Carcinogenesis vol.29 no.7 pp.1299–1305, 2008
doi:10.1093/carcin/bgn113
Advance Access publication May 29, 2008
REVIEW
Recent advances in the natural history of hepatocellular carcinoma
F.Trevisani, M.C.Cantarini, J.R.Wands1 and M.Bernardi
Dipartimento di Medicina Clinica, Università di Bologna, via Albertoni 15,
40138 Bologna, Italy and 1Liver Research Center, Rhode Island Hospital,
The Warren Alpert Medical School of Brown University, 55 Claverick Street,
4th floor, Providence, RI 02903, USA
To whom correspondence should be addressed. Dipartimento di Medicina
Clinica, Unità di Semeiotica Medica, via Albertoni 15, 40138 Bologna, Italy.
Tel: þ39 051 636 2923;
Fax: þ39 051 636 2930;
Email: [email protected]
Ongoing advances in liver disease management and basic research in recent years have changed our knowledge of the natural
history of hepatocellular carcinoma (HCC). Indeed, the natural
history of this tumor is fairly long and covers a preclinical and
a clinical phase. Some of the biological steps involved in cell transformation and different carcinogenic pathways have been identified, disclosing potential novel markers for HCC. Following the
progress in surveillance and early diagnosis, much more is now
known about precancerous lesions and the process leading to
overt HCC, including growth patterns, dedifferentiation and neoangiogenenesis. In particular, research has focused on clinical and
biological factors predicting tumor aggressiveness and patients’
prognosis. Lastly, clinical studies have described tumor presentation, evolution and causes of patients’ death and how the new
knowledge has influenced clinical management and patients’ survival in recent years. By addressing 10 key questions, this review
will summarize well-established and novel features of the natural
history of HCC.
Introduction
Hepatocellular carcinoma (HCC) is one of the commonest malignancies with .500 000 new tumors diagnosed annually (1). HCC usually
arises in the setting of chronic liver diseases, mostly related to viral
hepatitis B and C. Its incidence varies widely among the different
geographic areas (from 2 to almost 50 per 100 000 males/year), reaching peak values in Southeast Asia and sub-Saharan Africa, where
hepatitis B virus (HBV) infection is endemic. Nonetheless, the
HCC incidence has been increasing in Western countries in recent
years due to the spread of hepatitis C virus (HCV) infection in the
1960s and 1970s (2). The ‘natural history’ of a disease refers to its
course from the biological changes marking disease onset to the patient’s
death. Ongoing advances in liver disease research have added new
elements to our knowledge of the natural history of HCC. By addressing 10 key questions, this review will summarize well-established and
novel features of the topic.
Question 1: what is the natural history of HCC, and has it changed in
the last few decades?
Previously, HCC was invariably diagnosed at a late stage with the
development of clinical symptoms and was subsequently characterized by a rapidly fatal course. Following major advances in diagnostic
techniques and the establishment of surveillance programs, early tumors have been increasingly detected, leading to an important
advance in our understanding of the natural history of HCC.
Moreover, examination of liver removed from patients undergoing
Abbreviations: AFP, alfa-fetoprotein; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HGDN, high-grade dysplastic
nodule; IGF, insulin-like growth factor; MRN, macroregenerative nodule.
transplantation has provided the opportunity to identify and analyze
precancerous lesions and minute tumors. Lastly, progress in molecular biology has defined some of the biological steps involved in cell
transformation and different carcinogenic pathways leading to overt
HCC. As a result, we now know that the natural history of HCC is
fairly long and can be split into three distinct phases: (i) ‘molecular’;
(ii) ‘preclinical’ and (iii) ‘clinical or symptomatic’ (Figure 1).
The molecular phase includes the sequential genomic alterations
leading to cell transformation. It has been postulated that the transformed cell can be either a hepatocyte/biliary epithelial or a liver stem
cell (3). The genetic alterations involving differentiated cells (hepatocytes and biliocytes) are thought to confer a growth advantage by
promoting proliferation and inhibiting apoptosis, whereas those involving stem cells interfere with the differentiation process. In human
carcinogenesis, the time to acquire these genetic changes is unknown.
The preclinical phase covers an initial period, in which the tumor is
still too small to be detected by imaging techniques, and a second
period (‘preclinical diagnostic’ phase), during which the tumor is
detectable but still asymptomatic.
