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You can also sign up for a free trial of our premium membership to get access to

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hundreds of case-based microlearning courses across all key radiology

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subspecialties. Today we're honored to welcome Dr.

0:43

Sun Mi cha for an update on imaging and 2021 W H O C N

0:48

SS tumor classification. Dr.

0:50

Cha completed her neuroradiology fellowship at New York University Medical

0:54

Center.

0:55

She's a neuroradiologist with special interest in expertise in brain tumor

0:59

imaging at University of California San Francisco Medical Center,

1:03

where she also serves as the program Director of Diagnostic Radiology Residency

1:08

and the vice Chair of education. At the end of the lecture, please join Dr.

1:13

Cha in a live q and a session where she will address questions you may have on

1:17

today's topic today topic.

1:19

Please remember to use the q and a feature to submit your questions so we can

1:22

get to as many as we can before our time is up. With that,

1:26

we're ready to begin today's lecture. Dr. Cha, please take it from here.

1:31

Okay, great. Well, thank you so much for having me today. Um,

1:34

hello everyone out there.

1:36

I'm going to talk about some brain tumor imaging in the context of

1:41

W H O C N SS tumor classification. I don't have anything to disclose.

1:46

So objective today is to,

1:48

I'm going to highlight couple of key points from the 2021 W H O C N SS tumor

1:53

classification and really morph that into how is that

1:58

relevant to neural radiologist or general radiologists who are looking at brain

2:03

MRIs or spine MRIs for patients with brain tumor.

2:07

And I'm going to just illustrate some of the correlation of molecular genetic

2:12

markers in terms of what are you looking for on imaging?

2:17

'cause we are non neuropathologists, we're not basic biologists,

2:20

but we must keep abreast with this explosive knowledge coming from the

2:25

biological side because it does have implication for imaging.

2:30

So the three things that I'm going to highlight is W H O C N SS

2:34

classification and neuroimaging techniques that most of you are very familiar

2:39

with,

2:40

but put that in the context of the molecular generic era of brain tumors.

2:45

And then I'm just gonna show you, uh, case by case how things are relevant.

2:50

Imaging and neuropathology neuro molecular genetics are intertwined.

2:55

So first, let's start with C N S who classification.

2:59

So some of you are already familiar that World Health Organization has

3:04

been supporting, uh, classification of not just brain tumors,

3:08

but all tumors for c n s tumors.

3:11

The first version came out back in 1979 and 2000 up

3:16

to 2007. And the one,

3:18

these four classification schemes were purely based on histological.

3:23

And then something magical or something, uh,

3:26

really groundbreaking happened in 2016 classification where

3:32

molecular genetic information became part of the official

3:37

classification system.

3:38

So no longer just the histopathologic features of tumor was used

3:43

to classify tumor. Now there's this very,

3:46

very advanced technique looking at molecular genetics,

3:49

but more interesting to us radiologists, it's the,

3:54

for the first time ever since 1979,

3:58

M R I image made it to the cover of this book.

4:01

And then fast forward five years later,

4:04

2021 W H O classification, the fifth edition was published.

4:10

And you could see that now we have two M r I images.

4:14

So imaging is now really gaining attention to our

4:18

neuropathologic, our neuropathology and neurobiology colleagues.

4:22

That imaging plays a such an important role of how we actually look at tumors.

4:27

So we are well on our way to becoming a very important,

4:32

we were already were,

4:33

but now we are pushing towards being part of the classification of c n

4:38

s tumors. So

4:41

the nutshell of W H O 2021 is that there are molecular markers everywhere.

4:46

And this is the cartoon I made, and it seems like it's,

4:50

we are just touching the tip of the iceberg. And these,

4:54

these are some of the idea, um,

4:56

molecular markers that are part of now ordinary conversation in tumor board.

5:00

But there are actually many, many more to come and they're already here.

5:05

And next version of, uh, C N SS classification,

5:09

which will be coming in maybe five to seven years,

5:12

we are going to see even more. So what does this mean for radiologists?

5:16

We just have to make sure that we know what is changing the field

5:21

of classification of c n s tumors so that we could keep up with,

5:26

uh, how we interpret imaging.

5:29

So here's the nutshell of C N S U.

5:32

There are so many molecular markers and we're gonna,

5:34

I'm only gonna touch on the several really important ones, uh,

5:39

today and at U C S F, uh,

5:42

instead of just getting a histopathological report, we get something like this.

5:46

This is called U C S F 500 gene panel,

5:49

where we actually get not just a histological diagnosis,

5:53

but we get I D H status. But in addition to that,

5:57

we get whole host of additional information and this is really becoming

6:02

a part of our standard of care for brain tumor, uh,

6:06

pathological diagnosis.

6:08

So I'm gonna show you a couple of cases and we'll go over this at the end. Uh,

6:12

you may not know the answer now, but I could assure you at the end of this, uh,

6:16

50 minute talk, you'll be an expert at it. So here's a young, um,

6:21

19 year old came with a diagnosis of stroke because of the A D C

6:26

and D W I appearance and end up having these molecular features

6:31

when pathology was performed. Can you think of tumor type? This could be

6:37

second case. Here are three different, very different histologic tumor types,

6:42

pilocytic astrocytoma, ganglio glioma,

6:46

and pleomorphic anthro astrocytoma.

6:48

Can you think of a molecular marker that these three tumors

6:53

often, not always, but often share. So what is the molecular marker?

7:00

Third, here's a tumor with very interesting appearing calcification.

7:05

Does not enhance. Has this heterogeneous T two and diffusion abnormality,

7:11

can you think of a genetic marker that defines this tumor?

7:15

How about this one? Here are, uh,

7:19

six different patients with a large midline tumor.

7:23

All pediatric patients. Can you think about,

7:26

think of a diagnosis and a molecular marker that all these six different

7:31

patients share. And how about this one patient?

