(From M1 Patients and Populations at University of Michigan Medical School. Lecture by Gerald Abrams, MD.) I think a good place to start is with this slide again, just to remind you that
one of the defining
traits of malignant
neoplasms is the ability to invade
more importantly even
as
a second defining characteristic is the ability to set up
underlying distant
and
discontinuous
secondary foci of growth. What this involves is cells
breaking off, leaving, what we call, the primary cells
getting
into the moving currents or fluids that flow into the body, let's say into the blood
or into the lymph
lodging at a
distance, in other words, here is the primary
clump of cells, these cells
float over there, they lodge and
get out of the vessel they are in
and they form a new nodule.
That's the process of metastasis.
That's what the process is called. The focus itself is called him a metastasis (or plural metastases).
and the
ability to metastasize
by all odds is the most lethal aspect of cancer.
And
that's the the feature that most often
makes a cancer incurable.
Sometimes a cancer is incurable because of local invasion, you know,
something wraps around the aorta or some other structure, you can't get at it,
that could be
lethal but it's usually metastasis. The sad fact is that
if you exclude skin cancers, many of which are in a different category, if you exclude those
about
thirty to fifty percent of patients who present to their doctors
with some signs and symptoms that turn out to be cancer, about thirty to
fifty percent already have metastases.
So it's something that really
is the biggest roadblock
to successful treatment.
So again these defining characteristics
are invasion and metastasis. Now
these abilities, to talk first about invasion and metastasis together,
are not just a matter of cell proliferation
in other words, it's not the matter of fact
that the cancers proliferating in the primary so much that the cells get squeezed
out and they move. That's nonsense.
Some primaries grow very large and then
never leave
the local area. These neoplasms acquire
the
cells in the neoplasm gradually acquire the ability to invade
and to metastasize, and again these represent an accumulation
of different kinds of mutations very likely giving the cells the
the ability to
do this.
Now metastasis I would emphasize
is a very complex cascade of events,
it's not just whoops!
but involves the
cells first of all invading, getting through that extracellular matrix,
breaking through basement membrane,
getting into a vessel whether it's a blood vessel or a lymphatic, floating
with the stream and surviving during that flotation, which is another
nice trick, lodging
somewhere,
being able to extravasate, get out of that vessel where it lodged,
and set up housekeeping and get all of the requirements for growing another nodule.
this is sort of, its been likened to, a decathlon event. You have to
win
a lot of events to be a successful metastasis.
and
there are three primary roots, this one is the lesser but
cells
can metastasize via the bloodstream, via the lymph flow
and sometimes directly.
Now here
for instance, just to illustrate this,
here is a clump of cancer cells within a
tiny vein
within adipose tissue.
This was actually
in a breast that had been removed by mastectomy, this was, in other words,
primary cancer of the breast.
What had happened here
a tongue of cells had
broken through a venule wall somewhere upstream
and here you see it caught in the act of floating
with the blood.
Now there's a certain predictability to where the metastasis will go. In this case,
this is coming from the breast. Eventually
these venules are going to go into veins which are going to flow into
the superior vena cava. The cells
aren't going to lodge anywhere along there because the vessels are getting bigger
and bigger. And
they
go to the right side of the heart out the pulmonary artery.
Pretty soon, these cells
are going to encounter the capillaries in the lungs where they are going to lodge.
Metastasis,
a cell clump like this, if it's successful, may
very well
end up in the lungs.
Now you haven't studied this in gross anatomy yet, you're just beginning gross,
but
I'll tell you that for instance
the blood flow drainage, the venous drainage of the GI tract
goes into what we call the portal vein, which is
a big vein
that goes into the liver.
Now the cells, if these cells had broken out of a gastric cancer,
and
were in the veins draining the stomach, they would
go into this portal vein and then the first capillary bed
they hit is the liver.
So you'd
find metastases in the liver, you'd predict metastases in the liver.
Or if you had a malignancy in the soft tissues of the leg,
the cells would eventually get to the inferior vena cava, up to the heart,
and into the lungs.
