Book on hepatitis from page 338 to 345
338 Hepatology 2012
21. Diagnosis, Prognosis & Therapy of
Hepatocellular Carcinoma
Ulrich Spengler
Classification of HCC
Tumors are classified in order to stratify patients with respect to their survival
prognosis, to select and offer optimised therapeutic options at any tumor stage. In
HCC the Barcelona Clinic Liver Cancer (BCLC) Classification has been adopted as
the international standard, which is recommended by both the American Association
for the Study of Liver Diseases (AASLD) and the European Association for the
Study of the Liver (EASL) (Table 1). The BCLC classification takes into account
several aspects of the disease: the patient’s general state of health, the severity of the
liver disease as well as the extent of tumor spread (Llovet 1999). Patients in stages
BCLC 0 and A have a considerably better prognosis than patients in advanced
stages of liver cancer (Mazzaferro 1996). Nevertheless approximately only 25% of
patients with liver cancer are diagnosed at an early stage. Both EASL and AASLD
guidelines also provide recommendations regarding which therapy is best suited to
treat patients at each stage of the BCLC classification. Unlike classification schemes
in other types of malignancies, the BCLC classification is particularly helpful
because it is entirely based on clinical parameters - molecular characteristics are not
yet able to reliably assess individual prognosis of patients with HCC.
Table 1. Barcelona Clinic Liver Cancer (BCLC) Classification.
Tumor stage General state of health Tumor characteristics Child stage
0 Very early Good Single nodule <2 cm A & B
A Early Good Single nodule <5 cm,
3 nodules <3 cm
A & B
B Intermediate Good Large, multiple nodules A & B
C Advanced Reduced Vascular invasion,
extrahepatic secondaries
A & B
D Terminal Severely reduced Any form C
Diagnosis, Prognosis & Therapy of Hepatocellular Carcinoma 339
Epidemiology
HCC constitutes the sixth most frequent form of cancer worldwide, and it holds
third place concerning malignancy-related mortality (Parkin 2005). Incidence rates
of HCC are steadily rising both in Europe and the US.
Chronic hepatitis B is the major risk factor for developing HCC in Africa and
Asia, while in the US, Europe and Japan chronic hepatitis C is the leading cause of
HCC. Eighty percent of liver cancers are found in cirrhotic livers, which themselves
carry a high risk for HCC. Chronic carriers of hepatitis B virus (HBV) have a 100-fold increased risk as compared to a non-infected healthy reference population.
Recent reports from Taiwan indicate a direct link between HBV viral loads and the
risk of developing liver cancer within 10 years (Chen 2006, Iloeje 2006). The risk of
HCC is significantly increased once HBV viral loads exceed 2000 IU/ml
irrespective of the degree of hepatic inflammation. In developing countries exposure
to aflatoxins further increases this risk of HCC.
Approximately 130-170 million people are infected with the hepatitis C virus
worldwide, 20 to 30% of whom will develop liver cirrhosis, which carries a 3-5%
annual risk of ultimately progressing to liver cancer. In practical terms this means
that approximately one third of cirrhotic patients with hepatitis C will go on to
develop HCC. Unlike hepatitis B a close relationship between HCV viral loads and
the risk of developing HCC apparently does not exist (Bralet 2000). As a general
rule patients will not develop liver cancer in chronic hepatitis C before their disease
has progressed to the stage of cirrhosis. Consumption of alcohol or tobacco
enhances the risk of HCC (Donato 2002, Gelatti 2005). Beyond that, obesity (Calle
2003) and diabetes mellitus (Davila 2005) must be considered neglected but
nevertheless pivotal factors that can multiply the risk of liver cancer in western
countries resulting in 4 to 40-fold increased HCC rates among patients with chronic
viral hepatitis. Finally a genetic polymorphism in the adiponutrin gene seems to
predispose patients with alcoholic and non-alcoholic fatty liver disease to develop
cirrhosis and HCC (Fallet 2011, Nischalke 2011)
Surveillance of patients at high risk and early HCC
diagnosis
Surveillance is cost effective if the expected HCC risk exceeds 1.5% per year in
hepatitis C and 0.2% per year in hepatitis B. Surveillance has to be based on
ultrasound examination at 6-month intervals. When 3- versus 6-month surveillance
intervals were compared in a randomized study involving 1200 patients, there was
no evidence that the shorter interval improved rates of early diagnosis and
therapeutic outcomes. However, if patients with cirrhosis harbour nodular lesions,
the 3-month control interval is preferred due to the high potential of malignancy and
growth characteristics of such lesions (Yao 2006). Alpha-fetoprotein (AFP) has
insufficient sensitivity and specificity, and thus is no longer recommended for HCC
surveillance. The consistent use of ultrasound in patients with a high risk for HCC
enables us to diagnose early carcinoma in 30% of patients who then have a
reasonable chance of curative therapy.