7:36

Two different patients with an extra axial tumor kind of look like

7:40

meningioma, but they do not have the typical dural tail.

7:44

This one looks very destructive.

7:46

Can you think of a molecular marker that can, um,

7:50

unify these two at very different type?

7:53

But now we know that they're very related. How about this one,

7:56

two different patients with posterior fossa, append omas.

8:01

Do you know the molecular genetic difference between the patient up at the top

8:07

versus patient up at the bottom?

8:10

And here are four different patients with four different types of

8:15

medulloblastoma.

8:16

Can you name the four main subtypes of medulloblastomas?

8:21

So we will go over the answer at the end of this talk. So, imaging,

8:26

uh, neuroimaging of 2023.

8:28

Still the most important technique is the structural m r

8:33

i.

8:34

We cannot interpret physiologic or any other fancier imaging

8:39

technique without actually seeing what the tumor looks like on structural

8:44

imaging.

8:44

But we also do physiology based m r i to assess where their

8:49

vascularity their metabolism. And another very important, uh,

8:54

type of technique that we use is this hybrid imaging called PET CT or PetMR.

8:59

And many institutions are beginning to use this technique to look at

9:04

is this a recurrent tumor or is this a radiation necrosis?

9:09

So today I'm only going to highlight couple of the structural and couple of

9:14

physiologic M R I. And as I said before,

9:18

structural m r i post con precon, T one,

9:21

T two flare multimodality multiplanar imaging.

9:25

This is the bread and butter of what we do. And this will never go away,

9:30

but we put additional tests to look for hyper

9:35

vascularity, whether they're leaky VA permeability,

9:39

and whether there is a hyper cellularity or where there's high

9:43

choline metabolism. So physiologic,

9:46

M R I gives us a lot of insight into very non-invasive

9:51

way of gland, um, glancing at their tumor biology.

9:55

It's not as good as obviously actually looking at pathology,

9:59

but it's a really powerful non-invasive tool.

10:04

And this is what we do at U C S F and it's pretty standard at most institution.

10:09

Pre post T one,

10:11

T two F S C flare and D W I and a D, C, uh, D uh,

10:16

a D, C and dwi. This is a must. And we also do, uh,

10:20

s w i and a s l perfusion imaging.

10:24

S w i is becoming more and more important in brain tumor imaging because we

10:29

use this primarily to look for areas of blood products,

10:33

especially after radiation therapy.

10:36

And we use this for assessing where the,

10:39

the extent of micro and macro hemorrhages and also vascular lesions that are,

10:44

uh, mimicking brain tumors and primarily in the brain tumor arena.

10:49

We use this to assess for the extent of radiotherapy, uh,

10:53

related injuries.

10:54

So here are three different patients with susceptibility weighted imaging.

10:59

You could see this patient as literally innumerable punctate dots of

11:03

susceptibility or micro hemorrhage.

11:06

This is a patient who received whole brain radiotherapy for

11:10

medulloblastoma 15 years prior.

11:14

Here's a patient with very peculiar looking branching pattern of ss. W i.

11:18

This is a person with a vitis.

11:22

This whole thing was removed and it's not glioblastoma.

11:26

This is a ven neuritis or veins that are partially thromboses.

11:31

And this is a patient with hyper, um, very clear,

11:35

large vascular mass. And that's cavernous malformation. So SS w i, very helpful.

11:41

Here's an example that we saw at tumor where patient had a, a re enhancing,

11:46

very aggressive looking, right? Brachial pontus mass in the posterior fossa.

11:51

But if you look at patients SS w i,

11:54

there are new innumerable punctate micro hemorrhages.

11:59

This is a telltale sign that patient probably had a radiation therapy.

12:04

And lo and behold,

12:05

we got the history after the fact that patient had on nasopharyngeal

12:09

carcinoma and a tumor that were radiated twice

12:14

before. Uh, we did not have the radiation field.

12:17

But with that history and with that S W I appearance,

12:20

we feel very comfortable calling this radiation necrosis.

12:24

And patient was treated for steroids to control some of the edema related mass

12:28

effect and paid this lesion slowly, uh, disappeared.

12:34

D w i very important sequence. We use this to, uh,

12:38

assess for acute infarct, abscess, cellular tumor,

12:42

and uh, actively demyelinating lesion. So here are three different patients.

12:47

Here's the D W I imaging without even looking at structural imaging.

12:51

When you see this homogeneous in, uh,

12:54

reduced diffusion with an irregular mass like this,

12:58

this is a intracranial abscess until proven otherwise.

13:03

Here's a patient, you can barely make it out.

13:06

The lesion on D W I kind of disappears.

13:09

This is what diffuse glioma looks like on, uh, diffusion.

13:14

Here's a patient with two lesions, have a leading edge, reduced diffusion.

13:19

This is pretty classic for non neoplastic,

13:22

usually inflammatory, uh,

13:26

actively demyelinating type of lesion. And this young, uh,

13:29

patient was biopsied and that's a tumor effective demyelinating lesion.

13:34

So diffusion is a must sequence when you're interpreting a brain brain

13:39

mass. Here's another example.

13:41

This patient came to us with a preoperative diagnosis from elsewhere,

13:46

right? Frontal glioblastoma. I think that's not a bad diagnosis.

13:50

There's a lots of mass effect.

13:52

There's edema crossing the corpus callosum with central necrosis ri

13:57

of enhancement. But once you see the D W I and a d c,

14:01

you know that there's homogeneous reduced diffusion within end necrotic tumor.

14:06

So that is a very unusual appearance of a glioblastoma.

14:11

So this is more classic appearance for biogenic abscess.

14:15

And indeed pathology proved that this is genic abscess.

14:19

Our surgeons going in knew that this was going to be a puss

14:24

'cause we told them and they end up just doing a little bur hole and sucking

14:28

that puss out. And patient did great.

