Primary malignant tumours of the liver

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Primary malignant tumours of the liver

Chetana Lim and Olivier Farges

Introduction

With the exception of hepatocellular carcinoma (HCC), which is one of the most common malignancies, primary tumours of the liver are relatively rare in adults. HCC arises from hepatocytes, and cirrhosis is its main aetiological factor. This tumour remains a subject of considerable interest due to its rising incidence and the development of innovative treatments. Intrahepatic cholangiocarcinoma (ICCA) arises from the peripheral intrahepatic biliary radicles and other rare primary tumours arise from mesodermal cells, and include angiosarcoma, epithelioid haemangio-endothelioma and sarcoma.

Hepatocellular carcinoma

HCC accounts for 90% of all primary liver malignancy and its incidence continues to increase. It is the sixth most common neoplasm, accounting for more than 5% of all cancers, and is the third most common cause of cancer-related death. The International Agency for Research on Cancer has estimated in 2008 through its GLOBOCAN series that primary liver cancer caused more than 690 000 deaths worldwide, similar to colon or rectal cancer.¹

HCC usually occurs in male patients, and cirrhosis precedes its development in most cases. Due to better medical management of cirrhosis, survival of cirrhotic patients has steadily increased in recent years, resulting in a greater risk of developing HCC. Cohort studies have reported that in patients with HCC, the death rate due to cancer is 50–60%, while hepatic failure and gastrointestinal bleeding are responsible for approximately 30% and 10% of the deaths, respectively. HCC may now be identified at an early stage, particularly through the screening of high-risk patients.

Control of HCC nodules may be achieved successfully by surgical resection and by percutaneous treatment. The indications for these therapies depend on the morphological features of the tumour and the functional status of the non-tumorous liver. Unfortunately, these treatments are associated with a high incidence of tumour recurrence due to the persistence of the underlying cirrhosis, which represents a preneoplastic condition. Liver transplantation may seem a logical alternative treatment but has its own limitations, including tumour recurrence, the limited availability of grafts, and cost. The most exciting areas of progress are the control of hepatitis B virus (HBV) or hepatitis C virus (HCV), the prevention of carcinogenesis in patients with chronic liver disease, early radiological screening and the development of medical therapies. In the setting of liver surgery, better liver function assessment and understanding of the segmental liver anatomy with more accurate imaging evaluation are the most important factors that have led to a decrease in postoperative mortality. Active follow-up and treatment of recurrence have also contributed to increased 5-year survival rates as high as 70%.²

Incidence of HCC

The world age-adjusted incidence of HCC in men is 14.9 per 100 000, but has geographical variation related to the prevalence of HBV and HCV infections, which are the two main risk factors worldwide and account for more than three-quarters of all cases (Table 5.1). The incidence may be as high as 99 cases per 100 000 in Mongolian men; other high-rate areas include Senegal, Gambia, South Korea, Hong Kong and Japan. By contrast, North and South America, Northern Europe and Oceania are areas with low incidences (less than 5 cases per 100 000); in these areas, HCV is the main risk factor, together with alcohol abuse, non-alcoholic fatty liver disease and obesity. Southern European countries have intermediate rates.

Table 5.1

Age and prevalence of HBV and HCV among patients with HCC in different geographical areas

The rising incidence of HCC was first documented in the USA, where this doubled between the late 1970s and the early 1990s, reaching 3 cases per 100 000. The recent epidemic of HCV infection probably accounts for a large part of this increase. Alternative explanations include ageing of the population, increased detection, improved survival of cirrhotic patients, and the recent epidemic of obesity and type II diabetes.

It has been estimated that HCV began to infect large numbers of young adults in North America and South and Central Europe in the 1960s and 1970s as a result of intravenous drug use. The virus moved into national blood supplies and circulated until a screening test was developed in 1990, after which rates of new infection decreased dramatically. In Canada, Australia, Japan and various European countries, where HCV infection spread earlier than in the USA, a similar trend was observed but in some countries the incidence of HCC is now decreasing. In the USA, the incidence of HCV-related HCC is still increasing and is projected to peak in 2019 if the risk in HCV-infected persons with fibrosis remains stable.

Risk factors for HCC

The main risk factor for HCC is liver cirrhosis. Once present, male gender, age (as a marker of the duration of exposure to a given aetiological agent), stage of cirrhosis and diabetes are additional independent risk factors.

Cirrhosis

Up to 80–90% of all HCC arises in patients with underlying liver disease. The risk of tumour development varies with the type of cirrhosis; the highest risk is reported for chronic viral hepatitis (78% of HCC worldwide), whereas lower risks are associated with other forms of cirrhosis such as primary biliary cirrhosis.

