appunti del dott. Claudio Italiano link in tema: cfr anche argomenti di epatologia
Hepatocellular
carcinoma or hepatocellular carcinoma is one of the most frequent neoplasia,
representing globally with about 560,000 new cases per year, the fifth most
frequent human neoplasm in the world. The incidence of this tumor varies
significantly according to the geographic areas considered, reaching the maximum
value in the areas of sub-Saharan Africa and the Far East. The marked
geographical variability of hepato-cell carcinoma is related to the variable
prevalence of environmental risk factors that play a critical role in hepatic
carcinogenesis. In particular, the incidence in the various countries of the
world almost faithfully reflects the incidence in the same countries of chronic
infection of the hepatitis B virus (HBV). In fact, more than 85% of cases of
hepatocellular carcinoma develop in countries with a high prevalence of chronic
HBV infection, such as China, Japan, countries of Southeast Asia and sub-Saharan
Africa. In Europe, Greece and Italy represent the countries with the highest
incidence and in particular in southern Italy, the incidence of hepatocellular
carcinoma reaches values among the highest in the western world in relation
especially to high incidence of chronic HBV and HCV infections. For reasons that
are still unclear, male sex, especially in high-incidence areas, is more
frequently affected by the female sex, to the extent of 3: 1. The variability of
the incidence of chronic HBV infection and its mode of transmission also appear
to be responsible for some clinical-pathological differences that can be
observed in this neoplasm in the various geographical areas considered. In fact,
while in countries with a high incidence of chronic HBV infection and with
mother-child vertical transmission of the virus, hepatocellular carcinoma
develops frequently in non-cirrhotic livers, often in relatively young subjects
between 20 and 40 years of age, in Western countries with low prevalence of HBV
infection and prevalently horizontal virus transmission, carcinoma occurs in
about 80-90% of cases in cirrhotic livers and / or with advanced chronic liver
disease and rarely before 60 years of age . In the last two decades, the
incidence seems to show a notable increase especially in countries such as Great
Britain, Japan and North America, this phenomenon probably connected to the
increase in chronic HCV cirrhosis. However, the noticeable recent advances in
diagnostic imaging techniques and the increase in the average life expectancy of
the cirrhotic patient are likely to contribute decisively to the increased
incidence of hepatocellular carcinoma in more developed countries.
Hepatocellular carcinoma also recognizes, as in most neoplasms, a
multifactorial etiology. The main etiological factors that play a role of
primary importance in hepatic carcinogenesis are:
• viral infections from HBV and HCV;
• chronic alcoholism and food contaminants such as aflatoxin B1;
• hereditary diseases, such as hemochromatosis, tyrosinemia and
alpha1-antitrypsin deficiency.
We have already said that the incidence of hepatocellular carcinoma in the
world reflects in a very faithful way the geographical distribution of chronic
HBV infection. This association has been proven in numerous case-control studies,
in prospective clinical trials and in laboratory studies susceptible to HBV-like
virus infection. HBV acts as a potent oncogenic virus through two fundamental
mechanisms. of action: 1) the development of a chronic hepatitis that, with
repeated cycles of necrosis and hepatocyte generation, leads to the
establishment of a cirrhosis that, regardless of the etiology that spreads it,
represents in itself a pre-nasal condition; 2) a direct oncogenic effect by
integrating the HBV virus into the host DNA. The HBV virus is in fact a DNA
virus that by means of "reverse transcription" mechanisms common to many other
oncogenic viruses (eg RNA type retrovirus) can integrate its DNA into the genome
of the host cell, giving rise to a series of mutations of genes that control,
for example, the repair mechanisms of DNA or the activation of proto-oncogenes.
In particular, the protein of 154 amino acids encoded by the "X" gene of HBV
DNA, seems to play an important oncogenic role especially for the ability to
interact with oncogenes and growth factors such as c-fos, c-jun, c-myc or genes
suppressors like p53.
