Hepatocellular carcinoma (HCC, also called
malignant hepatoma) is a primary
malignancy (cancer) of the
liver. Most cases of HCC are secondary to either a
viral
hepatitide infection (
hepatitis B or
C) or
cirrhosis (
alcoholism being the most common cause of hepatic
cirrhosis). In countries where hepatitis is not
endemic, most
malignant cancers in the liver are not primary HCC
but
metastasis (spread) of cancer from
elsewhere in the body, e.g.,
the
colon. Treatment options of HCC and prognosis are dependent on
many factors but especially on
tumor size and
staging. Tumor grade is also
important. High-grade tumors will have a poor prognosis, while
low-grade tumors may go unnoticed for many years, as is the case in
many other organs, such as the breast, where a
ductal carcinoma in situ (or a
lobular carcinoma in situ)
may be present without any clinical signs and without correlate on
routine imaging tests, although in some occasions it may be
detected on more specialized imaging studies like MR mammography
(it should be stated, however, that the sensitivity of this
technique remains, even with current state-of-the-art technology,
below 50%).
The usual outcome is poor, because only 10 - 20% of hepatocellular
carcinomas can be removed completely using surgery. If the cancer
cannot be completely removed, the disease is usually deadly within
3 to 6 months. This is partially due to late presentation with
large tumours, but also the lack of medical expertise and
facilities. This is a rare tumor in the United States. A new
receptor tyrosine kinase
inhibitor,
sorafenib has been shown in a
Spanish phase III clinical trial to add two months to the lifespan
of late stage HCC patients with well preserved liver function
[(Child -Pugh A.)]
Signs and symptoms
HCC may present with
jaundice, bloating
from
ascites, easy bruising from blood
cloting abnormalies.
Cause
Hepatitis and excessive alcohol are the leading causes of
HCC.
Pathogenesis
Hepatocellular carcinoma, like any other cancer, develops when
there is a mutation to the cellular machinery that causes the cell
to replicate at a higher rate and/or results in the cell avoiding
apoptosis. In particular, chronic
infections of
hepatitis B and/or
C can aid the development of
hepatocellular carcinoma by repeatedly causing the body's own
immune system to attack the
liver cells,
some of which are infected by the virus, others merely bystanders.
While this constant cycle of damage followed by repair can lead to
mistakes during repair which in turn lead to carcinogenesis, this
hypothesis is more applicable, at present, to hepatitis C. Chronic
hepatitis C causes HCC through the stage of
cirrhosis. In chronic hepatitis B, however, the
integration of the viral genome into infected cells can directly
induce a non-cirrhotic liver to develop HCC. Alternatively,
repeated consumption of large amounts of
ethanol can have a similar effect. Besides,
cirrhosis is commonly caused by alcoholism,
chronic
hepatitis B and chronic
hepatitis C. The toxin
aflatoxin from certain
Aspergillus species of fungus is a
carcinogen and aids carcinogenesis of hepatocellular cancer by
building up in the liver.
The combined high prevalence of rates of
aflatoxin and hepatitis B in settings like China
and West Africa has led to relatively high rates of
heptatocellular carcinoma in these regions. Other viral
hepatitides such as
hepatitis A have no
potential to become a chronic infection and thus are not related to
hepatocellular carcinoma.
Diagnosis
Hepatocellular carcinoma (HCC) most commonly appears in a patient
with chronic viral hepatitis (hepatitis B or hepatitis C, 20%) or
with cirrhosis (about 80%). These patients commonly undergo
surveillance with
ultrasound
due to the cost-effectiveness.
In patients with a higher suspicion of HCC (such as rising
alpha-fetoprotein and
des-gamma carboxyprothrombin
levels), the best method of diagnosis involves a
CT scan of the abdomen using
intravenous contrast agent and
three-phase scanning (before contrast administration, immediately
after contrast administration, and again after a delay) to increase
the ability of the
radiologist to detect
small or subtle tumors. It is important to optimize the parameters
of the CT examination, because the underlying liver disease that
most HCC patients have can make the findings more difficult to
appreciate.
On CT, HCC can have three distinct patterns of growth:
- A single large tumor
- Multiple tumors
- Poorly defined tumor with an infiltrative growth pattern
A biopsy is not needed to confirm the diagnosis of HCC if certain
imaging criteria are met.
The key characteristics on CT are hypervascularity in the arterial
phase scans, washout or de-enhancement in the portal and delayed
phase studies, a pseudocapsule and a mosaic pattern.Both
calcifications and intralesional fat may be appreciated.
