00:01
Welcome!
With this talk,
we're going to cover
cancer in the liver.
00:06
And there's primary
cancer in the liver,
which is hepatocellular
carcinoma,
and they're also liver
metastases from someplace else.
00:14
As we'll see,
liver metastases are much,
much, much more common
than primary liver cancer,
but we'll talk about that.
00:23
Let's do a little
epidemiology first.
00:26
So primary,
hepatocellular carcinoma
accounts for about 90%
of primary liver cancers.
00:33
The other primary liver cancers
are cholangiocarcinomas
for the most part.
00:37
The overall incidence
is relatively low.
00:40
So primary
hepatocellular carcinoma,
only an incidence of about
5 per 100,000 people.
00:46
The vast majority
of liver cancers.
00:49
30 times more frequently
or metastatic.
00:51
For example, up to about
a quarter of colon cancers
will metastasize to the liver.
00:57
And overall malignancy in the
liver, primary or secondary
is the fourth most common
cause of all cancer deaths
because we lose liver function.
01:08
We're going to talk mostly
about hepatocellular
carcinoma in this part
at the very end, we will return
to talk about metastatic cancer.
01:16
But let's talk here about
risk factors for HCC.
01:20
Cirrhosis of any cause,
confers about a 35%
lifetime risk of developing
primary hepatocellular
carcinoma.
01:29
So you want to avoid cirrhosis.
01:31
Cirrhosis can be
due to infections
such as hepatitis B or C
and can be non alcoholic
fatty liver disease,
alcoholic liver disease,
iron overload, hemochromatosis,
copper overload,
Wilson's disease,
Alpha-1 antitrypsin deficiency,
and there are other
causes of cirrhosis,
including autoimmune
hepatitis etc.
01:54
The other causes
to be considering
in terms of driving
hepatocellular carcinoma
are primary toxins
such as aflatoxin.
02:03
This is associated with
Aspergillus flavus,
which is a fungal contamination
of peanuts and
corn, for example.
02:11
That will actually
cause primary mutations
within the liver and is not
associated necessarily with cirrhosis.
02:18
Smoking, alcohol,
chronic biliary disease,
sclerosing cholangitis,
for example,
and autoimmune hepatitis,
or other causes for having
hepatocellular carcinoma.
02:30
Let's discuss pathophysiology.
02:32
You see here the normal
hepatocyte architecture
with cords of hepatocytes
in a nice linear array
sitting on a basement membrane,
and they will be
interfacing with a space,
a virtual space between
the hepatocyte cord
and the sinusoids which
are lined by endothelium.
02:51
In that space are
quiescent stellate cells,
these are precursor cells.
02:55
They regulate fibrosis
within the liver,
and a variety of
other activities.
03:00
And then, cruising
around in this space,
the space of disse and
also within the vasculature
are the macrophages of the
liver called Kupffer cells.
03:09
In the normal liver,
everybody is happy.
03:11
The stellate cells
are acquiescent,
the Kupffer cells
are not activated,
and we are going
about our business.
03:19
With liver injury, we cause
damage to the hepatocytes
and that will elicit an
inflammatory response,
so that we will activate
the Kupffer cells
which will make
inflammatory cytokines.
03:30
A combination of
hepatocyte injury
and the activated Kupffer cells
will then crank the
stellate cells into action.
03:39
They will proliferate and
their response to injury
and inflammatory cytokines etc.
03:45
Is going to be making
increased extracellular matrix,
they will make a fibrosis
and this is the process by which
with recurrent bouts
of injury to deliver,
we can end up with cirrhosis.
03:58
I would refer you back
also to the cirrhosis talk
in the series of gastrointestinal
pathology lectures
in the Lecturio series.
04:07
The pathogenesis of
hepatocellular carcinoma
is that typically
arises not always
but typically arises in
chronic liver disease
when there is cirrhosis.
04:16
So about 80% of the cases of HCC
are with a pre
existing cirrhosis.
04:23
What happens in cirrhosis
is that you have
ongoing hepatocyte
proliferation, regeneration,
the hepatocytes are
constantly turning over.