Finally, the clinical or symptomatic phase starts with the occurrence of symptoms caused by the tumor burden: in patients with
chronic liver disease, HCC usually becomes symptomatic when it
reaches 4.5–8 cm (4,5).
Retrospective cohort studies focused on HCV-infected patients suggest that the development of HCC requires 10 years from the diagnosis of cirrhosis and 30 years from exposure to HCV (6). The
temporal sequence has not been defined for the other main risk factors, but a similar time course may be applicable to alcoholic liver
disease. Conversely, the time course of HBV-related carcinogenesis is
less predictable since HCC may precede the occurrence of cirrhosis,
particularly with chronic HBV infection in endemic areas (7).
Question 2: what is the sequence of mutations leading to hepatic
transformation?
During the ‘preneoplastic’ phase (chronic hepatitis and cirrhosis),
genetic alterations are almost entirely ‘quantitative’, occurring by
epigenetic mechanisms without changes in the structure of genes. In
this phase, hepatocytes undergo an intense mitogenic stimulation due
to exposure to elevated levels of growth factors [such as insulin-like
growth factor (IGF)-2 and transforming growth factor-a] as well as
inflammatory cytokines, which may lead to activation of the major
signaling pathways involved in cell proliferation. The enhanced expression of growth factors and cytokines is driven by inflammation,
the action of viral proteins and regenerative response to cell loss. The
mechanisms whereby these factors affect gene expression include cisand trans-activation and altered chromatin methylation and acetylation, with consequent activation or inactivation of gene promoters (8).
Moreover, viral proteins, such as the protein X (HBX) produced by
HBV, can directly stimulate the major cytosolic kinase signaling
cascades (9–11).
Hepatocyte proliferation rate, telomere shortening and telomerase
reexpression progressively increase from the preneoplastic phase to
dysplasia and HCC (8).
‘Structural’ alterations of genes slowly develop during the preneoplastic phase and significantly increase in dysplastic and neoplastic
hepatocytes. They can result from multiple mechanisms: (i) HBV is
directly mutagenic following integration of the viral genome or fragments into the cellular DNA; (ii) molecular products of both HBV
(HBX) and HCV (core, NS5A and NS3) may impair the function of
the tumor suppressor p53 and retinoblastoma genes, and alter the
efficiency of enzymes involved in gene repair and stability (8,12);
(iii) erosion of telomere length in highly replicative cells results in
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chromosome disruption and mitotic alteration; (iv) oxidative DNA
damage may occur in the setting of chronic inflammation (8,11).
Finally, HBV genotoxicity is enhanced by exposure to aflatoxin B,
a contaminating mycotoxin found in food in certain regions of the
world (13).
Genomic alterations in HCC are very heterogeneous, suggesting
that the neoplastic phenotype can result from different ‘genomic
routes’. Indeed, multiple genes and loci alterations have been documented in HCC cells but any single aberration has a low prevalence in
tumors (8). Nonetheless, recurring genomic losses or gains on some
chromosome arms have been documented (losses: 1p, 4q, 5q, 6q, 8p,
9p, 13q, 16p, 16q and 17p; gains: 1p, 6p, 7q, 8q and 17q); some of the
loci affected by the recurrent chromosome losses contain well-known
tumor suppressor genes, such as p53 on 17p, retinoblastoma on 13q,
axin1 on 16p, Cdkn2A (p16INK4) on 9p and IGF-2-receptor on 6q,
which often undergo allelic deletion (8,10,13,14). In addition, gains
may involve certain oncogenes, such as c-myc which is contained in
a chromosomal region frequently amplified in HCC (8,10,13).
As a result, many genetic and epigenetic aberrations and the corresponding alterations in molecular pathways have been found during
hepatocarcinogenesis: (i) inactivation of the tumor suppressor gene
p53 through gene mutation and posttranscriptional interaction with viral
proteins (10,11,13,14); (ii) activation of the Wnt/Frizzled/b-catenin
pathway through mutations in b-catenin or in other components of
its destruction complex (glycogen synthase kinase-b/adenomatous
polyposis coli protein/axin) as well as through upregulation of
upstream elements such as Frizzled receptors (9,10,13,14); (iii) alteration of the tumor suppressor retinoblastoma and p16INK4 genes
through mutations or promoter methylation (10,13,14); (iv) alteration
of the IGFs/IRS/MAPK signaling pathway through IGFs overexpression, IRS overexpression (9) and, probably, IGF-2 receptor mutations
(10,13) and (v) alteration of the transforming growth factor-b pathway
(10,13). More recently, activation of phosphatidyinositol 3-kinase/
AKT pathway and activation of the janus kinase/signal transducer
and activator of transcription pathway through aberrant methylation
of suppressor of cytokine signaling genes have been also identified
(10,13). Moreover, upregulation of genes involved in angiogenesis,
such as vascular endothelial growth factor, and genes in cell dissemination and metastases, such as matrix metalloproteinases, have been
shown to play a role in hepatocarcinogenesis (14).
