need for patient informed consent was waived. Clinical, pathologic, and imaging findings were retrospectively evaluated in 22 men (mean age, 64.5 years) with HCC and NAFLD. Helical CT and MR images were reviewed for morphologic features such as tumor size, margins, necrosis, and degree of enhancement.
Results: Obesity, diabetes, and hypertension were common findings and were observed in 12 (55%), 14 (64%), and 13 (59%) of the 22 patients, respectively. The serum 
-fetoprotein level was elevated in eight patients (36%). All patients had pathologic evidence of NAFLD. HCC was well-differentiated in seven patients, moderately differentiated in 11, and poorly differentiated in four. Large tumors (mean diameter, 8.4 cm) were depicted at CT and/or MR imaging in all patients. Twenty-one patients had a solitary or dominant mass. At imaging, tumor margins were well defined in 17 patients, with a smooth surface in 17, and there was evidence of a tumor capsule in 15. Necrosis was depicted in 16 patients. There was no evidence of calcifications, central scar, fat, or abdominal lymphadenopathy. CT was performed in 20 patients. HCC was hypoattenuating on unenhanced CT scans in 14 patients, heterogeneously hyperattenuating in the arterial phase in 20, and hypoattenuating in the portal phase in 14. MR imaging was performed in 16 patients. HCC was hyperintense compared with liver parenchyma at T2-weighted MR imaging in all 16 patients, hypointense at T1-weighted imaging in 14, heterogeneously hyperintense at arterial phase T1-weighted imaging in 16, and hypointense at portal phase T1-weighted imaging in 14.
Conclusion: HCC in patients with NAFLD is more likely to manifest as a large solitary or dominant mass characterized by smooth and possibly encapsulated margins, necrosis, and hypervascularity.
© RSNA, 2007
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONADVANCES IN KNOWLEDGEReferences |
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Although NAFLD may remain asymptomatic and stationary for long periods, it also may insidiously progress to cirrhosis and end-stage liver disease (6,8–11). Notably, there is evidence that a high percentage of patients who underwent liver transplantation for so-called cryptogenic cirrhosis probably had NAFLD (12). In addition, increasing evidence indicates that HCC may represent a late complication of NAFLD (1,10,11,13–26). Specifically, the risk of HCC in NAFLD-related chronic liver disease has been estimated to be 18%–27% (18,24). This is similar to the risk of HCC in hepatitis C–related cirrhosis.
The association of NAFLD with HCC has, to date, been described in some publications (1,10,11,13–26). However, to our knowledge, there has been no published study in which the helical computed tomographic (CT) and magnetic resonance (MR) imaging findings of HCC in patients with NAFLD were evaluated. Therefore, the purpose of our study was to retrospectively evaluate the clinical, pathologic, and helical CT and MR imaging findings of HCC in patients with NAFLD.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONADVANCES IN KNOWLEDGEReferences |
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One investigator at each of the two participating centers (R.I., M.H.) searched pathology databases for information obtained between January 1994 and July 2004 by using a Boolean search for the words HCC, steatosis, NAFLD, and NASH. Forty-seven patients were identified.
The diagnosis of NAFLD was based on the following criteria: (a) A weekly intake of less than 40 g of alcohol; (b) exclusion of other liver diseases such as acute drug-induced hepatitis, autoimmune hepatitis, hemochromatosis, Wilson disease, primary biliary cirrhosis, and primary sclerosing cholangitis; (c) absence of serologic or clinical evidence of ongoing hepatitis B or hepatitis C viral infection; and (d) strict pathologic criteria established in previous studies (4) (see below).
Seventeen patients were excluded because the pertinent CT and MR images were not available for review. In addition, eight patients with HCC treated with chemoembolization, radiofrequency ablation, or other forms of ablative treatment were also excluded. Therefore, our retrospective study included 22 patients who had complete clinical and pathologic information and helical CT and/or MR images available for review.
