What’s in a Name: Current Understandings of Infantile Fibrosarcoma & “NTRK Rearranged” Spindle Cell Neoplasms

January 07, 2022

Information

January 6, 2022

Yale Pathology Grand Rounds

Jessica Lee Davis, MD

ID7329

To CiteDCA Citation Guide

00:00Welcome everybody.
00:02This is the first ground round
00:06of 2022 and I am very glad to
00:11hoster with Doctor Jessica Davis.
00:13That is an incredible uprising.
00:16Star pediatric pathology and in
00:19bone and soft tissue I will give
00:22you a brief review of our career.
00:25Doctor Jessica Davis.
00:26Ryan now is a pathologist at Oregon.
00:30At the Science University in Portland,
00:33OR where since 2019,
00:37she also redirector of surgical pathology.
00:41She gotta do it actually from
00:43the same university in Portland.
00:46And then she did a monatomic AP and
00:50CP Fellowship in a University of
00:53California in San Francisco and did
00:57also a short fellowship which started
01:01coughing and you can see that from
01:04the beginning of her career she was
01:07interested not only in pediatric pathology,
01:10but in bone.
01:12And so for a tissue she did Ben,
01:18a pediatric pathology fellowship
01:22in Seattle Children Hospital
01:25over Seattle and she's board
01:29certified in pediatric pathology.
01:32Jumping ahead,
01:33I want to mention that in
01:392020 she was nominated by our Society
01:43of Pediatric Pathology for the lot.
01:46Strauss Award visa is an award that
01:51recognizes the best paper published by one of
01:56our members in a reputable journal and the.
02:01And then the presenter has
02:04to be under 40 years of age.
02:07So she is young and the paper that point,
02:11which is actually the main focus of air
02:14of strongest focus of our career area,
02:18was responding with spectrum
02:20of pediatric ENT tracker,
02:22arranging missing comma tumor.
02:25So coming back, she has been very productive.
02:30She is being the Co author of more
02:34than 40 peer reviews article.
02:38She obviously has participated in a
02:42huge number of abstract and she is
02:45a very author of two books and Co.
02:49Author of numerous chapters,
02:51particularly as she has a five chapter in VW.
02:55In the recent every 5th edition of A WHO.
03:00Book The Blue Book for a soft tissue sarcoma.
03:04Also entering about obviously
03:06soft tissue of the pediatric age.
03:10She is more than anything,
03:14a very sought after speaker.
03:17She started with a couple of
03:19international talk at the beginning
03:20of his career over career,
03:22but now she is talking about at
03:25least five international talk.
03:28In the in the recent year,
03:31international class,
03:33regional and local talk.
03:36She is some grant funding and some
03:41collaboration with pharmaceutical society
03:44is pharmaceutical company which she
03:46will disclose in relation to her work.
03:50She is is doing and in addition she
03:53does enormous amount of work as a
03:57central pathology review for a number.
04:00Over protocol,
04:01either inside the way Children,
04:04Oncology society and some Phase 1B and
04:09another trial again for the children.
04:14Oncology society she is.
04:20Part of a research Society of
04:23pediatric pathology research group
04:25interest and she is very busy because
04:29she's very director over large.
04:34I theology department,
04:36I am sure I haven't not cover everything
04:39in addition to she is very active.
04:41She is energetic person during a young
04:44year she was in Africa in Tanzania,
04:47working in a center that was
04:51covered in medicine in Tanzania.
04:54But besides that she is splendid speaker.
04:58So welcome Jessica and
05:00I give the floor to you.
05:03Thank you so much for that very,
05:05very kind introduction.
05:06It's really my pleasure to
05:08speak to all of you today.
05:10I really hope you guys enjoy this talk.
05:17Hopefully you can see my screen.
05:19Please let me know if you have any
05:20problems with viewing the PowerPoint.
05:24This slide shows you my university as I was
05:27talking to Raphaela earlier this morning.
05:30My hospital is situated up on a
05:31hillside which is not the most
05:33strategic planning for our hospital,
05:34but it does give us the unique
05:36opportunity for me to commute to work
05:38sometimes via the Portland aerial tram.
05:40So if you have not visited Portland,
05:43please, I welcome you to come visit.
05:45I'm always happy to take guests
05:47and provide tours of our hospital.
05:49You can commute between our two campuses
05:51via the Portland Aerial tram, which.
05:53The main campus is up on this hillside and
05:56our other campuses down at the waterfront.
05:59Without further ado,
06:00I will go into our talk,
06:02which today I've been titled,
06:04What's in a name as we Kind of delve
06:06into the somewhat controversial topic
06:08with lots of recent discoveries talking
06:11about our current understanding
06:13of infantile fibrosarcoma,
06:14which I've spent a lot of my
06:16career focusing on,
06:17and this newer provisional category,
06:20called Entracque,
06:20rearranged spindle cell neoplasms,
06:22which was a new entity.
06:24In the recent edition of the
06:265th edition of the 2020 bonus,
06:28soft tissue WHO.
06:31As alluded to,
06:32I do need to disclose that I serve as a
06:34consultant for the conglomerate of Bear,
06:36Laakso and Illy Eli Lilly Pharmaceuticals.
06:39This has to do with the work
06:42within tyrosine kinase inhibitors.
06:45So,
06:46as a pathologist I like to start
06:48with the case.
06:49I think it's very Lester Tieve
06:51as we get through this topic.
06:54So this is a case that I first became
06:57interested in and track tumors.
06:59So this patient initially presented in 2011.
07:03This was an infant boy who presented
07:06at birth with somewhat of an ambiguous
07:09mass or asymmetry of his foot,
07:12and there was a biopsy performed
07:13at 9 days of age and that was.
07:15Subsequently followed by resection.
07:17This is a photomicrograph of that
07:20resection and you can kind of see
07:22the spectrum of morphology seen at
07:25this low power image. On the right.
