Let's look at some examples.
Again, going down the microscope
and again, not trying to
turn you into pathologists,
but to just have you be able
to think about the concepts
and how that relates to the biology of neoplasia.
This is our lipoma, remember that
little yellow ball ditzl in the middle
of the small bowel?
It's very well differentiated, in fact,
if I showed you or I showed myself,
this, and a normal amount of fat,
I couldn't tell the difference,
this looks like normal fat,
so, it's very well differentiated.
There are very few mitoses in here, in fact,
I couldn't find any on this particular image,
but needless to say, in benign tumors,
there's very low mitotic rate turnover
and all the mitosis look entirely normal,
they have the normal bipolar appearance.
And there's no hemorrhage or necrosis,
that big red thing in the upper right-hand
corner, that's just a blood vessel
and there's no necrotic tissue, no hemorrhage,
so, that's a benign tumor, completely benign.
In comparison, here is our liposarcoma,
it is very much dedifferentiated,
looking at this no one would
be able to say up front,
“Oh my God, I think that
that came from a fat cell.”
No way, it has lost all of
its normal differentiation,
so, it's poorly differentiated.
There are a bunch of mitosis here
and many of them are abnormal,
instead of being nice bipolar,
they tend to be kind of in a circle
and there are many zones
of hemorrhage and necrosis.
So, I can say, even without knowing
exactly what the cell of origin was,
this is a malignant tumor.
Now, to figure out what it is,
I’d have to do some additional studies,
including molecular diagnoses
and including special stains.
Let's talk about a concept that is somewhere,
in between benign and malignant.
Dysplasia is, the state where the
cell is on its way to invasive cancer,
it's pre-invasive, but it is not benign,
so, we're kind of in between.
Dysplastic cells/dysplastic tissues,
have acquired some of the features of malignancy,
but have not yet developed into an independently
and wildly mutating cell.
Some mutations have occurred, but
not enough to call it malignant.
So, this can be a little bit
fuzzy and difficult to comprehend,
but it is our way of saying, if we think
that this is on its way to becoming cancer,
if we see it, we need to treat
it and not just let it go.
So, we're looking here on the left-hand side,
normal cells stacked up,
this could be a stratified cuboidal epithelium,
it could be any stratified epithelium,
sitting on a basement membrane.
With mild dysplasia, some of the
cells nearest the basement membrane,
where the stem cells are,
will have acquired some of the
features allowing independent growth
and you may be starting to lose
some degree of differentiation
and you may have some genetic
mutations that you can identify.
With severe dysplasia, almost the entire
thickness of this stratified epithelium,
has cells that are proliferating and
have acquired some additional mutations
and are well on their way to
becoming malignant, but not yet.
Carcinoma in situ, is where
the cells have completely now,
ticked over, spilled over and become malignant,
but they haven't advanced
beyond the basement membrane.
So, that means it's carcinoma in situ
and if we catch a cancer, in that period of time,
before it invades beyond the basement membrane,
it will not have had a chance to metastasize.
However, once it has invaded
beyond the basement membrane,
it can then access lymphatics and
blood vessels and other things
and potentially can metastasize.
As we talked about in a previous lecture,
there are many additional
steps that cells have to have,
in order to be able, to become metastatic.
They have to separate from their neighbors,
they have to crawl through the basement membrane,
they have to crawl through the
underlying extracellular matrix,
they have to crawl into blood vessels etc.
So, there are many additional steps
between carcinoma in situ to invasive.
So, dysplasia think of it as being
between benign and malignant,
it has some of the features of malignancy,
but not enough to formally call it cancer,
but left alone, it will develop into cancer.
A good example of this sequence of events,
happens in cervical malignancies, driven
typically by human papillomavirus (HPV).
We're looking here on the left-hand side,
at normal cervical epithelium
and there is a polarity, we have
the basal cells at the bottom,
the small round blue cells,
that are going to be where the proliferation is
and they only proliferate for
the first two or three layers up
and then they stop proliferating
and they start differentiating and
they become bigger flatter cells
with smaller nuclei until after a couple weeks,
they slough off at the top.
Here we have mild dysplasia,
otherwise known as,
cervical intraepithelial neoplasm (CIN I).
So, this is low level dysplasia, there is
a greater density of cells near the base,
that have a slightly increased
nuclear to cytoplasmic ratio,
that's what's being indicated in the box,
but they are still differentiating,
on their way to the surface
and eventually the surface cells are
sloughing off reliably in the normal way
and so, we have some of the features,
we have increased proliferation,
but we haven't yet acquired
enough other genetic mutations
for this to become malignant.
By the time that we're half filling up,
half of the layer of the normal
stratified squamous epithelium,
with now these proliferating cells with
an increased nuclear cytoplasmic ratio,
an increased nucleoli and increased pleomorphism,
we are at cervical intraepithelial
neoplasm stage (CIN II).
And you can see that there are still at the top,
cells that are becoming more squamoid
and we are not yet fully there.
By the time that we get to CIN III,
the entire thickness of this epithelium
has been replaced by tumor cells,
so, at this point, this we would actually call,
a cervical intraepithelial neoplasm (CIN III)
or carcinoma in situ,
the entire thickness is abnormal with
cells that have increased in ratio,
hyperchromasia, all the other
features that we've talked about.
So, in this process of going
from benign to fully malignant,
there's loss of maturation and differentiation
and at this point the basement
membrane is still intact.
So, this is pre-invasive
this is carcinoma in situ.
I gave you just the example
with the cervical epithelium,
same thing goes on in epithelial
malignancies, anywhere else.
And we've seen this before,
talking about the transition
from a normal colonic epithelium,
to a frankly malignant colonic epithelium.
So, we have our normal structure,
everything's going to of interest is
going to be occurring in the mucosa
and you can have germline or acquired
mutations of tumor suppressor genes,
such as the adenomatous, polyposis coli, APC gene.
That, single hit is not enough to really do much,
but that mucosa is now at risk
because we have lost one copy
of our APC tumor suppressor gene.
If we get a second hit of the APC gene,
in a cell or we alter some of
the other associated proteins,
that are going to interact with the APC protein,
such as B-catenin, now we have
increased proliferative capacity.
Those cells that are proliferating there,
are still not malignant, they are proliferative,
they are mildly dysplastic,
but they're not malignant.
As we acquire additional other oncogene mutations,
for example, K-RAS,
now we can get actual growth of adenomas
and depending on what mutations are occurring,
this may be mildly dysplastic still.
If we lose if we have normal
P53 in the entire equation,
then, we will see oncogene-induced senescence,
as they get more and more replicative,
they shorten and shorten,
the telomeres wild type P53, says
no, now you have to stop growing
and we have just a benign mildly dysplastic polyp.
But if we have other mutations,
loss of other tumor suppressors,
a loss or addition of other tumor oncogenes,
then we can get into frank malignancy.
Now, this example that I’m
showing here for colon cancer,
it doesn't always progress in
the sequence that I’ve shown you
and different genes can actually
get you to the same endpoint.
But again, it makes the point that along the way,
we will have varying degrees of dysplasia,
that we can recognize as pathologists
and we know that with that dysplasia,
there is potential to become,
that in fact that dysplasia is premalignant.
And if we don't deal with it,
additional mutations will occur
and you'll end up with cancer.
So, carcinoma can occur, coming off dysplasia,
dysplasia all by itself is not yet cancer.
This pathway, that I’ve shown here,
is only worked out for some epithelial tumors,
it's not exactly well worked out for other tumors,
such as, in lymphoma or melanoma or glioblastoma,
or any of those others.