So it turns out that the lungs
and the liver constitute the two big filters in the body
and they catch a lot of metastases.
Now this is nowhere
near being entirely predictable for the
following reasons,
the cancer cells don't necessarily lodge
permanently
in the lungs or the liver.
they change their shape, they squiggle around,
let's say coming from the GI tract, they may get through the liver
into the
inferior vena cava up to the
heart and out anywhere in the body.
So it turns out that really practically
speaking, cancer cells once again in circulation are all
over the place
and
it also turns out that there are secondary factors
that determine where the metastases will occur
For instance,
we know that cancer cells get out systemically. We rarely see metastases
in skeletal muscle. I have no idea
why.
But we rarely do.
It turns out that certain cancers have a propensity
to set up metastases in one
set of tissues and certain cancers
have a propensity to set up metastases in another set of tissues. It's as if they
favor the "taste"
of
one tissue
over another, and you'll learn these patterns, I'm not going to afflict you with them.
They are
to an extent predictable.
So that's the situation with hematogenous metastases, liver, lung,
many other places as well. It's a systemic process
Here are cancer cells in a lymphatic.
You probably know less about lymphatic channels than you do about blood channels but these are
basically
they start from small, thin walled
vessels like this and
and any particular organ
almost all organs in the body have a rich lymphatic drainage. The lymph
is drained
into bigger
bigger lymphatics. These enter what we call regional lymph nodes.
which we'll study in detail, but these are basically like little filter beans
and
a clump of
cells like that may well lodge in a regional lymph node.
Now
what denotes a regional lymph node?
In the case of the bowel,
the regional lymph nodes are in the mesentery. In the case of the
breast, the regional
lymph nodes are in the armpit, that's where the lymph is draining.
In the
case of the mouth and throat, the regional lymph nodes are here in the neck.
And there's
a certain predictability
so that if you have a big cancer in the mouth, you're going to
worry about the cervical lymph nodes or the
or the breast you're going to worry about what's going on in the axilla.
Cancer operations generally involve
either excavation or sampling of the regional lymph nodes to see whether the cancer
has spread from the primary there.
Now
this predictability again can break down because
lymph nodes are not perfect filters,
whatever you might think,
these cells might lodge temporarily in a lymph node and some of their progeny
maybe goes scooting out the other side in the
efferent lymph which
is going to go to other lymphatic channels and eventually dump into the
superior vena cava and
join
the systemic circulation.
So it turns out that cancer,
we have to conceive of it is a potentially systemic disease,
One comment
here about metastasis is the possibility of direct metastasis.
By that I mean
the cells are not picked up in the blood or lymph, but
if they enter
a cavity, let's say the peritoneal cavity,
and can drift
or swim or float
across the peritoneal cavity and lodge
anywhere in the lining
of the peritoneal cavity, it's a sort of direct
metastasis.
We see this
one
that comes to mind is the ovary.
The ovary sit out in the pelvis,
in the open so to speak, in the peritoneal cavity. Ovarian cancers notoriously
will just seed cells into the peritoneum and they'll land
anywhere in the peritoneum
and set up these metastases.
A variation on
this that we don't often see is that the surgeon's knife
may pick up
some cancer cells and
we'll find a recurrence in the incision or something of that sort.
More or less
a direct, iatrogenic (physician caused) metastasis.
But again
metastases
represent a hop skip and jump, it's not direct invasion to
get over here, it's a jump
to get over there.
A thing to point out is that the
metastasis does not have the
the characteristics of the organ that it lands in, it keeps the
characteristics of the primary tumor. In other words,
these metastasizing cells are the genetic progeny
of the primary, so they're going to look like it. If the neoplasm
neoplasm in the primary was making funny glands, the metastasis
will probably make funny glands.
It's a chip off the old block.
That has some some interesting implications there which you'll get into
in future years.
But just
think of it as as a process whereby a single primary can give rise to many metastases.
They can be
at a great distance, it can be four feet away from
the primary and
it can
be very devastating and I will show you
some examples of this.
This is carcinomatosis which refers to a diffuse spread
of
cancer.