Finally, the recent microarray techniques have identified the ‘genetic profiles’ that reflect progression from preneoplastic lesions to
Fig. 1. The natural history of HCC can be divided into three distinct phases:
(i) molecular, (ii) preclinical and (iii) clinical or symptomatic. The
preclinical phase covers an initial period, in which the tumor is too small to
be detected by imaging techniques, and a second period (preclinical
diagnostic phase), during which the tumor is detectable but still
asymptomatic. Finally, the clinical or symptomatic phase starts with the
occurrence of symptoms caused by the tumor burdens. In patients with
chronic liver disease, HCC usually becomes symptomatic when it reaches
4.5–8 cm.
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early and advanced HCC (15): many genes were differentially expressed at each stage of the disease, some of which may be potential
novel markers for HCC. In particular, the development of HCC is
associated with changes in the expression of gene regulating the immune response in the early stages, whereas an upregulation of genes
controlling DNA replication and cell cycle can be found in the late
stages of disease.
Question 3: what are the histological ‘precancerous’ lesions in
hepatocarcinogenesis?
Cirrhosis is the substrate of HCC in 80–90% of cases. In this setting,
HCC can develop inside macroregenerative nodules (MRNs). This
type of carcinogenesis is called ‘nodule in nodule’ (Figure 2) (16).
The MRNs are detectable in 25% of cirrhotic livers as nodules macroscopically distinguishable from the surrounding liver in terms of
color, size (diameter .0.5 cm, usually 1–2 cm) and tissue texture
(17). The histological structure resembles that of cirrhotic nodules,
although increased cell proliferation is common. The MRN may present as polyclonal or monoclonal lesions at molecular analysis and
with various degrees of atypia/dysplasia (17,18). Although they generally appear hypoechoic on ultrasonography, a hyperechoic aspect
may be observed due to diffuse fatty change (19,20). The hyperechoic
pattern is more frequent in high-grade dysplastic nodules (HGDNs)
(19). Finally, the lack of a florid neoangiogenesis process makes most
of these lesions hypovascular (21,22).
According to the degree of cellular and structural atypia, MRN can
be classified as large regenerative nodules without dysplasia, lowgrade dysplastic nodules and HGDNs (17). The risk of progression
to HCC increases along with the degree of dysplasia. During a mean
follow-up of 33 months, Borzio et al. (20) observed a transformation
rate toward HCC in 22% of large regenerative nodule, 25% of lowgrade dysplastic nodule and 63% of HGDN. Nonetheless, 15% of the
MRN disappeared during follow-up (87% of whom were large regenerative nodule/low-grade dysplastic nodule). Another feature suggesting the commitment to neoplastic transformation is monoclonality (18).
HGDN may be difficult to distinguish from well-differentiated HCC,
particularly from the so-called ‘indistinctly nodular’ type of HCC
(see below). Japanese pathologists view ‘stromal invasion’, i.e. hepatocyte invasion of portal tracts inside the nodules, as the hallmark of
HCC (23).
Fig. 2. HCC can develop inside MRNs. This type of carcinogenesis is called
nodule in nodule. However, most HCCs develop outside MRNs, and
precancerous lesions can be identified in areas of large and small cell
dysplasia or irregular regeneration (de novo carcinogenesis). (The
histological images, stained with hematoxylin–eosin, have been kindly
provided by Prof. W.F.Grigioni and Prof. A.D’Errico, Alma Mater
Studiorum,University of Bologna).
Natural history of hepatocellular carcinoma
However, most HCCs develop outside MRNs, and precancerous
lesions can be identified in areas of large and small cell dysplasia
(24) or irregular regeneration (25) (de novo carcinogenesis) (Figure 2).
Question 4: what are the morphological features of HCC at the early
phases of its detectability, and how do they change over time?
