- Okay, now most of the time,
we still survey low grade.
We keep people under surveillance.
How comfortable are we doing this?
Well, again, a lot of this literature is based
on older resolution white-light colonoscopy,
but here's what we know.
As I said, there's a 20% chance
that you're missing a cancer already.
If you wait five years,
there's as much as a 23 to 50% progression
for high grade or cancer.
An important concept is that only one focus
of low-grade dysplasia, we think,
is the same risk as multifocal.
(electronic beeping) It's like being pregnant.
Okay, you don't have to wait for there
to be multifocal low-grade dysplasia
before the risk goes up because it may not happen.
So very few studies have looked at that.
I'll show you the one slide in a moment.
But unifocal is just as likely to progress as multifocal.
Once low grade is diagnosed,
you know, some patients say or doctors say, "You know what?
"I'm not sure I believe that there was low grade there.
"I'm gonna do another colonoscopy in six months.
"And if there's no dysplasia, maybe it was a mistake,
"maybe it went away, maybe I'm okay."
No, if the second exam is normal, meaning no dysplasia,
it doesn't lower the risk of subsequent dysplasia or cancer.
We know that low grade doesn't have
to progress through high grade to get to cancer.
The other thing is chromoendoscopy
clearly finds more dysplasia,
but we don't yet know whether that changes anything.
I'll get to that in a few minutes.
And there's an entity that I'd like to share with you.
And the pathologists in the room are aware of this,
but not all the clinicians are.
There's an entity that Dr. Harpaz at my institution
has termed low-grade tubulo-glandular adenocarcinoma.
It's a long, complicated term,
but it basically is a type of colon cancer
that seems to occur only in IBD patients
or primarily in IBD patients.
Dr. Harpaz tells me he doesn't see this type
in sporadic colon cancer, Lynch, or FAP.
These are cancers that arise directly
from low-grade dysplasia.
And I'll show you, if my images will transfer,
I'll show you that in a moment.
So here's the unifocal, multifocal argument.
Okay, this is work from Tom Ullman at our center.
And basically he looked at the five-year rate of progression
in people who had unifocal low grade versus multifocal,
and the curves are superimposable.
So we think that even unifocal
has a similar risk to multifocal.
This gets to the issue of
what if the second exam is negative for dysplasia?
This is an older study from Burt Korelitz at Lenox Hill,
where they took all of their patients under surveillance,
and they found that 22% had dysplasia.
The ones that had a polyp or a cancer went to colectomy.
So they were left with 22 low-grade dysplasia patients
who stayed in surveillance.
On the next exam, and the interval might've varied,
but at the next colonoscopy, 69% of them had no dysplasia
after the initial finding of low grade.
Were they out of the woods?
No, because if you look at the subsequent exam,
40% of them still went on to dysplasia,
three of them had cancers.
In fact, the three of them had cancers in five to 10 years
without going through high-grade dysplasia.
So having dysplasia, then not having it
doesn't mean you're gonna continue to not have dysplasia.
You may still get it again.
Okay, this slide from Tom's study shows that you don't have
to go through high-grade dysplasia to get cancer.
This is the seven patients
who developed cancers in our program,
and you can see the various stages.
One patient under surveillance developed high grade,
which prompted the colectomy that found the surprise cancer.
But all these other patients remained in surveillance
and had no dysplasia, indefinite, low grade,
and then boom, cancer,
okay, no high grade.
And in fact, the two patients that had
node-positive cancers, the colonoscopy that preceded
the detection of the cancer had no dysplasia at all.
So patients can peter along,
you know, have dysplasia, no dysplasia,
and then all of a sudden have cancer.
Low-grade tubulo-glandular adenocarcinoma,
so again this arises directly from low grade.
It's associated with IBD.
It accounts for 11% of the cancers that we see in IBD.
It can be found in UC or in Crohn's.
And some people have more than one of these things.
There can be multiple.
And it's rare that we find this pre-operatively.
It's usually done, oh, good, it transferred.
Okay, so here is a slide that I lifted
from Noam Harpaz and Gabe Levi's paper from a few years ago.
So here's a colectomy specimen.
You can tell from the depth.
When we biopsy the colon,
our biopsy forceps go about this deep, right?
The muscularis mucosa is somewhere around here.