This was the lining of the diaphragm, in other words if i took a piece of diaphragm,
cut it out
and you're
looking at the under surface of the diaphragm lined by peritoneum,
this was from a patient with ovarian cancer,
and every one of these little plaques is a
few million cancer cells growing as a direct
metastasis.
Now I'm going to give you a long shaggy dog story, here is a
specimen of peritoneum,
this is if I took a couple of pieces of body wall
cut them out and you're looking at the peritoneal surface
of the inside of those pieces
and you can see studded
with a couple a hundred little tiny black
spots and here it's actually become kind of almost a confluent
sheet of neoplasm.
And
you'd say yeah this looks like
many little nodules, why do you suppose it's black like that?
Any thoughts?
Well, the cells are making melanin, this is a malignant melanoma
which may have heard about. Now
I'm
getting ahead of your knowledge of histology, but there are no cells in the
peritoneum that make
melanin normally, so that means these are visitors from somewhere else,
so clearly just by
the sheer numbers and by the fact that it's melanoma
we can say that these are metastases from somewhere else.
I'll let the plot thicken a little bit, here was the liver
from the same case.
The normal liver is studded with probably thousands of metastases.
This is grown together in a big, horrible
mass which had broken through the hepatic capsule,
and the normal liver does not contain melanin producing cells.
That fact and the fact that that these are so multiple
says that this liver is riddled with hematogenous metastases.
Where do you think the primary was?
Someone said it.
Skin. That'd be your first bet.
Because melanoma is a common story.
But you're wrong. Eyeball.
This is a bad picture, I screwed up and am not a photographer, but there you see the
reflex from the flash, but just behind it
there's a little lump
there
and that is the primary neoplasm.
Now this tells another story.
This patient presented with a visual disturbance and the ophthalmologist saw this
and said this eyeball has to come out.
And the eyeball was taken out.
It is our job as pathologist to assess whether the excision
has been complete.
And so we sample the various coats of the eye thoroughly to see if the melanoma
cells had penetrated through and if there any left in the in the orbit.
And the answer
to it is no.
Looks clean.
I hope the surgeon didn't say this but this sometimes gives rise to the statement:
we got it all!
Now this patient did fine after removal of the eyeball, did fine for several years.
With
absolutely no evidence of metastases.
Then something happened, God knows what,
the patient just
went downhill within a period of weeks and died
and had metastases all over the body.
That brings up another interesting point which I'll just tease you with and
that's the phenomenon we call dormancy.
It was very clear from the story
that we had taken out the primary
and there was never any recurrence in the orbit and so that what that says is
these melanoma cells have gotten into circulation
that there were tiny occult metastases
at the time the eyeball was taken out
and they chose not to grow
for several years
and then something changed and they grew.
And we see that sometimes.
In other words earth eighteen months survival or two years survival or five year survival
is a statistical thing, but
sometimes
it doesn't
matter.
So this illustrates
the fact that that metastases can be very distant from the primary,
they can
be
millions of metastases from one primary
and also I threw in this whole phenomenon of dormancy which is a bit unusual
but it happens.
I'll show you some other mets.
Here's a lung of a youngster.
Every one of these is a nodule of neoplasm, the other lung looked just like this.
This happens
to have been a primary in the kidney which
got to the lungs through the renal veins, the vena cava, and on up.
The good news is that we can cure many of these, not at this stage, but we
can prevent it from reaching this
stage now.
Here's an interesting one that we see very often, this is a vertebral column which
I sliced in a band saw
so you're looking at a couple of mirror images and this is a pretty normal
vertebra up here, this is an intervertebral disc up here.
These two lower vertebrae you see these whitish areas
here and here.
These were very
dense bone, and interestingly
what this represents is metastasis to the bone,
it stimulates bone formation around the cancer cells, it's something
we call an osteoblastic
phenomenon
or an osteoblastic metastasis.
This would have shown up
as a density on the x-ray
under the microscope, there's a lot of bone there but cancer cells throughout
and usually cancer cells reach the bone
via the hematogenous route.