HCC developing in the absence of cirrhosis is found in 10–20% of patients. The term ‘absence of cirrhosis’ appears more appropriate than ‘normal liver’ as these patients frequently have some degree of mild fibrosis, necroinflammation, steatosis or liver cell dysplasia. HCC in the absence of cirrhosis may be related to some of the same aetiological factors as those responsible for HCC in cirrhotic livers, such as HBV infection or alcohol abuse. Alternatively, HCC may occur as a result of conditions that infrequently lead to cirrhosis such as α₁-antitrypsin deficiency, haemochromatosis, or in the setting of specific aetiological factors that do not result in cirrhosis such as hormonal exposure or glycogenosis.

HBV infection

Chronic HBV infection is the most frequent risk factor for HCC worldwide, and accounts for more than 50 % of all cases. It is estimated that 40 million people are currently affected by HBV, particularly in developing countries; HBV infection should, however, begin to decline as a result of increased utilisation of HBV immunisation.

There is evidence that HBV-DNA sequences integrate into the genome of malignant hepatocytes and can be detected in the liver tissues of patients with HCC despite the absence of classical HBV serological markers. HBV-specific protein may also interact with liver genes. HBV is therefore a direct risk factor for HCC and can occur in patients without cirrhosis.

The risk of HBV-associated HCC increases with the severity of the underlying hepatitis, age at infection and duration of infection, as well as level of viral replication. An Asian patient with HBV-related cirrhosis has a 17% cumulative risk of developing HCC over a 5-year period. In the West, this cumulative risk is 10%. This may be explained by the earlier acquisition of HBV in Asia through vertical transmission (rather than horizontal transmission in the West through sexual or parenteral routes), longer duration of disease, or additional exposure to environmental factors. Ongoing HBV replication or hepatitis B e-antigen (HBeAg) infection accelerates the progression to cirrhosis and also to HCC. A study conducted in Taiwanese men reported that the risk of HCC increased 10-fold when HBsAg was present and 60-fold when HBeAg was present. Similarly, HBV-DNA levels greater than 10⁴ or 10⁶ copies/mL are associated with a 2.3 and 6.1 hazard risk, respectively, compared to patients with lower levels of replication.³ Additional cofactors that increase the risk of HCC are male gender (three- to sixfold), age > 40 years, concurrent HCV infection (twofold), HDV co-infection (threefold), heavy alcohol consumption (two- to threefold) and, in endemic regions, aflatoxin ingestion.

HCV infection

The expansion of HCV infection probably accounts for a significant proportion of the increased incidence of HCC observed over the past 10 years. In Western countries, up to 70% of HCC patients have anti-HCV antibodies in their serum and the mean time for developing HCC following HCV infection is approximately 30 years.

In HCV-positive patients with initially compensated viral cirrhosis, HCC is both the most frequent and first complication. The annual incidence of HCC is 0–2% in patients with chronic hepatitis and 1–4% in those with compensated cirrhosis, although rates as high as 7% have been reported in Japan. In patients with cirrhosis, additional independent risk factors increasing the risk of HCC are age > 55 years (two- to fourfold), male gender (two- to threefold), diabetes (twofold), alcohol intake greater than 60–80 g/day (two- to fourfold) and HBV co-infection (two- to six fold). Obesity is also a likely cofactor. In contrast, the viral genotype or viral concentration has no impact on the risk of HCC.

The mechanism of HCV-related HCC is still not very clear. The great majority of patients with HCV-related HCC have cirrhosis, suggesting that it is the presence of cirrhosis that is crucial for the development of this tumour.

Because anti-HCV vaccination is not available, prevention of HCV infection and minimising the risk of progression of chronic HCV infection to cirrhosis using antiviral treatment is the only means to reduce the incidence of HCV-related HCC. Sustained virological response in HCV-infected patients is associated with a significantly decreased risk of developing HCC.⁴

Human immunodeficiency virus (HIV) infection

The incidence of HCC is expected to rise in HIV-positive persons predominantly because of the higher prevalence of associated well-known risk factors: not only co-infection with HCV and HBV, but also alcohol abuse, non-alcoholic steatohepatitis (NASH) and diabetes. HIV-positive patients who are co-infected with HBV or HCV may have more rapidly progressive liver disease, and when they develop cirrhosis they also have an increased risk of HCC. The Mortavic study indicated that HCC caused 25% of all liver-related deaths among HIV patients.⁵

Cirrhosis and HCC occur 15–20 years earlier in HIV–HCV co-infected patients than in patients infected by HCV alone. The course of the disease is also considered more aggressive.⁶ Screening for HCC should, however, be the same as in HIV-negative patients.

Other viral infections

Infection with the hepatitis delta virus (HDV) is found in patients who are also infected with HBV (see above). Hepatitis A virus (HAV) and hepatitis E virus (HEV) infection cause neither chronic hepatitis nor HCC.