07:27You can see these somewhat monotonous
07:29land spindle cells infiltrating
07:32into skeletal muscle.
07:33Over here on the right you can
07:35see them infiltrating into fiber
07:37adipose tissue in the center of
07:38the photo micrograph and more
07:40cellular confluence of sheets of
07:41spindle cells on the left.
07:46This is the same tumor
07:48at higher magnification.
07:49Again, looking at the end of the
07:52individual cell cyto morphology,
07:54the tumor cells are bland within this tumor,
07:58that mitotic rate was quite low.
08:00At highest you could get to about
08:022 mites and 10 higher power fields,
08:05but cells are ovoid,
08:07somewhat primitive,
08:08looking in a collagenase to mix
08:09with drama but quite infiltrative
08:11infiltrating between the individual
08:13skeletal muscle fibers or reaching
08:15in somewhat fibrous septae
08:16between fibroadipose tissue.
08:18But other areas were more cellular
08:19in confluent sheets of tumor cells.
08:24So the initial biopsy in the resection
08:26specimen looked quite similar,
08:27both histologically and by immunophenotype,
08:29that IHC profile was fairly nonspecific,
08:34with patchy expression of SMAD CD34
08:39and beta catenin were negative.
08:41Classic curious type was performed.
08:43I'm not sure if you still
08:45do this at your institution.
08:46I think that this is largely going away,
08:49although I would argue
08:51there's still some utility.
08:53And trisomy eight was present in classic
08:55karyotype and ATV 6 fluorescence
08:58inside 2 hybridization or fish
09:00was performed which was negative.
09:02So at the time of this biopsy and resection,
09:05a descriptive diagnosis was rendered
09:07of low grade spindle cell neoplasm
09:10with a fairly robust comment written
09:13and a differential diagnosis of
09:16infantile fibrosarcoma as a diagnostic,
09:19possibility or some sort of fibromatosis
09:21and if this were some sort of.
09:24Fibromatosis really the question is,
09:26well, what type?
09:28This wasn't classic morphology
09:29for a desmoid type fibromatosis
09:32and beta catenin was negative.
09:34I'll be it.
09:35We know.
09:36Particularly in infantile forms of desmoid,
09:39often beta catenin could be negative and
09:41upward of 25% of cases, although again,
09:44the morphology was not classic for for this.
09:47Could this be some sort of Lipo fibromatosis?
09:49Again,
09:50the morphology is not classic for this.
09:52There were cellular areas and so.
09:54I said this was rendered a
09:56descriptive diagnosis was rendered
09:58with a differential diagnosis.
10:02So I think it's important for us
10:04to kind of delve into the past to
10:06understand our where we are today
10:09with our understanding of infantile
10:11fibrosarcoma as well as other tumors.
10:13And so you know, where did this
10:16term infantile fibrosarcoma begin?
10:18So this term was first coined in 1976.
10:21In this paper written by Chung and Denzinger.
10:24Prior to this point in time,
10:25other terms were used to
10:27obviously describe the same tumor.
10:28The tumor existed before this paper.
10:30Terms such as just fibrosarcoma,
10:32juvenile fibrosarcoma,
10:33etc were used in this paper,
10:37which was a study out of the FIP,
10:39the Armed Forces Institute of Pathology.
10:42These two authors looked specifically at
10:45tumors only in young pediatric patients,
10:48so it's not that these tumors didn't
10:50exist in older patients and or adults,
10:52but they only looked at cases
10:54in children 5 and under.
10:57They found 53 cases that they thought
11:01had recurrent morphologic features and
11:05some similar clinical demographics.
11:07This included ultimately children from
11:09birth to four years of age with a median.
11:12Age of three months.
11:14The locations are what we now kind of
11:17except for infantile fibrosarcoma or IFC,
11:19including locations in the extremities,
11:21back trunk, head and neck,
11:22and retroperitoneum.
11:23They were able to kind of define
11:26the recurrent morphology.
11:29I'll be it they note in this manuscript
11:33the morphology was quite heterogeneous
11:36with the most common morphologies that
11:38which we know today of spindle cells,
11:41arranged in long fascicles,
11:42including some cases with a
11:44herring bone like morphology,
11:45which is pictured here on the right.
11:47Other cases had spindled,
11:49or primitive stellate cells
11:52arranged haphazardly in a
11:54myxoid to collagenous stroma.
11:55Often with admix,
11:56chronic inflammation and many
11:58cases have what they described
12:00as parasitic vascular pattern,
12:01which we would now probably
12:03described as Hemangioma,
12:03parasitic or branching actrec vessels.
12:08They noted in this paper
12:09that of these 53 cases,
12:11many of them had prior diagnosis
12:14of many other tumor designations,
12:17ranging from schwanoma to
12:20Rhabdomyosarcoma to many other entities,
12:23and indeed only nine of these 53 cases
12:25were actually diagnosed as fibrosarcoma
12:27prior to their histologic review.
12:30So I'm gonna dump this.
12:31I FS 1.0 AKA the old,
12:33although 1976 isn't actually that long ago.
12:36Moving forward from 1976.
12:40Morphology really was the mainstay of
12:44diagnosis for infantile fibrosarcoma.
12:46In that original manuscript,
12:47in several manuscripts moving forward,
12:49it became apparent that using
12:51conventional karyotype could also be
12:54a useful diagnostic adjunct because
12:56there was nonrandom chromosomal gains
12:59in infantile fibrosarcoma which was
13:01different than in adult fibrosarcoma,
13:04which shared similar morphology but
13:06lacked these nonrandom chromosomal gains.
13:09Specifically nonrandom chromosomal.
13:10Gains could be seen in chromosomes 2,
13:13eight, 1117 and 20,
13:15and as highlighted in this
13:17specific karyotype,
13:18we can see TRISOMIES in 1117 and 20.
13:21So many manuscripts highlighted
13:23this and moving forward,
13:25particularly through the 70s,
13:27eighties and early 90s.
