0:01

I'm gonna be discussing WHO glioma classification

0:04

update and important genetic markers.

0:09

This slide kind of shows you one of the reasons

0:12

why genomic studies are getting integrated into

0:15

almost every aspect of health care sciences.

0:18

The cost of obtaining a whole genome expression

0:21

was around $100 million just 20 years ago.

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And that cost has come down

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to just over $1000 or so.

0:28

In 2019-2020

0:33

this is, you know,

0:34

the older 2007 WHO classification

0:37

of central nervous system tumors,

0:39

you can see gliomas were divided into

0:43

astrocyte morphology or oligodendroglia

0:46

morphology based on the histopathology and then

0:48

were graded as grade 2, 3, or 4 astrocytoma,

0:52

grade two and 3, 4 oligodendroglioma. However,

0:55

one of the major issue was that, you know,

0:59

there was a group of cases which the

1:03

neuropathologist could not separate clearly into

1:06

astrocytoma or oligodendroglioma and they

1:09

were calling these as oligoastrocytoma.

1:12

So the biggest issue with this kind of

1:15

classification was that there was very

1:17

high inter observer variability.

1:19

The second issue was inability to predict

1:23

clinical outcome based on this kind

1:25

of classification system only

1:28

and fast forward to 2008, discovery of IDH

1:32

mutation in gliomas led to a paradigm shift

1:36

in not just the classification but

1:38

also management of these gliomas.

1:40

And this was one of the earliest papers showing

1:42

that if you have a glioblastoma and

1:46

it's a one histological diagnosis,

1:48

but if you have IDH mutated GB MS,

1:51

they do much better than IDH wild type GB MS.

1:54

Another paper a year later in Negm showed

1:58

that this beneficial effect of IDH mutation

2:01

continues not just in the GB M world,

2:04

but also in the other gliomas. For example,

2:07

anaplastic astrocytoma. Over here,

2:09

IDH mutated ones doing much

2:12

better than IDH wild type.

2:15

The same paper also showed that majority

2:18

of the lower grade gliomas,

2:19

they have IDH mutation,

2:22

majority of the secondary GB

2:24

MS also have IDH mutation.

2:26

Whereas primary de novo GB MS only

2:30

5 to 7% have IDH mutation.

2:35

And as you can see from the slide,

2:37

you know IDH being the primary driver mutation

2:41

and then you get into the secondary mutations,

2:44

for example, one P nine Q,

2:46

which kind of decides that these gliomas will

2:49

become oligodendroglioma or if you don't have

2:53

one P nine Q co-deletion you have either TPTP 53 or a

2:58

TRX loss and that leads to these glioma tumor

3:02

cells propagating as astrocytoma.

3:08

Now,

3:08

this paper in Negm showed that very clearly

3:13

if you divide these tumors lower grade

3:16

gliomas grade two and grade three based

3:19

on histologic classification.

3:21

Versus if you divide them

3:24

based on molecular subtypes,

3:26

you actually do a much better job by dividing

3:29

them into molecular subtyping.

3:31

And that was one of the reasons this paper

3:34

proposed and who came up and removed

3:37

this category of oligoastrocytoma.

3:40

And we'll discuss a little bit more about that.

3:42

So this paper showed that if you have grade

3:45

two and grade three, lower grade gliomas,

3:47

the first mutation you wanna look at is IDH.

3:50

The next thing you wanna look at is one P 19 Q

3:52

co-deletion status. And if you have both,

3:55

these are your molecular oligo if you have only

3:59

IDH and no one P 19 Q co-deletion but

4:03

you have TP 53 and A TRX loss.

4:05

These are your molecular astrocytoma.

4:08

One more important thing this paper

4:12

described is that there is a smaller percentage

4:16

around 20 to 22% of low grade gliomas which do

4:20

not have ID mutation. These are ID wild type,

4:24

low grade gliomas which actually behave

4:27

much worse, almost similar to A G PM.

4:30

And we used to call them molecular

4:32

GB MS or pre GB MS.

4:35

So this is from the same paper, you know,

4:38

looking at the survival curves if you divide

4:40

these tumors based on histopathology,

4:43

there is the only thing which comes

4:45

out is the GB M is doing poorly,

4:47

but the rest of the groups kind of overlap

4:49

and there is not much distinction.

4:51

But if you divide them based

4:53

on the molecular subtyping,

4:55

you can see that the IDH Wild type GB MS as

4:59

expected are doing very badly. However,

5:03

lower grade gliomas,

5:05

these are tumors which were graded,

5:07

grade two and three.