Alcohol

Heavy (> 50–70 g/day) and prolonged alcohol ingestion is a classical risk factor for cirrhosis and therefore HCC. Data available from cohort studies of European or US patients with alcohol-related cirrhosis suggest an annual incidence of HCC of 1.7% (as compared with 2.2% and 3.7% in patients of the same geographical area with HBV- or HCV-associated cirrhosis). Alcohol is also a very frequent additional risk factor in patients with HBV or HCV cirrhosis, as well as in those patients with chronic liver disease associated with the metabolic syndrome.

Non-alcoholic fatty liver disease (NAFLD)

NAFLD has been recognised as being one of the most common causes of liver disease in the USA (and other Western countries). Histological changes in the liver range from simple steatosis to more severe forms of non-alcoholic steatohepatitis (NASH), including cirrhosis. It is closely associated with type II diabetes, central obesity and dyslipidaemia as part of the metabolic syndrome, the prevalence of which has increased as an epidemic.

NAFLD (and the metabolic syndrome) accounts for a substantial portion of what was considered in the past as cryptogenic cirrhosis and carries an inherent risk for the development of HCC. Obesity has definitely been established as a risk factor for the development of HCC, with a 1.5–4 times increased risk.⁷

An association between NAFLD and HCC was first identified in 2002 by several studies focusing on HCC patients with chronic liver disease in the absence of HBV/HCV infection or alcohol abuse. In this population, there was a much higher prevalence of obesity, diabetes, hypertriglyceridaemia and pathological features of NAFLD. At the same time, evidence was accumulating linking common features of the metabolic syndrome/NASH with HCC. In particular, obesity was noted to increase the mortality from liver cancer far more than for any other cancer.⁷ Similarly, diabetes was found to increase the risk of HCC with and without acute or chronic liver disease.⁸

Precise figures on the incidence of HCC in patients with NAFLD are still lacking. It increases with male gender, increasing age, sinusoidal iron deposition and severity of underlying liver disease. In surgical series, overt cirrhosis is present in only one-third of patients while the others have less severe liver damage.⁹ In addition, there is also evidence that NAFLD may act synergistically with other risk factors, such as chronic HCV or alcoholic consumption, in the development of HCC.

Hereditary haemochromatosis

Hereditary haemochromatosis (HH) is an autosomal recessive disorder associated with homozygosity for the C282Y mutation in the haemochromatosis gene and characterised by excessive gastrointestinal absorption of iron. HH is a long-known risk factor for HCC, and the risk increases in patients with cirrhosis. Other risk factors include male gender and diabetes. Several additional risk factors such as HBV infection (4.9-fold), age greater than 55 years (13.3-fold) and alcohol abuse (2.3-fold) may act synergistically with iron overload to increase the risk of HCC in patients with cirrhosis caused by hereditary haemochromatosis. In a recent meta-analysis of nine studies including 1102 HCC cases, mainly from European populations, it has been reported that C282Y mutation was associated with increased risk of HCC (fourfold) in patients with alcoholic liver cirrhosis, but not in those with viral liver cirrhosis.¹⁰ Interestingly, pathological conditions other than haemochromatosis that are associated with iron overload, such as homozygous β-thalassaemia or the so-called African overload syndrome, are also associated with an increased risk of HCC. Similarly, there is evidence of a link between iron deposits within the liver and HCC in patients with and without cirrhosis.

Cirrhosis of other aetiologies

Primary biliary cirrhosis (PBC) has been considered as a low-risk factor for HCC, not only because of its rare incidence but also because it predominantly affects women (with a sex ratio of 9:1). A recent meta-analysis of 12 studies has reported that PBC is significantly associated with an increased risk of HCC (18.8-fold) compared to the general population.¹¹ However, there were several confounding factors in this meta-analysis, such as advanced histological stage of PBC, history of blood transfusion, and smoking or drinking habits that might be associated with an increased probability for HCC development in PBC patients, or may be directly associated with PBC development. In contrast, HCC development in patients with secondary biliary cirrhosis is exceptional if it even exists.

Autoimmune hepatitis has a low risk of HCC development. Potential reasons are the female predominance and the delayed development of cirrhosis through corticosteroid therapy. HCV infection needs to be ruled out as it may induce autoantibodies. Recent data reported that cirrhosis at presentation is an important prognostic risk factor for HCC. In a prospective multicentre cohort study evaluating 193 Japanese patients with autoimmune hepatitis, seven (3.6%) developed HCC during an 8-year period, all of whom had underlying cirrhosis.¹²

Aflatoxin

Aflatoxin B1 has also long been associated with the development of HCC because areas with a large consumption of this toxin coincide with areas with a high incidence of HCC (Asia and sub-Saharan Africa). Aflatoxin is ingested in food as a result of contamination of imperfectly stored staple crops by Aspergillus flavus. It is thought to induce HCC through mutation of the tumour suppressor gene p53. Although some studies suggest that it is an independent risk factor, others suggest that it could be a co-carcinogen only in patients with HBV infection. HCC in this setting frequently develops in a non-cirrhotic liver.