Could be anything, I mean if someone showed me this, I'd say it's metastatic something or other
from somewhere or other
but you will learn for instance that breast
very often breast cancer very often goes to bone. Prostate cancer notoriously goes to bone.
I won't bore you with the list, but you're going to learn as you study oncology
what the likelihood of
I mean if this came from a
middle-aged woman with
with a breast nodule, I'd say breast cancer. If it came from an elderly guy with
urinary tract obstruction, I'd say look at his prostate.
So that is an osteoblastic kind of metastasis.
Here is a different one,
this one has another story associated with it.
This was a 42-year old guy
who came in with back pain and he was a manual laborer that did heavy labor
and everyone thought at first well you know it's some orthopedic
injury
until they got an x-ray of his back and discovered that one of the vertebrae was
essentially turned to mush.
Here's a normal vertebra here and here.
Here's a disc and this is a
osteolytic metastasis, it turned out that there was a metastasis
that completely destroyed the bone and it simply collapsed.
Now this man presented because of his metastasis, that sometimes happens,
it may not be the primary, it turned out he was a heavy smoker
and had a small,
inapparent
bronchogenic primary, in other words, a lung cancer
and it metastasize to his bone without even causing any ruckus.
He probably had a little cough as all smokers do
but presented because of the metastasis
This was
another smoker incidence, I remember
this one very well,
the patient came in convulsing, signs of
increased intracranial pressure.
They
had to take him to the operating room very quickly to decompress the brain
and save him from dying from
the pressure and
my colleague
sent me a piece of this
to look at it quickly with what we call a frozen section. You freeze a tissue and
make a quick section of it
It was easy to say this isn't
cancer arising in the brain
because it didn't look like that. It looked like a cancer that came from somewhere else.
This is not rocket science, you'll learn how to do it in the spring.
But it's because the
metastasis resembles the primary that we looked at it and said, no, this isn't brain, this is
metastasis to the brain.
Poor fellow died shortly after operation, it turned out again he was riddled with metastases
with a small lung primary.
Lung primary
very often goes to brain like that.
Oh
one last lovely image
there is a liver
riddled with metastases.
And if
someone showed me this liver and said where did this come from, I'd say
gee, well look at the GI tract.
It can be elsewhere, this was a lung cancer
that had metastasized and gotten into the bloodstream, had gotten around and liked the taste
of liver
and produced metastases in the liver. There were metastases in many other
places as well.
Well, i guess that
gives you a little bit of an example, a little bit of a feeling for the the destructiveness
of this process of metastasis. Again benign neoplasm
do not metastasize, only malignant
ones do.
Benign neoplasms do not invade, only malignant ones.
With
those concepts
of neoplasia, hope you've all got benign and malignant invasion, metastasis sort of
under your belts.
I want to talk for a little bit on how neoplasms are
put together microscopically.
Again, don't worry about being able to do this kind of diagnosis yourself,
just listen to the concepts.
I want to review the concept of stroma,
the concept of differentiation,
and ideas of grading
and staging.
All right, let's let's begin with the business of stroma and angiogenesis.
One of things that I should emphasize
that I didn't really emphasize so far is that
a given module of neoplasm
take one of those metastases in the liver for instance
A given nodule of neoplasm
is just not a spherical
collection of 100% cancer cells.
This is a very important concept
and it makes perfect sense
because
you could not possibly grow
a lump literally that big
and have
a blood supply
for the cells in the center,
you follow me?
In other words, if they were pure cancer cells
the blood would be out here
and the cells would be proliferating here.
It doesn't work that way, the cancer needs a blood supply in order to grow.
and it turns
out that
cancers
are able and this is an very interesting phenomenon
to
induce the formation of what we call a stroma
it's a fibrous
particularly a vascular framework
which supports the neoplasm.
Now the stroma
is not part of the malignant clone
or the neoplastic clone.
It comes from
the connective tissue cells and the blood vessels cells
around
the neoplasm.
The neoplastic cells
and probably some of the inflammatory cells accompanying the neoplasm are able
to induce
the formation of this stroma. It's
very much
like the the induction of granulation tissue which you're very familiar with from
last week.
