1. Introduction

Hepatocellular carcinoma (HCC) is a primary malignant liver tumour exhibiting hepatocellular differentiation [1]. It is well known for the strong association with preceding chronic liver disease and liver cirrhosis [2]. However, nowadays an increasing proportion of HCCs develops in non-fibrotic liver or on the background of mild fibrosis [3, 4]. The changing patterns of presentation influence the diagnostic approach both because of alterations in risk groups that could be targeted by surveillance and limits of non-invasive diagnostics in non-cirrhotic cases. In addition, the differential diagnostics of liver nodule differs in regard to the presence or absence of background liver cirrhosis. In cirrhotic liver, 59–94% (depending on size) of new mass lesions are malignant [5]. Thus, in patients with liver cirrhosis or preceding chronic liver disease, new nodule favours the diagnosis of HCC, as metastases and benign liver tumours are uncommon in cirrhotic liver [6, 7]. Hence, any mass lesion in cirrhotic liver must be considered HCC until proven otherwise [7].

histologically proved HCC in USA has increased from 1.4/100,000 persons per year between 1976 and 1980 to 2.4/100,000 persons per year between 1991 and 1995 [11] followed by further growth of HCC incidence rate reaching 6.2/100,000 persons per year in 2011 as shown by

Diagnostic Algorithm of Hepatocellular Carcinoma: Classics and Innovations in Radiology and Pathology

Similarly, although death rates attributable to other frequent cancers, including lung, breast, colorectal and prostate cancers, are declining in USA, mortality from liver cancer has increased by 2.8% per year (2003–2012) in males and by 2.2% per year in females. The growing mortality from liver cancer in USA contrasts with the general decline in cancer mortality reaching 1.5% per year. Among all cancers, HCC is the fastest growing cause of death in the USA [2] and

The spectrum of risk factors in HCC (see Table 1) explains the geographic heterogeneity. Awareness of these factors is important to understand the incidence and the associated needs for diagnostics and treatment. Worldwide, men have a higher incidence than women; gender ratio ranges around 3:1 both in global epidemiological studies of liver cancer [8] and more

Liver cirrhosis of any aetiology represents the single largest risk factor of HCC and is found in 70–90% of cases. Worldwide, hepatitis B virus (HBV) infection accounts for more than 50% of HCC cases. In comparison to non-infected individuals, the relative risk of HCC is increased 100-fold in HBV-infected persons, and the risk further increases if HBV-infected patient develops cirrhosis, has longer duration of infection and higher virus burden in blood. The yearly risk of HCC in HBV-infected patients is 2% [18]. In East Asia and sub-Saharan Africa,

Hepatitis C virus (HCV) infection is implicated in 25–31% of patients [13, 19]. Although the presence of HCV infection holds 17-fold risk of HCC in comparison with non-infected persons [13], risk is significantly higher in cirrhotic patients. Thus, surveillance is limited to those having

More than 4 times higher [16]

about 25,200–155,000 may be attributable to aflatoxin exposure

The risk of HCC for PSC patients with cirrhosis is up to 2% per

[15]

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[14]

[17]

Risk factor Risk assessment References Hepatitis B virus infection 100-fold higher [13] Hepatitis C virus infection 17-fold higher [13] Alcohol consumption 2.2 times higher in people who consume at least 50 g of alcohol

Aflatoxin exposure Of the 550,000–600,000 new HCC cases worldwide each year,

Primary biliary cirrhosis Incidence of HCC is 3–5% per year [12]

Hemochromatosis Approximately 20-fold higher [12]

targeted analysis of HCC [9]. Incidence starts to increase at the sixth decade of life [2].

SEER-based analysis [9].

poses a significant economic burden on healthcare [10].

HBV is the most common risk factor for HCC [12].

per day

year

Table 1. Risk factors of hepatocellular carcinoma [12–17].

Non-alcoholic fatty liver

Primary sclerosing cholangitis (PSC)

disease

In the global cancer statistics, HCC represents a frequent and aggressive tumour although different geographic regions face various burden of it. Worldwide, liver cancer is estimated to range sixth by incidence and second by oncological mortality causing 5.6% of global cancer incidence and 9.1% of mortality [8]. HCC is the most frequent primary liver cancer (>90%) being significantly more widespread than cholangiocarcinomas, hepatoblastomas and other primary liver malignancies [1]. Number of death cases per year (recently assessed by Ferlay et al. for the year 2012 as 745,000) is virtually identical to the incidence throughout the world (782,000; the same source) underlining the unfavourable course. The high ratio of mortality to incidence (0.95) reflects the dismal prognosis. As the geographical patterns of incidence and mortality closely follow each other [8], liver cancer is still an unsolved problem in the whole world.