Metabolic liver diseases

An increased risk of HCC is recognised in some other forms of metabolic liver diseases such as α₁-antitrypsin deficiency, porphyria cutanea tarda, tyrosinaemia and hypercitrullinaemia. Patients with glycogenosis type IV, hereditary fructose intolerance and Wilson disease may also develop HCC, but with a lower risk. There is evidence that iron and copper overload in haemochromatosis and Wilson disease generate, respectively, oxygen/nitrogen species and unsaturated aldehydes that cause mutations in the p53 tumour suppressor gene.

Adenoma, contraceptives and androgens

Like adenoma in other locations, hepatocellular adenomas (HCAs) have a risk of malignant transformation and hepatocyte dysplasia is the intermediate step between HCAs and HCC. A recent systematic review estimated the risk to be 4.2%.¹³ This risk and the treatment strategy to prevent it may, however, be refined.

HCAs are most classical in women of child-bearing age and are associated with the prolonged use of contraceptives and oestrogen treatments. Discontinuation of oral contraceptives does not completely avoid the risk of malignant transformation. Malignancy within HCAs measuring less than 4 cm in diameter is exceptional. There is also recent evidence that HCAs may develop in men, especially if there is a background of a metabolic syndrome. The risk of malignant transformation in men is 50% (10 times higher than in women) and malignancy can occur in HCAs as small as 1 cm.¹⁴ Therefore, whereas resection of HCAs larger than 4 cm is recommended in women, all HCAs irrespective of size should be resected (or ablated) in men.

The number of HCAs does not appear to increase the risk of malignant transformation and, in particular, patients with polyadenomatosis are not at increased risk.14–16

Malignant transformation of HCAs has also been linked to the genotype and phenotype of HCAs. It is more prevalent in telangiectatic or atypical HCAs than in steatotic HCAs. Most importantly, the presence of a β-catenin mutation (observed in approximately 10–15% of HCAs) confers a particularly high risk of malignancy.¹⁷

Malignant transformation of HCAs may also occur within known specific aetiologies, such as with type I glycogenosis, anabolic steroid use, androgen treatments and Fanconi disease. Recreational anabolic steroid use is also known to potentially result in the development of adenoma, and malignant transformation to HCC has been reported.

Pathology of HCC and nodular lesions in chronic liver disease

Preneoplastic lesions are morphologically characterised by dysplastic lesions in the form of microscopic dysplastic foci and macroscopic dysplastic nodules (DNs).

Dysplastic foci are microscopic lesions composed of dysplastic hepatocytes of less than 1 mm in size, and occur in chronic liver disease, particularly in cirrhosis. DNs are defined as a nodular region of less than 2 cm in diameter with dysplasia but without definite histological criteria of malignancy. They are divided into low and high grade depending on the degree of cytological or architectural atypia. Low-grade DNs are approximately 1 cm in diameter, slightly yellowish, and have a very low probability of becoming malignant. High-grade DNs are less common but are typically slightly larger nodules (up to 2 cm) characterised by increased cell density with an irregular thin-trabecular pattern and occasionally unpaired arteries. These are often difficult to differentiate from highly differentiated HCCs. They may contain distinct foci of well-differentiated HCC and are therefore considered as precancerous lesions and become malignant in a third of cases. It must, however, be appreciated that lesions smaller than 2 cm may also represent HCC.

HCCs can be subdivided according to their gross morphology, degree of differentiation, vascularity, presence of a surrounding capsule and presence of vascular invasion. All of these criteria have practical implications.

On gross morphology, HCCs can be solitary or multinodular, consisting of either a collection of discrete lesions in different segments that develop synchronously (multicentric HCC), or as one dominant mass and a number of ‘daughter’ nodules (intrahepatic metastases) located in the adjacent segments. Diffuse HCCs are relatively rare at presentation and consist of poorly defined, widely infiltrative masses that present particular diagnostic challenges on imaging. A third type is the infiltrating HCC, which typically is less differentiated with ill-defined margins.

Microscopically, HCCs exhibit variable degrees of differentiation that are usually stratified into four different histological grades, known as Edmondson grades 1–4, which correspond to well-differentiated, moderately differentiated, poorly differentiated and undifferentiated types. The degree of differentiation typically decreases as the tumour increases in diameter. Very-well-differentiated HCCs can resemble normal hepatocytes and the trabecular structure may reproduce a near normal lobar architecture so that histological diagnosis by biopsy or following resection may be difficult. A number of immunomarkers have been described to selectively identify the malignant nature of these HCCs, not only in resected specimens but also in liver biopsies: glypican 3 (GPC3), heat shock protein 70 (HSP70) and glutamine synthetase (GS). Positive immunomarker staining for any two markers can detect early and well-differentiated HCC in 50–73% of cases, with 100% specificity when the analysis is performed on resected specimens.¹⁸

Vascularisation is a key parameter in differentiating HCC from regenerating nodules. Progression from macroregenerative nodule to low-grade DN, high-grade DN and frank HCC is characterised by loss of visualisation of portal tracts and development of new non-triadal arterial vessels, which become the dominant blood supply in overt HCC lesions. This arterial neoangiogenesis is the landmark pathological feature of HCC diagnosis, and the rationale for chemoembolisation and anti-angiogenic treatment.