And
what
happens
is this fibrous and vascular stroma grows into the nodule and enables it
to proliferate.
Now we talk about
tumor angiogenesis, I mean the emphasis being on the blood vessels.
There is abundant
experimental evidence to show
that
and i won't go into the details, but if you create a situation where you got
a bunch of neoplastic cells growing pure
where they can't pick up a stroma,
the module will never get bigger than a millimeter or two at the very most,
probably less because
because the oxygen and nutrients cannot diffuse in the solid mass any further.
There are many experiments that show
you grow neoplastic cells in these little balls and they stopped growing.
and then if you do something to induce angiogenesis, BOOM,
as soon as they pick up
the vascular stroma
they begin
to grow
so tumor angiogenesis is exceedingly important. You can
read a
I won't bother you with the details, but we are beginning to know a little bit about how
this is mediated and what it looks like is this:
again without too much detail
this was a lump in a breast.
This was a breast cancer.
These dark clumps are the cancer cells
and the
pink in the background
is the stroma.
I'll emphasize in particular there is a capillary there,
there is a capillary cut lengthwise there, there's another capillary here
and so forth
so that any given
clump of cancer cells isn't very far from
a capillary.
That's the concept
of the stroma and tumor angiogenesis and what it means.
If we could stop angiogenesis
we could stop tumor growth.
It would be wonderful and some of these attempts have reached the clinical testing
testing stage but nothing terribly dramatic yet.
But it's certainly a handle.
Here is kind of a loose stroma, not very fibrous but a lot of blood vessels.
Sometimes
you can be
very dense.
These are cancer cells
in a very dense collagenous stroma.
This kind of a lump has a
consistency about like wood.
We call that, it's an adjective you'll hear occasionally, it's a scirrhous
s-c-i-r-r-h-o-u-s
scirrhous
mode of growth
But whatever the variation, any
lump of
neoplasm has this vascular stroma
that it has induced.
Okay.
Now go onto the next concept, that is related to the fact that
since neoplastic cells are derived
from a previously normal cell population, they're
going to share many of the genetic traits and are going to have some new ones
because of these mutations but they're going to share a tremendous genetic
background
with the parent issues so they're going to resemble the parent tissue
to some variable extent.
I mean sometimes very sharp resemblance, sometimes maybe not much of a resemblance.
When the neoplastic tissue
resembles the parental tissue, the normal tissue,
through a high degree
very close resemblance we speak about that neoplasm as being well-differentiated.
Funny phrase, I didn't invent it.
When we say well differentiated, it means looks just like mom and pop.
On the other extreme, it may look nothing, I'll show you some examples,
it may look nothing like the parental tissue, we say that is a poorly differentiated
or
undifferentiated
tissue.
There's another phrase, another word we sometimes use, that's anaplastic.
Anaplastic refers to
well, some people say de-differentiated, but undifferentiated
just immature or undifferentiated tissue
we refer to
as anaplastic.
There's a complete range
of possibilities.
Let me illustrate
this for you in two extremes
Here is normal colonic
mucosa, and we're going to talk about this in detail on Wednesday.
The mucosa has these
kind of tubular glands, that's all I want you to get out of this, this is perfectly normal
The next slide will be a cancer derived from this mucosa, looks like that.
Now you say, that doesn't look anything like it, but
in a sense it does.
it's got glands, they're kind of funky and kinky and so forth
but they're clearly glands.
You'll also notice that the pink to blue ratio has changed, a lot of hyperchromatism
a lot more nuclei here and so forth but basically
a pathologist looking at this would take about a nanosecond as you will learn
this spring and say oh!
this is a glandular type of
neoplasm.
So we say
this is at least moderately differentiated.
Now I'll show you a step down,
here's a normal bronchial mucosa, again don't worry about the details, but they're these tall
columnar cells,
some of them are secreting mucus
others have cilia on them
they're very well
organized there
The next line is a neoplasm derived
from that cell population
If someone showed me that I'd say that I don't know what that is,
that is an undifferentiated, malignant
neoplasm,
or anaplastic neoplasm.