14:31

Here's a young woman that I showed a little bit earlier. This, uh,

14:35

young woman was diagnosed with stroke at an outside hospital and you could see

14:40

why, why?

14:40

Because there is actual homogeneously reduced diffusion and

14:45

it's very dark on a d c.

14:47

But I think most of you would also notice that that shape is not a good,

14:52

good, uh, shape for a territorial infarct. But nonetheless,

14:57

patient was fine. The workup was negative,

14:59

was transferred to our hospital and patient underwent surgery.

15:04

And this is a hyper hypercellular,

15:06

unfortunately what's called a molecular glioblastoma

15:11

perfusion. We use it to look for hyper vascularity hypervascular tumors.

15:16

We also use perfusion for,

15:19

to detect recurrent tumor assessed for glioma grade and sometimes

15:23

postictal changes.

15:25

Here's a patient who came to us with a homogeneously

15:29

enhancing right cerebellar mass.

15:32

And you could see that D W I is not reduced.

15:36

There's a little bit of a rim of susceptibility, but not much else.

15:40

So the question is, is this a metastasis or something else?

15:43

Patient did undergo whole body workup and there was no mass.

15:48

And if you add a s l perfusion,

15:51

you could see that the whole lesion is very,

15:54

very vascular in the cerebellum.

15:56

And this is pretty classic appearance for a heman glioblastoma.

16:01

And that's indeed what it was on pathology.

16:05

Here's a person who's been coming to us for, um,

16:09

serial imaging after patient had a subtotal resection.

16:13

But you could see here that we don't know where the recurrent tumor here is.

16:17

Patient had a seizure, they controlled the seizure.

16:20

So after they controlled the seizure,

16:22

we brought the patient back and did a profusion imaging and you could see that

16:27

there is a clear unmistakable lump of hyper vascularity

16:32

associated with non mass like flare here.

16:35

So our neurosurgical colleagues went in and resected this, uh,

16:39

hyperperfusion area.

16:41

And the whole thing was a live recurrent diffuse glioma,

16:46

i d h wild type spectroscopy.

16:49

We use this tool now as a problem solving tool.

16:53

Here is a normal single of oxil spectroscopy,

16:56

normal n a a creatine and colon.

17:00

This is what you wanna see.

17:04

And we've done many, many spectroscopy studies,

17:08

both two D uh, single voxel, two D and three D.

17:12

But I still find this single voxel very powerful.

17:15

And here's an example of some of our patients, um,

17:19

that we did on spectroscopy. Oh, by the way,

17:22

a single voxel only requires about less than three minute of imaging.

17:26

So it's a really powerful tool that does not take up much in terms of

17:31

additional imaging.

17:33

And we've now kind of developed four different types of

17:37

spectroscopic appearance of an abnormal lesion.

17:40

So what we call the proliferative, where there's high,

17:43

high choline hypoxic profile where there is clear lactate,

17:48

peak infectious profile where we see amino acids,

17:52

alanine and acetate,

17:54

and the necrotic pattern where we see predominantly very high

17:59

lipid and lactate.

18:01

And here's an example of how we use this single voxel two minute of

18:06

additional imaging.

18:07

So this patient came to us with a left frontal glioblastoma as

18:12

the preoperative diagnosis does look like glioblastoma with central

18:16

necrosis. But once you get D W I,

18:19

you know that inside of that reen enhancing lesion,

18:22

there is a clear reduced diffusion that looks like pus.

18:26

So we brought the patient down and with a single voxel spectroscopy

18:31

using TE of 35 milliseconds and 2 88 milliseconds,

18:36

and we saw all the metabolites that classically seen in

18:41

biogenic abscess such as amino acid,

18:45

lactate acetate, and the choline, which is not a tumor marker,

18:50

it's a, uh, membrane turnover marker is very, very low.

18:54

So our confidence putting the together with the diffusion that this is going to

18:59

be a genic abscess was near 100%.

19:03

And our neurosurgical colleagues just did a very small bur hole

19:08

and sucked out the fluid. And lo and behold,

19:11

there is that yellowish purulent material and this is a path proven

19:16

genic abscess. So let me now, uh,

19:20

focus more on the brain tumors based on the molecular genetics and I'm going to

19:25

start with three different types of pediatric tumors and go on

19:30

to adult tumors using the, uh, imaging techniques that I just described to you.

19:36

So pediatric brain tumors in the W H O scheme from

19:40

2016 to 2021, many different, um,

19:45

classification changes have been made. The first is these two tumor types,

19:50

one medulloblastoma, the other appendamoma.

19:54

And you could see that without knowing anything about the tumor.

19:58

So here's post con T one, you could see that the,

20:01

this patient has a tumor that is relatively homogeneously reduced on

20:05

diffusion.

20:06

So this is going to be some type of a cellular tumor patient.

20:11

On the other hand, this tumor both are midline enhancing lesion.

20:15

You could see that D W I is not reduced.

20:18

So D W I is single most helpful sequence after looking at post

20:24

contrast imaging.

20:25

So we already know this patient has a hypervascular,

20:29

a hypercellular tumor and that's a mesoblast stomach.

20:32

And this patient on the right, this is a patient with APPENDAMOMA

20:38

and D W I is really the first step towards honing down

20:43

into the molecular or biologic feature of their tumor.

20:47

So let's start with medulloblastoma. Medulloblastoma.

20:51

Now genetically are divided into four main types and

20:56

these,

20:56

some of you're already familiar with the wint sonic hedgehog and

21:01

group three and group four and our colleagues from Stanford

21:06

published this beautiful paper and this was already nine years ago,

21:11

uh, showing the imaging difference between the four subtypes,

21:15

the wind, the Sonic HEA group three and group four. And it turns out that,

21:20

uh, wind type of medulloblastoma are almost always,

21:25

um, off midline. And they're not in the fourth ventricle only.