A distinct fibrous capsule may surround tumour nodules. This capsule, present in 80% of resected HCCs, has a variable thickness, which may not be complete, and is frequently infiltrated by tumour cells. Capsular microscopic invasion by tumour cells is present in almost one-third of tumours smaller than 2 cm in diameter, as compared with two-thirds of those with a larger diameter.

HCC has a great tendency to spread locally and to invade blood vessels. The rate of portal invasion is higher in the expansive type, in poorly differentiated HCCs and in large tumours. Characteristically, microscopic vascular invasion is seen in 20% of tumours measuring 2 cm in diameter, in 30–60% of cases with nodules measuring 2–5 cm and in up to 60–90% when nodules are more than 5 cm in size. The presence of portal invasion is the most important predictive factor associated with recurrence. The tumour thrombus has its own arterial supply, mainly from the site of the original venous invasion. Once HCC invades the portal vein, tumour thrombi grow rapidly in both directions, and in particular towards the main portal vein. As a consequence, tumour fragments spread throughout the liver as the thrombus crosses segmental branches. Once the tumour thrombus has extended into the main portal vein, there is a high risk of complete thrombosis and increased portal hypertension. This accounts for the frequent presentation with fatal rupture of oesophageal varices, or liver decompensation including ascites (Fig. 5.1), jaundice and encephalopathy. Invasion of hepatic veins is possible, although less frequent. The thrombus eventually extends into the suprahepatic vena cava or the right atrium and is associated with a high risk of lung metastases. Rarely, HCC may invade the biliary tract and give rise to jaundice or haemobilia. Mechanisms of HCC-induced biliary obstruction include:

Figure 5.1 CT scan of a patient with a tumour thrombus originating from an HCC located in the right liver. The thrombus extends in to the main portal vein. Ascites is present.

• intraductal tumour extension;

• obstruction by a fragment of necrotic tumour debris;

• haemorrhage of the tumour resulting in haemobilia;

• metastatic lymph node compression of major bile ducts in the porta hepatis.

The rate of invasion of the portal vein, hepatic vein and bile duct at the time of diagnosis is 15%, 5% and 3%, respectively. However, it is estimated that during the natural history of HCC, approximately 1 in 3 patients will develop portal vein thrombosis.

When present, metastases are most frequently found in the lung. Other locations, in decreasing order of frequency, are: adrenal glands, bones, lymph nodes, meninges, pancreas, brain and kidney. Large tumour size, bilobar disease and poor differentiation are risk factors for metastatic disease.

Clinical presentation

HCC rarely occurs before the age of 40 years and reaches a peak at around 70 years of age. The age-adjusted incidence in women is two to four times less than in men and the difference is most pronounced in medium-risk south European populations and premenopausal women. Reasons for this higher rate in men include differences in exposure to risk factors, higher body mass index and higher levels of androgenic hormones.

There are basically three circumstances of diagnosis: (1) incidental finding during routine screening; (2) incidental finding during investigation of abnormal liver function tests or of another pathological condition; and (3) presence of liver- or cancer-related symptoms, the severity of which depend on the stage of the tumour and the functional status of the non-tumorous liver. In developed countries, a growing number of tumours are discovered incidentally at an asymptomatic stage. As tumours increase in size, they may cause abdominal pain, malaise, weight loss, asthenia, anorexia and fever. These symptoms may be acute as a result of tumour extension or complication.

Spontaneous rupture occurs in 5–15% of patients and is observed particularly in patients with superficial or protruding tumours. The diagnosis should be suspected in patients with known HCC or cirrhosis presenting with acute epigastric pain, as well as in Asian or African men who develop an acute abdomen (Fig. 5.2). Minor rupture manifests as abdominal pain or haemorrhagic ascites, and hypovolaemic shock is only present in about half of the patients. Portal vein invasion may manifest as upper gastrointestinal bleeding or acute ascites, and invasion of hepatic veins or the inferior vena cava may result in pulmonary embolism or sudden death.

Figure 5.2 CT scan of a patient with a ruptured HCC. Note that the rupture is limited at the upper part of the liver. This patient had haemorrhagic ascites.

Clinical symptoms resulting from biliary invasion or haemobilia are present in 2% of patients. Possible paraneoplastic syndromes associated with HCC include polyglobulia, hypercalcaemia and hypoglycaemia. Finally, in patients with underlying liver disease, a sudden onset or worsening ascites or liver decompensation may be the first evidence of HCC formation.