Nodularity and growth type. HCC usually arises as a single nodule in
most patients with chronic liver diseases. Japanese authors have subclassified minute HCCs (up to 2 cm in diameter) as ‘indistinctly’ and
‘distinctly’ nodular due to this macroscopic feature (16). Indeed, indistinctly nodular HCCs are well-detectable nodular lesions on ultrasonography but appear rather indistinct at surgical examination, their
texture being similar to the surrounding cirrhotic tissue. Histologically, they are very well-differentiated tumors containing portal tracts
and bile ducts, with a ‘replacing’ type of growth and a scarce arterial
vasculature leading to a hypovascular imaging pattern. By contrast,
distinctly nodular HCCs are usually easily identifiable even at surgical
inspection. Pressure on the surrounding liver caused by an ‘expansive’
type of growth of the tumor promotes collagen deposition in the
stromal reticulum and its thickening, leading to the formation of
a fibrous pseudocapsule around the tumor. These nodules are moderately differentiated, hypervascular and frequently disclose a microvascular portal invasion (up to 22%) (16). Since the histological features
of indistinctly nodular HCCs suggest a lower degree of malignancy,
a better course may be anticipated. Although a comparison of the
natural history of these two types of tiny HCCs is unavailable, this
assumption is supported by their outcome after curative resection. The
‘less malignant’ nodules recur later, less often, never locally and with
fewer multiple recurrences, so that the 5-year rates of both overall
survival (93%) and recurrence-free survival (47%) are much better
than those of patients bearing minute but ‘overtly malignant’ HCCs
(54 and 16%, respectively) (26). Therefore, the indistinctly nodular
HCC marks a very initial stage of carcinogenesis as far as both the
index lesion and the surrounding liver are concerned.
As the tumor further enlarges, it can maintain an expansive growth
or assume an infiltrative pattern characterized by the wedging of
malignant cells into sinusoids and cellular trabecula of the surrounding tissue, making the tumor boundary ill defined.
More than one-third of HCCs appear as multiple nodules (5,27).
Multinodularity may result from either intrahepatic metastases from
a primary focus or the occurrence of synchronous tumors. Synchronous tumors occur more frequently in chronic HBV infection, accounting for half of the multinodular cases (28). In a few patients
(5%), HCC appears as an infiltrative tumor (5). Again, HBV infection (alone or in combination with HCV infection) seems to be
a risk factor for the development of infiltrative HCC (29).
Grade of differentiation. The grade of differentiation tends to be
correlated with the tumor size in HCCs characterized by expansive
growth (30). Although this phenomenon cannot be considered a hard
and fast rule (see previous paragraph), tumors ,2 cm are generally
well differentiated and, over time, the original neoplastic tissue is
replaced by moderately to poorly differentiated cell clones because
of the sequential accumulation of genomic mutations.
Vasculature. Along with its growth and loss of differentiation, HCC
blood supply becomes more and more dependent on newly formed
arterial vessels (tumoral neoangiogenesis) and proportionally less dependent on the portal contribution. In parallel, sinusoid-like blood
spaces go through a process of capillarization. This progressive imbalance between arterial and portal blood supply is responsible for the
hypervascular pattern that characterizes HCC using enhanced imaging techniques (Figure 3) and represents the rationale for the use of
transarterial chemoembolization in clinical practice and antiangiogenetic agents in experimental studies to control tumor growth (31).
Microvascular invasion. The risk of microvascular invasion in HCC
with expansive growth increases with tumor size and dedifferentia-
Fig. 3. (A) The grade of differentiation tends to be correlated with the tumor
size in HCCs characterized by expansive growth. Along with its growth and
loss of differentiation, HCC blood supply becomes more and more dependent
on newly formed arterial vessels (tumoral neoangiogenesis) and
proportionally less dependent on portal contribution. (B) The progressive
imbalance between arterial and portal blood supply is responsible for the
pattern characterizing HCC at enhanced imaging techniques: hypervascular
in the arterial phase and hypovascular in the portal phase. Typical images of
monofocal HCC at contrast enhanced ultrasonography (top) and computed
tomography scan (bottom) are reported.
tion. However, among tumors 2 cm microvascular invasion is detectable in 20% of cases (32,33). Considering the indistinctly and
distinctly nodular HCC ,2 cm, portal microinvasion is found in
2 and 22%, respectively (16).
Question 5: how fast do tumors grow?
