W34 AJR:203, July 2014 more prevalent in Europe and North America and are uncommon in Asia and Africa. The age-adjusted incidence of fibrolamellar HCC in the United States is approximately 0.02 cas- es per 100,000 individuals, which is almost 100 times lower than classic HCC [7]. Up to one third of the HCCs developing on a noncirrhot- ic background could be fibrolamellar HCC [8]. Whereas classic HCC is often detected dur- ing surveillance imaging of patients with cir- rhosis, noncirrhotic HCCs commonly affect patients without known underlying liver dis- ease. Consequently, these tumors are often de- tected at an advanced stage and are more likely to cause symptoms [5, 6]. Common presenting symptoms include abdominal pain (52%), dis- tention (9%), weight loss (9%), anorexia (6%), and chest pain (6%) [9]. Occasionally, these patients present with fever of unknown origin or abnormal liver function test results. Etiopathogenesis A variety of congenital and acquired con- ditions can induce the development of HCC without underlying cirrhosis, often through alterations in cell cycle regulation, oxidative stress, and increased levels of tumorigenic growth factors (Fig. 1 and Table 2). Hepatocellular Carcinoma in the Noncirrhotic Liver Santhosh Gaddikeri 1 Michael F. McNeeley 1 Carolyn L. Wang 1 Puneet Bhargava 2 Manjiri K. Dighe 1 Matthew M. C. Yeh 3 Theodore Jay Dubinsky 1 Orpheus Kolokythas 4 Neeraj Lalwani 1 Gaddikeri S, McNeeley MF, Wang CL, et al. 1 Department of Radiology, University of Washington, 1959 NE Pacific St, Seattle, WA 98195. Address correspondence to N. Lalwani ([email protected]). 2 Department of Radiology, VA Puget Sound Health Care System, Seattle, WA. 3 Department of Pathology, University of Washington, Seattle, WA. 4 Institut für Radiologie, Kantonsspital Winterthur, Winterthur, Switzerland. Gastrointestinal Imaging • Review WEB This is a web exclusive article. AJR 2014; 203:W34–W47 0361–803X/14/2031–W34 © American Roentgen Ray Society H epatocellular carcinoma (HCC) accounts for approximately 90% of the primary hepatic malignan- cies in adults worldwide [1]. Al- though HCC typically occurs in the setting of hepatic cirrhosis, as many as 20% of HCCs may involve a noncirrhotic liver [2]. Because the imaging features of HCC in a noncirrhotic liver, when interpreted in the appropriate clinical context, often are dis- tinctive enough to suggest the diagnosis, an understanding of its appearance and of the predisposing clinical risk factors is neces- sary to prevent misdiagnosis. Epidemiology and Clinical Features HCC in a noncirrhotic liver, which we refer to here as “noncirrhotic HCC,” has a bimodal age distribution with peaks at the 2nd and 7th decades of life [3, 4]; although men are affect- ed by noncirrhotic HCC approximately twice as often as women, the male predilection for developing HCC in a cirrhotic liver is consider- ably stronger [5] (Table 1). Fibrolamellar HCC, which is a subtype of noncirrhotic HCC, com- monly occurs between the 2nd and 3rd decades of life and does not show any sex predilection [6]. Geographically, fibrolamellar HCCs are Keywords: cirrhosis, CT, hepatocellular carcinoma, MRI, noncirrhotic liver, risk factors DOI:10.2214/AJR.13.11511 Received June 26, 2013; accepted after revision November 6, 2013. OBJECTIVE. Hepatocellular carcinomas (HCCs) that arise in noncirrhotic livers have several histologic and biochemical features that distinguish them from HCCs occurring in the setting of cirrhosis. Because the presentation, management, and prognosis of these enti- ties are distinct, the accurate preoperative characterization of these lesions is of great clinical significance. We review the pathogenesis, imaging appearance, and clinical implications of noncirrhotic HCCs as they pertain to the clinical radiologist. CONCLUSION. HCCs that develop in noncirrhotic patients have distinct etiologic, cy- togenetic, histopathologic, and clinical features. Despite a larger tumor burden at the time of HCC diagnosis, noncirrhotic patients with HCC have better overall survival and disease-free survival than cirrhotic patients with HCC. Knowledge of the precise clinical and imaging fea- tures of this entity and of other diagnostic considerations for the noncirrhotic liver is essential for improved patient care. Gaddikeri et al. HCC in the Noncirrhotic Liver Gastrointestinal Imaging Review FOCUS ON: Downloaded from www.ajronline.org by 27.70.129.20 on 03/23/23 from IP address 27.70.129.20. Copyright ARRS. For personal use only; all rights reserved
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Hepatocellular Carcinoma in the Noncirrhotic LiverW34 AJR:203, July 2014
more prevalent in Europe and North America and are uncommon in Asia and Africa. The age-adjusted incidence of fibrolamellar HCC in the United States is approximately 0.02 cas- es per 100,000 individuals, which is almost 100 times lower than classic HCC [7]. Up to one third of the HCCs developing on a noncirrhot- ic background could be fibrolamellar HCC [8].
Whereas classic HCC is often detected dur- ing surveillance imaging of patients with cir- rhosis, noncirrhotic HCCs commonly affect patients without known underlying liver dis- ease. Consequently, these tumors are often de- tected at an advanced stage and are more likely to cause symptoms [5, 6]. Common presenting symptoms include abdominal pain (52%), dis- tention (9%), weight loss (9%), anorexia (6%), and chest pain (6%) [9]. Occasionally, these patients present with fever of unknown origin or abnormal liver function test results.
Etiopathogenesis A variety of congenital and acquired con-
ditions can induce the development of HCC without underlying cirrhosis, often through alterations in cell cycle regulation, oxidative stress, and increased levels of tumorigenic growth factors (Fig. 1 and Table 2).
Hepatocellular Carcinoma in the Noncirrhotic Liver
Santhosh Gaddikeri1 Michael F. McNeeley1
Carolyn L. Wang1
Gaddikeri S, McNeeley MF, Wang CL, et al.