13:29This was used as a diagnostic adjunct.
13:32And then we reached a really
13:34pivotal moment in 1998 where there
13:37was a paradigm shift in how we
13:39think about and diagnose infantile
13:42fiber sarcoma. 2 separate groups,
13:45including Paul Sorenson's lab up in
13:47British Columbia and Brian Rubin,
13:49who's now a very well known bonus of
13:53tissue pathologist at the Cleveland Clinic.
13:54Both of these groups identified a novel
13:59and recurrent translocation and 12 to.
14:02Health 15, which is the ET V6
14:04and track 3 gene fusion in both
14:07infantile fibrosarcoma as well as
14:09the analogous tumor in the kidney.
14:12Congenital mesoblastic nephroma,
14:13which is highlighted both in break apart
14:16fish for ETV Six which I'm sure many
14:18of us are very familiar with which is
14:20really become a mainstay of diagnosis.
14:22For these tumors.
14:24From this point on as well as by
14:27classic singer sequencing and so,
14:30this was really a pivotal moment
14:31in how we think.
14:32About infantile fibrosarcoma.
14:34Because this genetic translocation was
14:37identified in a very high frequency
14:40in these two tumor types and so
14:42moving on from this point in time,
14:45this was identified in upward
14:46of 70 to 90% of cases,
14:48and so this could be used
14:50as a diagnostic tool.
14:52So going back to the original case,
14:54I shared this case recurred three
14:57years following presentation.
14:58We're now at about 2014 and
15:01excisional biopsy, excuse me, and.
15:03Incisional biopsy was performed on
15:06that recurrence which now shows.
15:09Recurrence is the much more
15:10cellular component,
15:11arranged in long fascicles.
15:14Some admixed chronic inflammation
15:16scattered mitoses,
15:17but still the mitotic rate is fairly low.
15:20My toes is in this case were about
15:235:00 and 10:00 at this point in
15:26time the diagnosis still remained
15:28somewhat descriptive,
15:29unclassified spindle cell sarcoma,
15:31but now really favoring infantile
15:34fibrosarcoma despite the lack
15:36of any TV sticks.
15:38Rearrangement by fish and
15:39again at this point in time,
15:42in the way most pathologists practiced,
15:44without having an ATV.
15:4616 we arrangement because of
15:48that pivotal moment from 1998
15:50most people relied very heavily
15:52on identification of that ETV 6
15:55and track 3 gene rearrangement to
15:57diagnose infantile fiber sarcoma.
15:59This wasn't universal,
16:00and some institutions still would
16:02diagnose based on morphology,
16:04and that's what happened in this case,
16:06so following this diagnosis.
16:08The patient underwent chemotherapy,
16:10including two cycles of ifosfamide
16:13and doxorubicin,
16:13and then two cycles of ifosfamide alone.
16:16Unfortunately,
16:16the tumor continued to progress,
16:19and the patient underwent amputation.
16:23Here are some other photo
16:25micrographs of this tumor,
16:26demonstrating that there was significant
16:29intratumoral heterogeneity with
16:31other areas of the tumor having
16:34more significant myxoid stroma.
16:36There are areas of vascular highly gnosis
16:38which just this very eastern feel,
16:41like highland deposition around the vessels
16:43as well as increased chronic inflammation.
16:47The immunohistochemical profile remained
16:49unchanged with no expression of S 100
16:52or CD 34, but Patchy SM expression.
16:56Unfortunately, one year later,
16:59the patient presented with
17:01difficulty breathing was found to
17:04have innumerous lung metastasis,
17:06and on Histology the lung
17:08metastasis was very reminiscent.
17:10His original tumor and subsequent
17:13recurrence again with fibroblastic spindle
17:17cells arranged in these fascicles.
17:21At this point in time,
17:22this is now circa 2015,
17:252016 and luckily our understanding of
17:28these ETV six negative spindle cell
17:31tumors with Histology reminiscent IFZ
17:35had changed and we'll get into this a
17:37little bit more detail at this point in time.
17:39A pan track antibody was
17:41applied to this tumor,
17:42demonstrated here with diffuse
17:44cytoplasmic staining by Pan Track,
17:47IHC and next generation sequencing.
17:50At this point in time by a DNA
17:52hybrid capture methodology.
17:53Was performed which demonstrated ATP
17:56M3 and Track 1 gene rearrangement.
18:01So let's delve into end track for a minute.
18:05What is end track?
18:06Well,
18:06end track is actually a family
18:08of genes which encode a series of
18:10tropomyosin receptor kinase is there
18:12are three of them and track 1/2
18:14and three which encode the proteins
18:16Trek AB&C respectively.
18:17In normal development these play
18:19a really integral role,
18:21particularly in embryologic
18:23neural development.
18:24There's been a lot of work done
18:26by Eric Wong at UCSF on this.
18:29Unfortunately don't have time to go
18:30into details. That's very fascinating.
18:33In adults.
18:34There is probably still some role of
18:36entracque in synaptic pruning again
18:38and have time to get into this,
18:39but very fascinating.
18:40In general,
18:41these play a role in cell cycle regulation,
18:43cellular proliferation and cell
18:45differentiation.
18:46What we're going to focus on today,
18:47though, is end tracking cancer.
18:51So you know,
18:51while I am a bone and soft tissue
18:53in pediatric pathologist and we're
18:54gonna spend most of our time
18:56talking about that.
18:57Interestingly,
18:57Entrekin cancer was actually first described
19:01in the 1980s in colorectal cancer.
19:04So timeline of Discovery actually
19:06begins back in the 1980s.
19:07Not a lot of press was
19:09made at that point in time,
19:12because in track in carcinomas
19:14occur at very low frequencies.
19:17So we're talking less than 1%.
19:19Most of these.
19:20Maybe upward of 2% in colorectal cancer.
19:23Moving forward to the late 80s.