It should be noted that these two mechanisms of oncogenic action of HBV are not
mutually exclusive; on the contrary, it is reasonable to assume that the
continuous turn-over hepatocyte appears to be more susceptible to the direct
oncogenic action of the virus.
The hepatitis C virus is another hepatitis virus closely related to the onset of e-patocarcinoma. The majority of hepato-cell carcinomas in patients with chronic HCV hepatitis arise on cirrhosis. A direct oncogenic effect of HCV genes has not been shown yet. The "core" protein of HCV seems to be able to interact, altering them, with a series of intracellular "pathways" such as the activation of TNF-a receptor and NF-kb, which by inhibiting the cellular apoptotic mechanisms, can prolong the life of the infected cell, thus allowing the accumulation of genetic alterations favoring hepatic carcinogenesis.
In European countries and in North America, liver cirrhosis due to alcohol
abuse is the most frequent etiological factor for hepatocellular carcinoma
(32-45% of cases). Chronic alcohol intake greater than 80 grams per day for ten
years increases the risk of hepatocarcinoma by about 5 times. Although alcohol
may act as a potent inducer of the microsomal P-450 system, which is responsible
for the metabolic activation of various chemical carcinogens, a direct oncogenic
role of alcohol in hepatocarcinogenesis has not been demonstrated so far. A
particularly important role of alcohol in hepatocarcinogenesis also seems to be
represented by the synergistic effect with viral infections, in particular that
from HCV.
Aflatoxin B1 is a mycotoxin with a powerful oncogenic effect, produced by the
contamination of foods such as cereals, rice and peanuts by the fungus
Aspergilllus flavus, in countries with a warm and humid climate such as the
subtropical and South-East Asian countries.
Its carcinogenic effect occurs only in the presence of chronic HBV infection and
a mutation of codon 249 of the p53 suppressive gene.
Hepatocarcinoma that occurs in patients with hemochromatosis develops mainly
in cirrhotic liver with a relative risk about 93 times higher than in the
general population.
Type I. tyrosinemia
In the case of tyrosinemia the frequency of hepatocellular carcinoma is from 10
to 20% and also in this case occurs in cirrhotic liver. For this reason we
recommend transplantation within the second year of life.
 Yellow necrotic areas and reddish hemorrhagic areas, massive hepatocarcinoma, arrows |
Hepatocellular carcinoma is made up of cells that reproduce in a more or less faithful way the morphological aspect of normal hepatocytes. Like their normal counterparts, the neoplastic hepatocyte cells have a polygonal shape, a cytoplasm of eosinophilus, a very clear nucleolus and, in the most differentiated forms, can form biliary canaliculi and produce bile pigment.
 Trabecular pattern of HCC, under pseudo glandular |
 |
 Mixed form oh hepato-cholangiocarcinoma |
Sometimes the cytoplasm may contain lipid droplets, Mallory bodies, eosinophilic globular inclusions or significant amounts of glycogen which imparts a clear appearance in routine staining with hematoxylin-eosin. Neoplastic cells tend to aggregate forming distinct growth patterns, of which the most common are:
• trabecular, in which the cellular component forms cords and hepatocytes of variable thickness (usually more than 2-3-hepatocytes), separated by type-sinusoidal vascular spaces and covered by endothelial cells. Trabecular aspect of HCC, under pseudoglandular aspect Mixed form of hepatocolangiocarcinoma These vascular spaces represent "capillarized" liver sinusoids containing reduced amounts of reticulin fibers. The connective component in hepatocellular carcinoma is characteristically poorly represented;
• pseudo glandular or acinar, in which the dilation of the bile canaliculi can impart a frankly glandular aspect to the neoplasm; impact or solid, in which the type-sinusoidal vascular spaces are compressed and no longer visible;
• rather rare scirrose, in which there is a remarkable desmoplastic reaction around the neoplastic hepatocyte trabeculae. It is important to underline that not infrequently, in different areas of the same tumor, it is possible to observe different microscopic patterns as well as different degrees of cytological differentiation of the neoplasia (from well differentiated to undifferentiated). Histological varieties have no relation to the prognosis. In most cases, infiltration and / or neoplastic thrombosis of the portal vein and its branches (about 75% of cases) and hepatic veins (about 25% of cases) are observed. Hepatocellular carcinoma cells may secrete a-fetoprotein (AFP), a tissue-detectable oncophetal antigen using immunohistochemical techniques in 17-68% of cases.