1 Department of Radiology, University of Washington, 1959 NE Pacific St, Seattle, WA 98195. Address correspondence to N. Lalwani ([email protected]).
2 Department of Radiology, VA Puget Sound Health Care System, Seattle, WA.
3 Department of Pathology, University of Washington, Seattle, WA.
4 Institut für Radiologie, Kantonsspital Winterthur, Winterthur, Switzerland.
Gastrointest ina l Imaging • Review
WEB This is a web exclusive article.
AJR 2014; 203:W34–W47
© American Roentgen Ray Society
H epatocellular carcinoma (HCC) accounts for approximately 90% of the primary hepatic malignan- cies in adults worldwide [1]. Al-
though HCC typically occurs in the setting of hepatic cirrhosis, as many as 20% of HCCs may involve a noncirrhotic liver [2]. Because the imaging features of HCC in a noncirrhotic liver, when interpreted in the appropriate clinical context, often are dis- tinctive enough to suggest the diagnosis, an understanding of its appearance and of the predisposing clinical risk factors is neces- sary to prevent misdiagnosis.
Epidemiology and Clinical Features HCC in a noncirrhotic liver, which we refer
to here as “noncirrhotic HCC,” has a bimodal age distribution with peaks at the 2nd and 7th decades of life [3, 4]; although men are affect- ed by noncirrhotic HCC approximately twice as often as women, the male predilection for developing HCC in a cirrhotic liver is consider- ably stronger [5] (Table 1). Fibrolamellar HCC, which is a subtype of noncirrhotic HCC, com- monly occurs between the 2nd and 3rd decades of life and does not show any sex predilection [6]. Geographically, fibrolamellar HCCs are
Keywords: cirrhosis, CT, hepatocellular carcinoma, MRI, noncirrhotic liver, risk factors
DOI:10.2214/AJR.13.11511
Received June 26, 2013; accepted after revision November 6, 2013.
OBJECTIVE. Hepatocellular carcinomas (HCCs) that arise in noncirrhotic livers have several histologic and biochemical features that distinguish them from HCCs occurring in the setting of cirrhosis. Because the presentation, management, and prognosis of these enti- ties are distinct, the accurate preoperative characterization of these lesions is of great clinical significance. We review the pathogenesis, imaging appearance, and clinical implications of noncirrhotic HCCs as they pertain to the clinical radiologist.
CONCLUSION. HCCs that develop in noncirrhotic patients have distinct etiologic, cy- togenetic, histopathologic, and clinical features. Despite a larger tumor burden at the time of HCC diagnosis, noncirrhotic patients with HCC have better overall survival and disease-free survival than cirrhotic patients with HCC. Knowledge of the precise clinical and imaging fea- tures of this entity and of other diagnostic considerations for the noncirrhotic liver is essential for improved patient care.
Gaddikeri et al. HCC in the Noncirrhotic Liver
Gastrointestinal Imaging Review
HCC in the Noncirrhotic Liver
Viral Hepatitis The hepatitis B virus (HBV) is a DNA vi-
rus that can induce hepatic carcinogenesis in- dependent of cirrhosis, which occurs in up to 30% of all HBV-related HCCs [10]. On in- fection, the HBV genome integrates with the host hepatocellular DNA and may disrupt nor- mal cellular regulatory mechanisms by induc- ing genomic instability or producing genotox- ins such as the HBx protein [11] (Fig. 2). High viral load titers (104–5 copies/mL) have been linked with PIK3CA mutations and have been shown to be an independent risk factor for non- cirrhotic HCC. Overexpression of insulinlike growth factor–2 (IGF-2) and PIK3CA muta- tions are linked to activation of the Akt/PKB (protein kinase = B) pathway, which has been postulated as a major pathway to elicit HBV- induced carcinogenesis [12].
The hepatitis C virus (HCV) is an RNA vi- rus that does not integrate with the host ge- nome but generates several gene products (core, NS3, NS4B, and NS5A) that have shown carcinogenic potential in animal cell cultures [13, 14]. Approximately 46% of HCV-related HCCs exhibit CTNNB mutations [10]; of these, the majority arise in the absence of underlying cirrhosis [15]. Accelerated liver fibrosis—with- out frank cirrhosis—is also implicated in the pathogenesis of noncirrhotic HCC [16].
The risk of HCC significantly increases (2–4 times) in patients with chronic HBV- or HCV-related hepatitis who also consume alcohol [17, 18]. Postulated mechanisms of pathogenesis include oxidative stress, DNA methylation, decreased immune surveil- lance, and genetic susceptibility.
Genotoxic Substances Aspergillus flavus is a pathogenic fungus
that is endemic to several African and Asian countries and may contaminate cereals, le- gumes, spices, and fruits harvested in those locations. The aflatoxin B1 produced by A. flavus is associated with a selective mutation in the p53 tumor suppressor gene that com- monly underlies noncirrhotic HCC induction [19]. Concomitant exposure to HBV infec- tion leads to a 60-fold increased risk of non- cirrhotic HCC development [20].
Chemical and industrial carcinogens, such as nitrosamines, azo dyes, aromatic amines, vinyl chloride, organic solvents, pesticides, and arsenic, have been implicated in hepatic carci- nogenesis in patients who live in highly indus- trialized areas. Some specific mutations have been linked with certain carcinogens; for ex- ample, vinyl chloride–induced noncirrhotic HCC is linked to KRAS mutations, whereas HRAS mutations are associated with methy- lene chloride–induced noncirrhotic HCCs [10].
Thorotrast, a liquid suspension of radioac- tive thorium dioxide particles that was once used as a radiologic contrast agent, is a risk factor for noncirrhotic HCC, although it is classically associated with angiosarcoma and cholangiocarcinoma [21]. The thorium can retain in the body and emit carcinogenic alpha particles. Because of its carcinogenic potential, Thorotrast has long been discon- tinued and associated cases have become ex- ceedingly rare.