21:30

They almost simulate a CP angle schwannoma, that's the wind type.

21:36

Sonic hedgehog are usually the hemispheric tumors with this

21:40

multinodular solid component. And there's two different types of it,

21:45

but we are only going to just mention that this is a sonic hedgehog.

21:49

And then these are the more common pediatric babies and infants, uh,

21:54

can get this type of tumor where the tumor is in the dead midline and

21:58

some enhances avidly and some don't.

22:01

And it turns out that the fourth ventricular midline tumor of

22:06

mesoblast with avid enhancement are more likely to be grade group three.

22:11

And the less enhancing subtype tends to be group four.

22:15

I find this fascinating that imaging, although it's not a hundred percent,

22:20

can give us a glas into potential genetic and

22:26

molecular subtypes. So here's the fourth main subtypes.

22:30

How about appendamoma? So this is an interesting tumor too.

22:33

So most of you are familiar that usually sup tentorial

22:38

pomas are intraparenchymal.

22:41

The fourth ventricular or posterior fossa ones are inside the ventricle

22:46

and the core one is in the intramedullary.

22:49

I often wondered why we don't often see ependymomas right in the,

22:55

in the middle of third or fourth, um, lateral ventricle.

22:59

Most of the ependymomas supra temporally that I've seen,

23:03

they're all in the supra tentorial, uh, parenchymal compartment.

23:08

But then now all these uh, genetic information is coming out.

23:12

So 2016 and 2021 w h o now are classifying

23:17

super tentorial append omas,

23:19

particularly in pediatric age group based on this very

23:23

sophisticated molecular markers.

23:26

So the relay fusion positive super tentorial append omas

23:31

are one of the most aggressive append omas or commonly occurring in

23:35

pediatric age group.

23:37

And they look even worse than some of the more really aggressive

23:41

glioblastomas. And most of these appendamoma,

23:45

particularly the relay fusion ones that I've seen,

23:48

they tend to be intraparenchymal.

23:52

But then when they do recur,

23:54

they can recur all along the dural surface.

23:57

So their biology is very different than the typical appendamoma that I've seen.

24:04

So there are two subtypes that the W H O has, uh,

24:08

clearly defined in the 2021 are the relay fusion and

24:12

yap one I have yet to see a yap one molecular altered, uh, append omas.

24:18

But like I said before,

24:19

the super tentorial appendamoma in a young child,

24:24

they tend to be this very aggressive, um,

24:27

molecular variant called relay fusion is the most common one that I've seen.

24:32

And one thing that I wanna stress that relay appendamoma, when they do recur,

24:37

they can recur along the dura. So please, if you're,

24:41

if you know the molecular feature,

24:43

please look very closely at the dural margin 'cause it may be the first

24:48

sign of recurrence. How about intraventricular posterior fossa?

24:53

So now we know clearly intraparenchymal, sial,

24:59

appends and posterior fossa intraventricular appends

25:04

are genetically molecularly completely different.

25:08

They may look similar on histopath pathology, but they are not,

25:14

uh, related at all in terms of molecular genetics.

25:19

So what are the two subtypes that w h O defined in the 2021

25:24

and the two subtypes are posterior fossa, appendamoma type A,

25:29

posterior fossa, uh, appendamoma type B.

25:32

So what are the type A versus type B?

25:35

So the type A looks like this.

25:38

They almost look like a CP angle or lower, uh,

25:42

medullary cistern tumor going out into the foram and luka often.

25:48

And this is called the P F A or I call it the p f

25:53

appendamoma Asymmetric 'cause it's off to the one side.

25:57

And this is an awful prognostic appendant and unfortunately

26:02

much more common in pediatric age group.

26:06

And then there's this subtype,

26:08

the group B are the ones that sits usually in the midline,

26:13

kind of simulate the appearance of a medulloblastoma group three because

26:18

they are midline enhances.

26:21

But remember append omas are not reduced on diffusion.

26:25

And this is what I call the posterior fossa appendamoma that looks like a ball.

26:31

But here you could see that they are actually very different.

26:34

One is in the midline,

26:35

one is asymmetric and it also turns out that they're very different genetically.

26:41

So P F A I call it a stand for asymmetric

26:46

group B, B stand for ball.

26:48

So let's look at the tumor types a little diff um, more carefully.

26:52

So here's group a appendamoma type,

26:55

a asymmetric of midline and they tend to have more necrosis

27:00

hemorrhage.

27:01

And these are much more aggressive component and they have a unique genetic

27:06

and molecular marker. Very different from P F A A P F B,

27:11

excuse me. And this is much more common in pediatric age group.

27:16

Here's the P F B group,

27:18

more like ball shaped in the midline and not as much as

27:23

necrosis, little less hemorrhage, the midline location.

27:27

And this is the type of append omas that tend to occur older children or

27:32

adult patients.

27:34

And their main presenting symptoms they tend to present earlier because of the

27:39

obstructive hydrocephalus and they're very rarely invasive or

27:43

infiltrative at all compared to the P F A variant.

27:48

So here's P F A the awful, um,

27:52

much more prognostically worrisome type of appendamoma.

27:56

And this unfortunately is much more common in pediatric age group.

28:02

And they have a very specific molecular markers that are very different than

28:07

P F B, the one that looks like a ball shaped in the midline posterior fossa.

28:12

This is a ball shape,

28:13

it's a better prognosis and affects adults a little bit more

28:18

than pediatric age group.

28:20

Now moving on to second type of tumor that pediatric patients might get is

28:25

the diffuse midline glioma.

28:27

So these are tumors that are disorders primarily of

28:32

a histone.

28:33

And I think some of you know that each human cell D n a is about 1.8 meters,

28:38

but thanks to histone, which winds down the um,

28:42

D N A into 90 micrometers.

28:45

But you could see that if there is a histone related abnormality,

28:50

it could lead to just devastating tumors like this,

28:53

particularly the histone H three K 27 M locus

28:58

tends to cause tumors of this gigantic midline glioma.