340 Hepatology 2012
Diagnosis
The diagnosis of HCC can either be made by detecting malignantly transformed
hepatocytes in a liver biopsy or by dynamic contrast-enhanced radiological imaging
techniques demonstrating intense arterial uptake followed by wash-out of contrast in
the delayed venous phases reflecting arterialised perfusion of the tumor. Contrast-enhanced ultrasound may falsely suggest HCC in some patients with
cholangiocarcinoma, and it should not be used as the only diagnostic tool for HCC
(Vilana 2010). Nevertheless, novel diagnostic algorithms enable the diagnosis of
HCC in a cirrhotic liver without histopathology or reference to elevated tumor
markers.
The distinction between a dysplastic nodule and early HCC poses a particularly
challenging task for the pathologist. Staining for glypican 3, heat shock protein 70,
and glutamine synthetase is advised in this situation, and positivity for any two of
these three markers confirms the presence of HCC (International Working Party
2009).
Radiological diagnosis of HCC uses detection of hyper-vascularized nodular
lesions. Contrast-enhanced computed tomography (CT) or nuclear magnetic spin
resonance tomography (MRT) are considered to be equivalent diagnostic tools, and
international consensus guidelines accept a diagnosis of HCC without
histopathology if the patient with a nodular lesion in a cirrhotic liver exhibits the
following sequence of events: in the arterial phase, HCC enhances more intensely
than the surrounding liver, because arterial blood in the liver is diluted by venous
blood from the portal venous circulation, whereas HCC contains only arterial blood.
In the venous phase, HCC enhances less than the liver, reflecting the fact that HCC
does not have a portal venous blood supply and that the arterial blood flowing into
the lesion no longer contains contrast. This phenomenon is termed “washout”. In the
delayed phase “washout” persists, and occasionally HCC can only be detected in
this phase of a dynamic study. Thus, a four-phase dynamic study is needed to
reliably make a diagnosis of HCC (unenhanced, arterial, venous and delayed venous
phases). Contrast enhancement in the early arterial phase, which disappears in the
late venous phase, is highly specific for HCC.
The current recommendations for the diagnosis of HCC are summarized in Figure
1. For lesions smaller than 1 cm detailed investigation is not recommended because
most lesions will represent regenerative nodules rather than HCC. However, close
follow-up in 3-month intervals should be offered using the same imaging technique
that detected the lesion in the first place.
For lesions larger than 1 cm, either dynamic MRI or multidetector CT scans
should be performed. If findings are characteristic for HCC as described above, a
firm diagnosis of HCC can be made and no further studies are necessary. If the
findings are not typical for HCC, then the alternative dynamic imaging technique
should be applied. If this supplementary radiological investigation yields typical
features, the diagnosis of HCC is confirmed. Otherwise, a guided biopsy of the
lesion should be performed. Contrast-enhanced CT and MRI exhibit excellent
diagnostic sensitivity and specificity if the rules regarding early hypervascularity
and washout are strictly applied. The presence of arterial hypervascularisation alone
is not sufficient for a diagnosis of HCC, which requires the presence of venous
washout as an essential second diagnostic component. In equivocal situations the
Diagnosis, Prognosis & Therapy of Hepatocellular Carcinoma 341
diagnosis must be clarified by biopsies, which may have to be repeated within a
short period of time.