All patients included in this study were men, with the age at diagnosis ranging from 44 to 78 years (mean age, 64.5 years). For 12 patients, the HCC was an unexpected finding at ultrasonography (US) performed for unrelated reasons. Other patients had abdominal symptoms or signs, including pain (n = 7), abnormal liver function tests (n = 2), or a palpable mass (n = 1).
All patients underwent surgical resection, which consisted of segmentectomy (n = 9), left hepatectomy (n = 5), or right hepatectomy (n = 8). All imaging studies were performed 6–30 days before surgery. Fourteen patients underwent both helical multiphasic CT and MR imaging, six underwent CT alone, and two underwent MR imaging alone.
Data Collection
The following data were recorded for all patients by one investigator at each of the two participating centers (R.I., M.H.): height, weight, presence of diabetes (defined with the American Diabetes Association criteria [27]), hypercholesterolemia (defined as a serum cholesterol level >200 mg/dL [5.17 mmol/L]), hypertriglyceridemia (defined as a serum triglyceride level >200 mg/dL [2.26 mmol/L]), and hypertension (defined as blood pressure of at least 140/90 mm Hg or receipt of antihypertensive treatment). Laboratory evaluations included assessment of aspartate transaminase, alanine transaminase, total bilirubin, alkaline phosphatase, 
-glutamyl transferase and -fetoprotein levels and viral serology for hepatitis B and C. Body mass index was calculated with the standard formula, as follows: weight in kilograms divided by height in meters squared. Obesity was defined as a body mass index of at least 30 kg/m2. A patient was considered overweight with a body mass index of 25–29.9 kg/m2.
Helical CT
Twenty of the 22 patients underwent abdominal helical CT, which included unenhanced and contrast material–enhanced imaging through the liver with both hepatic arterial and portal venous phase imaging with delays of 25–35 seconds and 60–70 seconds, respectively, after initiation of intravenous injection of contrast material. In addition, nine patients also underwent delayed-phase imaging through the liver 5–10 minutes after initiation of the contrast material administration. All CT examinations were performed by using multi–detector row scanners (CT Twin, Marconi, Cleveland, Ohio; Aquilion, Toshiba, Tokyo, Japan; or LightSpeed Ultra, GE Medical Systems, Milwaukee, Wis) with 180–250 mAs and 120 kVp. All patients received nonionic intravenous contrast material (350 mg of iodine per milliliter), which was administered at a rate of 3–5 mL/sec and a volume of 120–150 mL by using a mechanical power injector (Medrad, Pittsburgh, Pa). The section thickness and reconstruction interval was 5 mm, and the pitch was adjusted to allow scanning of the complete liver within one breath hold.
MR Imaging
MR imaging was performed in 16 patients with a 1.5-T system (Gyroscan Intera, Philips Medical Systems, Best, the Netherlands; or Signa Horizon LX 1.5T, GE Medical Systems). Imaging was performed with a variety of software upgrades that continuously evolved during the study period. Sequences included T2-weighted fast spin echo and T1-weighted gradient echo. Fat-suppression techniques were used in six patients. In-phase and opposed-phase gradient-echo sequences were used in eight patients. T1-weighted imaging was repeated in all patients after contrast material administration during the hepatic arterial (20–25-second delay) and portal venous (60–70-second delay) phases. Delayed-phase imaging (5–10 minutes after contrast material injection) was performed in 12 patients. All patients received a gadolinium chelate at a dose of 0.1 mmol per kg of body weight, followed by a 20-mL saline flush.
Image Analysis
Images were reviewed on hard-copy film, retrospectively and jointly, by two abdominal radiologists (V.V. and R.I., with 18 and 5 years of experience, respectively). The radiologists had knowledge of the diagnosis of HCC but were blinded to all clinical information, the specific types of NAFLD, and the presence or absence of cirrhosis. CT and MR images of the same patient were reviewed together. Because we were not attempting to determine the accuracy of CT and MR imaging diagnosis, we accepted consensus interpretation of CT and MR findings.