29:03

So comes the name of diffuse midline glioma,

29:07

H three K 27 M alter. So this is um,

29:12

in 2021 version change its name and it affects these midline

29:17

structures and they look like this, uh, just terrible tumor in the midline.

29:22

Patient is sometimes very minimal symptomatically altered,

29:26

but it's a tough tumor.

29:28

Surgical resection is not a possibility because they tend to involve the deep

29:33

thalamic nuclei like this. It's just an awful tumor.

29:37

But here's the six different patients with the same awful diagnosis.

29:41

And they're all, even though histologically they may look very different,

29:46

but they have histone H three K 27 M altered

29:51

and they tend to occur in the midline and hence the name diffuse midline

29:56

glioma and some of these spinal cord tumor.

29:59

And most of them now are called a diffuse midline glioma.

30:04

Only when they could,

30:05

our pathologist can actually definitively identify the histone

30:10

alteration, particularly H three K 27 M.

30:15

And here's an example of a spinal cord.

30:18

We used to call this spinal cord astrocytoma or glioblastoma and

30:23

that's, that's not wrong.

30:25

But once they get a tissue and our pathologists look for this particular

30:30

mutation, that's how we know that this is a diffuse midline glioma.

30:34

H three K 27 M altered. Here's a patient iso,

30:38

but what does it mean for radiologists?

30:40

So we're not the one who's gonna diagnose H three K 27 M molecular

30:45

features,

30:46

but I want you to remember that these are really terrible tumors they sneak

30:51

around.

30:51

They actually can spread all along the C S F as if they are metastatic

30:57

pineoblastoma or mesoblast stomachs and keep an eye on brain.

31:02

Any lesions in the brain cannot be ignored. So let me show you,

31:06

this is one of our patient from many years ago, uh,

31:10

when we first to, uh, our pathologist start to test for the H 20,

31:15

um, H three K 27 M after radiation therapy,

31:20

our radiation oncologist did a great job. Uh,

31:23

some of these enhancing tumor looks better, the flare looks better too.

31:27

But remember this original flare imaging of the brain,

31:31

we were not sure whether this was really a real finding or is that a tumor?

31:36

But five months later you could see all of those areas are now nodular

31:42

and patient recurred. And unfortunately the real um,

31:46

down, uh,

31:48

the tumor that they couldn't control was not the spinal cord diffuse midline

31:52

glioma.

31:53

It was the C S F ependymal leptomeningeal spread of

31:58

the original tumor.

31:59

And this is how diffuse midline glioma H three K 27 M

32:04

altered tumor behave on follow-up imaging.

32:08

So please make sure you get brain imaging to make sure we don't miss this

32:13

very subtle, uh, lesions that show up on flare imaging alone.

32:17

These areas may not enhance at all

32:22

adult tumors.

32:22

I'm just gonna show you some of interesting molecularly conjoined uh,

32:27

tumor types. One is this.

32:29

So meningioma and heman cytoma back in the day when molecular genetics

32:33

was not the not a thing in terms of our daily conversation,

32:38

I used to think that meningiomas and he angio cytomas were related and

32:43

just that the heman cytomas were much more aggressive and angrier looking and

32:48

destroying the bone. And it turns out that uh,

32:51

molecular genetics have proven that these two tumors are not related at

32:56

all. But it turns out that solitary fibrous tumor,

33:01

which is a pretty rare extra axial tumor that we see,

33:04

but elsewhere in the body too,

33:06

is intimately associated with he angio cytoma

33:11

even though they look very different.

33:13

This is what's called the grade one and cytoma is grade two

33:18

or three and they are related by this particular nuclear

33:22

expression called stat six.

33:25

So W H O now lumps solitary fibers,

33:28

tumor and hagio per cytoma as a one single tumor type

33:33

with a varying degree of aggression.

33:36

So S F T is usually grade one heman cytoma

33:41

is usually grade two and three and heman cytomas can

33:46

recur anywhere else in the body.

33:48

But both these tumor types have stats six nuclear

33:52

expression and that is really needed to make the diagnosis

33:57

of SS F T and heman uh,

34:00

cytomas in the brain here, the circumscribed tumor.

34:04

And if you look at these three very different histologically tumors have a

34:08

nodule and cyst nodule and cyst nodule and assist.

34:15

These are pilocytic astrocytomas ganglio gliomas and pleomorphic

34:20

antho astrocytomas and some of the super tentorial of these

34:25

three types share a molecular marker call

34:30

B A V 600 E mutation at our institution in some of these

34:34

patients with this particular mutation,

34:37

they have a anti BRAF F therapy they're in clinical trials for and

34:42

we are getting pretty good response to therapy. There. Again,

34:47

three very different histologically but imaging wise

34:52

I always knew they kind of looked similar because they share this shape, uh,

34:56

this pattern of nodule and cyst and a lot of these super

35:01

tentorial pilocytics ganglio and PX A have B R

35:06

A F V 600 E mutation. Very interesting.

35:10

And this is a paper from more than decade ago that already looked at

35:15

over 1000 tumors, uh,

35:17

P X A pilocytic and glioma and has shown that up to 60

35:22

70% of these tumors will harbor B R A F V

35:27

600 E mutation.

35:29

So these work has been going on for decades even though it now

35:34

just made it to the 2016 and 2021 W H O,

35:39

the work has been going on for decades to come to the fruition and make it into

35:44

the classification scheme. So molecular glioblastoma,

35:48

before I talk about molecular,

35:50

let me tell you the classic glioblastomas here are eight patients that I've

35:54

known in the past have the classic central necrosis,

35:58

very aggressive irregular retinal enhancement.