Clinical examination may only reveal large or superficial tumours. There may be clinical signs of cirrhosis, in particular ascites, a collateral circulation, umbilical hernia, hepatomegaly and splenomegaly.

Liver function tests and tumour markers

Liver function tests

Abnormal liver function tests are a non-specific finding and reflect an underlying liver pathology or the presence of a space-occupying lesion. Because most HCCs develop within a cirrhotic liver and since HCCs in normal livers are usually large, entirely normal liver function tests are exceptional. Jaundice is most frequently the result of liver decompensation.

Serum tumour markers

α-Fetoprotein: Serum α-fetoprotein (AFP) is the most widely recognised serum marker of HCC. It is secreted during foetal life but residual levels are very low in adults (0–20 ng/mL). It may increase in patients with an HCC, and serum levels greater than 400 ng/mL can be considered as diagnostic of HCC with 95% confidence. Levels may exceed 10 000 ng/mL in 5–10% of patients with HCC. Very high levels usually correlate with poor differentiation, tumour aggressiveness and vascular invasion. An AFP > 20 ng/mL has a sensitivity of 60% and therefore a surveillance programme using this cut-off value would miss 40% of tumours. If a value of > 200 ng/mL is used, 22% of tumours would be missed. Only 10% of small tumours are associated with raised AFP levels, whereas 30% of patients with chronic active hepatitis without an HCC have a moderately increased AFP. This usually correlates with the degree of histological activity and raised levels of transaminase, and it may therefore fluctuate. Tumours other than HCC can also be associated with increased AFP levels, but these are rare (non-seminal germinal tumours, hepatoid gastric tumours, neuroendocrine tumours).

Others serum tumour markers: Alternative serum markers for HCC, such as des-γ-carboxy prothrombin (DCP) or prothrombin induced by vitamin K absence (PIVKA-II; > 40 mAU/mL) and AFP-L3 (> 15%) have not come into common practice except in Japan, where they are covered under the national health insurance. A prospective study of at-risk patients comparing the accuracy of AFP and DCP in the early detection of HCC showed that the combination of both markers increased the sensitivity from 61% and 74%, for each marker alone, to 91% for both markers combined.¹⁹

Radiological studies

The aims of imaging in the context of HCC are to screen high-risk patients, differentiate HCC from other space-occupying lesions and select the most appropriate treatment.

Differentiation of HCC from other tumours relies on its vascularisation. The most reliable imaging features of an HCC are the presence of hyperarterialisation of the nodule in the early (arterial) phase and washout during the portal or late phase following injection (the tumour becomes hypovascular compared to the adjacent parenchyma). By definition, the term ‘washout’ can only be applied to tumours that are hypervascular in the arterial phase (although this may be very transient).

Critical in choosing the most appropriate treatment are the number of lesions, their size and extent, and the presence of daughter nodules, vascular invasion, extrahepatic spread and underlying liver disease.

These aims may be achieved by ultrasound (US), contrast-enhanced US, computed tomography (CT), magnetic resonance imaging (MRI), angiography or a combination of these.

Imaging aims to:

• screen patients for the development of HCC, and this is best achieved by US;

• differentiate potential HCC from other tumours, and this is best achieved by demonstrating the presence of hypervascularisation during the arterial phase and washout during the portal or late phase.

Ultrasound

US is the first-line investigation for screening because of its low cost, widespread availability and high sensitivity in identifying a focal liver mass. In experienced hands, US may identify 85–95% of lesions measuring 3–5 cm in diameter and 60–80% of lesions measuring 1 cm. Differences in accuracy worldwide may be explained by steatosis rates, heterogeneity of the liver disease and in operator variability. Typically, small HCCs are hypoechoic and homogeneous and cannot be differentiated from regenerating or dysplastic nodules. With increasing size, they may become hypo- or hyperechoic but most importantly heterogeneous. A hypoechoic peripheral rim corresponds to the capsule. The infiltrating type is usually very difficult to identify in a grossly heterogeneous cirrhotic liver. Besides echogenicity, the accuracy of US depends on the dimension and location of the tumour, as well as operator experience. A 1-cm-diameter tumour can be visualised if it is deeply located, whereas the same lesion located on the surface of the liver can be missed. Similarly, tumours located in the upper liver segments or on the edge of the left lateral segment may be missed. Tumours detected at an advanced stage despite surveillance are frequently located at one of these two sites. Obesity may also prevent accurate assessment of the liver (thickened abdominal wall or steatotic liver). Doppler US may demonstrate a feeding artery and/or draining veins. US is also accurate in identifying vascular or biliary invasion and indirect evidence of cirrhosis such as segmental atrophy, splenomegaly, ascites or collateral veins. Tumour thrombosis is associated with enlargement of the vascular lumen, and duplex Doppler may detect an arterial signal. Contrast US is addressed below.