Helical multiphasic CT and MR images were reviewed in each patient to analyze the following imaging criteria: (a) number of lesions, (b) lesion location (hepatic segments were classified as caudate, right anterior, right posterior, left medial, and left lateral), (c) lesion diameter (measured with calipers), (d) lesion margins (well defined or ill defined), (e) lesion surfaces (smooth or lobulated), (f) attenuation of the lesions at unenhanced and contrast-enhanced CT (classified as hypoattenuating, isoattenuating, or hyperattenuating compared with the attenuation of the adjacent liver parenchyma), (g) signal intensity of the lesions at unenhanced and contrast-enhanced T1-weighted MR imaging with regard to adjacent liver parenchyma (hyperintensity on T2-weighted MR images was defined as slight if the signal intensity of the lesion was between that of the liver and spleen or strong if it was equal to or greater than that of the spleen), and (h) homogeneous or heterogeneous lesion appearance.
In addition, readers were asked to document the presence of a capsule (defined as a thin curvilinear border that surrounded at least half of the tumor and had a distinct attenuation or signal intensity difference), calcifications, hemorrhage (defined as amorphous fluid that was hyperattenuating to the unenhanced liver at CT and hyperintense to the unenhanced liver on T1-weighted MR images), necrosis (defined as nonenhancing areas with an attenuation similar to that of gallbladder contents and as signal hyperintensity on T2-weighted images), fat (when the tumor components had attenuation coefficients lower than those of water and/or bile or urine on nonenhanced CT scans and as signal hypointensity on T1-weighted fat-suppressed MR images or opposed-phase gradient-echo MR images), and central scar (defined as an area of distinctly different attenuation or signal intensity in or near the center of the lesion on unenhanced images or on images obtained at different phases of enhancement). Tumor venous and/or portal obstruction was defined as distention of the hepatic and/or portal vein lumen by enhancement of the thrombus or by the proximity of the tumor and the thrombosed vessel. At CT, intrahepatic dilated bile ducts were defined as hypoattenuating linear bands parallel to branches of the portal vein, better seen on portal venous phase images; at MR imaging, intrahepatic dilated bile ducts were defined as hyperintense linear bands, better seen on T2-weighted images. Encasement was deemed present when the vessel was not distinctly visible but was surrounded by the tumor mass. Upper abdominal lymphadenopathy was diagnosed when ovoid or round extravisceral masses were identified that were at least 2 cm in diameter and had attenuation or signal intensity less than or equal to that of skeletal muscle (28).
In addition, readers made a subjective judgment of hepatic size relative to patient size. The sizes of the whole liver and of each segment were estimated on the CT and/or MR images; manual mapping and three-dimensional volumetric analysis were not performed. Hepatic segments were classified by using the same classification system as that used for HCC location (see above). Hepatic segments were defined as hypertrophic or atrophic if the volume of the individual segments was abnormally increased or reduced compared with that of the other hepatic segments. Because the left medial segment (segment IV) is often small in cirrhotic livers (29), we noted whether its size was normal or atrophic.
CT and MR images were also analyzed to evaluate whether hepatic steatosis was present. Specifically, the assessment of steatosis at CT was based on visual evaluation comparing the attenuation of the liver with that of the spleen. Because of the fact that images of the cases included in the present study were available only on hard copy, no quantitative measurement of hepatic steatosis could be performed. Steatosis was deemed present at unenhanced CT if the attenuation of the liver was less than that of the spleen. The assessment of steatosis at MR imaging was based on visual evaluation of the loss of signal intensity of the hepatic parenchyma compared with that of the spleen, either on T1-weighted fat-suppressed images or opposed-phase gradient-echo images.
The readers were also asked to document the presence of features characteristic of chronic liver disease, including portal hypertension, splenomegaly, and nodularity of the liver surface.
Pathologic Analyses and Comparisons
Resected specimens were reviewed by two pathologists (one at each participating center) (V.P. and K.W., with 15 and 24 years of experience, respectively, in liver pathology).