36:02

These are all glioblastomas and the classic G B M

36:07

now have all these extra molecular genetic diagnosis that our

36:12

pathologist is testing for and some of them will be MG M TM

36:16

methylated. And most, some of you know the implication of M G M T,

36:20

hypermethylated G B M,

36:22

these are actually the ones that respond quite well to

36:26

temozolomide chemotherapy.

36:28

But there's all these other things that they test for.

36:31

But the unifying one is that all glioblastomas are

36:37

IDH one wild type.

36:39

So there's no more what's called the glioblastoma.

36:42

I d H mutant does not exist anymore.

36:46

All glioblastomas are I D H wild type.

36:51

Now what is molecular glioblastoma?

36:54

These have a genetic mutation. The three component here,

36:58

TER promoter mutation, E G F R, gene amplification,

37:02

trisomy seven and MONOSOMY 10.

37:04

And on imaging they do not look like the classic glioblastoma I just

37:09

showed you. Uh,

37:10

this is the 19 year old who was originally uh,

37:14

misdiagnosed as a stroke. If you look at her post con imaging,

37:18

it does not enhance at all. And on D W I,

37:22

it has really hyperintensity D W I signal intensity

37:27

and very low A D C.

37:30

This is a path proven molecular glioblastoma with these

37:35

three molecular alterations. TURT promoter, E G F R,

37:40

trisomy seven and monosomy 10. And this is new.

37:44

This is a separate tumor, but nonetheless,

37:47

molecular glioblastoma are just as aggressive as classic

37:53

glioblastoma. And this young lady who uh,

37:58

received T P A and cerebral angiogram looking for a source of stroke elsewhere

38:03

came to us. This was resected. This is a molecular glioblastoma,

38:08

but if you look down,

38:10

patient has a second focus of additional tumor and this

38:15

is really bad news. Additional lesion.

38:18

And that is the lesion that turns five months later into a frank

38:22

glioblastoma. And this is a terrible prognostic uh,

38:27

situation.

38:28

Diffuse gliomas not to be confused with diffused midline gliomas.

38:33

Diffuse gliomas are what we used to call astrocytomas

38:38

oligodendrogliomas or all uh, astro oligo astrocytoma.

38:42

So we don't call oligo astro anymore.

38:45

Diffuse gliomas are non glioblastomas and they're infiltrating

38:50

either astrocytomas or oligo dendro gliomas.

38:55

And these are the three molecular markers that define diffuse gliomas.

38:59

I D H being the most important.

39:02

It signifies that it's going to be a lower grade one P 19

39:07

Q chromosome number one,

39:08

chromosome number 19 locus of code deletion.

39:13

This is a disease defining chromosomal marker for

39:18

oligo dro glioma.

39:21

A T R X is a marker defining astrocytoma.

39:25

So at our institution almost all diffuse gliomas on imaging

39:31

and at initial pathology,

39:32

a histologic analysis will undergo I D H for sure

39:37

and one P 19 Q of to make sure that it's not an oligo.

39:42

And if one P 19 Q is intact,

39:46

then they will go ahead and do a T rx to prove that this is an astrocytoma.

39:50

So this is how it's divided.

39:52

Diffuse gliomas is either mutant or wild type.

39:56

I already told you wild type diffuse gliomas are def facto

40:01

molecular glioblastoma in the mutant variant they will undergo MP 19

40:06

Q co deletion testing. If that is deleted,

40:10

that's an oligodendroglioma period N if it's one P 19 Q

40:15

intact,

40:16

then a T RX is lost then that's an astrocytoma,

40:21

the wild type. These are much more aggressive tumors.

40:25

They if they have a tur promoter,

40:27

E G F R amplification trisomy seven and monosomy 10,

40:32

this is called the molecular glioblastoma.

40:37

And diffuse astrocytoma i D H mutant was newly um,

40:42

graded uh, based on grade two,

40:44

three and four on WH for 2021.

40:48

And this the most aggressive variant is now called the grade four.

40:53

But it has to have this particular molecular deletion called CDK

40:58

N two A B homozygous deletion. But looking at the imaging,

41:02

you could tell that this tumor is already trying to enhance and there's some

41:06

areas of central necrosis but doesn't really look like a frank

41:11

glioblastoma.

41:12

You should think about grade four diffuse astrocytoma I D

41:17

H mutant.

41:18

And if your institution has the capability to do this molecular analysis,

41:24

CDK N two A B homozygous deletion,

41:27

this confirms that this is a grade four diffuse

41:32

astrocytoma.

41:34

I D H mutant I D H is the king right now of

41:39

determining the fate of a glioma.

41:41

Whether it's going to glioblastoma route or diffuse lower grade glioma.

41:46

It was discovered in 2008. And if there is a I D H mutation,

41:52

it leads to this particular molecule to hydroxy glu rate

41:56

accumulating. And it's much, much more common in lower grade gliomas.

42:01

And in primary GBMs it's almost never seen.

42:05

But in some cases of a glioblastoma that D differentiated from

42:10

a lower grade, you may actually detect this,

42:13

but in classic glioblastoma it's never seen.

42:17

So what does this mean that we at least have to know what IDH one

42:22

mutation one P 19 Q code deletion A T RX loss means that

42:27

I just already told you.

42:29

So here's some of the tumors that this is from literature where T two is super

42:33

bright flare, it becomes darker.

42:36

This has been called a T two flare mismatch and this is not a

42:41

100% rule,

42:42

but this has been described as T two flare mismatch meaning

42:47

T two is super bright, flare gets darker.

42:51

This has been a molecular imaging correlate of a diffuse

42:56

astrocytoma I D H mutant A T R X loss.

43:00

Not a hundred percent rule, but you could uh,

43:03

assess at least guess before the surgery.

43:07

Now here's a patient with diffuse glioma and how do I know

43:11

it's more likely to be i D H mutant or wild type?

43:14

The D W I is going to be one of the most helpful technique.

43:18

You could see that the tumor kind of disappears in D W I.