The mean volume doubling time of small (,5 cm) HCCs ranges from
112 to 204 days; the interindividual variability of tumor growth is also
very high, the individual doubling time ranging from 30 to 600 days
(34–38). The tumor growth may be linear (constant over time) or
hyperbolic (initially slow then increasing) or parabolic (declining over
time) (37).
To describe the risk of HCC progression in patients listed for liver
transplantation, Cheng et al. (39) assumed that small HCCs may have
either a Gompertzian type of growth, in which the initial exponential
growth decreases as tumor size increases, or a rapid exponential
growth. According to the Gompertzian model and a mean volume
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doubling time of 204 ± 132 days, a tumor 1 cm in diameter takes
150 months (confidence interval 95%: 53–248) to grow beyond 5 cm
of diameter. According to the model of rapid exponential growth, the
same nodule takes a median time of only 48 months (confidence interval 95%: 17–79) to grow beyond 5 cm. By expanding these figures
into the prediagnostic phase (Figure 1), some HCCs would take years
to reach dimensions allowing their detectability (1–2 cm), whereas
others can appear a few months after a previous negative imaging
procedure.
Question 6: what are the factors predicting tumor growth and
aggressiveness?
Both tumoral and extratumoral factors determine the growth rate and
biological aggressiveness of HCC. Although not invariably (37), faster growth rate signifies a worse prognosis and tendency to relapse
after surgical resection (36,40).
Tumoral factors. Grade of differentiation and histological type. The
universally accepted criteria to classify HCCs, encompassing four
degrees of cellular dysplasia and architectural tissue disarrangement,
were proposed by Edmondson et al. in 1954 (41). There is clear
evidence that the less differentiated the tumor is, the faster its growth
and the higher the risk of vascular invasion and metastases (32,37,42).
The trabecular type HCC is associated with longer volume doubling
time (37).
Growth type. With an expanding growth, the pressure of tumoral
mass on the surrounding liver promotes the formation of a fibrous
pseudocapsule. If the capsule is either absent or discontinuous, tumor
cells may spread among non-tumoral liver cells and along sinusoids
(infiltrative growth). A peritumoral capsule heralds a better prognosis
after hepatic resection (43).
Neoangiogenesis. Tumoral neoangiogenesis is a key process and
appears to be a marker of aggressive tumor growth. Microvessel density predicts relapse after tumor resection (44) and biomolecular indicators of neoangiogenesis also have a prognostic meaning (see
below).
Serum alfa-fetoprotein. Alfa-fetoprotein (AFP) is a fetal glycoprotein whose circulating level quickly decreases after birth to ,10 ng/ml.
About 30–70% of HCCs produce AFP causing an elevation in plasma
levels; in 50% of these cases, AFP levels are directly proportional to
cancer size (35). Moreover, AFP levels tend to parallel the tumor
volume doubling time (34). An elevated AFP is an established predictor of recurrence after resection (45) and reflects a poor prognosis
(5,46). A fucosylated variant of AFP, the so-called Lens culinaris
agglutinin A-reactive AFP, correlates with cancer infiltrative growth,
vascular invasion, low-grade differentiation, multiple cancer recurrence and poor prognosis (47,48). Although Lens culinaris agglutinin
A-reactive AFP is assumed to be a more specific marker of HCC than
total AFP, its advantage in clinical practice awaits further confirmation.
Biomolecular markers. Following the advances in molecular biology,
increasing efforts have been made to identify biomolecular predictors of
tumor aggressiveness, as recently revised by Mann et al. (49).
Enhanced expression of ‘markers of proliferation’, such as proliferating cell nuclear antigen, Ki67, and ‘positive cell-cycle regulators’,
including a variety of cyclins and cyclin-dependent kinases, have been
found to predict relapse of HCC after resection and influence patients’
survival (49,50). Similarly, reduced expression of ‘cell-cycle inhibitors’, such as p27, is an independent predictor of poor prognosis (49).
Mutation of ‘proapoptotic’ genes, such as p53, is associated with
a decreased survival (49). Enhanced activity of ‘apoptosis inhibitors’,
such as BCL-xL, survivin and the recently identified PTMA and SET
(which are involved in the caspase-dependent and caspase-independent
apoptotic pathways, respectively), is related to HCC progression and
indicate a poor prognosis (49,50).