04:31
They're constantly proliferating
in a sea of inflammatory mediators,
including reactive
oxygen species,
and other mediators that
can cause new mutations.
04:42
Proliferation in the setting
of possible mutations
is a recipe for
malignancy disaster.
04:50
And that's what happens,
we just have hepatocytes
that are proliferating,
they are being bathed in
reactive oxygen species,
they acquire mutations
as they proliferate
and then we cement
those new mutations
into the progeny of the
proliferating hepatocytes.
05:07
In many cases, we can
identify the driver mutations.
05:10
So mutations in the
beta catenin gene
occurs in about 40% of
hepatocellular carcinomas.
05:17
Upregulation of
telomerase activity,
so mutating the
TERT gene promoter
will occur and over half of
hepatocellular carcinomas.
05:27
And inactivation
mutations of p53,
which are important for
protecting the genome
and identifying mutations.
05:36
So these are very common,
they're not the only mutations,
they don't always have to occur,
but these are
relatively frequent.
05:44
In non cirrhotic livers,
so about 20% of
the cases of HCC,
other damages occurring I've
already mentioned aflatoxin,
which will be converted by
the liver by the hepatocytes
to a very toxic epoxide,
which will cause
primary DNA damage,
particularly involving p53
and it will inactivate p53.
06:05
Rarely, hepatocellular adenomas
that are associated with
beta-catenin activating mutations
will acquire additional
mutations and become malignant.
06:15
But when we talked about
benign hepatic neoplasms,
we talked about
hepatocellular adenoma
and it's a relatively
rare occurrence
that it mutates into
hepatocellular carcinoma.
06:27
There is a fibrolamellar variant
of hepatocellular carcinoma,
typically associated
with a fusion gene
that will lead to increased
constitutive activity
of protein kinase A,
and that in turn
will drive cyclic-AMP
to be involved in increased
proliferation of the hepatocytes.
06:50
So how will your patients present
with hepatocellular carcinoma.
06:54
For small tumors,
they're going to be
largely asymptomatic
and the cancer will only
be found incidentally
on imaging for
some of the reason.
07:02
And in most cases,
80% of the time,
when the cancers will
arise in a cirrhotic liver.
07:09
The signs and symptoms are all
going to be about cirrhosis.
07:12
So I'd refer you to
the talk elsewhere
within Lecturio on cirrhosis.
07:18
With decompensated cirrhosis,
there's variceal bleeding,
there's uncontrolled ascites.
07:23
You may also have extension of
the hepatocellular carcinoma
into the hepatic or portal veins
which will cause
obstruction of blood flow
from the lower extremities.
07:33
When hepatocellular carcinoma
does become symptomatic,
it's usually as a
vague abdominal pain
or right upper
quadrant discomfort.
07:41
There may be associated malaise,
fatigue and weight loss.
07:44
The liver will be enlarged,
palpably enlarged below the
right lower costal margin.
07:51
There will be splenomegaly usually
because of associated cirrhosis,
and a mass may be
actually palpable.
08:00
Making the diagnosis formally.
08:03
There are biochemical markers,
Alpha-fetoprotein is
actually pretty good.
08:08
It is not entirely specific,
so you wouldn't use it
as a screening tool.
08:14
But once you have
identified that a patient
has hepatocellular carcinoma,
you can follow
alpha-fetoprotein levels
as a marker of disease
or tumor burden.
08:22
Ultrasound, CT or MRI,
all of these will identify
tumor lesions within the liver.
08:29
It's indicated on the panels
on the right hand side
and to confirm the diagnosis
and make sure it's
not something else
that's potentially benign.,
you would do a biopsy.
08:40
On biopsy or on excision,
there are kind of
two general patterns.
08:46
On the left hand side here
is a well differentiated,
hepatocellular carcinoma.
08:50
It looks a lot
like normal liver,
except it doesn't have the
normal portal triad architecture,
doesn't have the
normal sinusoids
but it does have
cords and sheets,
a reasonably well differentiated
in this case, hepatocytes.
09:05
On the right hand side
is a different stain.
09:07
This is a trichrome stain,
with trichrome stains fibers
connective tissue blue.