CT scans use contrast agents, which are typically iodine or barium
based. Some patients are allergic to one or both of these contrast
agents, most often iodine. Usually the allergic reaction is
manageable and not life threatening.
An alternative to a CT imaging study would be the MRI. MRI's are
more expensive and not as available because fewer facilities have
MRI machines. More important MRI are just beginning to be used in
tumor detection and fewer radiologists are skilled at finding
tumors with MRI studies when it is used as a screening device.
Mostly the radiologists are using MRIs to do a secondary study to
look at an area where a tumor has already been detected. MRI's also
use contrast agents. One of the best for showing details of liver
tumors is very new: iron oxide nano-particles appears to give
better results. The latter are absorbed by normal liver tissue, but
not tumors or scar tissue.
In a review article of the
screening,
diagnosis and
treatment of hepatocellular carcinoma, 4 articles
were selected for comparing the accuracy of CT and MRI in
diagnosing this
malignancy. Radiographic
diagnosis was verified against
post-transplantation
biopsy as the gold
standard. With the exception of one instance of
specificity, it was discovered that MRI was more
sensitive and
specific than CT in all four studies.
Pathology
Macroscopically, liver cancer appears as a nodular or infiltrative
tumor. The nodular type may be solitary (large mass) or multiple
(when developed as a complication of cirrhosis). Tumor nodules are
round to oval, grey or green (if the tumor produces bile), well
circumscribed but not encapsulated. The diffuse type is poorly
circumscribed and infiltrates the portal veins, or the hepatic
veins (rarely).
Microscopically, there are four architectural and cytological types
(patterns) of hepatocellular carcinoma:
fibrolamellar,
pseudoglandular (
adenoid),
pleomorphic
(giant cell) and clear cell. In well differentiated forms, tumor
cells resemble hepatocytes, form trabeculae, cords and nests, and
may contain bile pigment in cytoplasm. In poorly differentiated
forms, malignant epithelial cells are discohesive,
pleomorphic,
anaplastic, giant. The tumor has a scant stroma
and central necrosis because of the poor vascularization.
Staging
Important features that guide treatment include: -
- size
- spread (stage)
- involvement of liver vessels
- presence of a tumor capsule
- presence of extrahepatic metastases
- presence of daughter nodules
- vascularity of the tumor
MRI is the best imaging method to detect the presence of a tumor
capsule.
Management
- Surgical resection to remove
a tumor together with surrounding liver tissue while preserving
enough liver remnant for normal body function. This treatment
offers the best prognosis for long-term survival, but unfortunately
only 10-15% of patients are suitable for surgical resection. This
is often due to extensive disease or poor liver function. Resection
in cirrhotic patients carries high morbidity and mortality. The
expected liver remnant should be more than 25% of the total size
for a non-cirrhotic liver, while that should be more than 40% of
the total size for a cirrhotic liver. The overall recurrent rate
after resection is 50-60%.
- Liver transplantation to
replace the diseased liver with a cadaveric liver or a living donor
graft. Historically low survival rates (20%-36%). Recent
improvement (61.1%; 1996-2001), likely related to adoption of the
Milan criteria at US transplantation
centers. If the liver tumor has metastasized, the
immuno-suppressant post-transplant drugs decrease the chance of
survival.
- Percutaneous ethanol
injection (PEI) well tolerated, high RR in small
(<3&NBSP;CM) solitary="" tumors;="" as="" of="" 2005,=""
no="" randomized="" trial="" comparing="" resection="" to=""
percutaneous="" treatments;="" recurrence="" rates="" similar=""
those="" for="" postresection.=""></3&NBSP;CM)>
- Transcatheter arterial
chemoembolization (TACE) is usually performed for unresectable
tumors or as a temporary treatment while waiting for liver
transplant. TACE is done by injecting an antineoplastic drug (e.g.
cisplatin) mixed with a radioopaque
contrast (e.g. Lipiodol) and an embolic agent (e.g. Gelfoam) into
the right or left hepatic artery via the groin artery. As of 2005,
multiple trials show objective tumor responses and slowed tumor
progression but questionable survival benefit compared to
supportive care; greatest benefit seen in patients with preserved
liver function, absence of vascular invasion, and smallest tumors.
TACE is not suitable for big tumors (>8 cm), presence of
portal vein thrombus, tumors with portal-systemic shunt and
patients with poor liver function.