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Enhanced ‘telomerase activity’ predicts recurrence after hepatic
resection (49). Among the ‘adhesion molecules’ studied, reduced expression of E-caderin predicts a poor prognosis, whereas the prognostic value of b-catenin expression and its cellular localization are
controversial (49).
Alterations of ‘hormonal receptors’, ‘growth factors and related
receptors’ may also be predictors of cancer aggressiveness. Namely,
activating mutations of estrogen receptors are associated with poor
prognosis (51), as well as the overexpression of the growth factors
c-myc, ras and hepatocyte growth factor or the receptors c-met and the
epidermal growth factor receptor family (49). Moreover, an overexpression of leptin receptors would predict a better survival (49), and
high levels of placenta growth factor would herald an early recurrence
of HCC after resection (52).
A variety of ‘matrix metalloproteinases’ and the ‘plasminogen activator system’ is involved in the process of metastasis and appear to
have prognostic value in HCC (49).
Another category of prognostic determinants is that of the angiogenetic regulators. Serum and/or tissue levels of vascular endothelial
growth factor are directly proportional to microvascular density and
correlate with the degree of cellular dedifferentiation (49). They would
herald tumor relapse with a poor prognosis, but this association has not
been confirmed by other studies (49). Enhanced expression of hypoxiainducible factor1a, the master regulator of hypoxia-induced gene expression, promoting neoangiogenesis, has been found in tumors with
poor prognosis and high recurrence rate after resection (49,50).
More recently, DNA microarray techniques, which analyze the simultaneous expression of multiple genes, have been used in an attempt
to identify survival subclasses; the low survival subclass included
tumors with a strong expression of cell proliferation and antiapoptosis
genes, higher expression of genes involved in ubiquitination (probably
responsible for selective degradation of critical proteins including cellcycle inhibitors), enhanced expression of histone variants (involved in
chromosome breaks response) and higher expression of hypoxiainducible factor1a (50). Finally, a new subtype of HCC that shares
a gene expression pattern with fetal hepatoblasts has been recently
identified (53). This subtype probably arises from adult hepatic progenitor cells (hepatoblast subtype) and has a poorer prognosis compared with the hepatocyte subtype, which would derive from mature
hepatocytes (Figure 4). Differential expression of genes involved in
invasion and metastasis may account for the different prognosis in
the two subtypes.
The number of ‘genetic and karyotypic alterations’ is inversely
related to the degree of differentiation (13,49,54), and several authors
have observed a relation between poor prognosis and chromosomal
losses or gains. Chromosomal loss on 17p13.3 and gain on 8q11 as
well as the total number of genetic alterations and loss of 13q are
Fig. 4. Shared gene expression patterns between some HCCs and fetal
hepatoblasts suggest that a subtype of HCC (hepatoblast subtype) may arise
from bipotential adult hepatic progenitors cells, whereas the majority of
human HCCs (hepatocyte subtype) would derive from mature hepatocytes.
However, the expression profile of the hepatoblast HCC could also result
from a dedifferentiation process of transformed mature hepatocytes.
Individuals with the hepatoblast subtype have a worse prognosis than those
with the hepatocyte subtype.
Natural history of hepatocellular carcinoma
independent predictors of poor prognosis (49). Laurent-Puig et al.
(55) reported that chromosomal instability and mutation in p53 were
related to HBV infection, poorly differentiated tumors, and chromosome losses on 9p and 6q were specifically associated with a poor
prognosis. On the other hand, chromosomal stability and b-cateninactivating mutations were associated with 8p loss of heterozigosity
and non-HBV large-size HCCs (55). Other authors report more frequent b-catenin mutations in well-differentiated HCCs (49).
Extratumoral factors. Immune response. As for other tumors, the
natural history of HCC is influenced by the host immune response.
For example, the immune suppression of transplanted patients is associated with a very aggressive clinical course and high tendency to metastasize of recurrent or de novo tumors (56). Similarly, in patients with
HIV infection, HCC more frequently exhibits a multinodular pattern
with infiltrative growth and seems to have a worse prognosis (57).
Moreover, the density of lymphocyte infiltration in the nodule (58),
a surrogate marker of the antitumoral immune response, and the activation of the host natural killer cells (59) are inversely correlated with
biological aggressiveness and the risk of recurrence after resection of the
tumor. Finally, the relative predominance of negative immune modulator
CD4þ/CD25þ lymphocytes in the blood or peritumoral tissue seems to
be associated with both the risk and rapid progression of HCC (60).