According to the data provided by Surveillance, Epidemiology and End Results (SEER) Program of the National Cancer Institute, the 5-year survival for liver cancer is 16.6%, ranging from 30.5% in localised stage to 10.7% in regional stage and 3.1% in distant stage [2]. Different but similarly discouraging estimates have been reported, including 1-, 5- and 10-year survival of 31.3, 5.1 and 0.8%. The median survival is 6 months. However, significantly better outcome can be reached in early cases. Thus, median survival reaches 107 months in patients receiving liver transplantation for early HCC [9].

The incidence of liver cancer is high in Eastern and Southeastern Asia, followed by Northern and Western Africa [8]. China, Mongolia and Japan experience high occurrence [10]. In Europe, the highest age-standardised incidence rate of liver cancer is observed in Southern Europe [8] including Italy and France [10]. Although more developed regions generally show lower incidence of liver cancer (except Japan, France and Italy), its incidence is growing in many countries [8, 10]. Thus, although the total cancer incidence in the United States of America (USA) decreased in males and remained stable in females over time period 2003–2012, liver cancer incidence rates increased in both genders: 3.7% yearly in males and 3.0% in females. According to the National Program of Cancer Registries and SEER database, liver cancer incidence rate (2008–2012) in USA has increased by 2.3% per year [2]. The incidence rate of histologically proved HCC in USA has increased from 1.4/100,000 persons per year between 1976 and 1980 to 2.4/100,000 persons per year between 1991 and 1995 [11] followed by further growth of HCC incidence rate reaching 6.2/100,000 persons per year in 2011 as shown by SEER-based analysis [9].

1. Introduction

18 Hepatocellular Carcinoma - Advances in Diagnosis and Treatment

HCC until proven otherwise [7].

liver transplantation for early HCC [9].

world.

Hepatocellular carcinoma (HCC) is a primary malignant liver tumour exhibiting hepatocellular differentiation [1]. It is well known for the strong association with preceding chronic liver disease and liver cirrhosis [2]. However, nowadays an increasing proportion of HCCs develops in non-fibrotic liver or on the background of mild fibrosis [3, 4]. The changing patterns of presentation influence the diagnostic approach both because of alterations in risk groups that could be targeted by surveillance and limits of non-invasive diagnostics in non-cirrhotic cases. In addition, the differential diagnostics of liver nodule differs in regard to the presence or absence of background liver cirrhosis. In cirrhotic liver, 59–94% (depending on size) of new mass lesions are malignant [5]. Thus, in patients with liver cirrhosis or preceding chronic liver disease, new nodule favours the diagnosis of HCC, as metastases and benign liver tumours are uncommon in cirrhotic liver [6, 7]. Hence, any mass lesion in cirrhotic liver must be considered

In the global cancer statistics, HCC represents a frequent and aggressive tumour although different geographic regions face various burden of it. Worldwide, liver cancer is estimated to range sixth by incidence and second by oncological mortality causing 5.6% of global cancer incidence and 9.1% of mortality [8]. HCC is the most frequent primary liver cancer (>90%) being significantly more widespread than cholangiocarcinomas, hepatoblastomas and other primary liver malignancies [1]. Number of death cases per year (recently assessed by Ferlay et al. for the year 2012 as 745,000) is virtually identical to the incidence throughout the world (782,000; the same source) underlining the unfavourable course. The high ratio of mortality to incidence (0.95) reflects the dismal prognosis. As the geographical patterns of incidence and mortality closely follow each other [8], liver cancer is still an unsolved problem in the whole

According to the data provided by Surveillance, Epidemiology and End Results (SEER) Program of the National Cancer Institute, the 5-year survival for liver cancer is 16.6%, ranging from 30.5% in localised stage to 10.7% in regional stage and 3.1% in distant stage [2]. Different but similarly discouraging estimates have been reported, including 1-, 5- and 10-year survival of 31.3, 5.1 and 0.8%. The median survival is 6 months. However, significantly better outcome can be reached in early cases. Thus, median survival reaches 107 months in patients receiving

