Primary and secondary liver
tumours
§
benign and malignant
tumours may arise in liver
·
from hepatocytes
·
bile-duct epithelium
·
supporting mesenchymal tissue
§
except HCC, all primary
malignant tumours of liver
® rare
§
but liver is frequently
site of metastatic deposits
Hepatocellular carcinoma
Cholangiosarcoma
Angiosarcoma (Kupffer-cell sarcoma)
Epithelioid haemangioendothelioma
Other primary malignant tumours
Hepatic metastases
Benign tumours
Hepatocellular carcinoma
o
epidemiology
o
aetiology
o
clinical features
o
investigations
o
screening
o
prognosis
o
treatment
§
occurs either as
·
single mass, or
·
scattered nodules of tumour
§
pre-existing cirrhosis in
» 80% of patients
§
tumour tends to invade
portal and hepatic veins
§
spreads to
·
abdominal lymph nodes
·
bone
§
histologically, tumour
typically composed of cells resembling hepatocytes
·
arranged in cords
§
other distinct histological subtypes recognized
·
including fibrolamellar variant
o clumps of eosinophilic
carcinoma cells, surrounded by characteristic fibrous stroma
o occurs in young-adults in
a non-cirrhotic liver
Epidemiology
·
comparatively rare tumour in Western Europe and North America
o
annual incidence in these areas
» 1-2 per 100,000
o
recent evidence suggests it is becoming more common
·
incidence 20-30 times higher
·
in patients with underlying cirrhosis
o
males greatly outnumber females
·
in non-cirrhotic cases
o
sex difference less striking
·
in areas of high incidence
o
peak age – 3rd and 4th decades
·
in Europe and North America
o
most cases occur in 5th and 6th decades
Aetiology
§
cirrhosis, particularly macronodular form, present in
» 80% of cases.
§
in Western Europe and United States, usually due to
·
chronic alcoholism
·
chronic hep B/C
§
in Africa and Asia,
chronic liver disease usually associated with
·
Hep B/C virus infection
§
rare cases
·
complicate cirrhosis due to other causes
·
may follow
o prolonged use of oral
contraceptive pill
o prior investigations
using radioactive contrast agent Thorotrast
§
in parts of Africa and Far East
·
increasing evidence implicating aflatoxin
o potent carcinogen derived
from Aspergillus flavus
§
a mould which often
contaminates food
§
Hep B virus recognized to have an important role in development of
hepatocellular carcinoma
·
particularly in areas of high incidence
·
risk of developing HCC in HBV carriers is at least 100 times higher than
in matched uninfected controls
·
HBV can be identified in
o tumour, as well as
o surrounding liver
·
integration of viral DNA in genome of HCC has been shown
o may result in
§
major structural
rearrangements in adjacent cellular DNA
§
deletions, duplications
and translocations have been reported
·
in geographical areas with high HBV endemicity as well as exposure to
aflatoxins
o one of a variety of
mutations of p53 on chromosome 17 is a frequent finding
o mechanism of initiation
and progress of these molecular events unclear
§
Hep C virus also closely
linked with HCC development
·
especially in North America, Western Europe and Japan
o areas where HBV is not
hyperendemic
·
almost all cases associated with cirrhosis
·
latent period may be as long as 25-30 years post-infection
§
HCC is largely preventable
·
in Taiwan extensive use of HBV vaccination has led to reduced incidence
·
until HCV vaccination is available, measures must be taken to reduce
transmission
·
there are indications that successful treatment of chronic Hep B and C
will reduce cancer risk
Clinical features
·
In Africa and other high-incidence areas,
o
a short history of right upper abdominal pain
o
often associated with
§
fever
§
weight loss
o
may be considerable abdominal swelling
§
due to liver enlargement
§
with or without ascites
o
catastrophic intraperitoneal bleeding sometimes,
§
due to tumour rupture.