Figure 1. Diagnostic algorithm for the diagnosis of hepatocellular carcinoma depending
on tumor size.
Stage-adapted therapy for liver cancer
Patients with early HCC have excellent chances for curative cancer treatment. They
can achieve 5-year survival rates of 50-70% by surgical resection, liver
transplantation or percutaneous ablative procedures. With more advanced HCC,
local transarterial embolisation and multikinase inhibitor therapy can still prolong
life. Figure 2 gives a summary and concise overview of stage-adapted therapy for
hepatocellular carcinoma.
Potentially curative therapy in BCLC stages 0-A
Surgical resection constitutes the backbone of curative treatment in patients with
early HCC. It is the treatment of choice in patients with localised tumor spread and
small-sized cancers and tumors in a non-cirrhotic liver (evidence grade IIIA).
Prognosis after surgical resection is excellent, if the tumor is not larger than 2 cm in
diameter (5-year survival rates 70-90% with rates of tumor recurrence below 10%).
Excluding patients with poor liver function keeps perioperative mortality below 5%.
Favourable criteria for surgical resection comprise single nodules less than 5 cm in
size or a maximum of 3 nodules in a single liver lobe. Patients should be carefully
selected to diminish the risk of postoperative liver failure. Patients should have only
moderately impaired liver function (cirrhosis stage Child’s A), should not have
342 Hepatology 2012
portal hypertension (hepatic-portal-vein pressure gradient >10 mm Hg, presence of
esophageal varices or splenomegaly together with reduced platelet counts
<100,000/µl) and should have a serum bilirubin in the normal range. Right
hepatectomy in cirrhotic patients has a higher risk of inducing hepatic
decompensation than left hepatectomy.
Liver transplantation is an alternative therapeutic option, if the liver cancer
cannot be cured by local resection due to anatomical reasons, if residual liver
function after resection is anticipated to be poor, or if there is multi-nodular tumor
spread into both liver lobes (evidence grade IIIA). Commonly patients with HCC
are selected for liver transplant according to the so-called Milan criteria, i.e., the
patient has a single nodule of less than 5 cm in diameter or at most 3 nodules, none
of which exceeds 3 cm in diameter (Mazzaferro 1996). Milan criteria patients
usually achieve survival rates of 80% and 70% one and five years after liver
transplantation. However, it has been demonstrated that selected patients with more
extensive stages of liver cancer can be transplanted with reasonable long-term
outcomes (Yao 2001). Selection of patients according to the so-called San Francisco
criteria comprises solitary large nodules up to 6.5 cm as well as multi-nodular HCC
with a maximum of 3 nodules, each of which must be smaller than 4.5 cm with a
total sum of all nodule diameters below 8 cm. Patients who remain within these
extended selection criteria can still reach 70-80% five-year survival rates after liver
transplantation. However, there is very limited data to support extending selection
criteria for liver transplantation (Pomfret 2010).
A central issue in liver transplantation is the process of fair organ allocation.
Shortage of donor organs is particularly critical in patients with liver cancer,
because the tumor will continue to expand while the patient is on the waiting list,
and can ultimately reach a stage that makes liver transplantation a futile option. It
has been estimated that after one year on the waiting list approximately 40% of
patients can no longer be cured by liver transplant (Poon 2007). In the
Eurotransplant registry donor livers are allocated to patients according to their
MELD scores. To circumvent the problem that patients with early HCC who are
eligible for liver transplantation have rather low MELD scores, Eurotransplant
accepts the diagnosis of HCC within the Milan criteria as a so-called standard
exemption, allocating additional points on top of the patient’s lab-MELD score in an
incremental time-dependent fashion.
Most transplant centres treat liver cancers locally while the patient is on the
waiting list, mostly using transarterial chemoembolisation. This strategy probably
also facilitates patient selection for liver transplantation, because those with stable
disease after chemoembolisation achieve a greater than 90% five-year survival rate
after liver transplantation, while only 35% of patients in the group with progressive
tumor expansion survive five years post-liver transplantation (Otto 2006).