The incidence of liver cancer is high in Eastern and Southeastern Asia, followed by Northern and Western Africa [8]. China, Mongolia and Japan experience high occurrence [10]. In Europe, the highest age-standardised incidence rate of liver cancer is observed in Southern Europe [8] including Italy and France [10]. Although more developed regions generally show lower incidence of liver cancer (except Japan, France and Italy), its incidence is growing in many countries [8, 10]. Thus, although the total cancer incidence in the United States of America (USA) decreased in males and remained stable in females over time period 2003–2012, liver cancer incidence rates increased in both genders: 3.7% yearly in males and 3.0% in females. According to the National Program of Cancer Registries and SEER database, liver cancer incidence rate (2008–2012) in USA has increased by 2.3% per year [2]. The incidence rate of Similarly, although death rates attributable to other frequent cancers, including lung, breast, colorectal and prostate cancers, are declining in USA, mortality from liver cancer has increased by 2.8% per year (2003–2012) in males and by 2.2% per year in females. The growing mortality from liver cancer in USA contrasts with the general decline in cancer mortality reaching 1.5% per year. Among all cancers, HCC is the fastest growing cause of death in the USA [2] and poses a significant economic burden on healthcare [10].

The spectrum of risk factors in HCC (see Table 1) explains the geographic heterogeneity. Awareness of these factors is important to understand the incidence and the associated needs for diagnostics and treatment. Worldwide, men have a higher incidence than women; gender ratio ranges around 3:1 both in global epidemiological studies of liver cancer [8] and more targeted analysis of HCC [9]. Incidence starts to increase at the sixth decade of life [2].

Liver cirrhosis of any aetiology represents the single largest risk factor of HCC and is found in 70–90% of cases. Worldwide, hepatitis B virus (HBV) infection accounts for more than 50% of HCC cases. In comparison to non-infected individuals, the relative risk of HCC is increased 100-fold in HBV-infected persons, and the risk further increases if HBV-infected patient develops cirrhosis, has longer duration of infection and higher virus burden in blood. The yearly risk of HCC in HBV-infected patients is 2% [18]. In East Asia and sub-Saharan Africa, HBV is the most common risk factor for HCC [12].

Hepatitis C virus (HCV) infection is implicated in 25–31% of patients [13, 19]. Although the presence of HCV infection holds 17-fold risk of HCC in comparison with non-infected persons [13], risk is significantly higher in cirrhotic patients. Thus, surveillance is limited to those having


Table 1. Risk factors of hepatocellular carcinoma [12–17].

HCV-associated cirrhosis or advanced fibrosis [12]. Annually, HCC develops in 2–8% of HCVinfected patients [13]. In North America, Latin America, Europe and Japan, HCV infection, together with alcohol abuse, represent the main risk factors [3, 13]. In Europe and Japan where HCV infection spread earlier than in the United States, HCC incidence has almost reached a plateau, while in the United States it is still increasing. HCV infection may have a synergistic effect with other risk factors, such as non-alcoholic fatty liver disease [3].

The aim of the present chapter is to highlight the current approach and innovations for diagnostic evaluation of a liver nodule, suspected to be hepatocellular carcinoma. Noninvasive radiologic assessment represents the gold standard in certain patients. In contrast, difficult cases need biopsy evaluation, supplemented by immunohistochemistry, and may

Diagnostic Algorithm of Hepatocellular Carcinoma: Classics and Innovations in Radiology and Pathology

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Radiological imaging and functional evaluation are significant in screening and diagnostics of HCC [26]. The gold standard techniques comprise ultrasonography (US), computed tomography (CT) and magnetic resonance imaging (MRI). A major advance in the diagnostics of HCC was reached in 2001, when non-invasive criteria were developed and accepted by the European Association for the Study of the Liver (EASL) to diagnose HCC in cirrhotic liver [27]. In addition to the presence of liver mass, radiologic studies of HCC evaluate the typical vascularity. HCC receives enhanced arterial blood supply reflected histologically by unpaired arteries. The blood supply via portal vein decreases in comparison with surrounding parenchyma. However, in early stages of development, HCC can be hypovascular if the portal flow has

According to the guidelines, ultrasonography is advocated for screening and surveillance of patients having high risk to develop HCC due to HBV or HCV infection, cirrhosis or other known risk factors [28]. The specificity is mostly higher than 90%, ranging 45–94% [5, 27]. The reported sensitivity ranges widely from 33 to 96%, at least partially because of differences in the equipment and qualification of radiologists [18]. The sensitivity decreases in advanced chronic liver disease because of the coarse cirrhotic nodularity seen both grossly and by US [5]. In a large group of 200 patients undergoing US and liver transplantation, the sensitivity for HCC diagnostics was 29.6% in regard to patients and only 20.5% counting the tumours