And when
you look at that, what it really says is it's a population of cells
that's not maturing
you can't tell what it's doing or where it came from,
but it sure as the dickens looks malignant, look at those huge nuclei
increased n-to-c ratio (nucleus to cytoplasm)
they are actually pleomorphic, they are hyperchromatic,
there are
tumor giant cells there.
Really, you'll learn to look at those things and loathe them, to say that is an ugly
cell population
so that is a highly anaplastic cell population.
Now,
it turns out
well, let me give you
a rule of thumb first.
Benign neoplasms
are always splendidly well differentiated, sometimes you get in the
middle of a benign neoplasm, you can't tell it from the normal tissues, so a benign
neoplasms are always
well-differentiated.
Almost perfectly differentiated.
Malignant neoplasms show the whole range,
there are very well differentiated but nonetheless malignant neoplasms
and there are highly anaplastic
like this.
In some situations, in many situations,
in malignant neoplasms,
there is a a rough correlation, I emphasize rough,
between the degree
of differentiation and the behavior.
This is not uniform for all neoplasms
and remember well differentiated neoplasms/cancers can still kill.
But for
some situations, it's a
useful label that we
give it to send to our colleagues
where we say
we label it
depending on the degree of differentiation we call this ''grading'',
histological grading of neoplasm.
The grading of neoplasms is really
an assessment of the degree of differentiation of the neoplasm based on,
i mean we look under the microscope,
and we say oh! this looks just like
such-and-such tissue that's well differentiated
we sometimes take into account in these grading systems
the number of mitoses
that's a little less usual
but it's based basically on the degree of differentiation
and we talk about grade one, usually grade one means
the best differentiated grade, grade two to grade three, some grading systems are all
the way through grade four.
You get the idea, I mean you will get the details, but when we label with the grade
we say this is well differentiated and our colleagues at the other end say, well
maybe that'll behave a little better than if Abrams said it was anaplastic.
And Illl show you what this amounts to visually, again don't worry about being
able to pick these out.
Here is a carcinoma,
cancer derived from a squamous epithelium, like the epidermis of the skin
and a trained pathologist, which you will be
next spring, would look at this kind of arrangement or all this pinky cytoplasm
which represents keratin and
in the cells
and you'd say oh easy!
That's a well-differentiated
squamous cell carcinoma, this might be a grade one
for
instance
This one is might not look like much to you, but
a trained pathologist would look at this and say, well,
this isn't terribly
well differentiated but I can still see areas where I'll bet that's coming
from the squamous epithelium, so that would be maybe a grade two or moderately
differentiated
Here again is a completely
anaplastic cell population, someone showed me that and said where is this coming from
and I'd say
God only knows this is cancer.
When i don't know what kind,
this is really an anaplastic, probably grade three to grade four cancer
and again there's a rough correlation between
the degree of differentiation and how it might behave.
behave
Now grading,
this is all microscopic, grading is different than staging.
Please keep these two straight
and read and understand, you're going to deal
with these two concepts all your lives.
Staging a neoplasm is very important
because of the stage that we assigned to a neoplasm tells the observer
how far along in its natural history that neoplasm is, in other words,
how big is it at the primary, how much tissue has it penetrated,
has it advanced to the point where it's spread
elsewhere in the body.
That is staging.
It's based on first of all the size and the extent of the primary,
the presence or absence of regional lymph node metastases, and
the presence or absence of distant metastases.
This is sometimes referred to as the TNM system, T for tumor,
what's he doing with the primary,
N for regional nodes,
M for distant metastases.
Every organ has
a slightly different staging scheme, but they're all based on this
and what it gives you,
if it's a low stage
or a favorable stage, that says this tumor hasn't advanced
as far, maybe it's restricted just to
the organ, the lymph nodes are negative,
and there are no distant metastases,
or it may be that it's penetrated quite a way through
whatever organ it's started in, and there are already
lymph node mets but we don't know of distant mets
that's quite a different situation which may take a different therapeutic approach
and finally if they're already distant mets, that's a very different thing.