·
In low-incidence areas
o
disease is often more insidious
o
general deterioration in health of a patient known to have cirrhosis
o
usually hepatomegaly
o
bruit may be heard over the liver
o
non-metastatic systemic manifestations (rare):
§
hypogycaemia
§
hypercalcaemia
§
porphyria cutanea tarda
·
Because of screening in high-risk groups,
o
more small (less than 3 cm in diameter), asymptomatic tumours are now
being detected.
Investigations
·
Haematological and biochemical indices
o
non-specific (apart from
a-foetoprotein)
o
reflect the
§
space-occupying lesion
§
underlying cirrhosis (present in about 80% of cases)
o
a-foetoprotein
§
glycoprotein
§
synthesised by foetal liver
§
plasma concn maximum at end of first trimester (3-4 mg/ml),
then decline
§
after birth, concentrations fall rapidly to adult levels (1-10 ng/ml)
§
levels
·
raised in 80% of hepatocellular carcinoma patients
·
tend to be higher in African and Far Eastern patients
·
than those in low-incidence areas and those with small tumours
§
concentrations > 500 ng/ml in a patient with liver disease
® highly suggestive of hepatocellular carcinoma
§
sequential readings of great diagnostic value
·
high plasma levels also found
o
in some patients with germinal-cell
tumours of
§
testis
§
ovary
o
in occasional patients
(usually with hepatic metastases) with carcinoma of
§
stomach
§
pancreas
·
below 500 ng/ml
o
diagnostic “grey zone”
o
such levels may be found
in
§
severe viral hepatitis
§
active cirrhosis
·
but subsequent readings tend to fall towards normal in patients with
these conditions
·
measurement of hepatoma specific isoforms may improve specificity and
sensitivity
o
other tumour markers have been described
§
abnormal vitamin B12 binding protein (usually present in
fibrolamellar histological variant)
·
liver imaging
o
real-time ultrasound
§
sensitive
§
specific
§
picks up hepatocellular carcinoma in 85-90% of cases
§
false negatives usually with tumours < 2 cm in diameter
o
Abdominal computed tomographic scanning
§
no more accurate than US
§
reserved for cases in which doubt persists
§
sensitivity increased by contrast enhancement
§
dynamic spiral contrast-enhanced CT scanning even more sensitive
o
magnetic resonance imaging
§
useful in identifying and characterising focal liver masses
o
hepatic arteriography
§
excellent visualisation can be obtained
§
major vascular supply to HCC usually arterial
·
therefore diagnostic changes seen in high proportion of cases
§
information on anatomical distribution of the tumour, vascular anatomy
·
essential if surgical resection/transplantation being contemplated
·
intra-arterial chemotherapy, hepatic artery embolisation can be
considered
§
sensitivity can be increased by
·
combining it with dynamic spiral CT scanning together with late films to
portal venous system
·
injection of iodine-containing contrast medium Lipiodol
o
CT scanning 10-14 days
later can visualise Lipiodol selectively retained in tumours
·
liver biopsy
o
essential for definitive diagnosis
§
has not always been possible because of prolongation of prothrombin time
§
diagnosis can be regarded highly likely without liver biopsy proof if
·
a-fetoprotein > 500
ng/ml, and
·
hepatic arteriogram shows a tumour circulation
o
biopsy may be conveniently done at time of laparoscopy or US
§
suspicious areas can be sampled directly under vision
o
risk of tumour spread
§
biopsy often avoided if curative resection/transplantation planned
Screening
·
consider for regular screening patients with increased risk of
developing HCC
o
cirrhosis
o
chronic Hep B/C infection
·
a-fetoprotein
·
abdominal ultrasonography
·
strategy has been shown
o
to pick up early tumours
o
evidence for improved survival figures for patients in Far East
·
benefits of screening disappointing in Europe
Treatment
·
curative
o
only complete resection or orthoptic transplantation hold chance of cure
o
consider in every case
o
resection
§
only possible in
» 10% of cases
·
underlying cirrhosis
·
or tumour in both lobes
§