Microscopic sections were reviewed to confirm the diagnosis of HCC. The gross specimens were evaluated for features similar to those defined by imaging characteristics, namely, tumor size, margins, and encapsulation, and the presence and extent of necrosis, hemorrhage, fat, or calcification. In addition, HCC grade was classified according to the definition of the World Health Organization (high differentiation, G1; moderate differentiation, G2; and poor differentiation, G3) (30) on the basis of the definitions of Edmondson and Steiner (31).
The nonneoplastic tissue was evaluated only in areas distant from the tumor to avoid changes such as inflammation and fibrosis caused by the proximity of the tumor itself. In particular, pathologists assessed necroinflammatory activity (hepatocyte necrosis and ballooning, lobular and portal inflammatory infiltration), the presence of Mallory bodies, perisinusoidal fibrosis, iron deposition, and cirrhosis (4). Pathologists were also specifically asked to categorize the nonneoplastic liver as having simple NAFLD or NASH (a subtype of NAFLD, in which steatosis is accompanied by hepatocyte ballooning and necrosis with or without Mallory hyaline and fibrosis) (4).
In addition, the degree of steatosis was evaluated and graded by using an ordinal scale (31), as follows: mild (10%–30% of hepatocytes affected), moderate (30%–70% of hepatocytes affected), and severe (>70% of hepatocytes affected). Moreover, the pathologists were asked to document whether steatosis was predominantly macrovesicular, microvesicular, or mixed.
These findings were used to compare the imaging and gross pathologic features of the HCCs.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONADVANCES IN KNOWLEDGEReferences |
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-fetoprotein level was elevated (>20 ng/mL [20 µg/L] for our laboratory) in only eight of the 22 patients (36%); of these patients; only four (18%) had a marked increase in serum -fetoprotein level (ie, >400 ng/mL [400 µg/L]). An increase in the -glutamyl transferase level (>40 U/L for our laboratory) was the most frequent laboratory finding, occurring in 16 of the 22 patients (73%).
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With regard to the 20 patients who underwent CT (Fig 1), HCC was predominantly hypoattenuating to liver on unenhanced images in 14 patients (70%), hyperattenuating in four, and isoattenuating in two. At hepatic arterial phase CT, the HCC nodules were heterogeneously hyperattenuating in all patients (100%). At portal venous phase CT, the neoplasms were hypoattenuating in 14 of the 20 patients (70%), hyperattenuating in four, and isoattenuating in two.
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We observed liver morphologic abnormalities (segmental hypertrophy or atrophy) in 17 of the 22 patients (77%). Overall, the most frequent morphologic abnormalities were atrophy of the left medial segment (13 of 22 patients, 59%) and hypertrophy of the caudate lobe (13 of 22 patients, 59%). Notably, all six patients with evidence of cirrhosis at pathologic examination had atrophy of the left medial segment and/or hypertrophy of the caudate lobe.
Despite the presence of steatosis at pathologic examination in 21 of the 22 patients (Table 2), steatosis could be seen on imaging studies in only four of the 22 patients (18%). Hepatic steatosis was detected with helical CT alone in one patient, with both helical CT and MR imaging in one patient, and with MR imaging alone in two patients. All of these patients were in the group that underwent both CT and MR imaging.
With regard to signs of chronic liver disease, only one of the 22 patients (5%) had evidence of nodularity of the liver surface. None of the patients had signs of portal hypertension or splenomegaly.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONADVANCES IN KNOWLEDGEReferences |
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To address potential bias in the selection of patients with NAFLD, hepatitis virus B and C infections represented one of the key exclusion criteria in our series. Because several histologic features of NAFLD can mimic alcoholic liver disease, the final diagnosis of NAFLD can also be supported clinically by our having used a cutoff for alcoholic consumption (<40 g/wk) that is more stringent than that used in most previously published series.
With regard to clinical and laboratory data, first, we failed to demonstrate the higher prevalence of female sex, as reported in several studies (20,21,24,25) but not confirmed in other series (6,7,10,17). It can be hypothesized that the striking male sex predilection in our study results from the higher prevalence of HCC in males, regardless of origin (32).