43:21

This is more likely to be I D H mutant the better prognostic

43:26

uh, glioma,

43:28

this is that patient with molecular glioblastoma not enhancing but look how

43:33

very much aggressive the D W I looks very reduced on D W I,

43:38

very dark on a D c. This is not a lower grade tumor at all,

43:43

despite the fact that it hardly enhances, has apparent circumscribed border.

43:48

This is not a good tumor. This is a I D H wild type.

43:53

This is molecular glioblastoma. How about this one?

43:56

This patient has a serpiginous looking calcium

44:01

and that calcific marker is pretty good.

44:05

Not a hundred percent rule for a specific type of tumor.

44:09

And you could see that the fluorescent in cyto hybridization,

44:12

that's what that is,

44:13

shows you that one P 19 Q code deletion.

44:18

You could see that there should be two pink and too green.

44:21

Our pathologist confirmed for me, but there's one missing.

44:25

So this is so-called the one P 19 Q code deletion.

44:30

And this is a disease defining marker of an oligo dendro glioma.

44:35

We don't do CT anymore to confirm the presence of calcification.

44:40

We may do SS w I but um,

44:44

CT to confirm calcification is no longer a standard of care practice.

44:50

This is a patient, this is the last case that I'll share with you.

44:53

He came back at 2003 and our um,

44:57

this was discovered after he had a car accident and CT detected a

45:02

low density lesion. So he came, he was completely asymptomatic.

45:06

I looked at this and I said, Hmm,

45:09

I'm not sure if it's tumor so why don't we just see get serial imaging.

45:13

So he came back every year and then it started to grow in about

45:18

three years. Here's 2012.

45:21

So nine years this lesion has almost double.

45:26

So I scratched my head and said, does lower grade gliomas grow this slowly?

45:32

Probably could. But during 2020, patient called,

45:35

emailed me and said my, can you take a look at my M R I?

45:39

And I look at it and I look at from the 2003. So these are 17 years apart.

45:45

And I explained to the patient, this is growing.

45:48

We no longer can just sit around and do nothing.

45:52

And our neurosurgical colleagues, after hearing my um,

45:56

brain tumor talk about two hg, he said to me,

46:00

why don't we get a two HG M R s? And I thought really an idea.

46:05

So we brought the patient to our research scanner and our

46:09

outstanding postdocs and PhDs there helped us to do a

46:14

two HG scan. And lo and behold,

46:17

this patient within this lesion had an unmistakable,

46:21

not an artifactual,

46:23

a two hydroxy peak that you can only really see in

46:29

I D H mutant gliomas.

46:32

So this pushed us over the edge. Patient went for surgery, gross,

46:36

totally resected.

46:38

And this is a gross totally resected I D H mutant

46:43

one P 19 Q co-ed oligo dendro glioma.

46:48

And this is the first time that I was just stunned at how this

46:53

non-invasive technique really helped us. So this is um,

46:57

already three years ago now. Um,

47:00

and patient is doing very well that um,

47:03

two HG is indeed a marker for I D H mutant

47:08

gliomas.

47:08

And this happens to be an I D H mutant oligo dendro glioma.

47:13

So let's go over some of the cases that I showed you earlier.

47:17

Patient has these three molecular markers altered.

47:21

So what is the tumor type?

47:23

I showed you this case already twice with this really profound reduced diffusion

47:28

young lady who are initially thought to have a stroke.

47:31

Unfortunately this is a molecular glioblastoma.

47:35

How about these three tumor types? Pilocytic ganglio, P X A,

47:40

they all share sometimes this nodule and cystic appearance.

47:45

What would be the um, defining molecular markers?

47:50

The B R A F V 600 E mutation.

47:53

How about this tumor that I just showed you? Calcification.

47:58

This is a one P 19 Q code deletion of an oligo

48:03

dendro glioma. So if you see a tumor and you happen to have a CT and uc,

48:08

calcium and putting together with M R I features,

48:11

you could be with reasonable confidence tell that this is going to be an oligo

48:16

dendro glioma.

48:17

And if you're ever doubt you can actually do a two HG M R SS scan and

48:22

see if you can detect two hg.

48:24

That will be a slam dunk that this is an I D H mutant tumor. How about this one?

48:29

Midline,

48:30

just awful looking expansile tumors in pediatric age group.

48:35

What will be the histologic marker and diagnosis?

48:38

This is diffused midline glioma.

48:42

H three K 27 M altered.

48:45

These are histone mutated, really aggressive tumors.

48:50

How about these two tumors? Extra AAL tumors,

48:53

not a meningioma but they are joined together.

48:57

SS F T and heman. Cytoma,

48:59

what is the molecular marker that defines these two tumor types into

49:04

one? That's the STAT six nuclear expression.

49:10

We already discussed the two different types of posterior fossa pomas,

49:15

they're completely different genetically.

49:17

One is called the P F A, the asymmetric type.

49:23

The other one is called A P F B as in ball shaped in the

49:27

midline.

49:29

A is asymmetric pediatric age group and it's an

49:34

awful prognosis.

49:36

The one in the midline looks like ball shaped.

49:40

These are better prognostic, uh,

49:43

and very rarely these will be infiltrated.

49:46

So the two different types subtypes of a posterior fossa appendamoma

49:51

are posterior fossa, appendamoma type A.

49:55

The other one is posterior fossa.

49:57

Appendamoma type B B is better ball

50:01

shaped. P F A is asymmetric.

50:05

Asymmetric and it's a awful prognosis.

50:09

The four main subtypes of medulloblastomas, we already discussed this.

50:14

The one that is off midline kind of looks like CP angle or lower

50:19

cranial nerve schwannoma.

50:21

That actually is the one of the best prognostic, uh, subtype of the melo.

50:26

And that's the wind hemispheric multinodular.

50:31

Solid aggressive looking reduced on diffusion.

50:34

That is going to be the sonic hedgehog.