Radiofrequency ablation can also cure HCC that is limited to a distinct region of
the liver and is especially applied in older patients or patients with significant co-morbidity. A cohort study on percutaneous radiofrequency ablation demonstrated
that complete ablation of lesions smaller than 2 cm is possible in more than 90% of
patients with local recurrence in less than 1% (Livraghi 2008). In larger tumors five-year survival rates are somewhat lower, at 70-80% for nodules less than 3 cm in
diameter, and 50% for tumors between 3 and 5 cm (Lopez 2006). A cumulative
Diagnosis, Prognosis & Therapy of Hepatocellular Carcinoma 343
meta-analysis has suggested that survival is better after radio frequency ablation
than after ethanol injection (Cho 2009).
Adjuvant therapy, in the context of resection, liver transplantation or local-ablative procedures, does seem to offer additional benefits. Thus far, antiviral
treatment of hepatitis B with nucleos(t)ide analogs remains the single approved
treatment after removal or local destruction of HCC.
Tumor recurrence is frequent after putatively curative treatment of HCC. The
best predictors of HCC recurrence are microvascular invasion and/or additional
tumor sites besides the primary lesion. There is no effective adjuvant therapy to
reduce recurrence rates. However, it is noteworthy that even the most modern CT
and MRT scanner still underestimate the extent of vascular invasion in 30% of
patients with early HCC. Treatment of recurrence is a poorly studied area. Solitary
nodules might be amenable to repeat resection, but HCC recurrence is frequently
multifocal owing to intrahepatic dissemination of the tumor. Some patients with
HCC recurrence after primary resection might benefit from salvage transplantation.
Palliative therapy in BCLC stages B and C
Palliative treatment remains the only therapeutic option for patients with advanced
stages of liver cancer that cannot be controlled by local therapy.
Arterial chemoembolisation is the most frequent palliative intervention offered
to patients with HCC and is considered for patients with non-surgical HCC that are
also not suited for percutaneous ablation and do not have extrahepatic tumor spread.
HCC exhibits intense neoangiogenic activity, so that even well-differentiated HCCs
become highly dependent on arterial blood supply. Thus, hepatic arterial obstruction
is performed either by angiographic transarterial embolisation or transarterial
chemoembolisation. Usually lipiodol combined with an embolising agent such as
gelatin or microspheres is mixed with cytostatic drugs and applied to the liver via an
intra-arterial catheter. Suitable cytotoxic agents are doxorubicin, mitomycin and cis-platinum, but the optimal combination of drugs and treatment schedules has not
been established. In randomised studies demonstrating a benefit of
chemoembolisation, doxorubicin or cis-platinum were administered in 3-4
angiographic sessions per year. Chemoembolisation carries the risk of ischemic
damage to the liver, potentially leading to fulminant liver failure. To minimize this
risk chemoembolisation should be offered only to patients with good residual
hepatic function, who have asymptomatic multi-nodular liver cancer without
vascular invasion or extrahepatic tumor spread. Vice versa patients with
decompensated liver disease (liver cirrhosis, Child’s B or C) or imminent hepatic
failure should not undergo chemoembolisation. The side effects of interarterial
chemoembolisation are the same as for systemic chemotherapy and comprise
nausea, vomiting, bone marrow depression, alopecia and renal damage. As a
complication of hepatic ischemia, more than 50% of patients also develop a so-called post-embolisation syndrome with fever, abdominal pain and a moderate
degree of ileus. Fasting and fluid replacement is mandatory, but the post-embolisation syndrome is usually self-limited and patients can be discharged safely
after 2 days.
Objective response rates vary between 16% and 60%, but less than 2% of patients
achieve complete remission. Residual tumor cells recover their blood supply and the
tumors continue to grow. Thus, repeated therapy is needed.
344 Hepatology 2012
Chemoembolisation is currently the only palliative treatment demonstrated to
significantly improve patient survival in controlled studies (Llovet 2002). However,
it cannot be offered to patients with portal vein thrombosis or HCC-induced portal
vein occlusion.
