(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 <i>at</i> 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.