often major resection needed
§
in presence of cirrhosis, only limited resection possible
·
liver regeneration defective
·
but procedure may be curative if tumour is small
·
in China, screening programmes to detect early HCC have led to
o
higher rates of tumour
resection in cirrhotic patients
o
improved long-term
survival figures
§
best results achieved with
·
well-compensated cirrhosis
·
small tumours (less than 3 cm)
§
5-year survival – only 20-30%, due to
·
progression of underlying liver disease
·
tumour recurrence
·
development of new tumours
o
transplantation
§
attractive option for those with cirrhosis and hepatocellular carcinoma
§
procedure can cure both tumour and underlying cirrhosis
§
long-term results best for tumours less than 5 cm in diameter
·
5-year survival – up to 70%
§
best results obtained when
·
HCC discovered incidentally in resected liver when transplantation
performed for liver failure
·
fibrolamellar histological variant
·
Palliation
o
radiotherapy
§
external-beam X-irradiation does not produce consistent improvement
§
some encouraging results with intra-arterial Lipiodol mixed with I-131
o
cytotoxic drugs
§
doxorubicin
·
one of few drugs that may produce worthwhile regression
·
only 20-30% of cases respond
·
no survival benefit established
§
hormone receptors present in hepatocytes
·
has prompted attempts to modify tumour growth
·
results poor with tamoxifen
·
octreotide reported to be of value
·
targeted therapies
o
wide variety developed and assessed in recent years
o
very few submitted to prospective randomised controlled trial
o
percutaneous ethanol injection
§
alcohol injected directly into tumour under US guidance
§
causes tumour necrosis
§
repeated injections may be given into more than one tumour mass
§
best results with tumours less than 3 cm in diameter
§
survival figures comparable with limited surgical resection
o
Lipiodol-targeted chemotherapy
§
cytotoxic drugs may be emulsified with Lipiodol
§
delivered directly into liver at selective hepatic arteriography
§
some data show that duration of action of drugs is prolonged because of
retention of Lipiodol in tumour
§
however, no convincing evidence of benefit
o
transcatheter arterial embolisation
§
embolisation with foreign materials, e.g. gel foam, can be done at time
of hepatic arteriography
§
may result in substantial tumour necrosis
·
particularly in highly vascular tumours
·
which derive bulk of blood supply from hepatic artery
§
contraindicated in patients with
·
decompensated cirrhosis
·
portal vein occlusion
§
broad spectrum antibiotics given for some days
·
risk of anaerobic infection in ischaemic liver
§
tumour necrosis is never complete
·
combine embolisation with targeted chemotherapy –
chemoembolisation
o
gel foam particles may be soaked in doxorubicin/cisplatin
o
TAE may be immediately preceded by Lipiodol targeted chemotherapy
o
treatment may result in
§
tumour necrosis,
§
shrinkage,
§
symptomatic improvement
o
but three consecutive trials have not established survival benefit
o
cryoablation and thermal ablation
§
intended to destroy tumour cells by physical means
§
no controlled trials have been reported
§
cryotherapy
·
probes inserted into tumour at laparotomy or laparoscopy
·
liquid nitrogen circulated
§
thermal energy
·
applied via probes placed percutaneously in tumour
o
using laser,
o
radiofrequency, or
o
microwaves
·
all three techniques safe
·
few side-effects
·
can be repeated
·
current data insufficient for comparison of efficacy of these techniques
Cholangiosarcoma
o
epidemiology
o
aetiology
o
signs and symptoms
o
diagnosis
o
prognosis
o
treatment
Epidemiology
·
much less common than HCC
o
accounts for about 7-10% of primary malignant tumours, except
§
in the Far East, where it makes up
» 20%
o
peak age – 6th and 7th decades
o
sex incidence – only slight male predominance
Aetiology
·
Thorium dioxide (Thorotrast) –
o
well-recognised, but rare cause of intrahepatic variety
·
in Far East
o
infestation of distomes such as Clonorchis sinensis, Opisthorchis
