0:01

IDH mutant Gliomas.

0:05

As we already know, majority of the lower

0:08

grade gliomas, grade 2 and grade 3,

0:11

they have IDH mutation.

0:13

Majority of the secondary GBMs which arise from

0:17

lower grade gliomas and get into

0:20

malignant transformation,

0:20

they also have IDH mutation, and only a small

0:25

percentage of primary De Novo GBMs

0:27

5 to 7% have IDH mutation.

0:32

Now, this is an example over here,

0:35

a large well-defined heterogeneous, enhanced

0:38

tumor in bilateral frontal lobes.

0:41

You can see more importantly,

0:43

it's a younger patient,

0:45

28-year-old, clinically intact,

0:47

presenting only with headaches.

0:49

And if I show you the CT scan,

0:52

we do see some curvilinear calcification within

0:55

the left frontal portion of this tumor.

0:59

And once we see that, and based on,

1:02

of course,

1:03

the young age and how the tumor looks,

1:05

we can very clearly say that this is an

1:08

IDH-mutated glioma. And more importantly,

1:11

based on the calcification,

1:12

we could also suggest that this could be an

1:16

oligodendroglioma, and this is what it

1:17

turned out to be. It's a grade two.

1:19

IDH was mutated, one P90Q was co-occurring.

1:24

And based on that,

1:25

the neuropathologist gave an integrated

1:27

diagnosis of oligodendroglioma.

1:28

And one more thing we know,

1:32

these mutated gliomas,

1:34

especially oligos, they grow rather slowly.

1:38

The median survival for these patients is

1:41

around 15 years versus around eight years for IDH

1:45

mutated astrocytoma. And this is an example,

1:47

you know, a patient who had a non-enhancing tumor,

1:50

I'm not showing you the post-contrast images,

1:53

but you can see there is very slow

1:56

progressive growth. And in fact,

1:58

the neurosurgeon and the neuro-oncologist, because

2:00

the patient was otherwise clinically intact,

2:03

um decided to wait and watch this.

2:07

And finally, in 2018,

2:09

when the tumor was still not showing any

2:12

contrast enhancement, was large enough, you know,

2:14

they decided that they're gonna take it out.

2:17

And this one turned out to be again an oligo.

2:20

And

2:22

uh another thing we discovered in 2017 is uh

2:27

this group of uh tumors which

2:30

show this imaging sign,

2:31

we call it T2 Flair mismatch sign where these

2:34

tumors which are non-enhancing,

2:36

uh they're very homogeneously bright on T2

2:40

weighted images. And more importantly,

2:43

dark on FLAIR images in the central part and

2:45

except maybe a peripheral rim of bright

2:47

signal on the FLAIR images.

2:49

And this is what we call T2 Flair mismatch sign.

2:51

These are tumors which show very low blood

2:52

volume uh and hardly any restricted diffusion

2:55

in the central part of the tumor.

2:57

And more importantly occurring in younger

2:59

patients and patients who are clinically intact.

3:02

And this one just presenting with headaches.

3:05

And we learned about these tumors that these

3:08

are IDH-mutated molecular astrocytoma,

3:12

which have a TERT loss.

3:16

And this is what we called

3:21

as the T2 Flair mismatch sign.

3:23

Um The important thing was um with this

3:25

paper in Clinical Cancer Research,

3:28

we showed that this sign was 100% positive

3:31

predictive value. Once we see this sign,

3:33

it's almost certain that this tumor is gonna

3:35

be an IDH-mutated non-core it or molecular

3:39

astrocytoma with one very big caveat that

3:42

not all astrocytomas show this sign,

3:45

only 15 to 18 or maybe 20% of astrocytomas show

3:49

the sign. But once we see see the sign,

3:51

you know,

3:52

we are fairly certain that this

3:54

is a molecular astrocytoma.

3:55

And this study has been validated by multiple

4:00

different research groups,

4:02

multiple publications.

4:05

So this is another patient, slightly older,

4:08

57-year-old, presenting with

4:10

anxiety and headaches.

4:12

And what we noticed is that there is a non-

4:15

enhancing infiltrative signal abnormal in the

4:17

left frontal lobe with slight expansion of the

4:21

gyri. Um there's hardly any enhancement.

4:23

And as we know,

4:25

um majority of the lower grade

4:27

gliomas are IDH-mutated gliomas.