Computed tomography

CT is more accurate than US in identifying HCCs and their lobar or segmental distribution, particularly with the development of helical and multislice spiral scanners. Spiral CT is undertaken without contrast and during arterial (25–50 s), portal (60–65 s) and equilibrium (130–180 s) phases after contrast administration. In addition, it is useful for identifying features of underlying cirrhosis, accurately measuring liver and tumour volumes, and assessing extrahepatic tumour spread. HCCs are usually hypodense and spontaneous hyperdensity is usually associated with iron overload or fatty infiltration, which is seen in 2–20% of patients. Specific features are early uptake of contrast and a mosaic shape pattern. During the portal phase, the density diminishes sharply and results in washout (tumour is hypodense compared to adjacent parenchyma) during the late phase (Fig. 5.3). HCCs may show variable vascularity depending on tumour grade and some are poorly vascularised. The capsule, when present, is best seen during the portal or late phase as an enhanced thickening at the periphery (delayed vascular enhancement is characteristic of fibrosis). Vascular invasion of segmental branches may also be identified. Intratumoral arterioportal fistula may develop and present as early enhancement of portal branches or as a triangular area distal to the tumour with contrast enhancement different from the adjacent parenchyma. Nonetheless, such fistulas are seen frequently in cirrhotic patients without HCC as infracentimetric hypervascular subcapsular lesions.

Figure 5.3 Typical vascular kinetics of an HCC. There is early uptake of contrast at the arterial phase (a) that becomes isodense during the portal phase (b), with washout during the late phase (c).

Magnetic resonance imaging

MRI tends to be more accurate than other imaging techniques in differentiating HCC from other liver tumours, especially those > 2 cm in diameter. As for CT, the technique of MRI should be accurate with T1- and T2-weighted images and with early, intermediate and late phases following contrast injection of gadolinium. The characteristics of an HCC are the mosaic shape structure and the presence of a capsule. Tumours are hypointense on T1-weighted images and hyperintense on T2-weighted images, but these characteristics are present in only 54% of patients; 16% of HCCs demonstrate hypointensity on both T1 and T2 images. Hyperintensity on T1-weighted images is also possible, and associated with fatty, copper or glycogen infiltration of the tumour. The kinetics of vascular enhancement following injection of contrast are the same as during CT, with early uptake and late washout. Recently, liver-specific magnetic resonance contrast medium such as Gd-EOB-DTPA that accumulates in Kuppfer cells (due to phagocytosis) or in hepatic cells has increased the accuracy of MRI, but has not yet come into common practice except in Eastern countries.

Contrast-enhanced ultrasound

Contrast-enhanced US (CEUS) is the most recent technique to assess vascularisation of tumours. A contrast agent (stabilised microbubbles) is administered intravenously via a bolus injection followed by saline flush. Enhancement patterns are typically described during the arterial (10–20 s postinjection), portal venous (30–80 s) and late phase (120–360 s). Whereas US microbubbles are confined to the vascular spaces, contrast agents for CT and MRI are rapidly cleared from the blood into the extracellular space. The sensitivity of CEUS to detect arterial enhancement is greater than that of CT or MRI because of the continuous monitoring of the images. Washout is slower for well-differentiated than for poorly differentiated tumours. However, it is subject to the same limitations as other US modes: if the baseline scan is unsatisfactory, the CEUS study will also be unsatisfactory. The advent of the second-generation US contrast agent Sonazoid, approved exclusively in Japan in 2007, has made Sonazoid-CEUS more effective for screening and staging than CEUS using other vascular agents such as SonoVue. Sonazoid contrast agent is taken up by Kupffer cells in the postvascular phase or Kupffer phase (starting 10 min postinjection) and provides extremely stable Kupffer images suitable for repeated scanning from 10 to about 120 min after injection.²⁰

Other imaging

Angiography: Although the diagnostic usefulness of angiography has been considerably reduced, it is still widely used as part of arterial chemoembolisation. Arteriography shows early vascular uptake (blush) and, if used, lipiodol injection is retained selectively for a prolonged period by the tumour. On subsequent CT, the retained radiodense lipiodol reveals the tumour as a high-density area. Uptake within the liver is not specific for HCC, since all hypervascular liver tumours, including focal nodular hyperplasia, adenoma, angioma and metastases, will retain Lipiodol. False-negative results may be observed with an avascular, necrotic or fibrotic HCC.