Second, in agreement with previous observations (17,24,26), obesity and type 2 diabetes were common in our patients (present in 55% and 64% of our patients, respectively). Type 2 diabetes has been shown to be a risk factor for both chronic liver disease and HCC (33). Obesity has also been demonstrated to be a risk factor for HCC (34). In this regard, it should be noted that only the body mass index at HCC diagnosis was taken into account here. This could, therefore, lead us to underestimate the effect that obesity has on NAFLD and HCC. Currently, the relative role and interaction of NAFLD, obesity, and diabetes in the development of HCC is unclear.
Third, although liver transaminase levels, including aspartate transaminase (12 of 22 patients, 55%), alanine transaminase (11 of 22 patients, 50%), and -glutamyl transferase (16 of 22 patients, 73%), were frequently elevated, the serum -fetoprotein level was elevated (>20 ng/mL for our laboratory) in only 36% of our patients (ie, eight), and only four of the 22 patients (18%) had a marked increase (ie, >400 ng/mL) in this level despite the large size of the tumors. Conversely, in patients with HCC that developed as a result of chronic viral hepatitis, serum -fetoprotein levels have been reported to be elevated in approximately 60% (35). Hashimoto et al (25) reported similar findings, with normal serum -fetoprotein levels in all eight of their patients with HCC and NAFLD. Therefore, normal serum -fetoprotein levels cannot be used to consistently rule out the presence of HCC in patients with NAFLD.
With regard to the histologic characteristics of the primary tumor, our results showed a predominance of well- to moderately differentiated tumors without histologic features that would differentiate them from HCC arising in other types of liver disease. This finding is in agreement with those of two previous studies (17,25).
In our series, HCC nodules in patients with NAFLD tended to be solitary (19 of 22 patients, 86%) or dominant with satellites (three of 22 patients, 14%); these results are in concordance with those of previous studies (17,25). Notably, HCC in patients with other forms of chronic liver disease is more often multifocal (36).
In general, the HCCs in this study were large masses (average diameter, 8.4 cm). This finding is in agreement with that of Marrero et al (24), who reported an average tumor diameter of 7.6 cm in patients with cryptogenic cirrhosis. Conversely, the HCCs in the study by Shimada et al (17) were small. This discrepancy can be due to the fact that, in the study by Shimada et al, patients underwent HCC screening with use of serum -fetoprotein level, protein induced by vitamin k absence-II level, and US every 3–6 months (17). In general, however, patients with NAFLD are less likely to undergo HCC surveillance programs than are patients with viral hepatitis (24). This may result in a delay in diagnosis and, therefore, larger tumors at diagnosis (24), as occurred in our series.
A tumoral capsule (15 of 22 patients, 68%) and intratumoral necrosis (16 of 22 patients, 73%) were observed in most of our patients. The presence of a capsule is an important prognostic factor because it is correlated with a better outcome after surgical resection (37) and a better response to transcatheter arterial chemoembolization (38).
With regard to the attenuation and/or signal intensity characteristics of HCCs in our study, the most frequent findings were heterogeneous hyperattenuation and hyperintensity during the hepatic arterial phase at CT and MR imaging, respectively. In addition, all tumors were hyperintense to liver on T2-weighted MR images. These findings, however, do not differ from those of HCCs that occur in other types of liver diseases (39).
With regard to the histologic findings of nonneoplastic parenchyma, fibrosis alone was present in nine of the 22 patients (41%); fibrosis with cirrhosis was found in only six patients (27%). This consideration is important because most authors agree that NAFLD without cirrhosis has a relatively benign clinical course (11,40), and progression of NAFLD to cirrhosis is considered a prerequisite to HCC. Notably, seven of the 22 patients (32%) in our study had no evidence of fibrosis at pathologic examination (so-called nonfibrotic liver). This result is in contrast with those of previous studies of NAFLD-related HCC (17,24,25). To our knowledge, however, there have been four previous cases of HCC in patients with NAFLD and without fibrosis (13,16,22). Our seven additional cases support the hypothesis that HCC may develop in patients with NAFLD before the disease has reached its cirrhotic stage. Notably, only two of our 22 patients had evidence of NASH at pathologic examination. Further studies are necessary to clarify the mechanisms of hepatocarcinogenesis in the nonfibrotic liver.