19:27In Trek 1 fusions were described
19:29in papillary thyroid carcinoma.
19:30This is kind of an intermediate frequency,
19:34particularly in pediatric.
19:36PT sees.
19:37Fusions occur at higher
19:39frequency frequency than,
19:40say adults where B RAF point
19:42mutations are much more common,
19:44but really this was kind of underated.
19:47Discoveries, interesting biologically,
19:48but really this.
19:50Pivotal moment again was in 1998,
19:52where ENTRACQUE gene fusions
19:53were discovered in a tumor where
19:56they occurred at a high frequency
19:58and at this
19:59point in time the the game kind of
20:01changed because now end track could be
20:03used as a diagnostic adjunct because
20:05it occurred at such a high frequency.
20:07Then again there was kind of this lulove.
20:10Yes, this is interesting.
20:11We can use it diagnostically until kind of
20:14about the time of this patients metastasis,
20:18because something else different unchanged.
20:20Have no tank and have changed this
20:22figure a little bit because an important
20:24thing that happened was we introduced
20:27next generation sequencing into the
20:29clinical realm and then another
20:30important thing that happened was
20:32first generation in truck inhibitors.
20:34Entered clinical trial testing and
20:38so with this and with the development
20:40of these new pharmaceutical agents,
20:42including Larry checked and interest and
20:44if getting FDA approval for treatment of
20:48entracque fusion positive solid tumors.
20:50Now discovery of end track fusions not
20:53only could be used as diagnostic adjuncts,
20:55they actually were predictive of
20:58therapeutic response and so this
21:01really led to a lot of excitement in
21:04clinical treatment as well As for
21:06testing and wanting to make sure
21:09we could discover these tumors and
21:11diagnose diagnose them appropriately.
21:13This led to an explosion of
21:16literature in pathology.
21:16This led to an explosion of kind of
21:19revisiting morphology of these tumors.
21:21So between 2016 and 2019 there was
21:26numerous publications going back and
21:29looking at these tumors with nonclassic,
21:32the noncanonical translocations
21:34and re describing them.
21:37Some were described as fibromatosis like some
21:39were described as having HPC like features,
21:41some as I FS like some is imt like and
21:46that really led to the paper that I was.
21:51We had the fortune of presenting
21:54Mylotte Strauss.
21:55Presentation on which was this
21:57paper that we published in a JSP,
21:59really looking at a the largest series
22:02to date of molecularly characterized
22:05pediatric tumors with molecularly
22:07confirmed entracque January arrangements.
22:09Our goal of this was to characterize
22:12these tumors and look at the relationship,
22:15if any,
22:16to those ifz harboring the canonically
22:19TV's eccentric 3 gene rearrangement.
22:23This is our case selection.
22:25Most of our cases came from a
22:27retrospective review from 2 institutions,
22:29including Seattle Children's with the
22:31help of Doctor Aaron Rasinski and then
22:34from UCSF where I was faculty at the time.
22:36A few other cases came from a wonderful
22:39group of collaborators which we used for
22:42morphology but not from for outcome studies.
22:45Ultimately,
22:46we had 30 patients,
22:48which doesn't seem like a lot for large
22:50clinical trials between New Years,
22:52studying very rare tumors.
22:53It's actually like I said,
22:55the largest cohort to date.
22:57We had 12 classic fusions and 18
23:00variant fusions.
23:01And you'll note here that there is
23:04a variety of diagnosis rendered.
23:07The cases that were diagnosed as
23:09IFS up front were those cases where
23:12we could confirm with fish for ETV
23:146 some cases without confirmation
23:16of fish word called IFC upfront.
23:19Again,
23:19that's really institutional preferences.
23:22If you relied on fish or not,
23:24you'll note by classic karyotype
23:26that there were nonrandom chromosomal
23:29gains in those chromosomes
23:30I mentioned and both.
23:32The canonical translocation,
23:34as well as the non canonical translocations.
23:38The clinical summary of patients age,
23:40sex, location and the size of the tumor.
23:43There was no statistical difference
23:45between any of the fusion subtypes.
23:48Really, we wanted to take
23:49a look at the morphologies.
23:51The morphologic patterns were
23:53similar between all fusion subtypes,
23:56with a few exceptions which I'll point
23:59out the most common patterns were indeed
24:02these long fascicles of spindle cells.
24:05Other tumors second most common
24:07pattern was haphazardly arranged.
24:09Delatorre spindle cells in a
24:11myxoid matrix and many tumors.
24:13Had these HPC like vessels.
24:16A couple exceptions existed
24:18the canonical translocation.
24:20Fusions were more likely to have abundant,
24:24chronic inflammatory cells,
24:26which could be mistaken for
24:29an IMT and the variant.
24:31Fusions were more likely to have
24:32this biphasic pattern, noted here.
24:34On the bottom left with more collagen eisd
24:37stroma juxtaposed to a more primitive cells.
24:41Other patterns that we're
24:43seeing were a myoid appearance.
24:45Many of the tumors,
24:46almost all of them had at least
24:48focal areas that were fibromatosis.
24:50Like a few of the tumors
24:52which has been written about,
24:53particularly in this provisional category,
24:56written in The Who of quote and
24:58track rearranged spindle cell tumors,
25:00or these prominent hyalinized
25:01vessels and a few tumors had this
25:04very prominent nuclear palisading,
25:05which could be mistaken for
25:08save Eric bodies in Schwannoma.
25:11So when I look back at our study
25:13and I look this time we looked
25:15at patients 25 and under,
25:17but yet our median age was still
25:18four months in the locations,
25:20essentially the same as in that
25:22original paper from the 1970s.
25:24And you know,
25:26our three common patterns in our main image,
25:29and I ask myself,
25:31is this IFS 2.0 AKA the the new and yes,
25:35we molecularly characterize all this case.
25:38But I have flashbacks to FS 1.0 AKA the old.