Positron emission tomography: The contribution of fluorodeoxyglucose (FDG)-positron emission tomography (PET) in the diagnosis of HCC remains limited because of low sensitivity (60%). FDG-PET can detect poorly differentiated but not-well differentiated HCC due to similarities between the metabolism of FDG in normal hepatocytes and hepatocellular cells. Recently, [¹⁸ F]fluorocholine (FCH), a PET tracer of lipid metabolism, has been shown to be significantly more sensitive than [¹⁸ F]FDG at detecting HCC, particularly in well-differentiated tumours.²¹ Interestingly, in metastatic HCC, FDG-PET has a high sensitivity and is more suitable for the detection of bone metastases than CT or bone scintigraphy.²²

Accuracy of imaging techniques

CT and MRI with contrast enhancement have the highest diagnostic accuracy (> 80%) and the techniques can be combined. However, pathological analysis of explanted livers from transplant patients shows that both techniques lose accuracy in assessing extension of the disease. For any technique, additional intrahepatic tumours, especially those less than 1 cm, are not diagnosed preoperatively in 30% of cases. MRI angiography with 2-mm sections is currently considered the most accurate technique, with a sensitivity of 100% for nodules more than 20 mm, 89% for nodules 10–20 mm and 34% for nodules < 10 mm.

Requirement for and reliability of histological assessment

Pathological confirmation of HCC can be obtained by cytology, histology or a combination of these with increasing accuracy. The accuracy of pathological assessment is increased if a sample of non-tumorous tissue is available for comparison. Liver biopsy is limited by the potential for haemorrhage and pain, and may occasionally be responsible for neoplastic seeding and vascular spread. The reported incidence of needle tract seeding is 1–5%. Tumour involvement is generally limited to subcutaneous tissues, has a slow progression and it is possible to perform local excision without apparent impact on survival. Even if the false-positive rate is low, the risk of needle tract seeding is balanced by the risk of pursuing an aggressive treatment such as resection or transplantation in a patient without malignancy. Every attempt should be made not to puncture the nodule directly but to access the nodule through a thick area of normal liver. As described below, several studies have shown that expert pathological diagnosis of HCC can be reinforced by staining for GPC3, HSP70 and GS, particularly in biopsies of small lesions that are not clearly HCC.

There is a significant false-negative rate for fine-needle biopsy, especially in small lesions, lesions that are difficult to access or those developing on the background of a multinodular parenchyma. A negative result should therefore never rule out malignancy.

Diagnosis of HCC

The standard for the diagnosis of HCC is histology. This is particularly true for tumours measuring 3 cm or less or when active treatment is required. Ideally, these samples should be associated with a biopsy of the non-tumorous liver and be made available for research, with patient consent. Non-invasive diagnosis (using radiological imaging alone) requires rigorous technique and interpretation.

The first attempt to standardise the diagnostic criteria was in 2000 by the European Association for the Study of Liver Disease (EASLD). Since the last publication of the AASLD practice guidelines for the management of HCC in 2005, several studies have reported that AFP determination lacks adequate sensitivity and specificity for effective surveillance and diagnosis.¹⁹ The advocated strategy in the 2011 updated version of the diagnostic criteria²³ was based on imaging techniques and/or biopsy as follows:

• For nodules less than 1 cm found on US, it was considered that other imaging techniques would be unlikely to reliably confirm the diagnosis. Since the accuracy of liver biopsy for such small lesions and the likelihood of HCC are low, it was felt reasonable to repeat an US at 3- to 6-month intervals until the lesion disappeared, enlarged or displayed characteristics of HCC. If there has been no growth over a period of up to 2 years, routine surveillance can be resumed.

• For nodules larger than 1 cm found on US screening of a cirrhotic liver, diagnosis of HCC can be established by one contrast-enhanced imaging technique (multidetector CT or dynamic contrast-enhanced MRI). The specific imaging pattern of HCC is defined by intense contrast uptake during the arterial phase followed by contrast washout during the venous or delayed phases. The value of these non-invasive criteria for HCC in cirrhosis has been confirmed prospectively.24–26 These typical imaging features have a specificity and predictive positive value of approximately 100% and sensitivity of 71%.

• If the findings are not characteristic or the vascular features are not typical, and in other clinical settings (e.g. absence of cirrhosis), a diagnostic biopsy was recommended, although it was acknowledged that a negative biopsy did not exclude the diagnosis.

Subsequent to these recommendations, several studies have reported that CEUS may give a false-positive HCC diagnosis and cannot selectively differentiate intrahepatic cholangiocarcinoma from HCC. This technique has therefore been withdrawn from the diagnostic algorithm proposed by the AASLD.

Current guidelines ²³ for the positive diagnosis of HCC are:

• For nodules > 1 cm with cirrhosis, early uptake and delayed washout on a single dynamic imaging study (triphasic CT or MRI with gadolinium) is considered characteristic of HCC.

• For nodules > 1 cm without cirrhosis or if the vascular features are not typical, a diagnostic biopsy is recommended.

• Biopsy of small lesions should be evaluated by expert pathologists. Tissue that is not clearly an HCC should be stained with CD34, CK7, GPC3, HSP70 and GS to improve diagnostic accuracy.

• If the biopsy is negative for HCC, it is recommended that the lesion should be re-evaluated using US at 3- to 6-month intervals. If the lesion enlarges but remains atypical for HCC, a repeat biopsy is recommended.

Natural history of HCC and staging systems

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