Excess iron within hepatocytes may act as a genotoxic cocarcinogen factor as suggested by the mild iron accumulation found in the
nonneoplastic liver parenchyma of most pa- tients with noncirrhotic HCC [22].
Heritable Diseases HCC in a noncirrhotic liver may occur in
the setting of rare inherited metabolic and congenital diseases such as hemochroma- tosis, porphyria, α-1-antitrypsin deficiency, hypercitrullinemia, Wilson disease, type I glycogen storage disease (GSD-I), Alagille syndrome, and congenital hepatic fibrosis [2].
The postulated hypothesis suggests that ac- cumulating mutant proteins or an aggregation of a substance within the hepatocytes acti- vates a number of stress responses at the ge- netic and cellular levels that, in turn, induce proliferation and tumor formation [23]. For example, Hemochromatosis induces cellular proliferation and direct damage to the DNA, resulting in the inactivation of tumor suppres- sor genes (p53), formation of reactive oxygen species and lipid peroxidation, and accelera- tion of fibrogenesis, which when taken togeth- er induce the formation of noncirrhotic HCC.
Metabolic syndrome (a synergistic con- comitance of dyslipidemia, hypertension, obesity, and type 2 diabetes mellitus) is an im- portant and evolving risk factor for HCC. The hypothesized mechanisms of carcinogenesis include lipid peroxidation (oxidative stress in- duced by free radicals) and elevated levels of insulin and insulinlike growth factor–1 (IGF- 1) [24, 25]. The unopposed and persistent ac- tion of these carcinogens provokes cellular proliferation and activation of hepatic progen- itor cells and also stimulates p53 mutations and epigenetic aberrations [26, 27].
TABLE 1: Summary of the Differences Between Hepatocellular Carcinoma (HCC) in a Cirrhotic Liver and HCC in a Noncirrhotic Liver
Difference HCC in Cirrhotic Liver HCC in Noncirrhotic Liver
Cause Underlying viral hepatitis or alcohol abuse leading to cirrhosis Underlying hereditary disorders, metabolic syndromes, viral hepatitis, or genotoxins exposure
Carcinogenesis Stepwise carcinogenesis: regenerative nodule → dysplastic nodule → HCC
De novo carcinogenesis
Major molecular alterations Mutations or deletions of tumor suppressor genes such as p53, Rb, IGF2R, and p16INK4 and activation of protooncogenes such as β-catenin and ras-MAPK pathway; loss of heterozy- gosity is frequent
Lower rate of p53 mutation, higher prevalence of β-catenin mutation, p14 inactivation, and DNA mismatch repair; increased levels of Y654–β-catenin in fibrolamellar HCC; loss of heterozygosity is infrequent
Multifocal or solitary Usually multifocal Usually solitary
Tumor size Variable size, often small Large (mean size, 12.4 cm)
Demography High male preponderance (male-female ratio, 8:1); common in elderly age group
Relatively lower male preponderance (male-female ratio, 2:1); bimodal distribution in 2nd and 7th decades
Clinical presentation Hepatomegaly, abdominal pain, jaundice, and ascites Hepatomegaly, abdominal pain, asthenia, malaise, fever, weight loss, and anorexia
Note—MAPK = mitogen-activated protein kinase.
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Miscellaneous Factors Approximately 5–10% of hepatic adeno-
mas (HCAs) show malignant potential, often in the setting of β-catenin mutation [28].
Malignant transformation can occur in 0–18% of HCAs [29]. A higher risk of malig- nant degeneration of HCA exists in patients with glycogen storage disease, patients who take oral contraceptive pills (OCPs) or male hormones, and patients with familial adeno- matous polyposis syndrome [10, 30].
Scarce information on the carcinogenesis associated with OCPs is available in the liter- ature. The risk of malignant degeneration has been directly linked with the duration of intake
of OCPs and the size (> 5 cm) of the tumor [31]. The results of one recent study that evalu- ated 23 patients with malignant transformation within HCA revealed that five patients had tak- en OCPs for more than 2 years [30].
Patients with GSD-I are prone to develop HCA (22–75%) and, rarely, HCC. The precise degree of risk is unknown because of the rar- ity of this condition. However, of 14 reported GSD-associated adenomas, four (28%) had a β-catenin mutation and two (14%) had both a β-catenin mutation and malignant degenera- tion [32]. Anabolic C17-alkylated androgenic steroids and contraceptive steroids have been implicated as initiators or promoters of hepat-
ic carcinogenesis, particularly after long-term use [33]. Interestingly, patients with GSD-I commonly have steatosis in the liver paren- chyma surrounding the adenomas, which may also be a contributory risk factor.
Budd-Chiari syndrome, nodular regenera- tive hyperplasia, and hepatoportal sclerosis have been implicated as risk factors for HCC in the absence of cirrhosis [4, 34].
Nonalcoholic steatohepatitis (NASH) has been acknowledged as the most common cause of chronic liver disease [35]. The enig- ma—whether NASH itself or NASH-induced cryptogenic cirrhosis leads to HCC—remains unsolved and long-term prospective studies are needed to elucidate this mystery [36].
Histopathology According to the histologic classification
criteria of the World Health Organization [37], the trabecular form is the most common histologic subtype of HCC in both cirrhotic and noncirrhotic livers (41–76%). The scir- rhous and mixed HCC-cholangiocarcinoma subtypes are generally rare but occur more frequently in noncirrhotic livers, specifically in western populations [2]. Well-differentiat- ed HCC is frequent in noncirrhotic liver and shows microscopic fat.
The fibrolamellar subtype of HCC oc- curs almost exclusively in noncirrhotic liv- ers [2]. Fibrolamellar HCCs are charac- terized as polygonal neoplastic cells with abundant eosinophilic cytoplasm arranged in sheets, cords, or trabeculae divided by parallel sheets of fibrous tissue into lobules. Approximately 20–60% of fibrolamellar HCCs show a central scar [38] that may cal- cify (35–68%) [10].