4:29

They occur in younger age groups,

4:31

but some of them can also be seen in

4:33

older individuals. For example,

4:35

this one turned out to be an IDH-mutated

4:38

grade two astrocytoma and you,

4:41

you can see there was a CT scan available from

4:44

almost eight years ago and this tumor was there,

4:47

um just not called,

4:49

it's very difficult to call

4:50

on just on the CT scan.

4:52

Uh But you can see there was some hyperdensity

4:55

suggesting that these,

4:56

these tumors can be lying innocuous uh in,

4:59

in the brain and may not present.

5:02

Uh and and may not progress uh rather quickly.

5:08

Uh Another thing which our discovery of IDH

5:10

mutation has led to is a paradigm shift in

5:13

management of these tumors because they

5:15

grow rather slowly. Uh For example,

5:17

this is another young female with

5:19

the left frontal lobe tumor,

5:21

well-defined nonenhancing uh turned out that

5:24

this was an anaplastic astrocytoma.

5:27

Uh IDH-mutated, one P19Q non-coordinated,

5:32

undergoes surgery undergoes complete resection.

5:34

This patient would have been offered

5:36

temozolomide and radiation therapy,

5:38

standard COOP regimen a few years ago,

5:41

not anymore. Um You know,

5:43

many of the neuro-oncologists will like to

5:46

actually wait and watch if this tumor is

5:48

completely uh resected. For example,

5:50

this one was completely resected.

5:52

They could even watch these tumors and will give

5:55

chemo and radiation only when the recurrence

5:58

occurs rather than going upfront

6:00

with chemo and radiation.

6:02

That's a little bit controversial but still a

6:05

paradigm shift in how these tumors are treated.

6:07

Now, another example over here,

6:10

another IDH-mutated astrocytoma in grade two.

6:13

This patient was diagnosed in 2003 was

6:16

offered chemo radiation. In fact,

6:19

the surgery happened in 2000 and,

6:21

and was offered a radiation and temozolomide.

6:24

The patient refused any chemo radiation at

6:27

that point. And you can see, you know,

6:30

10 years later, there is hardly any,

6:32

any progression.

6:33

All we see is a little bit increased signal

6:36

along the ante margin of the surgical resection

6:38

cavity, which was non-enhancing.

6:40

Uh The management team decided to watch it, and

6:44

this, this is what happens four years later,

6:46

it's around 14 years after the initial diagnosis,

6:49

actually 17 years after the initial diagnosis,

6:51

you can see the tumor is now progressing.

6:54

And that's when you know the,

6:56

the chemo and radiation could be offered to

7:00

these patients. So IDH mutated gliomas.

7:03

They occur in younger patients.

7:05

They're usually asymptomatic or maybe presenting

7:07

with headaches or even seizures.

7:09

They are usually large by the time, you know,

7:12

because they have been growing

7:13

very slowly over time.

7:14

So they could become rather large

7:16

when they present on imaging.

7:19

Uh One another important aspect,

7:21

IDH mutated gliomas,

7:22

they somehow love the frontal lobe.

7:25

Uh They could be partially

7:27

or completely non-enhancing.

7:29

They could have cysts and they

7:31

usually have good prognosis.

7:32

So I've shown you an oligodendroglioma.

7:34

Uh We have discussed, you know, astrocytoma.

7:37

Now, one caveat over here,

7:39

not all the tumors imitated tumors which show

7:42

calcification are gonna be oligodendroglioma.

7:44

This is an example.

7:46

This one turned out to be an astrocytoma

7:48

showing some dystrophic calcification,

7:50

not very common though. Now,

7:53

one more uh tumor I would like to discuss over

7:56

here is IDH mutated glioblastoma or grade four

8:00

IDH mutated tumors. And this is an example.

8:03

Um again, if you look at the age,

8:06

this is a relatively younger patient.

8:09

Uh right frontal lobe, again,

8:10

IDH mutated gliomas,

8:12

they prefer or they love the frontal

8:15

lobe location. Uh Now,

8:16

this is a large tumor showing some enhancement

8:20

and central necrosis and there is massive

8:23

edema, mild edema surrounding this tumor.

8:26

But more importantly,

8:27

this is a tumor despite showing this aggressive

8:31

necrotic enhancing features also has

8:33

a thick kind of non-enhancing tumor.

8:36

If you look at this part of the tumor

8:37

and this part of the tumor,

8:39

it's non-enhancing once I see an appearance like

8:42

that in a younger patient and especially a

8:44

frontal lobe tumor. Uh of course, you know,

8:47

based on histology,

8:48

this turned out to be a GBM.

8:50

But more importantly,

8:51

this one turned out to be an IDH mutated GBM.