25:41So I feel like we did a lot of work,
25:44but I think we can learn a lot from
25:47the past and attribute a lot to Cheng
25:50Enzinger where they really did a
25:52great job of of characterizing the
25:55morphology of these tumors back in 1976.
25:59I think we did learn a lot
26:00from this manuscript, however,
26:02so looking at those cases where
26:05fish was performed,
26:06this is a great example.
26:08This was a one year old with a very large
26:10hand mass of 6.4 centimeters and mass
26:12in a one year old is pretty gigantic.
26:15We performed hand track I see in all
26:18of these cases and you can see here
26:21that we have nice nuclear expression
26:23suggested that there is indeed a fusion.
26:25However, the fish was negative.
26:27However,
26:27on DNA hybrid capture.
26:29And yes,
26:30this indeed actually did have a fusion,
26:33so we did have a pretty significant
26:35subset of cases where fish
26:37essentially were false negatives.
26:39So going back and looking at our case
26:42selection of our retrospective review
26:44cases where we originally started with
26:4729 cases, we had five cases
26:49that had positive fish up front.
26:52We had 18 total cases.
26:56It didn't have that either
26:57had fish that was unknown or.
27:00Not performed or it was
27:01performed and was negative.
27:03Six of those ended up having
27:06Canonical translocation and
27:07four of those originally had
27:09ETV 6 fish that was negative,
27:12so you know what does that mean?
27:14Well, that means we had a false
27:15negative rate of our fish.
27:17There was about 1/3 of cases,
27:19so kind of a word to the wise if
27:21you're doing it V6 fish is your
27:23primary detection method for ifs.
27:25There is a significant risk of a
27:27false negative and you may want to
27:29perform another testing modality.
27:31Either pan track ihcc or
27:33next generation sequencing.
27:35If your clinical suspicion of IFS is high.
27:40By immunohistochemistry,
27:41kind of standard IIC,
27:44including SM, A CD34, and S-100.
27:47There was no difference
27:49between fusion subtypes,
27:51so in the literature there is a
27:53lot of things written about S.
27:56100 and CD 34 in the provisional
27:59category of entrec rearrange
28:01mesenchymal tumors and you know
28:04in this larger cohort we actually
28:07saw this both in the variant.
28:10Fusions,
28:10as well as the canonical translocations,
28:13so I'm not sure we can use this to
28:17differentiate between and track one
28:19and track 3 gene rearrangements.
28:22What was helpful in our hands
28:24was looking at the staining
28:26patterns in pan track.
28:28So we wrote a separate paper
28:30looking at Pan track sensitivity and
28:32specificity in the staining patterns.
28:34So looking at pan Track and
28:36the different fusions in Pan
28:38Track one and two fuse tumors,
28:40we saw very strong diffuse
28:44cytoplasmic staining.
28:45Whereas and in Trek 3 gene rearrangements,
28:48this typically had weaker.
28:49Although this is one of our
28:51robust training cases.
28:52Weaker staining,
28:53and most commonly we saw nuclear staining
28:56and this we published also in Asia.
29:02So moving forward and I think what's
29:04most important, we spend a lot of
29:06time looking at the pathology.
29:07But what does this mean
29:09clinically for these patients?
29:10And so moving forward and looking
29:11at the risk of recurrence,
29:13metastasis and outcome for these patients
29:15looking just at our retrospective review,
29:18we can't use the other donated
29:20cases from our collaborators
29:21'cause we'd have referral bias.
29:23Overall, we had a recurrence
29:25rate of about 24%.
29:26All of these cases had positive margins.
29:28The metastatic rate of about 12%
29:30overall survival was.
29:32Quite gutted about 90% of note
29:34about a third of these patients
29:36were on targeted therapy,
29:37so these were patients that were enrolled
29:39at the time on the clinical trial,
29:41primarily for lyrics.
29:44And similar to what was seen again
29:46in that paper from editing or Chung
29:49was there was no correlation between
29:51risk of metastasis or outcome
29:53on the patients age location,
29:55the fusion partner or mitotic
29:57rate or histologic pattern,
29:58and this is really important.
29:59'cause many of these cases,
30:01particularly those that did not
30:03have any TV 6 gene rearrangement,
30:06noted up front,
30:06were sent out to a variety of different
30:09institutions for second opinions,
30:11and many of these were actually
30:13called high grade sarcomas.
30:14So if you think about treatment
30:16modalities for high grade sarcomas,
30:17this is aggressive chemotherapy.
30:18So why were they called
30:20high grade sarcoma as well?
30:21Many of these had very high mitotic rates,
30:25which is very classic for IFC,
30:27and they had necrosis and so how
30:29we grade sarcoma is if you think
30:31about the French system of grading
30:33is based on my post using necrosis,
30:35so these would be over graded
30:38based on how we know these behave
30:40and then over treated,
30:42and yet we know for IFS mitosis.
30:44Necrosis don't matter for risk of outcome.
30:50So, as I alluded to in this original
30:52paper by Chung and Denzinger,
30:54they found the same thing that
30:56mitosis in necrosis aren't indicative
30:58of behavior other large studies.
31:00So this and the OR back study is a
31:03study clinical paper out of Europe
31:06from 2010 with about 90 FS cases.
31:10These are not molecularly confirmed,
31:12so this would be all comers
31:14based on morphology with again.
31:17No, the outcome was about
31:1990% serve overall survival.
31:23So in the years that
31:24followed this manuscript,
31:25which was published in 2018,
31:27moving on to now we're in 2022.
31:30The story is really moved beyond and trek,
31:34and so this figure is from a manuscript that
31:37actually just was published this month.
31:39I had the pleasure of getting asked to
31:42write a review article on this topic.
31:44And really,
31:45the last several years has been this
31:48explosion of literature of identification
31:50of other oncogenic drivers both in IFC.
31:53And in what we now need to put quotes around,
31:57quote and track rearranged spindle
31:59cell neoplasms because they're
32:01not just entracque anymore.