So staging
gives you a very important handle on how far
along the neoplasm is in the
particular patient and
what you should do therapeutically
because of that.
Now's not the time to dwell on how we tell benign from malignant and
in our daily work you will again get an appreciation for this next
spring, but suffice it to say
that we pathologists can look at a tumor
and make
some pretty good predictions about how it may behave.
In other words, if we look at a tumor and it looks very well-differentiated
and completely circumscribed and so on and so forth, we
say it's benign
and what that says is if you get the whole thing out, patient is home free.
If it's invasive anaplastic, it's a very different situation.
I can tell you that that the cornerstone
of clinical diagnosis
in the field of oncology is
getting something under glass,
getting in the microscope.
Very few instances where
therapy will be undertaken without confirmation
of the fact that under the microscope that it is such-and-such a cancer and such and such grade and so forth.
so it means we need a piece of the tissue
or at least
some cells from the tissue
to get under the microscope.
What we rely on there
as you might surmise from what you've seen is first of all
the cytologic features, how anaplastic looking are the cells, how bad is the
the pleomorphism, the hyperchromatism, etc, we rely on that
we rely on the relation of the cells to one another, the loss of polarity in the system
and so forth, and
we rely on the relation of the tumor to its surroundings, the nice pushing
margin vs boy! there goes invasion
it's that sort of thing. Now
I'll give you just a
very quick example of that.
Here is a
you can imagine that colon I showed you
in the cut,
here is a mucosa, a submucosa, here is a muscular wall,
here's the tumor arising in the mucosa.
You see under the microscope here, you can see kind of glandular spaces there.
Look what's happening,
you've got glands
penetrating clear down through the muscle there.
That's a no brainer
when we see something like that we say it's invading, it's malignant.
That make sense?
Sometimes we don't rely entirely on that, we rely on other things
The cytology, just quickly,
there are normal colonic epithelial cells
I'm not going to describe it, just let the pictures speak for themselves.
You'll catch up with this in the spring.
Here are neoplastic epithelial cells. Again, normal...neoplastic.
Here's a normal squamous
epithelium, we're back to cervix, here's normal squamous
here's dysplastic.
you saw that before, this variation, this loss of polarity, the individual features
of cytology here, that's a
degree of dysplasia, it's a step towards cancer.
This one we said was full thickness 'awfulness' with very anaplastic cells, I won't go into the details again.
The concept is important, when dysplasia gets severe
it's tantamount to
cancer in situ, whether or not it's invaded,
you see in the colonic example, we showed you invasion.
Here we can say this epithelium is cancerous, dammit!
Whether it invaded or not, we got to get it out or something bad is going to happen because
virtually 100% of these severe dysplasias will invade.
And that is
carcinoma in situ.
You'll hear a lot more about that
Now
clearly if you look at something like this
you realize that that individual cells in that population bear the
imprint
of their malignancy, in other words, they have these anaplastic traits and you
can say these are malignant cells.
A guy named the george papanicolaou
over half a century ago
realized that that this was a great handle, that if you
took cells that exfoliated, that is dropped off the surface, of
a place where there might be a tumor
that these exfoliated cells
would bear
some of these traits, these anaplastic traits, and all you'd have to do
is look at these cells and say WOW
this is so and so.
This is, as I'm sure you're aware, the origin of the so-called Pap smear,
and the beauty of the Pap smear is that you don't have to
cut out a piece of tissue from the person.
All you need is a sample
of the usually it's mucus
over the area, now
this has been perfected, this has changed the whole face of
how we deal with cervix cancer
but you can imagine a cervix...no let's back up,
looking like that
and that are
exfoliated, remember they come off here and getting a Pap smear
involves getting a little bit of mucus
scraped off the surface of the middle of some of these cells and
from a normal epithelium like this
you're going to see
and i'll show you a Pap smear
whereas from this
or this, you're going to get a different kind of cell exfoliating out
and without really having to get a big piece of tissue, you get a little bit a swatch of
mucus you can tell what you're dealing with.
I'll let you see this for yourselves.
Well, here are just some of cellular features of anaplasia.