5:08

But if you have an IDH Wild type,

5:10

lower grade the molecular GB M,

5:12

the pre GB M category, which just discussed,

5:15

these are also doing poorly,

5:16

almost similar to the IDH wild type GB MS.

5:20

On the other hand, if you have a GB M,

5:22

but it's IDH mutated,

5:24

it's doing a little bit better, right?

5:26

So that's kind of going into more detail

5:30

about how these genomic subclasses help better

5:34

prognostication of these gliomas. Now,

5:37

what is IDH it's isocitrate B hydrogen A

5:42

five genes encoding for three human IDH

5:45

catalytic isozyme IDH one and two being the two

5:47

most important immuno histochemistry detects

5:51

almost 85 to 90% of IDH mutations

5:55

but does not detect all.

5:56

And that's where you need either pyro sequencing

5:59

or next-gen sequencing to detect

6:01

all of the cases correctly.

6:05

IDH mutation occurs early in glioma genesis and

6:09

leads to production of onco-meta

6:12

like two hydroxyglutarate,

6:14

which also can be detected with Mr spectroscopy

6:17

and has been shown in some studies.

6:19

How IDH mutation leads to oncogenic

6:23

transformation remains controversial.

6:27

One of the reasons described is that the excess

6:30

production of NADPH in IDH wild type tumors

6:34

and that leads to this excess production of

6:38

NADPH protects the tumor cells against

6:42

the body's reactive oxygen species.

6:45

Hence making them more aggressive tumors

6:48

compared to IDH mutated tumors

6:53

a little bit about one P 19 Q co-deletion

6:57

which is basically correlation of

6:58

the short arm of chromosome,

6:59

one known as one P and long

7:02

arm of chromosome 19.

7:04

Also known as 19 Q fish has been used

7:09

extensively to detect one P 19 Q co-deletion.

7:11

However,

7:12

it's an imperfect technique and

7:15

may miss a few cases, for example,

7:18

partial or interstitial deletions and,

7:21

and those may not be detected correctly

7:24

by FISH. And that's where, you know, you get,

7:28

get into either next-gen sequencing or math

7:31

profiling where you can look at the loss of

7:34

complete arm of chromosome one and also

7:38

loss of complete arm of chromosome,

7:41

long arm of chromosome 19.

7:45

So once you detect that, it, it's,

7:49

it's known that it's a prognostic marker as a

7:52

as well as predictive of response to

7:54

PVC chemotherapy and radiation.

7:57

That means respond better to this therapy

8:01

based on this kind of genomic markers.

8:06

Now,

8:07

I don't diffuse gliomas if I have to

8:09

look at the first mutation is the IDH.

8:12

And if you have IDH mutation the next

8:14

thing to look at is one P 19 Q.

8:16

If you have both IDH and one P 19 Q coil,

8:20

these are your Lyden gliomas.

8:22

If you don't have one P 19 Q,

8:24

you have loss of either A TRX or TP 53.

8:27

These are your molecular astrocytoma. Now,

8:30

on the other hand,

8:33

slightly more than 50% of primary gliomas in

8:36

adult patients, they do not have IDH mutation.

8:39

They have another mutation

8:40

known as third mutation.

8:42

And these are known as IDH Y type gliomas.

8:45

And within that group,

8:47

you can look at the MGMT. And,

8:50

and there are two groups, you know,

8:51

MGMT methylated tumors and MGMT unmethylated tumors.

8:54

The reason to divide these gliomas based on

8:58

these genomic markers because the patient

9:01

prognosis is very clearly.

9:03

As you can see gliomas survive median survival

9:06

around 15 years compared to IDH Y type gliomas

9:11

where median survival could be anywhere

9:13

from 1 to 2 to 3 years.

9:14

But the MGMT methylated IDH Y type gliomas is

9:17

doing a little bit better than the

9:20

unmethylated ones. And of course,

9:22

another thing we learned is that IDH mutated

9:25

gliomas, they occur more in younger patients.

9:27

Whereas older individuals,

9:29

if you're gonna have a glioma in an individual,

9:32

more than 40 or 50 years old,

9:35

chances are that this is gonna be an IDH Y type.

9:39

Let's discuss a little bit about MGMT,

9:42

it encodes a DNA repair enzyme that removes

9:46

damaging alkyl adducts from DNA,

9:49

which normally functions to avoid double strand

9:52

breaks and hence base mismatch repairing

9:55

results in oncogenesis.

9:57

So what it means is that in gliomas which

10:01

have MGMT promoter hypermethylation or or decreased

10:05

activity of MGMT leaves these cancer cells

10:10

more prone to alkylating effects

10:13

of chemotherapy. For example,

10:15

temozolomide and hence better response to

10:18

temozolomide and is also associated with

10:21

higher incidence of pseudoprogression.