Sex. Male sex is an established risk factor for HCC in patients with
chronic liver diseases (61), whereas gender influence on HCC progression and prognosis remains controversial. Some studies (5,62),
but not others (63,64), report a worse prognosis in males. Androgen
hormones have been claimed as responsible for the greater cancer risk
and grim prognosis (61).
Age. Although advanced age resulted as a negative prognostic factor in some patient series (65,66), there is no evidence that advanced
age per se is associated with a greater cancer aggressiveness. Confounding factors such as shorter life expectancy, higher prevalence of
comorbidities and less ‘aggressive’ therapeutic management could
explain the negative impact of age on prognosis. In fact, the adverse
effect of age disappeared when patients were segregated according to
the treatment received (65,66).
Viral etiology. HBV infection has been associated with a worse
prognosis, especially in patients bearing the estrogen receptor mutation and patients with advanced tumors (67,68). A greater aggressiveness of these tumors is thought to derive from the high chromosomal
instability caused by HBV (28).
Question 7: what is the presentation of HCC and its evolution in the
clinical phase?
The clinical presentation of HCC is mainly determined by the degree
of liver dysfunction and the tumor burden. The latter greatly depends
on the ‘timing’ of diagnosis. Differences involving these factors can
largely explain the geographical variability in clinical presentation,
whereas the ethnic diversity is probably of secondary importance.
In Western countries and Japan, with implementation of surveillance programs of high-risk patients, HCC is frequently diagnosed at
an early asymptomatic stage. In Italy, 45% of HCCs occurring in the
setting of chronic liver diseases are diagnosed under surveillance and
in the preclinical phase (5). More than 60% of HCCs diagnosed under
surveillance are non-advanced cancer, whereas this percentage drops
to about one-third for the HCCs detected outside surveillance (5). The
most common presenting symptoms and signs are hepatomegaly,
abdominal pain/discomfort, jaundice, ascites and constitutional
syndrome (fatigue, malaise, fever and weight loss) (42). Less commonly, digestive or peritoneal bleeding and hepatic encephalopathy
reveal the presence of HCC.
On the contrary, HCCs arising in a non-cirrhotic liver usually present as large solitary symptomatic masses, detected outside surveillance
programs. They exhibit a fast and infiltrative growth with frequent
vascular invasion and metastases (42). These clinical features are probably due to delayed diagnosis since these tumors, as compared with
HCCs occurring on cirrhotic livers, present a similar or lower grade of
cell dedifferentiation, a higher prevalence of peritumoral capsule formation and an equally or less frequent vascular invasion (42,69).
Size and number of tumoral nodules, invasion of the main vessels,
metastases, general performance status, AFP value and liver function
are the most important clinical variables that have been combined to
create prognostic systems and to drive therapeutic decisions (70).
However, the prognosis of ‘untreated’ HCC, which is the best representation of the natural history, is still largely undefined. Considering
the ‘early’ HCC, a study including 22 Eastern cirrhotic patients
(a third with advanced cirrhosis) bearing a tumor ,3 cm in diameter,
reported survival rates of 91, 55 and 13% at 1, 2 and 3 years, respectively (35). The corresponding survival rates in 39 Italian patients
with HCC ,5 cm (multifocal in 15 cases) were 81, 56 and 21% (37).
After stratifying patients according to the stage of cirrhosis, the 2 year
survival rate attained 82% in Child-Pugh A patients and was only 36%
in Child-Pugh B–C cases.
Considering ‘advanced’ HCC, in two studies including Caucasian
patients with unresectable tumors, survival rates at 1, 2, 3 and 5 years
were 54–72, 40–41, 28–38 and 20%, respectively (51,63). Survival
was much better in the absence of systemic symptoms, vascular invasion or metastases with respect to patients with at least one of the
three variables (at 3 years: 50 versus 8%) (63).
Although HCC may show an early microvascular invasion and tend
to infiltrate large vessels over time, extrahepatic metastases generally
appear in the late stage. Indeed, although about one-third of patients
with unresectable HCC present vein invasion at 3 years after diagnosis, only 22% develop metastases over this period (63). The most
common sites of metastases are lungs, followed by local lymph nodes,
bone and adrenal glands (42,69).
The most frequent clinical features of tumor progression include
ascites, hepatic encephalopathy, bacterial infections and digestive
bleeding. In addition, more than half of patients with unresectable
HCC and without pain at diagnosis will develop these symptoms in
the following 3 years (63).