- Radiofrequency ablation
(RFA) uses high frequency radio-waves to destroy tumor by local
heating. The electrodes are inserted into the liver tumor under
ultrasound image guidance using percutaneous, laparoscopic or open
surgical approach. It is suitable for small tumors
(<5&NBSP;CM). A="" large="" randomised="" trial=""
comparing="" surgical="" resection="" and="" RFA="" for="" small=""
HCC="" showed="" similar="" 4="" years-survival="" less=""
morbidities="" patients="" treated="" with=""
RFA.=""></5&NBSP;CM).>
- Selective
Internal Radiation Therapy can be used to destroy the tumor
from within (thus minimizing exposure to healthy tissue). There are
currently two products available, SIR-Spheres and TheraSphere The latter is an FDA approved
treatment for primary liver cancer (HCC) which has been shown in
clinical trials to increase survival rate of low-risk patients.
SIR-Spheres are FDA approved for the treatment of metastatic
colorectal cancer but outside the
US SIR-Spheres are approved for the treatment of any non-resectable
liver cancer including primary liver cancer. This method uses a
catheter (inserted by a radiologist) to
deposit radioactive particles to the
area of interest.
- Intra-arterial
iodine-131–lipiodol administration Efficacy demonstrated in
unresectable patients, those with portal vein thrombus. This treatment is also used as adjuvant
therapy in resected patients (Lau at et, 1999). It is believed to
raise the 3-year survival rate from 46 to 86%. This adjuvant
therapy is in phase III clinical trials in Singapore and is
available as a standard medical treatment to qualified patients in
Hong Kong.
- Combined PEI and
TACE can be used for tumors larger than
4 cm in diameter, although some Italian groups have had
success with larger tumours using TACE alone.
- High intensity
focused ultrasound (HIFU) (not to be confused with normal
diagnostic ultrasound) is a
new technique which uses much more powerful ultrasound to treat the
tumour. Still at a very experimental stage. Most of the work has
been done in China. Some
early work is being done in Oxford and London in the UK.
- Hormonal therapy Antiestrogen
therapy with tamoxifen studied in several trials, mixed results
across studies, but generally considered ineffective Octreotide
(somatostatin analogue) showed 13-month MS v 4-month MS in
untreated patients in a small randomized study; results not
reproduced.
- Adjuvant chemotherapy: No
randomized trials showing benefit of neoadjuvant or adjuvant
systemic therapy in HCC; single trial showed decrease in new tumors
in patients receiving oral synthetic retinoid for 12 months after
resection/ablation; results not reproduced. Clinical trials
have varying results.
- Palliative: Regimens that included
doxorubicin, cisplatin, fluorouracil, interferon, epirubicin,
or taxol, as single agents or in combination,
have not shown any survival benefit (RR, 0%-25%); a few isolated
major responses allowed patients to undergo partial hepatectomy; no
published results from any randomized trial of systemic
chemotherapy.
- Cryosurgery: Cryosurgery is a new
technique that can destroy tumors in a variety of sites (brain,
breast, kidney, prostate, liver). Cryosurgery is the destruction of
abnormal tissue using sub-zero temperatures. The tumor is not
removed and the destroyed cancer is left to be reabsorbed by the
body. Initial results in properly selected patients with
unresectable liver tumors are equivalent to those of resection.
Cryosurgery involves the placement of a stainless steel probe into
the center of the tumor. Liquid nitrogen is circulated through the
end of this device. The tumor and a half inch margin of normal
liver are frozen to -190°C for 15 minutes, which is lethal to all
tissues. The area is thawed for 10 minutes and then re-frozen to
-190°C for another 15 minutes. After the tumor has thawed, the
probe is removed, bleeding is controlled, and the procedure is
complete. The patient will spend the first post-operative night in
the intensive care unit and typically is discharged in 3 – 5 days.
Proper selection of patients and attention to detail in performing
the cryosurgical procedure are mandatory in order to achieve good
results and outcomes. Frequently, cryosurgery is used in
conjunction with liver resection as some of the tumors are removed
while others are treated with cryosurgery. Patients may also have
insertion of a hepatic intra-arterial artery catheter for
post-operative chemotherapy. As with liver resection, your surgeon
should have experience with cryosurgical techniques in order to
provide the best treatment possible.
There is a new drug Sorafenib which was originally used for Renal
Cell Cancer that has shown promising results when used with
Hepatocellular Cancer
Abbreviations: HCC, hepatocellular carcinoma; TACE,
transarterial embolization/chemoembolization; PFS, progression-free
survival; PS, performance status; HBV, hepatitis B virus; PEI, percutaneous ethanol
injection; RFA, radiofrequency ablation; RR, response rate; MS,
median survival.