The hepatic parenchyma surrounding non- cirrhotic HCC can be entirely normal but usually shows some degree of inflamma- tion (50%), fibrosis (41–65%), early steatosis (36%), or iron accumulation [4, 39, 40]. Ste- atosis is frequently associated with conven- tional noncirrhotic HCC, whereas background parenchymal inflammation is frequently iden- tified with fibrolamellar HCC [40].
Diagnosis Role of Serum α-Fetoprotein
Elevated serum levels of α-fetoprotein (AFP) are less commonly associated with noncirrhotic HCC (31–67% of cases) than with cirrhotic HCCs (59–84% of cases); the serum AFP value is typically normal in the setting of fibrolamellar HCC. Serum AFP levels that exceed 400 ng/dL are considered
TABLE 2: Summary of Etiologic Factors Implicated in the Development of Hepatocellular Carcinoma (HCC) in a Noncirrhotic Liver and Proposed Mechanisms of Carcinogenesis
Etiologic Factors Proposed Mechanisms
HCV gene products (core, NS3, NS4B, and NS5A)
Induce TGF-β signaling
CTNNB mutations
Alcohol Synergistic role in the background of chronic HBV or HCV
Oxidative stress
DNA methylation
Genetic susceptibility
Aflatoxin B1 Selective codon 249 mutation in p53 gene (hot spot mutation)
Concomitant HBV infection further increases risk of HCC by sixfold
Chemical and industrial carcinogens
Activation of oncogenes
Tissue iron overload Oxidative stress
Inherited diseases Activation of stress response at genetic and cellular levels
Free radical formation leading to lipid peroxidation and acceleration of fibrogenesis
Metabolic syndromes Oxidative stress by free radicals
p53 mutations and epigenetic aberrations
Hepatic adenoma to carcinoma β-catenin mutation
Sex hormones Implicated as initiators or promoters in hepatic carcinogenesis
Hepatic vascular abnormalities Exact mechanism not clearly described in the literature
Note—HBV = hepatitis B virus, IGF-2 = insulinlike growth factor–2, HCV = hepatitis C virus, TGF-β = transform- ing growth factor–β.
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HCC in the Noncirrhotic Liver
diagnostic of HCC regardless of the presence or absence of underlying cirrhosis [5].
Cross-Sectional Imaging On imaging, noncirrhotic HCC generally
shows imaging features characteristic of clas- sic HCC except for the lack of cirrhosis on the background. Additionally, noncirrhotic HCC often presents as a large solitary mass or a dominant mass with satellite lesions [41]. Rarely there can be multiple masses without a dominant lesion. The right lobe appears to be commonly involved with the exception of fi- brolamellar HCC, which is more common in the left lobe [42]. The size of noncirrhotic HCC can range from 2 to 23 cm, with the average size of 12.4 cm (Figs. 3–10). Well-differenti- ated noncirrhotic HCCs typically are encap- sulated with distinct margins, whereas poorly differentiated and aggressive tumors tend to be nonencapsulated and poorly circumscribed. Varying amounts of central or peripheral cal- cification, necrosis, hemorrhage, and micro- scopic and macroscopic fat may be present. Occasionally, focal intrahepatic biliary dilata- tion can be seen; this feature may be related to mass effect rather than ductal invasion.
Extrahepatic extension of HCC via di- rect invasion of adjacent structures or me- tastasis is more common in noncirrhotic pa- tients than in cirrhotic patients (20.5% vs 6.5%, respectively) [5]; this tendency can be explained by the inherent biologic aggres- siveness of noncirrhotic HCC or, rather, by the typical delay in its diagnosis. The rela- tive tendency for early portal vein invasion by HCC in a cirrhotic liver versus HCC in a noncirrhotic liver remains controversial. Tu- mor thrombus can be seen in the portal or hepatic veins, but it is less common (≈ 15%) [41]. Upper abdominal lymphadenopathy can be seen in up to 21% of cases of noncir- rhotic HCC [9]. Fibrolamellar HCCs exhibit a distinct tendency for both nodal and perito- neal metastasis [10, 43].
Ultrasound—On gray-scale ultrasound, the appearance of HCC in the noncirrhot- ic liver is often nonspecific. Noncirrhotic HCC may appear hypoechoic, hyperecho- ic (due to fatty metamorphosis or hemor- rhage), or mixed echogenic (due to necrosis and hypervascularity).
CT—On unenhanced CT, noncirrhotic HCC tends to be hypoattenuating relative to the sur- rounding liver parenchyma. Areas of central or peripheral calcification, necrosis, and hem- orrhage may be seen. Fibrolamellar HCC sub- types show internal calcification in 68% of the
cases [38] (Fig. 8). The calcification often (91– 95%) involves the central scar [44].
After the administration of IV contrast ma- terial, the fibrolamellar HCC subtypes show hyperenhancement during the late arterial phase, isoenhancement compared with neigh- boring parenchyma during the portal venous phase, and contrast washout during the equi- librium phase, as seen in classic HCC in a non- cirrhotic liver (Figs. 4A and 4B). Capsular en- hancement, when present, is most apparent during the equilibrium phase. Fibrolamellar HCC may show predominant heterogeneous arterial enhancement, the presence of a cen- tral scar (20–60%), and a discontinuous cap- sule (35%) [44]. Some authors have reported that the central scar in fibrolamellar HCC is usually avascular and shows little or no en- hancement, and this imaging characteristic can be used to differentiate fibrolamellar HCC from focal nodular hyperplasia (FNH) [45] (Fig. 8). However, the results of some recent studies suggest that central scars in a signifi- cant number of fibrolamellar HCCs (25–56%) can retain contrast material [38, 42, 44, 46].
MRI—The appearance of noncirrhotic HCC on T1-weighted MRI sequences varies but is most commonly hypointense relative to the surrounding liver parenchyma. The presence of hemorrhage, fat, glycogen, copper, or protein- aceous matter within the lesion can increase its intensity on T1-weighted imaging [47].