32:02And really,
32:03this literature is shown a
32:05variety of genetic alterations
32:07and other tyrosine kinases,
32:09and we're going to walk through these
32:12membrane brown receptor tyrosine kinases
32:14and other downstream kinases and that
32:17are focused in the map kinase pathway.
32:21So one of the first kinases.
32:24To be discovered to have alterations
32:26in these tumors is in RET,
32:29so two papers really focused on RET.
32:34A paper by Cristina Antonescu
32:36and Chris Fletcher,
32:37and then a paper by myself and some
32:40wonderful colleagues looking at RET gene
32:42fusions and spindle cell neoplasms with
32:45significant overlap with the zentrack tumors,
32:48as demonstrated by these
32:50two photomicrographs.
32:50Here's a summary of the RET fusions.
32:53In these tumors that have been published
32:55to date and not to go through all of this,
32:58but to point out a few highlights.
33:00So when the RET story starts to unfold,
33:03we start noticing that this
33:05isn't just in soft tissue tumors,
33:07but again,
33:08we start seeing cases that
33:10are occurring in the kidney.
33:11So going back to 1998,
33:13when Brian Rubin starts identifying that
33:17the ETV's eccentric 3 gene rearrangement
33:19occurs not only in soft tissue,
33:21but in the kidney,
33:22and specifically in those tumors
33:23described as congenital music,
33:25plastic nephroma we start
33:26seeing the same thing happen.
33:28And this photo micrograph is of our
33:30tumor that we identified in the
33:32kidney with a clip 2 RET gene fusion,
33:35and we also start seeing that
33:37a subset of these tumors,
33:39despite S 100 and CD 34 expression
33:42which originally was touted as perhaps
33:44indicative of a benign entity and
33:46Lipo fibromatosis like neural tumor or
33:49actually a subset of these metastasis.
33:53Moving forward to ALK another
33:56receptor tyrosine kinase.
33:57I think most of us in the soft tissue
34:00world for many years kind of thought
34:03of alk of being may be part and parcel,
34:05but at least mostly thought of as
34:08being seen inflammatory myofibroblastic
34:10tumor IMT when you first start
34:13seeing a couple
34:14of publications and spindle cell
34:16tumors with that CD 34 and S 100
34:20coexpression and adults O2 case reports.
34:23And then we recently.
34:24Published this small case series of of
34:28four patients in histo paths 2IN soft
34:31tissue and again two in the kidney.
34:35So again, I FS and CMN's without
34:38prior arrangements that look
34:40like ifs rather than IMT.
34:42This was a real pleasure to to
34:45write 'cause I had the honor to
34:47write this paper with Cheryl Coffin,
34:49who's really an expert in this
34:51field as she subsequently retired
34:53but still stays active.
34:55These are some photomicrographs
34:56of these tumors, really.
34:58This is the the most inflammation
35:00that were present in these tumors,
35:02so really doesn't have the robust chronic
35:04inflammation that we associate with.
35:06IMT and again these spindle cell
35:09tumors arranged in fascicles or more
35:11primitive cells in a myxoid matrix.
35:14Here's a really great example of this kidney.
35:15This was a kidney tumor with this
35:18classic herring bone pattern
35:19associated with IFS or CMN,
35:20but with dual expression of CD 34
35:23and S 100 so again highlighting
35:25this can be seen and IFCMN.
35:30Additional work has been done
35:32with met gene rearrangements.
35:34This seems to be less frequent.
35:36There's been two case reports showing
35:39met Gene rearrangements and IFSI.
35:42This is published by two wonderful
35:45clinical pediatric oncologist,
35:47Ajay Gupta, Guvna City who are very
35:50active in the children psychology group
35:52and what I loved about their paper is
35:55that while many of us have moved away
35:57from classic karyotype, we now can.
35:59Essentially perform some of the
36:01same functions of classic karyotype,
36:03but by DNA and next generation sequencing.
36:05Looking at copper copy number changes
36:08and so in this particular tumor we
36:10see those same nonrandom chromosomal
36:13gains by DNA copy number evaluation.
36:16Looking at chromosomal gains in
36:18chromosome 1117 and 20 and so just
36:21like the original descriptions of
36:24IFS with compatible translocation,
36:26this IFS with A met gene fusion.
36:28Same shows those same.
36:31Copy number changes.
36:33FGFR 1 gene fusions have just recently
36:37been described in soft tissue tumors.
36:40For those of you who may be
36:42neuropathologist and the audience
36:44think you guys are more familiar
36:46with far in cleoma so FGFR also is
36:49a family of tyrosine kinase those
36:51one through 5 FGFR one specifically
36:54had previously been described in two
36:56cases of GI stromal tumors several
36:58years ago and just recently there's
37:01been one single case of a uterine.
37:03What was described as a neural fiber
37:05sarcoma within the spectrum of
37:07entrec fibrosarcomas with the uterus.
37:09So I'll talk about this briefly in a moment,
37:12but within this provisional category of
37:14entrec, rearranged spindle cell tumors,
37:16there is a subset of uterine fibrosarcoma
37:19as within traction rearrangements.
37:21That was originally described by
37:23Cristina Antonescu and then a more
37:26recent study by Stanford Group
37:27has described a series of these.
37:29As seen here, the large majority of these.
37:32These uterine.
37:34Cyber sarcomas have entracque
37:36gene rearrangements.
37:37However,
37:37one case in their series had an
37:40F for one gene rearrangement.
37:42Many of these tumors do show
37:45expression of CD 34 and S 100.
37:48As seen here,
37:50this tumor is somewhat haphazardly
37:52arranged mildly more pleomorphism
37:54than many of the other cases.
37:57Again, CD34 and S-100 expression.
38:01No pediatric cases had been
38:04described until recently.
38:06We described 2 cases of FGFR.
38:08One pediatric ifz like tumors.
38:11The first case we had actually was a
38:13case that we first sequenced when we
38:16were looking at our end Trek series.