8:54

So remember, from my previous discussions,

8:58

you know, GBMs,

8:59

majority of them are IDH wild type,

9:01

except 5 to 7% of GBMs will

9:04

have IDH mutation. And,

9:06

and uh the reason uh these are good tumors to

9:09

have. Uh this is an example over here,

9:11

the patient underwent surgery, radiation,

9:13

temozolomide, and DCVAX trial.

9:16

And this is nine years later. You know,

9:18

there is no recurrence.

9:19

Uh there are some post-treatment effects but

9:22

the patient actually is doing rather well.

9:24

And this kind of fits into um the category

9:27

I talked about the GBMs being good,

9:29

bad, and mad and this is a good GBM to have,

9:32

right?

9:33

Uh These are IDH mutated GBMs which are gonna

9:36

have a much better survival than

9:38

IDH wild type glioblastoma.

9:42

And uh knowing this fact,

9:45

uh who has the C impact has come up with this

9:49

update five, which includes a few other things.

9:52

For example,

9:53

uh the Arabic numerals are in and Roman

9:57

numerals are out. For example, you know,

9:59

the neuropathologist now will be calling

10:01

it grade two in Arabic numerals,

10:03

grade 234 rather than Roman numerals.

10:07

This is to avoid any kind of confusion.

10:09

There was one,

10:10

the second thing uh this update uh uh suggested

10:15

is that um IDH mutated astrocytoma,

10:18

which are grade four,

10:20

they should not be called glioblastoma just

10:22

to separate them out from IDH wild type glioblastoma.

10:25

Uh They will rather be called astrocytoma.

10:30

IDH mutated grade four and a couple

10:34

more uh important things.

10:35

This update mentioned that these tumors could be

10:38

upgraded from grade three to grade four based

10:41

on either microvascular proliferation or

10:44

necrosis seen on histopathology or homozygous

10:47

deletion of CDKN2AB,

10:50

which is also known as P16.

10:53

This is an important tumor suppressor gene

10:56

and we'll be discussing that a little bit more.

11:00

So P16 is a very well-studied and very well

11:03

known tumor suppressor gene implicated

11:06

in multiple malignancies.

11:07

And now also has been shown to be an important

11:11

factor in IDH mutated astrocytoma. So,

11:14

we know IDH mutated gliomas,

11:16

IDH mutated astrocytoma,

11:18

they do better than IDH wild type. Uh,

11:21

but another important,

11:22

think this very important paper showed, uh,

11:25

that if you have a GBM,

11:28

even if it's a grade four um astrocytoma, GBM,

11:32

if you do not have P16 loss,

11:35

P16 is intact on wild type.

11:37

These GBMs actually do much better than GBMs

11:41

with P16 loss, right? So that's very important.

11:44

The other important thing,

11:46

this paper showed that if you have,

11:49

even though it's an anaplastic

11:51

astrocytoma grade three,

11:52

if you have an anaplastic astrocytoma

11:54

with P16 loss,

11:56

they actually behave almost similar to GBMs

12:00

with P16 loss even worse than GBMs without

12:03

P16 loss. So, what does that mean?

12:06

Let me simplify that. So,

12:08

in IDH mutated astrocytoma is another important

12:11

thing to understand and it's,

12:13

it is now part of the C impact upgrade five is P

12:17

16 loss or CDKN2AB homozygous deletion.

12:21

Uh you wanna know if that is um there or not?

12:25

So if you have homozygous loss of P16,

12:28

that's gonna do poorly, right?

12:30

So this 5% these tumors should be classified as

12:34

um grade four. And if you don't have P16 loss,

12:38

the next thing,

12:39

this this this group of researchers looked at

12:42

its necrosis on histopathology

12:43

and and of course,

12:45

the tumors without necrosis are gonna do a

12:47

little bit better than the tumors with necrosis.

12:50

So, an example over here, um you know,

12:53

a slightly younger patient with a

12:57

non-enhancing large mass in

12:58

the left temporal lobe,

12:59

you can see that this mass is actually showing a

13:02

T2 flare mismatch sign. Also, as we know this,

13:05

this sign is seen in IDH astrocytoma.

13:08

And the there there is another example I have in

13:11

the lower panel, a similar age group patient,

13:14

uh similar tumor in the left temporal lobe

13:18

non-enhancing showing two flare mismatch sign.

13:20

What is different between these two patients?

13:23

The one in the upper row actually has

13:25

a P16 loss. What does that mean?

13:27

That means that's a bad tumor to have? So,

13:30

despite looking very similar on imaging and also

13:33

on histopathology and ID mutation status,

13:37

uh you know, this one is doing much worse.