Fat is seen in approximately 10–17% of noncirrhotic HCC and is a sign of a bet- ter prognosis [9, 48, 49]. An almost similar number of HCCs in cirrhotic livers (10%) may show the presence of fat [50].
Interestingly, intracellular fat accumulation is a relatively common feature (36% of cases) of well-differentiated noncirrhotic HCCs [47] (Fig. 5). Comparisons of in- and opposed- phase images can be helpful for detecting mi- croscopic fat within the tumor; parenchymal hypointensity on the in-phase series suggests underlying iron overload (Fig. 6).
On T2-weighted fast spin-echo images, noncirrhotic HCCs are usually isointense to hyperintense; however, lower-grade or well-differentiated tumors may be isoin- tense to hypointense [51].
Noncirrhotic HCC can show restricted dif- fusion on diffusion-weighted imaging (DWI) with a higher b value and may also show low apparent diffusion coefficient values (Fig. 6). DWI improves the detection of noncirrhotic HCC (especially tumors < 2 cm) and helps to differentiate it from potential mimics [52, 53]; however, DWI is less reliable for detecting
HCC lesions than it is for detecting hepatic metastases [54]. Higher-grade HCCs, regard- less of the degree of underlying fibrosis, may be more conspicuous on DWI than their low- er-grade counterparts. Dysplastic nodules and well-differentiated (low-grade) HCCs are rel- atively hypovascular. These findings probably are a function of the hypercellularity of high- er-grade carcinomas and could possibly also reflect the increased nuclear-cytoplasmic ra- tio inherent to aggressive tumors [55] (Fig. 7).
Dynamic fat-saturated gadolinium-en- hanced T1-weighted imaging shows an en- hancement pattern similar to multiphase CT, with hyperenhancement during the arterial phase, isoenhancement during the portal ve- nous phase, and washout during the equilibri- um phase. Moderately or poorly differentiated HCCs are often hypointense on T1-weighted imaging and show discernible washout during the portal phase [56] (Fig. 7). Moreover, the rapidity of washout has been correlated with the poorer differentiation of the tumor [56]. HCC may be surrounded by a capsule com- posed of fibrous connective tissue. Alterna- tively, the presence of prominent hepatic si- nusoids or nonbridging peritumoral…
more prevalent in Europe and North America and are uncommon in Asia and Africa. The age-adjusted incidence of fibrolamellar HCC in the United States is approximately 0.02 cas- es per 100,000 individuals, which is almost 100 times lower than classic HCC [7]. Up to one third of the HCCs developing on a noncirrhot- ic background could be fibrolamellar HCC [8].
Whereas classic HCC is often detected dur- ing surveillance imaging of patients with cir- rhosis, noncirrhotic HCCs commonly affect patients without known underlying liver dis- ease. Consequently, these tumors are often de- tected at an advanced stage and are more likely to cause symptoms [5, 6]. Common presenting symptoms include abdominal pain (52%), dis- tention (9%), weight loss (9%), anorexia (6%), and chest pain (6%) [9]. Occasionally, these patients present with fever of unknown origin or abnormal liver function test results.
Etiopathogenesis A variety of congenital and acquired con-
ditions can induce the development of HCC without underlying cirrhosis, often through alterations in cell cycle regulation, oxidative stress, and increased levels of tumorigenic growth factors (Fig. 1 and Table 2).
Hepatocellular Carcinoma in the Noncirrhotic Liver
Santhosh Gaddikeri1 Michael F. McNeeley1
Carolyn L. Wang1
Gaddikeri S, McNeeley MF, Wang CL, et al.
1 Department of Radiology, University of Washington, 1959 NE Pacific St, Seattle, WA 98195. Address correspondence to N. Lalwani ([email protected]).
2 Department of Radiology, VA Puget Sound Health Care System, Seattle, WA.
3 Department of Pathology, University of Washington, Seattle, WA.
4 Institut für Radiologie, Kantonsspital Winterthur, Winterthur, Switzerland.
Gastrointest ina l Imaging • Review
WEB This is a web exclusive article.
AJR 2014; 203:W34–W47
© American Roentgen Ray Society
H epatocellular carcinoma (HCC) accounts for approximately 90% of the primary hepatic malignan- cies in adults worldwide [1]. Al-
though HCC typically occurs in the setting of hepatic cirrhosis, as many as 20% of HCCs may involve a noncirrhotic liver [2]. Because the imaging features of HCC in a noncirrhotic liver, when interpreted in the appropriate clinical context, often are dis- tinctive enough to suggest the diagnosis, an understanding of its appearance and of the predisposing clinical risk factors is neces- sary to prevent misdiagnosis.
Epidemiology and Clinical Features HCC in a noncirrhotic liver, which we refer
to here as “noncirrhotic HCC,” has a bimodal age distribution with peaks at the 2nd and 7th decades of life [3, 4]; although men are affect- ed by noncirrhotic HCC approximately twice as often as women, the male predilection for developing HCC in a cirrhotic liver is consider- ably stronger [5] (Table 1). Fibrolamellar HCC, which is a subtype of noncirrhotic HCC, com- monly occurs between the 2nd and 3rd decades of life and does not show any sex predilection [6]. Geographically, fibrolamellar HCCs are
Keywords: cirrhosis, CT, hepatocellular carcinoma, MRI, noncirrhotic liver, risk factors
DOI:10.2214/AJR.13.11511
Received June 26, 2013; accepted after revision November 6, 2013.
OBJECTIVE. Hepatocellular carcinomas (HCCs) that arise in noncirrhotic livers have several histologic and biochemical features that distinguish them from HCCs occurring in the setting of cirrhosis. Because the presentation, management, and prognosis of these enti- ties are distinct, the accurate preoperative characterization of these lesions is of great clinical significance. We review the pathogenesis, imaging appearance, and clinical implications of noncirrhotic HCCs as they pertain to the clinical radiologist.