Mixed form of hepato-cholangiocarcinoma. About 1-5% of hepatocellular
carcinomas show a glandular component of cholangiocarcinoma type, with
production of mucin and immunophenotypical characteristics of biliary type (positivity
for cytokeratin 7 and 19). A part of these tumors can certainly represent forms
of "collision" between a hepatocellular carcinoma and a cholangiocarcinoma, but
for many other tumors it is hypothesized that it originated from a common
hepatic stem cell located in the Hering canals. The clinical features appear to
be the same as the classical form of hepatocellular carcinoma.
Fibrolamellar carcinoma. This variant usually occurs in the non-cirrhotic liver of young adults and without known risk factors. Morphologically it is characterized by the presence of dense collagenous bundles with lamellar appearance that intersect and separate the neoplastic cells only very well differentiated and with strongly eosinophilic cytoplasm due to the presence of numerous mitochondria. The prognosis of this form is usually more favorable than the classical form of hepatocarcinoma.
Hepatocellular carcinoma despite a marked tendency to multiple intrahepatic metastases, tends to metastasize at a distance only in the most advanced stages of the disease. Extrahepatic metastases, present up to about 60% of cases in autoptic cases, occur mainly by hematogenous route and mainly affect the lungs, adrenal glands and bones. Lymphatic metastases are more rare and mainly involve regional lymph nodes. Clinical aspects. In Western countries, hepatocellular carcinoma develops in the vast majority of cases in patients with advanced chronic disease typically cirrhotic. Therefore a hepatocellular carcinoma should be suspected in a cirrhotic patient with rapid deterioration of the general conditions, pain in the upper right quadrant or with a palpable hepatic mass. However, it should be emphasized that if one or more of the above symptoms are present, it is generally in the presence of an already advanced disease. Together with the ultrasound investigation, the serological determination of AFP (see 10-20 ng / ml) plays an important role in the screening of hepatocellular carcinoma. High AFP values (> 200 ng / ml) are found in 50-75% of cases.
 Chemoembolizzation of HCC |
The production of AFP is correlated in part with the size
of the tumor. In fact, about 66% of hepatocellular carcinomas smaller than 4 cm
show AFP values lower than 200 ng / ml. Finally, high values of this protein
are not specific for hepatocellular carcinoma, as they can be observed in
various non-neoplastic diseases, such as chronic cirrhotic hepatitis or spina
bifida, and tumors such as the yolk sac tumor (yolk sac tumor). ) or
adenocarcinoma with hepatoid differentiation. In cirrhotic patients, regular
monitoring with ultrasound allows to highlight "small" hepato-carcinomas (small
HCC), susceptible to local treatment (chemoembolization, thermal ablation,
radio-ablation). Hepatocellular carcinoma despite considerable efforts for its
early detection continues to have an unfavorable prognosis. The prognosis
depends mainly on the stage of the neoplasia, on the clinical stage of chronic
hepatopathy that usually underlies the hepatocarcinoma and, ultimately, on the
modality of therapeutic treatment that can be performed. In conclusion,
hepatocellular carcinoma, despite the efforts made for its identification in the
early phase and the multiple treatment modalities, continues to be the third
cause in the world of death due to neoplasia. However, it is a tumor that allows
an excellent strategy for primary prevention aimed at reducing viral
transmission through capillary vaccination campaigns for HBV and avoiding
excessive consumption of alcohol.
cfr anche index topics on the liver