13:40

Uh This patient comes back with a very

13:43

aggressive looking recurrence within 30

13:45

months and eventually ended up dying.

13:46

Uh On the other hand,

13:48

the one in the lower panel uh underwent

13:51

surgery and therapy,

13:52

chemo and radiation and this

13:54

is eight-year follow-up.

13:55

There is hardly um uh there there is no tumor

13:59

recurrence and the patient is

14:00

actually doing very well.

14:02

And that's based on what we know from this,

14:05

the impact upgrade five,

14:08

that the tumors with P16 loss,

14:10

even though they are imitated,

14:12

they're gonna do worse than, uh,

14:14

the ones with be with P16 intact.

14:17

Another thing we understand is that, uh,

14:20

many of these, I get mutated gliomas,

14:23

they progress rather quickly to glioblastomas

14:26

or secondary GBMs.

14:27

And this is a study which showed that, uh,

14:31

patients who uh have this quick progression

14:34

from uh a lower grade glioma into a GBM.

14:39

Uh These tumors actually show uh what we known

14:43

as chromosomal intimate. This is, you know,

14:46

chromosome profile,

14:47

methylation profile done at the baseline

14:50

and the recurrent tumor,

14:51

you can see all these tumors

14:52

when they reoccur uh they,

14:55

they show a very high degree

14:57

of chromosomal instability.

14:59

And this is another important uh factor which uh

15:02

another review article mentioned that, you know,

15:05

uh that this chromosomal instability can

15:08

negate the beneficial effects of IDH in,

15:12

in IDH mutated astrocytoma.

15:15

Um We have tried to correlate copy number,

15:19

um variability with imaging and

15:22

in IDH mutated astrocytoma.

15:24

And we have shown over here in this paper

15:27

is that uh IDH mutated astrocytoma,

15:29

if they have P16 loss,

15:31

they have a higher incidence of necrosis.

15:35

There are larger tumors.

15:36

Uh they also have restricted diffusion and more

15:39

importantly, also have high blood volume,

15:42

higher blood volume compared to the ones where

15:45

the chromosome um variability is not that

15:48

much or there is the chromosome.

15:50

Um chromosomal um um component is

15:54

much more stable in these cases.

15:56

Uh Here is an example of two different patients,

15:59

you know, um similar tumor imitated astrocytoma.

16:02

Um The one in the upper row is a

16:05

much smaller tumor non-enhancing.

16:07

The one in the lower row is a much larger tumor

16:10

with high blood volume and areas of restrict

16:12

diffusion. And of course, you know,

16:14

they have chromosomal profile,

16:16

which looks like that.

16:17

The one in the upper row is much more stable

16:20

chromosomal profile compared to

16:21

the one in the lower row.

16:23

Uh We also looked at uh blood volume data and

16:27

this is data we published from NYUTCGA and

16:31

Heidelberg um showing that blood volume um on Mr

16:35

perfusion would be high in tumors

16:38

which have P16 loss.

16:40

Whereas uh tumors which have P 16 intact,

16:44

uh they have lower blood volume.

16:46

And the same thing goes with

16:48

the copy number profile,

16:49

the tumors with uh higher chromosomal

16:52

instability, they have high blood volume,

16:54

high blood volume compared to the ones which

16:56

have a stable uh chromosome uh pattern.

17:00

Um Now, uh IDH mutated duo Blastoma,

17:05

as I said, uh they could have uh you know,

17:09

um a non-enhancing component to the tumor.

17:12

Another example over here is a necrotic

17:15

enhancing mass in the right occipital lobe.

17:16

But if you look closely there is a tumor tissue

17:20

which is showing you no enhancement along,

17:24

especially along the lateral aspect.

17:26

This is again,

17:27

a tumor which is showing high blood volume in

17:29

the enhancing portion of the tumor

17:31

in a relatively younger patient.

17:33

Uh This patient uh turned out undergoes surgery

17:37

comes back as an IDH mutated glioblastoma. Why,

17:40

why it's important because these

17:42

IDH mutated glioblastoma,

17:44

they um are gonna do better than

17:47

IDH wild-type glioblastoma.

17:50

Uh This patient undergoes complete

17:52

resection and uh and,

17:54

and this is a follow up uh a year later

17:58

uh at the primary tumor site.

18:00

But we also learned that this tumor actually

18:03

had P16 loss. What does that mean?