CONCLUSION. HCCs that develop in noncirrhotic patients have distinct etiologic, cy- togenetic, histopathologic, and clinical features. Despite a larger tumor burden at the time of HCC diagnosis, noncirrhotic patients with HCC have better overall survival and disease-free survival than cirrhotic patients with HCC. Knowledge of the precise clinical and imaging fea- tures of this entity and of other diagnostic considerations for the noncirrhotic liver is essential for improved patient care.
Gaddikeri et al. HCC in the Noncirrhotic Liver
Gastrointestinal Imaging Review
HCC in the Noncirrhotic Liver
Viral Hepatitis The hepatitis B virus (HBV) is a DNA vi-
rus that can induce hepatic carcinogenesis in- dependent of cirrhosis, which occurs in up to 30% of all HBV-related HCCs [10]. On in- fection, the HBV genome integrates with the host hepatocellular DNA and may disrupt nor- mal cellular regulatory mechanisms by induc- ing genomic instability or producing genotox- ins such as the HBx protein [11] (Fig. 2). High viral load titers (104–5 copies/mL) have been linked with PIK3CA mutations and have been shown to be an independent risk factor for non- cirrhotic HCC. Overexpression of insulinlike growth factor–2 (IGF-2) and PIK3CA muta- tions are linked to activation of the Akt/PKB (protein kinase = B) pathway, which has been postulated as a major pathway to elicit HBV- induced carcinogenesis [12].
The hepatitis C virus (HCV) is an RNA vi- rus that does not integrate with the host ge- nome but generates several gene products (core, NS3, NS4B, and NS5A) that have shown carcinogenic potential in animal cell cultures [13, 14]. Approximately 46% of HCV-related HCCs exhibit CTNNB mutations [10]; of these, the majority arise in the absence of underlying cirrhosis [15]. Accelerated liver fibrosis—with- out frank cirrhosis—is also implicated in the pathogenesis of noncirrhotic HCC [16].
The risk of HCC significantly increases (2–4 times) in patients with chronic HBV- or HCV-related hepatitis who also consume alcohol [17, 18]. Postulated mechanisms of pathogenesis include oxidative stress, DNA methylation, decreased immune surveil- lance, and genetic susceptibility.
Genotoxic Substances Aspergillus flavus is a pathogenic fungus
that is endemic to several African and Asian countries and may contaminate cereals, le- gumes, spices, and fruits harvested in those locations. The aflatoxin B1 produced by A. flavus is associated with a selective mutation in the p53 tumor suppressor gene that com- monly underlies noncirrhotic HCC induction [19]. Concomitant exposure to HBV infec- tion leads to a 60-fold increased risk of non- cirrhotic HCC development [20].
Chemical and industrial carcinogens, such as nitrosamines, azo dyes, aromatic amines, vinyl chloride, organic solvents, pesticides, and arsenic, have been implicated in hepatic carci- nogenesis in patients who live in highly indus- trialized areas. Some specific mutations have been linked with certain carcinogens; for ex- ample, vinyl chloride–induced noncirrhotic HCC is linked to KRAS mutations, whereas HRAS mutations are associated with methy- lene chloride–induced noncirrhotic HCCs [10].
Thorotrast, a liquid suspension of radioac- tive thorium dioxide particles that was once used as a radiologic contrast agent, is a risk factor for noncirrhotic HCC, although it is classically associated with angiosarcoma and cholangiocarcinoma [21]. The thorium can retain in the body and emit carcinogenic alpha particles. Because of its carcinogenic potential, Thorotrast has long been discon- tinued and associated cases have become ex- ceedingly rare.
Excess iron within hepatocytes may act as a genotoxic cocarcinogen factor as suggested by the mild iron accumulation found in the
nonneoplastic liver parenchyma of most pa- tients with noncirrhotic HCC [22].
Heritable Diseases HCC in a noncirrhotic liver may occur in
the setting of rare inherited metabolic and congenital diseases such as hemochroma- tosis, porphyria, α-1-antitrypsin deficiency, hypercitrullinemia, Wilson disease, type I glycogen storage disease (GSD-I), Alagille syndrome, and congenital hepatic fibrosis [2].
The postulated hypothesis suggests that ac- cumulating mutant proteins or an aggregation of a substance within the hepatocytes acti- vates a number of stress responses at the ge- netic and cellular levels that, in turn, induce proliferation and tumor formation [23]. For example, Hemochromatosis induces cellular proliferation and direct damage to the DNA, resulting in the inactivation of tumor suppres- sor genes (p53), formation of reactive oxygen species and lipid peroxidation, and accelera- tion of fibrogenesis, which when taken togeth- er induce the formation of noncirrhotic HCC.
Metabolic syndrome (a synergistic con- comitance of dyslipidemia, hypertension, obesity, and type 2 diabetes mellitus) is an im- portant and evolving risk factor for HCC. The hypothesized mechanisms of carcinogenesis include lipid peroxidation (oxidative stress in- duced by free radicals) and elevated levels of insulin and insulinlike growth factor–1 (IGF- 1) [24, 25]. The unopposed and persistent ac- tion of these carcinogens provokes cellular proliferation and activation of hepatic progen- itor cells and also stimulates p53 mutations and epigenetic aberrations [26, 27].