38:19Back from 2018 it was a case that
38:23was sent to us from CHLA.
38:27And then a second case through
38:29routine clinical practice.
38:30Both were in very young children,
38:33one in the Perirectal region and
38:35one in the thigh.
38:36Here are photomicrographs of those
38:38two cases and you can see here.
38:41Hopefully you can start to recognize
38:44these patterns that they're either very
38:47spindled or somewhat more primitive,
38:49appearing in ovoid and collogen eyes
38:51to myxoid stroma very infiltrative,
38:54so this case one is this fat
38:56that it's infiltrating.
38:57Here is actually submucosal
38:59fat in the perirectal region,
39:01and so I'm in the process
39:03of writing up this
39:04case series.
39:04Now this work was presented.
39:06This last fall at the Society
39:09for Pediatric pathology through
39:11next generation sequencing.
39:13These both had fusions that are
39:15thought to be considered at lead
39:17to constitutive activation of
39:19the kinase domain of FGFR 1.
39:23These two patients,
39:25one had a resection of the perirectal
39:27tumor and has no evidence of disease.
39:30Five years later, and the other patient,
39:32like I said, is the more recent
39:34patient is being treated with targeted
39:37therapy and is alive with disease.
39:39It's a very large tumor and
39:42was dubbed unrespectable.
39:44So now we've moved. Kind of.
39:45We're going down this map kinase
39:47pathway and we've finished the receptor
39:50tyrosine kinases that have to date
39:52been described and moving on to Abel,
39:55one which is a cytoplasmic kinase.
39:58We were able to describe 2 cases of gab.
40:02One able one fusions,
40:03one in an older adult woman who
40:06luckily had a partial response
40:08to treatment with imatinib.
40:10She had an unresectable tumor and when
40:13in a child you can see this tumor here,
40:16one of the highlights of
40:18recognizing these tumors,
40:19as I alluded to before this
40:21very dense perivascular Hila
40:23gnosis as seen in this tumor.
40:25Again,
40:25this tumor had coexpression
40:27of CD 34 and S 100.
40:31And then again, marching down this
40:34pathway to downstream effector
40:36molecules or cytoplasmic kinases.
40:38Is braf? I'm going to go back again
40:41to our original study and walk you
40:43down the rest of our key selection,
40:46'cause I kind of didn't walk down this
40:48part of our case selection on purpose.
40:51So in our original series,
40:54we started with 29 cases
40:58that morphologically.
40:59We thought fit with ISS and of
41:04those large majority ended up
41:06having ENTREC gene rearrangements.
41:09However, we excluded 5 cases from this
41:12paper because we either didn't have
41:15enough DNA for further sequencing or
41:19they had non entracque alterations
41:21by NGS and there was five of those
41:24of those two in our original series
41:28had been graph point mutations.
41:31And those were kind of set aside
41:32at at that point in time because
41:34we wanted to focus this initial
41:35manuscript really on end track.
41:37So we had these two initial index
41:39cases from this prior investigation,
41:42and ultimately we identified 12
41:45additional BRAF altered cases
41:48through routine clinical practice.
41:51Ultimately,
41:52these 14 cases were published
41:54in modern pathology.
41:56We had cases ranging from congenital
41:59presentation to 32 years of age,
42:01with a median age of 6.
42:02Months 20% percent at birth and
42:06large majority by the first end of
42:08life there was a male predominance
42:10and again the sites had involvement
42:12were very analogous to what we see
42:15and what we think about for IFS.
42:17Again,
42:18the morphology is very reminiscent to
42:20what we see in Canonical translocation,
42:23tumors,
42:24spindle cell tumors arranged in fascicles.
42:27Other tumors looked much more
42:28primitive arranged in myxoid matrix,
42:30and many had HBC like vessels.
42:34We don't need to go through this whole table.
42:35It's found in the manuscript,
42:37but to highlight a few things,
42:38there were indeed activating point mutations.
42:42Some were the very classic V 600 E,
42:46But there were also some novel point
42:48mutations and then some of the tumors.
42:50Excuse me,
42:51some of the tumors had novel fusions.
42:53A couple of the tumors had
42:56multiple fusion transcripts.
42:58Here are some other photo micrographs
43:00of what these tumors look like.
43:02A couple of interesting things
43:05where identified.
43:06One of the tumors had heterologous
43:08differentiation form in the form of
43:11cartilage deposition which we've also
43:13seen in a couple of our end track tumors.
43:16As far as clinical outcomes,
43:19we had one patient with metastatic disease.
43:23We had four patients that
43:24are alive with disease,
43:257 patients,
43:26no evidence of disease and and
43:28two patients died of disease.
43:30So while we have limited follow-up length,
43:32it seems to be similar to what we see
43:35in patients with entracque tumors.
43:38A smaller series was also published
43:41by Christina Antonescu of five
43:43patients with the RAF gene fusions,
43:46but not point mutations.
43:49These have also been described the
43:51RAF alterations in CMN by European
43:54Group looking at either BRAF
43:57internal duplications or entrenching
43:59gene rearrangements in CMN.
44:02So we're seeing the same spectrum
44:05of alterations in IFS&CMN.
44:07So last but not least RAF one
44:09which is also
44:10known as C.
44:11RAF has also been described in IFS.
44:15This is a case report I had the
44:17pleasure of writing with Cheryl
44:18Coffin looking at a case of infantile
44:22fibrosarcoma which was actually
44:25diagnosed in 2010 was called a variant
44:30IFC and then was sequenced later.
44:32This is a more recent case I had of am
44:35at 4 RAF, 1 Gene Fusion again showing.
44:38These spindle cells to avoid
44:39cells within the same tumor.
44:41In this case,
44:42we had these very large dilated vessels.
44:45So again, how do we put all of this together?
44:48I realize this is really kind of a
44:51potpourri of genetic alterations,
44:53and it's really through looking
44:55at this map RASC kinase pathway.