18:06

That makes this a little bit more aggressive

18:08

than IDH mutated glioblastoma,

18:11

which won't have a P16 loss. And,

18:13

and that's what happens with this patient,

18:15

you know,

18:15

within a year uh after the initial diagnosis,

18:19

patient comes back with a recurrence um in,

18:22

in the right uh frontal horn in the frontal lobe

18:25

region undergoes another resection. Uh and,

18:29

and comes back with another quick progression uh

18:32

a month later after the second surgery and,

18:35

and continues to grow this tumor despite multiple

18:38

therapy regimens, and then in fact,

18:41

even starts to have a recurrence at the primary

18:43

tumor site also and in and ends

18:46

up doing rather poorly.

18:48

So this is another example where IDH mutated

18:51

astrocytoma, if they have P16 loss, you know,

18:54

they will continue to do poorly.

18:56

So this patient's uh primary tumor and,

19:00

and the recurrent tumor,

19:02

they were uh they were sent

19:04

for uh methylation profile.

19:06

And another thing uh we noticed uh based on the

19:10

methylation profile and the

19:12

tumor mutation burden.

19:13

Uh you can see that the initial tumor uh had

19:16

a lower tumor tumor mutation burden,

19:19

uh which became really high, you know,

19:21

from six mutations per megabyte to 70 tumi

19:25

mutations per megabyte on the recurrent tumor.

19:27

What does it?

19:28

This means this means that tumors will develop

19:32

chromosomal instability and very high mutation

19:34

burden as uh they will become uh as they

19:38

will uh uh progress and recur. Now,

19:42

IDH mutated uh glioblastomas which are also

19:46

known as secondary GBM. Uh uh they are,

19:50

they could be large and as I said,

19:52

they could have uh nonenhancing component

19:55

in the tumor. Of course,

19:57

they have a high blood volume in the enhancing

19:59

portions. Uh But more importantly,

20:01

uh unlike IDH wild type glioblastomas,

20:04

which progress rather rather quickly.

20:06

Uh This patient, we had a follow up.

20:08

Uh we had a scan done six years earlier and you

20:12

could see there was a small signal of normality

20:14

which was actually uh not really called.

20:17

Um But you can see this tumor has grown over a

20:21

period of uh almost six years. And, and this,

20:25

this, this is the, this is an example,

20:27

you know that these IDH mutated tumors and,

20:29

and even secondary GBM,

20:31

they start as lower grade gliomas and slowly

20:34

progress over time. Unlike IDH wild-type gliomas,

20:37

which progress very quickly.

20:40

So,

20:41

are there any imaging features or imaging

20:43

modalities which help us determine IDH mutation

20:46

status of the dias preoperatively?

20:49

Apart from the T2-FLAIR mismatch sign,

20:51

we discussed is MR spectroscopy.

20:54

As uh we know that IDH mutated tumors,

20:57

they generate this on meta

20:59

light called 2-hydroxy.

21:00

And there are quite a few publications uh which

21:04

discuss that I this 2-hydroxy glu uh could

21:07

be detected with MR spectroscopy.

21:10

And this is another example over here.

21:13

Uh in 13 more patients,

21:14

you can see that the 2-hydroxy glut trade

21:17

signal has been detected on MR spectroscopy

21:20

amongst the other metabolites. Now,

21:23

this is probably one of the only ways you can

21:26

diagnose an IDH mutated tumor uh preoperatively

21:29

apart from the T2-FLAIR mismatch sign.

21:32

Um but the problem with MR spectroscopy

21:35

and 2-hydroxy glutarate detection,

21:37

it is technically very challenging and it's not

21:41

possible to use it in clinical practice.

21:44

Uh At most places, including at NYU,

21:48

we have been struggling with it.

21:50

So let me summarize a few facts about

21:53

IDH one and IDH two mutations,

21:56

majority of the lower-grade dias and only 5% of

21:59

the GB MS show IDH mutation. ID mutated

22:03

dias occur in younger patients.

22:05

IDH mutated dias tend to be far less aggressive

22:09

than their who-grade match

22:12

IDH Y-type counterparts.

22:14

And uh one important thing we learned in the

22:17

last few years is if we see this

22:20

T2-FLAIR mismatch sign,

22:21

it's almost 100% positive predictive value

22:24

uh to detect IDH-mutated astrocytoma.

22:27

But remember, not all astrocytomas show the sign,

22:30

you know,

22:31

around 15 to 20 or 22% of astrocytomas

22:34

show this sign.

22:36

Uh, another important factor to keep in

22:39

mind is um uh IDH-mutated tumors.

22:42

They love frontal lobe location.