TABLE 1: Summary of the Differences Between Hepatocellular Carcinoma (HCC) in a Cirrhotic Liver and HCC in a Noncirrhotic Liver
Difference HCC in Cirrhotic Liver HCC in Noncirrhotic Liver
Cause Underlying viral hepatitis or alcohol abuse leading to cirrhosis Underlying hereditary disorders, metabolic syndromes, viral hepatitis, or genotoxins exposure
Carcinogenesis Stepwise carcinogenesis: regenerative nodule → dysplastic nodule → HCC
De novo carcinogenesis
Major molecular alterations Mutations or deletions of tumor suppressor genes such as p53, Rb, IGF2R, and p16INK4 and activation of protooncogenes such as β-catenin and ras-MAPK pathway; loss of heterozy- gosity is frequent
Lower rate of p53 mutation, higher prevalence of β-catenin mutation, p14 inactivation, and DNA mismatch repair; increased levels of Y654–β-catenin in fibrolamellar HCC; loss of heterozygosity is infrequent
Multifocal or solitary Usually multifocal Usually solitary
Tumor size Variable size, often small Large (mean size, 12.4 cm)
Demography High male preponderance (male-female ratio, 8:1); common in elderly age group
Relatively lower male preponderance (male-female ratio, 2:1); bimodal distribution in 2nd and 7th decades
Clinical presentation Hepatomegaly, abdominal pain, jaundice, and ascites Hepatomegaly, abdominal pain, asthenia, malaise, fever, weight loss, and anorexia
Note—MAPK = mitogen-activated protein kinase.
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Miscellaneous Factors Approximately 5–10% of hepatic adeno-
mas (HCAs) show malignant potential, often in the setting of β-catenin mutation [28].
Malignant transformation can occur in 0–18% of HCAs [29]. A higher risk of malig- nant degeneration of HCA exists in patients with glycogen storage disease, patients who take oral contraceptive pills (OCPs) or male hormones, and patients with familial adeno- matous polyposis syndrome [10, 30].
Scarce information on the carcinogenesis associated with OCPs is available in the liter- ature. The risk of malignant degeneration has been directly linked with the duration of intake
of OCPs and the size (> 5 cm) of the tumor [31]. The results of one recent study that evalu- ated 23 patients with malignant transformation within HCA revealed that five patients had tak- en OCPs for more than 2 years [30].
Patients with GSD-I are prone to develop HCA (22–75%) and, rarely, HCC. The precise degree of risk is unknown because of the rar- ity of this condition. However, of 14 reported GSD-associated adenomas, four (28%) had a β-catenin mutation and two (14%) had both a β-catenin mutation and malignant degenera- tion [32]. Anabolic C17-alkylated androgenic steroids and contraceptive steroids have been implicated as initiators or promoters of hepat-
ic carcinogenesis, particularly after long-term use [33]. Interestingly, patients with GSD-I commonly have steatosis in the liver paren- chyma surrounding the adenomas, which may also be a contributory risk factor.
Budd-Chiari syndrome, nodular regenera- tive hyperplasia, and hepatoportal sclerosis have been implicated as risk factors for HCC in the absence of cirrhosis [4, 34].
Nonalcoholic steatohepatitis (NASH) has been acknowledged as the most common cause of chronic liver disease [35]. The enig- ma—whether NASH itself or NASH-induced cryptogenic cirrhosis leads to HCC—remains unsolved and long-term prospective studies are needed to elucidate this mystery [36].
Histopathology According to the histologic classification
criteria of the World Health Organization [37], the trabecular form is the most common histologic subtype of HCC in both cirrhotic and noncirrhotic livers (41–76%). The scir- rhous and mixed HCC-cholangiocarcinoma subtypes are generally rare but occur more frequently in noncirrhotic livers, specifically in western populations [2]. Well-differentiat- ed HCC is frequent in noncirrhotic liver and shows microscopic fat.
The fibrolamellar subtype of HCC oc- curs almost exclusively in noncirrhotic liv- ers [2]. Fibrolamellar HCCs are charac- terized as polygonal neoplastic cells with abundant eosinophilic cytoplasm arranged in sheets, cords, or trabeculae divided by parallel sheets of fibrous tissue into lobules. Approximately 20–60% of fibrolamellar HCCs show a central scar [38] that may cal- cify (35–68%) [10].
The hepatic parenchyma surrounding non- cirrhotic HCC can be entirely normal but usually shows some degree of inflamma- tion (50%), fibrosis (41–65%), early steatosis (36%), or iron accumulation [4, 39, 40]. Ste- atosis is frequently associated with conven- tional noncirrhotic HCC, whereas background parenchymal inflammation is frequently iden- tified with fibrolamellar HCC [40].
Diagnosis Role of Serum α-Fetoprotein
Elevated serum levels of α-fetoprotein (AFP) are less commonly associated with noncirrhotic HCC (31–67% of cases) than with cirrhotic HCCs (59–84% of cases); the serum AFP value is typically normal in the setting of fibrolamellar HCC. Serum AFP levels that exceed 400 ng/dL are considered
TABLE 2: Summary of Etiologic Factors Implicated in the Development of Hepatocellular Carcinoma (HCC) in a Noncirrhotic Liver and Proposed Mechanisms of Carcinogenesis
Etiologic Factors Proposed Mechanisms
HCV gene products (core, NS3, NS4B, and NS5A)
Induce TGF-β signaling
CTNNB mutations
Alcohol Synergistic role in the background of chronic HBV or HCV
Oxidative stress
DNA methylation
Genetic susceptibility
Aflatoxin B1 Selective codon 249 mutation in p53 gene (hot spot mutation)
Concomitant HBV infection further increases risk of HCC by sixfold
Chemical and industrial carcinogens
Activation of oncogenes
Tissue iron overload Oxidative stress
Inherited diseases Activation of stress response at genetic and cellular levels
Free radical formation leading to lipid peroxidation and acceleration of fibrogenesis
Metabolic syndromes Oxidative stress by free radicals
p53 mutations and epigenetic aberrations
Hepatic adenoma to carcinoma β-catenin mutation
Sex hormones Implicated as initiators or promoters in hepatic carcinogenesis
Hepatic vascular abnormalities Exact mechanism not clearly described in the literature
Note—HBV = hepatitis B virus, IGF-2 = insulinlike growth factor–2, HCV = hepatitis C virus, TGF-β = transform- ing growth factor–β.
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HCC in the Noncirrhotic Liver
diagnostic of HCC regardless of the presence or absence of underlying cirrhosis [5].