10:23

What it means MGMT methylated

10:26

IDH wild type gliomas.

10:27

They have much higher incidence of pseudoprogression after therapy. Now,

10:33

I do want to discuss a little bit two more

10:36

additional groups over here which are kind of

10:39

from the pediatric world but spillover into

10:42

the into the adult glioma world.

10:44

one of them is B which is basically your

10:48

who grade one tumors. They could be,

10:50

you then have a fusion mutation or a V 600

10:53

E mutation. And, and and these,

10:57

this group has a much longer survival.

11:00

Once you resect them completely,

11:03

you have potentially cured the patients

11:05

on the other end of the spectrum.

11:07

There is another tumor which is

11:09

seen more in young adults and,

11:11

and Children is H three K 27 mutant

11:14

diffuse midline glioma.

11:16

These are really bad tumors to have,

11:18

these are the ones which have, you know,

11:20

the median survival is around one year.

11:24

And of course, you know,

11:25

from one end of the spectrum to the other,

11:28

you have good survival on one side and

11:30

very poor survival on the other side.

11:32

But what I'm gonna be also discussing

11:35

later on each molecular subgroup

11:37

is in fact a clinical syndrome.

11:39

And the reason for that that these tumors

11:42

they present in different age groups and they

11:45

have different prognosis as

11:47

also shown on the slide.

11:49

This is just a reference in case somebody wants

11:52

to get more into detail about who

11:56

classification update which came

11:57

out in 2016,

12:00

based on this classification update,

12:03

who recommended that we need to

12:06

have a three layered diagnosis.

12:08

So the layer one and layer two is histology and

12:10

grading as was done in the past. So,

12:13

for example, if you have a glioma and a grade two,

12:17

the only important thing WHO added over here

12:21

that you need to know the IDH mutation and one P

12:24

Q 92 correlation status to really call this an

12:27

oligodendroglioma as I've shown you, you know,

12:30

next-gen sequencing showing you

12:32

complete loss of chromosome.

12:33

one P over here and loss of 19 Q and,

12:39

and the integrated diagnosis

12:41

should look like that.

12:42

The only way the neuropathologist will be able

12:45

to confirm or write a diagnosis of glioma is by

12:49

having done IDH mutation and one P 19

12:53

Q co-deletion status on the tissue.

12:57

Since this 2016 classification,

13:00

There is a consortium made to inform WHO

13:05

about further discoveries

13:07

of genetic mutations.

13:09

And this CIMPACT consortium has come

13:13

up with multiple updates,

13:15

six of them in the last

13:18

four years or so.

13:20

And these updates are gonna be forming the basis

13:23

for the new classification update.

13:26

Hopefully coming out in 2021 from WHO

13:32

this is a review article we wrote this year

13:35

looking at the WHO glioma

13:38

Classic Patient update,

13:39

genomics and imaging if somebody

13:41

wants to get more details.

13:44

One of the things I usually ask trainees is

13:47

what is precognition and it's the fact of

13:50

knowing something before it takes place for

13:53

knowledge and it becomes really

13:55

important in neuromyelitis.

13:57

So the two things you want to know before you

13:59

look at the MRI or the imaging I call it pre

14:03

image is one is the age and the reason

14:06

for that is that these tumors,

14:09

these genomics subclasses of glioma,

14:11

they occur in different age groups.

14:13

For example,

14:15

BRAF tumors and H3K27 midline gliomas.

14:18

They usually occur in young

14:20

kids or young adults.

14:22

IDH mutated tumors again occur

14:25

in mostly in young adults,

14:27

but young adults also may have some of the H3K27

14:30

mutant mid midline gliomas

14:33

if you're more than 40 years of age.

14:36

The chances are that you're gonna have

14:38

an IDH wild type glioma. Now,

14:40

the second thing I usually emphasize

14:43

a lot is the clinical presentation,

14:45

which is very important.

14:46

The reason being majority

14:48

of the IDH mutated tumors,

14:50

they're gonna be either asymptomatic or gonna

14:53

have some minor complaints like headaches

14:54

and maybe even seizures more with IDH

14:58

mutated astrocytoma. On the other hand,

15:01

the WHO grade one BRAF tumors they usually present

15:05

with seizures. And most importantly,

15:09

IDH wild type glioma which

15:11

occur in older individuals.

15:12

Most of the time will present with subacute

15:15

neurological deficit. For example, you know,

15:17

he or some kind of language and speech

15:20

difficulties going on for a few days,

15:22

a few weeks or maybe even a month or two months.