viverrini
commonly related
·
with long-standing ulcerative colitis
o
risk of biliary-tree carcinoma
» 10
´ risk for general population
·
primary sclerosing cholangitis, and various types of cystic disease of
the biliary tree
o
may all be complicated by the development of malignant change
·
unlike HCC, cholangiosarcoma does not appear to be predisposed to by
o
HBV/HCV infection, or
o
or cirrhosis
Signs and symptoms
·
peripheral intrahepatic type
o
upper abdominal pain
o
anorexia
o
malaise
o
weight loss
·
hilar tumours
o
jaundice – early feature
·
Hepatomegaly – usual
·
Splenomegaly may be found if
o
secondary biliary cirrhosis develops
§
owing to prolonged
biliary obstruction
Diagnosis
·
LFT
o
cholestatic features – elevation of
§
bilirubin
§
alkaline phosphatase
levels
·
a-foetoprotein concn
o
usually normal,
§
or only slightly raised
·
Ca and carcinoembryonic antigen levels may also be raised
o
although sensitivity and specificity do not approach 100%
§
raised levels found in
obstructive jaundice due to other causes
·
ultrasonography/CT scanning demonstrate tumour mass
·
with hilar tumours
o
show dilatation of the intrahepatic biliary tree
·
hepatic angiography
o
tumour tends to be avascular
o
but encasement and occlusion of vessels occurs
·
biliary tree obstruction in the hilum may be demonstrated – prior
to insertion of stent –
o
by MRI cholangiography, or
o
endoscopic retrograde cholangiography (ERCP)
Prognosis
·
most patients deteriorate progressively
·
average survival from
diagnosis – 12-18 months
·
if biliary drainage can be achieved with hilar tumours
o
prognosis better
§
these tumours often
slow-growing
Treatment
·
for peripheral tumours, same principles of treatment as HCC
·
response to therapy disappointing
·
hilar tumours
o
sometimes suitable for curative resection
§
with anastomosis of Roux
loop of jejunum to biliary tree in hilum
o
more usually,
§
curative resection not
possible
§
aim is to establish
biliary drainage
o
stent can be placed through growth
§
at laparotomy
§
at ERCP
§
or via percutaneous transhepatic route – thus avoiding surgery
§
recent advance – use of self-expanding metal stents
·
useful symptomatic relief may be obtained using
o
conventional radiotherapy
o
high-dose local irradiation within biliary tree with iridium-192 wire
·
if biliary drainage can be achieved using these procedures
o
survival for 1-2 years not unusual
·
liver transplantation seldom indicated
o
because of high risk of tumour recurrence
Angiosarcoma (Kupffer-cell sarcoma)
– highly malignant
·
rare tumour
o
consists of spindle-shaped malignant endothelial cells
·
often multifocal
·
may arise in a cirrhotic liver
·
occurs in patients exposed to Thorotrast 15-25 years earlier
·
chronic exposure to arsenic also implicated
·
has been found in workers in the vinyl chloride industry
o
since this discovery, strict safety regulations introduced, but
o
long latent period,
§
therefore new cases
continue to present
·
a few cases in long-term androgen users
o
no aetiological factor yet identified in majority of cases
·
patients present with
o
abdominal pain
o
hepatic enlargement
o
blood-stained ascites common
·
highly malignant tumour
o
curative resection rarely possible
o
no form of palliative treatment has proved effective so far
Epithelioid haemangioendothelioma
·
malignant tumour
o rare
·
origin: vascular endothelium
o characteristic
histological appearance
·
usually multifocal
·
occurs in younger patients than angiosarcoma
o
does not have same aetiological associations
·
usually slow-growing
·
prolonged survival reported after
o
resection
o
liver transplantation
Other primary malignant tumours
·
extremely rare, include
o
fibrosarcoma
o
leiomyosarcoma
o
lymphoma
·
children develop both
o
hepatoblastoma
o
HCC
Hepatic metastases
·
liver – favoured site for metastatic spread
·
» 50% of malignant tumours
in portal venous drainage eventually give rise to hepatic metastases
o diagnosis
o prognosis
o treatment
Diagnosis
·
easy when physical examination reveals a large nodular liver