50:38

Two midline tumors reduced on diffusion.

50:42

One enhances more avidly.

50:44

The other one in less enhancing the one that enhances more is

50:49

the group three and the less enhancing midline medulloblastomas

50:54

are the group four.

50:56

So here is your main four molecular genetic subtypes of

51:01

medulloblastomas and imaging not,

51:06

not as good as, uh,

51:07

pathology or molecular genetics or U C S F 500 gene panels,

51:11

but it does a pretty decent job guesstimating what the molecular

51:16

genetic abnormality might be of a given tumor. So with that,

51:21

I would like to summarize that I gave you some highlights of 2021

51:26

W H O C N SS tumor classification.

51:28

But I also wanna highlight that this is a field that's evolving every year.

51:33

So the next version,

51:34

which I am told might come out in 2025 or 2026

51:39

may actually have even more molecular genetic markers. So please,

51:44

uh, stay tuned about that.

51:47

And I showed you some update on structural and physiologic mr like diffusion

51:52

being super important to differentiate abscess versus, uh,

51:56

glioblastomas cellular versus less cellular tumors.

52:00

And Mr perfusion to detect recurrent highgrade gliomas

52:05

and spectroscopy methods that you can actually detect some of the onco

52:10

metabolite associated with I D H mutant,

52:13

such as two hydroxy glutamate.

52:17

And the imaging correlates a molecular and genetic profiles of c n s

52:22

tumors.

52:22

An example being the four subtypes of medulloblastoma and two

52:27

subtypes of appendamoma that you could actually guesstimate.

52:31

Not a hundred percent rule, but with a reasonable confidence.

52:34

You could predict their molecular subtypes without ever touching a

52:39

tissue or doing a craniotomy.

52:41

I think imaging is such a powerful technique and it's non-invasive.

52:46

So we are in a very interesting and very important field.

52:51

And as I said, molecular generic era of c n s tumors is here.

52:56

It's only gonna get more complex and advanced and imaging must

53:01

keep up with its pace. So with that,

53:04

I thank you for your attention and I will stop sharing my

53:08

screen and take any questions. So I think we got some, um,

53:13

in the chat q and a. Um, oh,

53:18

where does A T R T stand in this classification?

53:22

So A T R T stands for atypical OID roid tumor.

53:27

This is actually a tumor that is super aggressive,

53:31

but they're not melos. They're not appendamoma. And they have, uh,

53:35

their own very specific molecular marker called i n I one.

53:41

So our pathologist can specifically test that molecular marker

53:46

to differentiate 'cause A T R T can look just like medulloblastoma

53:51

can just like, um, aggressive appendamoma the P F A.

53:56

So we actually have the, our pathologists have the power and method to,

54:01

um, identify A T R T.

54:04

There's no formal classification of A T R T yet,

54:08

but it might be next time, next version might include that. But like I said,

54:12

the molecular marker that defines A T R T is this, um,

54:18

enzyme called i n i one mutation. If that is altered,

54:22

that's an A T R T and nothing else. Next question.

54:26

Since glio mitosis survives obsolete, now,

54:29

what is to be labeled according to recent recommendation?

54:33

This is an excellent question. Even though W h O said don't use this,

54:38

uh, frankly, at tumor board,

54:40

I use this term because some tumors entire hemisphere is

54:45

all infiltrated with non enhancing flare, bright lesion.

54:49

Nothing is enhancing, nothing is reduced. So now we use, I use the term,

54:54

this is the gliosis cerebral pattern

54:59

of, uh, diffuse glioma.

55:02

But these are usually when they do go for pathology,

55:06

they are i d h mutant, uh, tumors. And they're not oligos.

55:10

They're never, I've never seen glioma, mitosis,

55:13

cerebral tumors that are actually oligo or one P 19 Q code

55:18

deleted. So yes, it's, it's obsolete.

55:22

And yet we still use this term.

55:25

Is the term relay fusion still used or is it outdated?

55:30

Um, another good question. No,

55:32

it's the W H O 2021 came up with this Z F T A,

55:37

some other name. But in our tumor board,

55:40

we still use the term relay fusion because everybody understands

55:45

what that is. But the molecular genetic term has become much more, uh,

55:50

complicated. But when I'm reading out with a trainee, uh, we look at the,

55:55

uh, electro medical record and if we see the term relay,

55:59

we know that we have to really look for odd places for recurrence.

56:04

That's really what's important here, that relay fusion may, uh, append,

56:08

omas tend to occur at least maybe half a dozen cases that

56:13

I've seen in the dural surfaces.

56:16

So the probably next version might end up just getting rid of relay

56:21

altogether, but we still use it. And that is still,

56:24

that term is still exists in the very complex pathology report,

56:28

so you could search for it as well. Uh, is there any other question?

56:33

Let me just do that. There's a chat here. Um,

56:35

There's a chat about your painting if you wanna, um, say what painting that is.

56:41

So this is Georgia O'Keeffe. This is,

56:43

this is not a actual real painting,

56:47

but if anybody would like to donate this to me, I will be forever grateful.

56:51

Just kidding. This is a,

56:53

this is one of the most beautiful painting that I've ever seen.

56:55

This is a Georgia O'Keeffe's. I don't know the name,

56:59

I think she just named it flower.

57:01

But I've been using this for the entire pandemic and

57:06

thank you so much. So there's no molecular marker associated with this painting.

57:12

Uh, is there anything else that I could answer for our outstanding, um,

57:17

audience?

57:19

I think that's it. Dr. Cha, thank you so much for your lecture today, really.

57:23

Oh, thank you. Thank you so much everyone.

57:25

Have a wonderful rest of the week and thank you for this opportunity again.

57:30

Bye-bye.

57:31

Absolutely. Thank you.

57:32

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57:35

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57:39

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57:42

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57:45

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57:49

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57:54

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57:57

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