With regard to the imaging findings of nonneoplastic liver parenchyma, our results are in agreement with those of Saadeh et al (41). Specifically, in our study, both helical CT and MR imaging were unable to show any finding that could help point toward the diagnosis of NAFLD. Despite the presence of hepatic steatosis in 21 of our 22 patients, helical CT and MR imaging could demonstrate hepatic steatosis in only four patients (18%). There may be two reasons for this low sensitivity in the detection of steatosis. First, the vast majority of our patients had mild (<30%) steatosis at pathologic examination, and it is well known that the accuracy of diagnostic imaging in the depiction of steatosis is related to the amount of fat within the liver. Second, the diagnosis of hepatic steatosis was based only on qualitative assessment at both CT and MR imaging, and, in the latter, opposed-phase sequences were not performed systematically.
Helical CT and MR imaging were useful for depicting morphologic abnormalities of the liver parenchyma. In particular, atrophy of the left medial segment and hypertrophy of the caudate lobe were common findings (observed in 59% of our patients). Such abnormalities, however, are not specific and, therefore, cannot be used to help diagnose NAFLD. Therefore, at present, imaging studies are of limited value in the assessment of the liver parenchyma in patients with NAFLD. Indeed, several authors (2) advocate the use of systematic liver biopsy to diagnose NAFLD.
Overall, most of our findings for NAFLD-related HCC show substantial overlap with those reported for HCC arising from the so-called noncirrhotic liver (28,42–46). Specifically, similar to our findings, HCCs in the noncirrhotic liver have been described as large, solitary, encapsulated tumors that often have necrosis and are well to moderately differentiated (28,42–46). A precise comparison of our study with these previous studies is difficult. Indeed, patients with viral hepatitis or a history of alcohol abuse (28,42,45,46), as well as those with fibrolamellar HCC (28,42,43,46), were included in these studies. Moreover, often no detailed analysis of the nonneoplastic liver was performed (28,43–45). In this regard, Brancatelli et al (28) emphasized the presence of "nonspecific liver injury" (including inflammation, steatosis, and fibrosis) in 37 of their 39 patients with HCC in noncirrhotic livers. Therefore, it can be hypothesized that at least some HCCs in the noncirrhotic liver were, in fact, HCCs that developed in NAFLD.
Several limitations of our study require comment. First, we did not directly compare the patients with HCC arising from NAFLD with a matched group of patients with HCC arising from other chronic liver diseases, although we believe that the spectrum of CT and MR findings of HCC in this setting are already well established. Second, because of the retrospective design of our study, CT and MR imaging protocols were not standardized. Third, because our study included only patients who underwent surgical resection for HCC, we acknowledge that our series presents a selection bias. Clearly, a prospective study of patients with NAFLD is needed to determine the risk for developing HCC in this population.
In conclusion, HCC in patients with NAFLD is more likely to manifest as a large solitary or dominant mass characterized by smooth and possibly encapsulated margins, necrosis, and hypervascularity. CT and MR findings are currently of limited value in the diagnosis of NAFLD. The presence of a large hypervascular lesion with imaging features consistent with HCC in an otherwise normal liver should raise the diagnostic possibility of HCC in NAFLD.
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FOOTNOTES |
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Abbreviations: HCC = hepatocellular carcinoma • NAFLD = nonalcoholic fatty liver disease • NASH = nonalcoholic steatohepatitis
Authors stated no financial relationship to disclose.
Author contributions: Guarantors of integrity of entire study, all authors; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; manuscript final version approval, all authors; literature research, R.I., F.P., V.V.; clinical studies, R.I., F.P., V.V.; statistical analysis, R.I.; and manuscript editing, R.I., V.V.
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