·
detection of small/solitary deposits difficult
·
LFT’s may be normal
o
but alkaline phosphatase usually rises as tumour mass enlarges
·
US scanning should pick up tumours greater than 1 cm in diameter,
·
but accuracy is greatest when metastases large or numerous
·
targeted liver biopsy at laparoscopy or ultrasonography to confirm
diagnosis
Prognosis
·
worse when there is extensive liver replacement by tumour
o
severe disturbance in liver function tests or ascites
·
site of primary growth also relevant
o
deposits from colorectal cancer – better prognosis than most other
tumours
§
untreated mean survival
9-12 months
Treatment
·
same range of possible treatments as for HCC
·
partial hepatectomy to remove deposits may occasionally lead to
prolonged survival or cure
·
special situation with respect to hepatic metastases from carcinoid
tumour
o
slow-growing neoplasm
o
main problem is distress caused by flushing and diarrhoea
·
embolisation, or, resection of tumour bulk with no attempt at total
removal – often symptomatic relief for some years
·
consider transplantation for slow-growing tumours
·
choice of chemotherapy determined by origin of primary tumour
·
intra-arterial infusion with implantable pumps may give improved quality
of life with objective tumour regression
o
but little convincing evidence that survival is prolonged
Benign tumours
o
haemangioma
o
hepatic adenoma
o
focal nodular hyperplasia
o
other benign tumours
Haemangioma
·
Most common benign tumour
·
usually asymptomatic
·
found incidentally either during ultrasonography/CT scanning
·
occasionally, when large, it may cause abdominal pain/shock
o
due to rupture
o
leading to surgical excision
·
appearances with ultrasonography usually diagnostic
o
but, for certainty, may need
§
CT scan with contrast,
§
angiography, or
§
MRI
Hepatic adenoma
·
incidence of tumour seems to have increased markedly since introduction
of oral contraceptive pill
o most reported cases in
females who have been on the pill
³ 5 years
o however, risk for
individual woman is infinitesimal
·
patients often asymptomatic
o
mass discovered on physical examination
o
or incidentally on ultrasound examination
·
some patients complain of upper abdominal pain
·
others present acutely with shock due to intraperitoneal bleeding
·
tumour
o
usually solitary
o
but may be multiple
o
consists of cords/acini of hepatocytes without bile ducts or portal
tracts
§
fibrous tissue septa sparse
o
may be encapsulated
o
little or no disturbance in liver function
o
a-foetoprotein
concentrations normal
·
ultrasonography shows focal lesion of variable echogenicity
·
CT scanning shows marked arterial enhancement
o
sometimes areas of haemorrhage within tumour
§
can be confirmed on MRI
scanning
·
in some cases, tumour has regressed after withdrawal of contraceptive
pill
o
surgical resection usually recommended because of risk of
intraperitoneal bleeding
o
occasional development of malignant change
Focal nodular hyperplasia
·
benign condition
·
uncertain pathogenesis
·
frequently confused with hepatic adenoma
·
lesion composed mainly of
o
hepatocytes
o
Kupffer cells
·
typically
o
central stellate scar,
o
radiating septa containing
§
arterial channels
§
venous channels
§
bile ductules
·
much more frequent in women than men
o
but no relationship to oral contraceptive pill has been established
·
mass usually solitary and asymptomatic
o
but rupture with intraperitoneal bleeding occasionally occurs
·
imaging
o
findings often different from those of hepatic adenoma
o
may allow definitive diagnosis
o
Doppler US – may show an arterial signal within the tumour
o
CT scanning or MRI scanning – may demonstrate central stellate
scar
o
biliary scintiscanning may show a late hotspot in the tumour
·
prognosis is excellent
·
malignant change is not recorded
·
but, if imaging techniques do not provide definite diagnosis, surgical
excision often recommended
Other benign tumours
·
much rarer; include
o
fibroma,
o
lipoma,
o
leiomyoma,
o cystadenoma