In the ‘terminal stage’, characterized by a tumoral replacement exceeding 50% of the liver mass, vascular invasion and systemic symptoms, survival ranges from several weeks to a few months (46,63,71).
Question 8: what are the causes of death in HCC patients?
Cancer progression is the most frequent cause of death in HCC patients, both in those without chronic liver diseases, in whom it accounts for virtually all cases, and in cirrhotic patients (60% of
deaths). Other causes of death include liver failure (7–30%), digestive
bleeding (7–10%), infections (2%) and pulmonary embolism (1%)
(5,63,72). Intraperitoneal bleeding due to tumor rupture is uncommon
in Western countries.
Question 9: has the mortality rate for HCC changed in recent years?
A large retrospective population-based study, including .7000 unselected USA patients, showed that the 5 year survival rate remains
very poor (2% in the period 1977–1981 and 5% in 1992–1996) (73).
Similarly, in the different European regions, these figures were
0.9–4.9% in the early 1980s and 4.6–7.9% in the mid-1990s (74).
An advanced cancer stage at diagnosis and/or the frequent coexistence
of advanced cirrhosis precluding curative or effective treatments in
many patients are the reasons for such dismal figures. However, data
from population-based studies are much worse than those reported in
clinical investigations derived from referral centers. The discrepancy
can be explained not only by the selection bias affecting clinical
studies (including more patients with non-advanced tumors) but
also by the gap still separating the state-of-the-art management of
HCC—which is extremely complex—from the everyday practice,
where many patients are ‘undertreated’ or ‘overtreated’ (73).
Finally, there is evidence to suggest that the continuous refinement
of HCC treatment has a favorable impact even in centers dedicated to
this disease. A recent prospective study including 417 patients with
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F.Trevisani et al.
compensated cirrhosis maintained on regular surveillance demonstrated a sharp decline in the mortality over 15 years, mainly because
of the decrease in mortality of the treated patients (72). Therefore,
a general improvement in HCC prognosis is expected to occur in the
near future, due to the increasingly widespread implementation of
surveillance programs for high-risk patients and the application of
patient-tailored treatment (70).
Question 10: do the advances in the knowledge of the natural history
of HCC offer new perspectives for the management of HCC patients?
None of the human tumors has its natural history influenced by the
interaction of so many factors as HCC. In fact, such an interplay not
only involves the cancer cell biology and the host’s innate and specific
immune response but also different etiologies (hepatotropic viruses,
toxic agents and genetic conditions) and the very frequent coexistence
of liver cirrhosis. This unique condition accounts for the huge heterogeneity of molecular pathogenesis and biological aggressiveness of
HCC as well as the protean epidemiological and clinical features of
this neoplasm, such as the existence of well identifiable risk populations and precancerous conditions, its stringent dependence on the
development of cirrhosis, its variable period of clinical silence, its
non-specific presentation and the need for treatments tailored on both
tumor burden and severity of cirrhosis.
We think that our ‘Question–Answer’-based review has plainly
stated the case for an updated knowledge of the natural history of
HCC in order to decipher the heterogeneous and ever-changing clinical features of this cancer and to refine its management. Indeed,
a better understanding of the natural history achieved in the last two
decades has promoted practices able to improve the prognosis of HCC
patients. These include the implementation of surveillance programs
of risk patients aimed at diagnosing HCC at an early stage suitable for
radical treatments, a selection of the most appropriate treatment according to both tumor stage and hepatic function and a search for
agents selectively blocking growth factors or vital ‘molecular pathways’ of cancer cells and/or their vascular supply.
In the near future, further advances in the comprehension of pathogenesis and natural history of HCC—and the consequent positive
effects on its management—are expected from genomic and proteomic
research. Indeed, this is a very promising route to follow, as these
modern approaches may: (i) identify efficient tissue and serum markers
for the early diagnosis of the tumor; (ii) disclose gene signatures and
molecular profiles predicting the biological behavior of both HCC and
its histological precursors with much greater accuracy than that achievable at present; (iii) reveal specific molecular targets for the new pharmacological ‘bullets’ that are appearing in the armamentarium to battle
against HCC.
Acknowledgements
Conflict of Interest Statement: None declared.
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Received February 19, 2008; revised April 7, 2008; accepted April 30, 2008
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