If you biopsy this,
anybody in the room would say that's low-grade dysplasia,
not very interesting.
But this low-grade dysplasia is invading.
Okay, it's clearly going through into the wall of the colon.
And when you look at these glands under higher power,
these glands are very innocent-looking.
They're very benign-looking.
The nuclei are really pretty homogeneous.
They're not piled up.
It's a lot of cytoplasm.
There's very little desmoplastic reaction.
They look like they're behaving themselves,
but this is in the muscle.
Here's muscle fiber.
So this is an invasive
kind of benign-looking type of cancer,
and we think now maybe this could be one reason
by which people with low-grade dysplasia
might have a surprise cancer.
There could sometimes,
and I don't like to even raise this
because it scares people probably,
but it's possible that maybe sometimes
with low-grade dysplasia you've got a cancer already
underneath it or not too far away.
So it's an entity that I think we need to be aware of.
Every time I give a talk,
I try to make clinicians aware of this entity.
Maybe Henry can talk about that at the end
and shed some more light.
Now, what about indefinite dysplasia?
Not every pathologist of the country even uses the term
because it means different things to different people.
When you have an expert pathologist, like Henry,
or, at my center, I'm lucky I have Noam Harpaz,
if somebody really can reliably interpret
indefinite dysplasia, it is a separate entity.
And we went back and looked
at our natural history at Mount Sinai
of people who have indefinite dysplasia,
and here's the five-year, well, here's the progression rate.
This would be five years.
Here's the progression of people
who never had dysplasia on multiple exams.
This is somebody,
these are people who had indefinite.
There's about a 14% five-year progression rate
to getting high grade or cancer.
Now, I don't have the low grade curve.
But if you remember from before,
our data goes up to about 53% at five years.
So low grade is up here somewhere,
and indefinite is somewhere in between.
So we do feel that indefinite is a bona fide entity.
It really is different from no dysplasia.
It's not as bad as high grade,
but it is something to pay attention to.
Let's spend a minute or two talking about chemoprevention.
The data is mixed in many studies, but the one thing
that seems to emerge clearly of all the agents
that have been looked at is ursodeoxycholic acid.
And that's in the PSC patients.
So there's been two or three nicely done,
actually prospective studies
that show that people with PSC who take Urso
have a lower risk of developing colorectal cancer.
Okay, the problem is only 5% of IBD patients have PSC.
We don't know whether giving Urso to everybody
with IBD would lower their colon cancer risk.
It would be an interesting study to do.
There's a little bit of data
that Dean Brenner I'm sure is aware of.
In the general pop, in polyp prevention studies,
Urso has been shown to lower the risk
of future advanced adenomas in the sporadic population.
So there's some tantalizing evidence
that Urso not only works in PSC patients but might even work
in the general population or those with IBD.
I think, in the general population,
because you can get diarrhea from Urso,
people may not be too keen to use it.
But you take a colitis patient who's having four or five
bowel movements a day anyway, they might not blink.
Okay, 5-ASAs, can't go into all the details,
the data are mixed.
I think, in balance, 5-ASAs do work,
and I'll show you some of that data.
But it is mixed.
And if anybody cares,
they can go to the technical review, and there's a table
that lists every study that's been done in this area.
6-MP, azathioprine don't lower your risk of colon cancer,
as best as we can tell.
There's a neutral effect.
They don't increase your risk fortunately,
but they don't seem to lower your risk.
There was a study presented at DDW last year
from the French group, but they really didn't comment
on their duration of use and the dosages.
They claim that 6-MP and azathioprine do lower your risk
of getting colon cancer, but I need to see the primary data
before I can really be sure.
Folic acid, it's never been shown
in a statistically significant way to lower your risk.
People say it's cheap, it's a vitamin, whatever,
you know, use it.
No data on biologics.
Okay, the 5-ASA literature, this is a meta-analysis
from Fernando Velayos from a few years ago.
I think the data still applies.
What you can see here is he looked at all the studies,
cohort, case-control studies that looked at
whether 5-ASAs may be chemopreventive.
And if you look at the bottom line here,
it seems to lower your risk somewhat,
maybe to the tune of about, you know, .5, .6.
Again, not every study has shown an effect on cancer.
And in fact, a lot of studies hadn't even looked
at dysplasia as an endpoint, just cancer.