A
systematic review assessed 12
articles involving a total of 318 patients with hepatocellular
carcinoma treated with
Yttrium-90
radioembolization. Excluding a study of only one patient,
post-treatment CT evaluation of the tumor showed a response ranging
from 29 to 100 % of patients evaluated, with all but two studies
showing a response of 71 % or greater.
Prognosis
The usual outcome is poor, because only 10 - 20% of hepatocellular
carcinomas can be removed completely using surgery.If the cancer
cannot be completely removed, the disease is usually fatal within 3
- 6 months. However, survival can vary, and occasionally people
will survive much longer than 6 months.
Epidemiology
[[Image:Liver cancer world map - Death - WHO2004.svg|thumb|
Age-standardized death from liver cancer per
100,000 inhabitants in 2004.
]]HCC is one of the most common tumors worldwide. The epidemiology
of HCC exhibits two main patterns, one in
North America and
Western Europe and another in non-Western
countries, such as those in
sub-Saharan Africa,
central and
Southeast
Asia, and the
Amazon basin.
Males are
affected more than females usually and it is most common between
the age of 30 to 50 Hepatocellular carcinoma causes 662,000 deaths
worldwide per year, about half of them in China.
Non-Western Countries
In some parts of the world, such as sub-Saharan Africa and
Southeast Asia, HCC is the most common cancer, generally affecting
men more than women, and with an age of onset between late teens
and 30s. This variability is in part due to the different patterns
of
hepatitis B and
hepatitis C transmission in different
populations - infection at or around birth predispose to earlier
cancers than if people are infected later. The time between
hepatitis B infection and development into HCC can be years, even
decades, but from diagnosis of HCC to death the average survival
period is only 5.9 months according to one Chinese study during the
1970-80s, or 3 months (
median survival time)
in Sub-Saharan Africa according to Manson's textbook of tropical
diseases.
HCC is one of the deadliest cancers in
China where chronic hepatitis B is found in 90% of
cases. In Japan, chronic
hepatitis
C is associated with 90% of HCC cases. Food infected with
Aspergillus flavus
(especially
peanuts and corns stored during
prolonged wet seasons) which produces
aflatoxin poses another risk factor for HCC.
North America and Western Europe
Most malignant tumors of the liver discovered in Western patients
are
metastases (spread) from tumors
elsewhere. In the West, HCC is generally seen as a rare cancer,
normally of those with pre-existing liver disease. It is often
detected by ultrasound screening, and so can be discovered by
health-care facilities much earlier than in developing regions such
as Sub-Saharan Africa.
Acute and chronic hepatic
porphyrias
(acute intermittent
porphyria,
porphyria cutanea tarda,
hereditary coproporphyria,
variegate porphyria) and
tyrosinemia type I are risk factors for hepatocellular carcinoma.
The diagnosis of an acute hepatic porphyria (AIP, HCP, VP) should
be sought in patients with hepatocellular carcinoma without typical
risk factors of hepatitis B or C, alcoholic liver cirrhosis or
hemochromatosis. Both active and latent genetic carriers of acute
hepatic porphyriasare at risk for this cancer, although latent
genetic carriers have developed the cancer at a later age than
those with classic symptoms. Patients with acute hepatic porphyrias
should be monitored for hepatocellular carcinoma.
Society and culture
Awareness
The
Jade Ribbon Campaign is
used for awareness of liver cancer and hepatitis B in the Pacific
Islands, where such illnesses are more widespread than
elsewhere.
Famous people
- Morihei Ueshiba founder of the
Japanese martial art of aikido. Died in 1969 of hepatocellular
carcinoma.
- Chris LeDoux Country Music Hall of
Fame legend, and former Pro Rodeo rider.
- Munetaka Higuchi Drummer for
Japanese Heavy Metal band Loudness, Died in 2008 of hepatocellular
carcinoma.
- Mick Ronson British Rock'n'Roll
guitarist who died in 1993 of hepatocellular carcinoma.
- Ray Charles famous recording soulful
music artist, Rock And Roll Hall of Fame, died on June 10,
2004.
- Édith Piaf French singer and
cultural icon who "is almost universally regarded as France's
greatest popular singer."
- Gregory Hines Professional dancer,
film actor, and choreographer. Died in August 2003 of liver
cancer.
Research
Current research includes the search for the
genes that are disregulated in HCC,
protein markers, and other predictive biomarkers. As
similar research is yielding results in various other malignant
diseases, it is hoped that identifying the aberrant genes and the
resultant
proteins could lead to the
identification of pharmacological interventions for HCC.
Gallery
Image:Hepatocellular carcinoma histopathology
(1).jpgImage:Hepatocellular carcinoma histopathology (2) at higher
magnification.jpg
See also
References
External links
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