Cross-Sectional Imaging On imaging, noncirrhotic HCC generally
shows imaging features characteristic of clas- sic HCC except for the lack of cirrhosis on the background. Additionally, noncirrhotic HCC often presents as a large solitary mass or a dominant mass with satellite lesions [41]. Rarely there can be multiple masses without a dominant lesion. The right lobe appears to be commonly involved with the exception of fi- brolamellar HCC, which is more common in the left lobe [42]. The size of noncirrhotic HCC can range from 2 to 23 cm, with the average size of 12.4 cm (Figs. 3–10). Well-differenti- ated noncirrhotic HCCs typically are encap- sulated with distinct margins, whereas poorly differentiated and aggressive tumors tend to be nonencapsulated and poorly circumscribed. Varying amounts of central or peripheral cal- cification, necrosis, hemorrhage, and micro- scopic and macroscopic fat may be present. Occasionally, focal intrahepatic biliary dilata- tion can be seen; this feature may be related to mass effect rather than ductal invasion.
Extrahepatic extension of HCC via di- rect invasion of adjacent structures or me- tastasis is more common in noncirrhotic pa- tients than in cirrhotic patients (20.5% vs 6.5%, respectively) [5]; this tendency can be explained by the inherent biologic aggres- siveness of noncirrhotic HCC or, rather, by the typical delay in its diagnosis. The rela- tive tendency for early portal vein invasion by HCC in a cirrhotic liver versus HCC in a noncirrhotic liver remains controversial. Tu- mor thrombus can be seen in the portal or hepatic veins, but it is less common (≈ 15%) [41]. Upper abdominal lymphadenopathy can be seen in up to 21% of cases of noncir- rhotic HCC [9]. Fibrolamellar HCCs exhibit a distinct tendency for both nodal and perito- neal metastasis [10, 43].
Ultrasound—On gray-scale ultrasound, the appearance of HCC in the noncirrhot- ic liver is often nonspecific. Noncirrhotic HCC may appear hypoechoic, hyperecho- ic (due to fatty metamorphosis or hemor- rhage), or mixed echogenic (due to necrosis and hypervascularity).
CT—On unenhanced CT, noncirrhotic HCC tends to be hypoattenuating relative to the sur- rounding liver parenchyma. Areas of central or peripheral calcification, necrosis, and hem- orrhage may be seen. Fibrolamellar HCC sub- types show internal calcification in 68% of the
cases [38] (Fig. 8). The calcification often (91– 95%) involves the central scar [44].
After the administration of IV contrast ma- terial, the fibrolamellar HCC subtypes show hyperenhancement during the late arterial phase, isoenhancement compared with neigh- boring parenchyma during the portal venous phase, and contrast washout during the equi- librium phase, as seen in classic HCC in a non- cirrhotic liver (Figs. 4A and 4B). Capsular en- hancement, when present, is most apparent during the equilibrium phase. Fibrolamellar HCC may show predominant heterogeneous arterial enhancement, the presence of a cen- tral scar (20–60%), and a discontinuous cap- sule (35%) [44]. Some authors have reported that the central scar in fibrolamellar HCC is usually avascular and shows little or no en- hancement, and this imaging characteristic can be used to differentiate fibrolamellar HCC from focal nodular hyperplasia (FNH) [45] (Fig. 8). However, the results of some recent studies suggest that central scars in a signifi- cant number of fibrolamellar HCCs (25–56%) can retain contrast material [38, 42, 44, 46].
MRI—The appearance of noncirrhotic HCC on T1-weighted MRI sequences varies but is most commonly hypointense relative to the surrounding liver parenchyma. The presence of hemorrhage, fat, glycogen, copper, or protein- aceous matter within the lesion can increase its intensity on T1-weighted imaging [47].
Fat is seen in approximately 10–17% of noncirrhotic HCC and is a sign of a bet- ter prognosis [9, 48, 49]. An almost similar number of HCCs in cirrhotic livers (10%) may show the presence of fat [50].
Interestingly, intracellular fat accumulation is a relatively common feature (36% of cases) of well-differentiated noncirrhotic HCCs [47] (Fig. 5). Comparisons of in- and opposed- phase images can be helpful for detecting mi- croscopic fat within the tumor; parenchymal hypointensity on the in-phase series suggests underlying iron overload (Fig. 6).
On T2-weighted fast spin-echo images, noncirrhotic HCCs are usually isointense to hyperintense; however, lower-grade or well-differentiated tumors may be isoin- tense to hypointense [51].
Noncirrhotic HCC can show restricted dif- fusion on diffusion-weighted imaging (DWI) with a higher b value and may also show low apparent diffusion coefficient values (Fig. 6). DWI improves the detection of noncirrhotic HCC (especially tumors < 2 cm) and helps to differentiate it from potential mimics [52, 53]; however, DWI is less reliable for detecting
HCC lesions than it is for detecting hepatic metastases [54]. Higher-grade HCCs, regard- less of the degree of underlying fibrosis, may be more conspicuous on DWI than their low- er-grade counterparts. Dysplastic nodules and well-differentiated (low-grade) HCCs are rel- atively hypovascular. These findings probably are a function of the hypercellularity of high- er-grade carcinomas and could possibly also reflect the increased nuclear-cytoplasmic ra- tio inherent to aggressive tumors [55] (Fig. 7).
Dynamic fat-saturated gadolinium-en- hanced T1-weighted imaging shows an en- hancement pattern similar to multiphase CT, with hyperenhancement during the arterial phase, isoenhancement during the portal ve- nous phase, and washout during the equilibri- um phase. Moderately or poorly differentiated HCCs are often hypointense on T1-weighted imaging and show discernible washout during the portal phase [56] (Fig. 7). Moreover, the rapidity of washout has been correlated with the poorer differentiation of the tumor [56]. HCC may be surrounded by a capsule com- posed of fibrous connective tissue. Alterna- tively, the presence of prominent hepatic si- nusoids or nonbridging peritumoral…
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