Any look at a cell population like this with the huge nuclei
there's a tripolar division figure there,
those are the kinds of features we look for, all right here is a normal Pap smear.
You look at that without any training at all and you say well those cells look like one another
look like they're all out of the same cookie cutter, same N-C ratio
the nuclei are not pleomorphic, they are not very regular
etcetera etcetera etcetera
Normal pap smear next case,
now suppose that epithelium looked like
the bad one I showed you, there you are,
I'm showing you the extremes,
instead of being very regular, these are extremely pleomorphic cells with increased N-C ratio
hyperchromatism
and so forth,
the cytopathologist looking at this doesn't have to pause very often and say
this
has been exfoliated from a malignant cell population
and the nice thing is
that in between the cytopathologist can also
look at this and say well this probably came from a cervix with
moderate dysplasia
or minimal dysplasia or something like that,
so that not only can we catch cancers when they're perhaps too small to appreciate
by ordinary examination
we can actually
catch dysplastic epithelium
before it's become cancer or carcinoma in situ
before it's invaded, these things are all invisible pretty much
and they will show up on the cytological exam,
so it's become a very powerful screening tool
and it's changed the face of what we
see in the way of cervix cancer, when i was a kid in pathology we used to see
nothing but very advanced cervix cancer
that were clear into the rectal wall and bladder wall and so forth,
i haven't seen one of those thankfully in decades
because of the application of the Pap smear as screening.
That's something you'll hear a lot more about
so going back to generalities, a definition
of, or the diagnosis of neoplasm, requires getting something
under the microscope.
Now sometimes it's the whole
tumor, patient presents with lump sum or
you cut out the whole thing -- that's called an excisional, excisional biopsy,
and that's very nice because if it's benign, you're done.
If it's malignant,
you have to do some other things very likely.
Sometimes only a piece of tissue is removed, if it's a big mass
you don't want to go and do a commando operation until you know what you're
dealing with.
That may be an incisional biopsy, you take a wedge of it out.
There are various biting forceps where
bite a piece out
and there are punch forceps
particularly for skin things where you take a punch,
it's a little boring,
finally
very often there are a variety of needles that are used where you can
put a needle into a mass with very,
nothing beyond local anesthesia even,
put a needle in and draw out a core of cells
and get those
under the microscope
and the extreme of this
is putting in, and this can be done
you know with CT guidance into internal organs
put a very fine skinny needle in there
suck out some juice
from the
lump
and that juice will usually contain a few floating cells
and the trained cytopathologist could look at the degree of anaplasia and so forth
in those cells and make a diagnosis.
So, this is
always, almost always, what we do before undertaking treatment.
And
just to tell you, in conclusion, that this visual exam
under the scope is frequently augmented by other things.
Someone asked me, for instance,
can you always tell, looking at a met, where it came from, if it's an unknown
primary.
My answer was no, unfortunately
many different glandular neoplasms
look the same under the microscope,
so all we can say is this came from a glandular tissue. Sometimes we can use
immuno histochemical techniques,
in other words, there maybe certain proteins on the surface of certain cells
that identify them
we have a library of of antibodies directed against these various proteins
and they're labeled in a certain way and we can
make a cut of the tissue we have and put this on and if it lights up
we know that protein is represented, and to
give you a concrete example, suppose we had a lymph node that had a glandular cancer
and one of the possibilities
would be from the prostate
we could take an antibiotic to PSA (prostate specific antigen)
stain that tissue, and if it lit up,
those cancer cells had the prostate antigen, easy!
this came from prostate.
So we use those sorts of things
we've gotten into molecular methods of identifying this or that molecule and
in the cell population that augments what we can do visually and the ultimate
is something you're going to hear a lot more about and that is subjecting
the tumor to analysis with what we call microarrays which are the system
whereby you can screen for thousands of genes and see which ones
are activated
and we're beginning to
''beginning''
to be able to say well with this, this, this, these genes activated
this neoplasm is more likely to do this, and with this, this, this set of genes
activated it's more likely to do that. That's where it is all going.
Okay we'll continue this on Wednesday and feed you the rest.