Radiotherapy applyingYttrium-90 microspheres has been developed as a
novel alternative palliative treatment of liver cancer with unexpectedly impressive
anti-tumoral activity in selected individual cases (Sangro 2006, Jacobs 2007, Salem
2006, Liu 2004). Of note, unlike chemoembolisation, some types of microspheres
do not occlude the blood vessels and can also be applied in the presence of portal
vein thrombosis. Radioembolisation has been shown to induce tumor necrosis.
However, there are no data comparing its efficacy to other palliative treatment
modalities.
Molecular-targeted therapeutic strategies offer new hope for effective
palliative therapy in liver cancer. Sorafenib (Nexavar®) is an orally available multi-kinase inhibitor acting on several distinct tyrosine kinases (VEGFR2, PDGFR, c-kit
receptor) as well on serine/threonine kinases (b-Raf and p38). Thus, by inhibiting
angiogenesis and cellular proliferation, sorafenib can block two of the major
signalling pathways of HCC expansion. In a Phase III study (the SHARP trial)
involving 602 patients, sorafenib 400 mg BID was well tolerated and associated
with improved survival in 44% of patients resulting in 3 months extended survival
in treated patients (10.7 months in the sorafenib arm versus 7.9 months in the
control arm). Diarrhea, weight loss, hand-foot syndrome and hypophosphatemia
were the most important side effects in patients on sorafenib. The efficacy of
sorafenib has been confirmed in a second randomized placebo-controlled trial,
mostly involving patients with HBV-associated HCC (Cheng 2009). Sorafenib has
established itself as first option in patients with HCC who can no longer be treated
with potentially more effective local therapies. The SHARP trial largely included
patients with preserved liver function. Although the pharmacologic profile is
favourable, data in Child-Pugh class B patients are scarce (Abou Alfa 2011). It has
been demonstrated that sorafenib can be safely combined with chemoembolisation
therapy (Pawlik 2011), although it remains unclear if this strategy actually offers
any clinical benefit to the patients. Finally, further antagonists targeting VEGFR,
EGFR, ERBB2, Akt/mTor or Wnt/β-catenin signal transmission pathways are
currently under evaluation in Phase II studies.
Systemic chemotherapy has been proven repeatedly not to offer survival
benefits, whether given as a single agent or as part of combination chemotherapy
(Llovet 2003). Likewise, anti-hormonal therapy with tamoxifen or octreotide has
not provided improved patient survival when studied under controlled conditions
(Gallo 2006, Yuen 2002).
Diagnosis, Prognosis & Therapy of Hepatocellular Carcinoma 345
Figure 2. Overview of stage-adapted therapy of liver cancer relative to the BLCL criteria.
Prophylaxis of liver cancer
Despite conspicuous progress concerning the diagnosis and therapy of HCC, its
prognosis has not improved very much over time. Thus, prophylactic measures are
of pivotal importance. Vaccination against HBV, as is now recommended by many
national vaccination councils, has been proven in Taiwan to markedly reduce HBV
infection rates along with the incidence of HCC as a complication of chronic
hepatitis B in later life (Lok 2004).
Patients with chronic HBV and patients with chronic hepatitis C should be offered
antiviral therapy as effective secondary prophylaxis of HCC. Although HBe-antigen-positive (van Zonneveld 2004) and HBe-antigen-negative patients with
chronic hepatitis B showed reduced incidence rates of HCC when successfully
treated with interferon (Papatheoridis 2001, Brunetto 2002, Lampertico 2003),
antiviral therapy with nucleos(t)side analogs seems to reduce the risk of HCC less
convincingly (Papatheoridis 2010, Papatheoridis 2011). Also several meta-analyses
suggest that successful interferon therapy will reduce the risk of HCC in chronic
hepatitis C (Camma 2001, Paptheoridis 2001a, Veldt 2004). However, patients who
have cirrhosis prior to starting antiviral therapy should be maintained on close HCC
surveillance programs, since the risk of developing liver cancer remains high in
these patients even after sustained virologic elimination is achieved (Yu 2006).