The typical US presentation of HCC is a hypoechoic nodule although iso- or hyperechogenicity is possible as is nodule-in-nodule appearance [7]. Small HCCs (less than 2 cm in the greatest diameter) are mostly hypoechoic with or without posterior enhancement. Hyperechoic appearance is seen in 17% of small HCCs and can be associated with fat accumulation. Larger HCCs are heterogeneous reflecting necrosis (hypoechoic), calcifications and fibrosis. If hypoechoic halo (seen in 50% of HCC) and posterior enhancement is evident, these findings increase the specificity of diagnosis [5, 7, 18]. HCC in dysplastic nodule might seem hyperechoic within a larger hypoechoic area. If a nodule is identified on US, either CT or MRI is indicated for masses larger than 20 cm, while both methods are advocated for pathologic foci measuring 10–20 mm. If either CT or MRI confirms HCC, the diagnosis is reliable. Biopsy is indicated only for lesions that remain controversial after both imaging modalities. Nodules measuring less than 10 mm are

By Doppler US, HCC is characterised by so-called basket pattern reflecting rich arterial vascularisation. Benign cirrhotic nodules feature either low vascularity or arterial vessels with

themselves. Even a large tumour exceeding the diameter of 5 cm was missed [29].

already decreased but the arterial supply has not yet fully developed.

remain controversial even then.

followed up by US every 4 months [18].

2. Radiology

Globally, 15% of HCC cases can be attributed to alcohol-induced liver damage and non-alcoholic steatohepatitis [19], although the estimates range between 4 and 22% [20]. Non-alcoholic fatty liver disease (NAFLD) is the major hepatic manifestation of metabolic disturbances including obesity, type 2 diabetes mellitus, dyslipidaemia and metabolic syndrome [4]. As prevalence of these conditions is increasing, NAFLD has become the most common liver disorder in industrialised countries [21]. In NAFLD, HCC incidence reaches 44 (range, 29–66) per 100,000 personyears [22] contrasting with the general incidence of 6 per 100,000 in USA population [20]. The proportion of HCC related to NAFLD and non-alcoholic steatohepatitis (NASH) is increasing worldwide, especially in Western countries [20]. Although previously it was considered that HCC risk was limited to patients with liver cirrhosis, nowadays a significant fraction of NASHassociated HCC is found in non-cirrhotic liver or liver showing mild fibrosis [4].

Aflatoxins are a group of mycotoxins produced by Aspergillus fungi (A. flavus; A. parasiticus), which can contaminate food products such as grains, rice, cassava, soybeans, corn and peanuts, stored in hot climate and high moisture. Aflatoxins are major risk factors of HCC in sub-Saharan Africa and Eastern Asia [23]. Chronic exposure to aflatoxin results in DNA damage, including mutation of the tumour suppressor gene TP53 in hepatocytes [13]. In people subjected to aflatoxin ingestion and chronic HBV infection, HCC risk is 30- to 60-fold higher, versus HBV-uninfected people exposed to aflatoxin alone. Synergistic action is observed also between aflatoxin and HCV [14, 23, 24].

Planning the surveillance for individual patient, the presence of known risk factors must be considered and the relative risk must be taken into account. Organising surveillance measures in the society, population-attributable fraction (PAF) is also important. PAF depends both on relative risk and population prevalence of the corresponding risk factor. Thus, in USA, the risk increase of HCC is highest in HCV infection (odds ratio (OR), 39.9), followed by HBV infection (OR, 11.2), alcohol-induced liver disease (OR, 4.1) and diabetes mellitus and/or obesity (OR, 2.3). However, considering the prevalence of these conditions, diabetes and/or obesity are associated with the highest population attributable fraction (36.6%), followed by alcohol (23.5%), HCV (22.4%) and HBV (6.3%) as reported by Welzel et al. [25]. PAFs differ by the population. Worldwide, 54% of HCC occur in HBV-infected patients, 31% can be attributed to HCV and 15% to alcohol and NASH [19].

Considering the serious prognosis, early diagnosis is crucial, however, not always easy. Thus, correctly interpreted radiological findings, combined with biopsy when necessary, and appropriate immunohistochemical examination of biopsied tissues have diagnostic value. The molecular portrait of the tumour as well as easily available markers of the systemic inflammatory response, such as neutrophil-to-lymphocyte ratio or platelet-to-lymphocyte ratio, are recently reported to have prognostic and predictive value in HCC.

The aim of the present chapter is to highlight the current approach and innovations for diagnostic evaluation of a liver nodule, suspected to be hepatocellular carcinoma. Noninvasive radiologic assessment represents the gold standard in certain patients. In contrast, difficult cases need biopsy evaluation, supplemented by immunohistochemistry, and may remain controversial even then.