09:13
In the fibrolamellar variant
associated with the protein
kinase A fusion proteins,
you see these dense bands
of fibrous connective tissue
and you then see sheets of very
poorly differentiated hepatocytes.
09:27
Overall, this particular variant
has a much better prognosis
than the primary hepatocellular
carcinoma that you see on the left.
09:36
The gross appearance is one
of a infiltrating tumor mass,
there may or may not be
invasion into the portal vein
with extension into
the inferior vena cava
and even the right
side of the heart,
so tumor can extend
all the way up
and may actually present as
right sided heart failure,
which is fairly impressive.
09:56
Cancers of the kidney will
also do this incidentally.
10:01
So, how are we going
to manage this?
Well, overall the
prognosis is kind of poor
for primary
hepatocellular carcinoma.
10:10
There are non surgical options,
if the tumor is small,
you can do radiofrequency
ablation or microwave ablation,
you can freeze it,
you can do embolization.
10:20
Less than 10% of the tumors
are going to be resectable.
10:23
It's not because
they are way big,
although that can be a reason.
10:28
But it's limited by the poor
quality of the rest of the liver.
10:32
If there's pre
existing cirrhosis,
you don't really have
a lot of latitude
to carve out the tumor,
that liver will not
regenerate in the same way
that a normal
healthy liver will.
10:44
And in some cases, by
the time we detected,
it's rather large and
so non resectable.
10:50
The prognosis depends on the severity
of the underlying liver disease
on the size of the tumor
on how well or how far it is
extended into adjacent structures,
whether there is
metastatic disease.
11:03
The overall five year survival,
all comers is about 10%.
11:08
If we are able to get the
patient to liver transplantation,
so the underlying etiology
for a cirrhosis, for example,
is something that
I will not recur,
then you can do quite
well with those patients
and about three quarters of them
will have a decent
five year survival.
11:26
With tumor limited
just to the liver,
survival for five
years about 30%.
11:31
If there's regional extension
into adjacent structures
or into the draining veins,
the five year survival
goes down to about 10%.
11:40
And if there's
distant metastases,
it's a very bad prognosis and
2% to 3% five year survival.
11:49
Okay, so that's all about
hepatocellular carcinoma.
11:52
Very briefly, in the
last couple slides,
we're going to talk
about liver metastases.
11:56
These tumors, liver metastases,
30 times more common than
primary liver cancers.
12:03
Importantly, half of patients who
are going to die from malignancy
will have liver metastases,
and a significant portion
of them will be dying
because of liver metastases.
12:12
You can see the
long list of tumors
that like to go to the liver.
12:17
Colorectal cancer is probably
number one on the list,
mainly because when tumor
gets into the veins,
in the primary site in
the colon or rectum,
it goes via the
portal circulation
and the next capillary bed it
will encounter is the liver.
12:34
So GI malignancy going to the
liver is actually quite common,
but pretty much
any tumor anywhere
and it's travels
around the bloodstream,
we'll find its way to
delivering can metastasize.
12:48
The diagnosis is one of
imaging for the most part,
in the setting of a known
primary someplace else,
you can do a CAT scan,
a positron emission
tomography or a PET scan
will also allow you to
assess the degree of tumor.
13:04
Importantly, our imaging,
even our very best imaging
can only detect down to about
0.2 - 0.3 centimeter size.
13:11
So you can have multiple,
very small tumors
that have substantial number of
tumor cells up to 10 million,
and you can't detect
that on best imaging.
13:21
Imaging will typically show what
is shown here on the picture,
multiple rounded,
smooth border tumors,
often there will be a
central umbilication,
so called umbilication,
indicating that there is
central tumor necrosis.
13:37
The management depends on
the primary cancer site
and if the primary cancer is
going to be chemo responsive,
then you might be in good shape,
or if it's going to be
responsive to immunotherapy.
13:47
In general, it's going
to be very difficult,
especially with multiple
metastatic tumors
to surgically resect these
but if there's a limited number,
surgeons will attempt
to treat to achieve cure
by resecting those
known metastases.
14:06
With that we've covered
hepatocellular carcinoma
and metastatic carcinoma
within the liver.