44:59Even though this paper was
45:00just published this month,
45:01I have to alter my own figure
45:03and add for one,
45:05and I think what's really important
45:07to note in this figure is that all of
45:09these signals through the same pathway,
45:12but also what's important is that many
45:14of these can be targetable alterations,
45:18so identifying these alterations
45:20can help diagnostically,
45:21but they can also potentially
45:24help therapeutically,
45:24particularly in these patients.
45:26While you know the outcomes are very.
45:29Good for these tumors.
45:30Many of these tumors are quite large.
45:33They can wrap around vital in their own
45:36vascular structures and so resection
45:37can be quite morbid for these patients,
45:40so having alternative therapeutic
45:42options if resection is not a good option
45:46for the patient is very important.
45:49As I alluded to,
45:51talking about,
45:52you know what about this WO provisional
45:53category of quote and track.
45:55Rearrange spindle cell neoplasm.
45:58I had the unique opportunity of writing
46:01this chapter for the pediatric book
46:04and also for the derm soft tissue book.
46:07So what do we know about this category?
46:09It's a broad category.
46:11It encompasses morphologies
46:13reminiscent of IFS,
46:14IMT Lipo Fibromatosis or MPNST.
46:18One of the things that's described is
46:21that there can be variable CD34 and
46:24S-100 expression. As I alluded to.
46:25We can also see this in IFC.
46:28The median age of this tumor type
46:31as opposed to EFS is really that
46:34it's more broad.
46:35However,
46:35this can also be diagnosed in Pediatrics.
46:39It is controversial and unknown
46:41how this relates to IFC.
46:43Is this a spectrum of the same tumor,
46:46or these two different tumors,
46:48or these multiple tumors?
46:50And that's still up for debate.
46:53This came about by several early manuscripts,
46:56denoting it as a unique entity and
46:58now it's recognized that many of
47:00these tumors within this category
47:02actually have hybrid lesions,
47:03so this wasn't recent manuscript.
47:05Looking at what was purely by broma,
47:08ptosis like tumor and then many of
47:09them actually have a more cellular
47:11component that looks more like.
47:13If so,
47:13I think that there will be much more
47:16conversation about this tumor moving forward.
47:19The other controversial topic is
47:20the name of it as we now know that.
47:23This category has many more genetic
47:27alterations outside of entracque,
47:29so this begs the question,
47:30well, what's in a name in the
47:33review article for Hyster Path?
47:34Jason Hornick was like can you
47:36please come up with another name
47:37for these tumors and I told him,
47:38well, that's very hard,
47:41so there are some problems
47:43with the current nomenclature.
47:44Here are some examples, so you have
47:46a 15 year old boy with a lung mass,
47:49pure fascicular architecture.
47:50There's no inflammation,
47:51and it has an ATV's eccentric.
47:533 gene fusion. You know?
47:55What do you call that is an IMT?
47:56Is it a knife sits in the lung?
47:59You have a 76 year old woman with
48:01superficial soft tissue mass with fascicular
48:03architecture as a really high mitotic rate,
48:06it expresses CD34 and S-100 as retained.
48:11H3K27 trimethyl ace.
48:12Otherwise you might consider as
48:14an element centric 1 gene fusion.
48:16What do you call that?
48:18You have a one year old boy
48:19with a small intestinal tumor.
48:21Fascicular architecture and
48:22RAF 1 gene fusion.
48:23What do you call that?
48:25A CD,
48:26a 76 year old woman with a deep
48:28seated soft tissue mass CD 34 S
48:30100 with the gab one able fusion.
48:32What do you call that?
48:33So there's a lot of nuances in the
48:36nomenclature which I always ask my trainees.
48:38Well why do we name tumors?
48:40What's the point of naming tumors?
48:41Well,
48:42I think the first and foremost reason
48:43is to inform and to communicate to
48:45our clinicians on the current tumor.
48:47So the case in front of us and that
48:50information that we're communicating
48:52is about prognostication.
48:54So if I say I FS to clinician.
48:57That helps inform how that
48:58tumor is going to behave.
49:00It informs treatment and management
49:02decisions and is predictive.
49:04It also is to help classify
49:07biologically and distinct entities.
49:08So an example of that is the
49:10recent separation of chicken beak,
49:11or sarcomas,
49:12into new and distinct diagnostic categories,
49:15so we don't want to lump those
49:17anymore into what used to be
49:19called Ewing's family of tumor,
49:20because they're distinct and they have
49:23different implications for prognosis and,
49:25and they are different biologically.
49:27Something I think most people forget
49:29about is also to aid in category
49:32categorization of cancer registries.
49:33So for epidemiologic studies and
49:36for learning long term long term
49:38and this influences allocation of
49:41funding areas of future research etc.
49:44So you know when we look at the
49:46problems with our current nomenclature,
49:48we go back to these cases I presented,
49:50you know,
49:50one might think about this lung
49:52mass with the secular architecture
49:53and this 15 year old male.
49:55And you know,
49:56how does that affect the clinical outcome?
49:59Most imt's do really well,
50:00but this patient,
50:01this patient's disease metastasized
50:03and they died of disease.
50:05This 60 or 76 year old woman with this
50:08mask that had a really high mitotic rate.
50:11And you might think it
50:12it would have done bad.
50:13This patient actually was respected and has
50:16no evidence of disease many years later.
50:19This one year old boy that
50:21had this humor with
50:22a raft. 1 gene Fusion also was respected.
50:24No evidence of disease and this last case
50:26was one of the ones I presented earlier.
50:29Had a partial response to
50:31imatinib is alive with disease.
50:32So thinking about how we use nomenclature
50:35to inform clinical decisions and
50:38future research and classification of
50:41tumours I think is really important.
50:44So what do I do and what?
50:45How do I write my reports?
50:47I think there's several different
50:48ways you can go.
50:50You can do an integrated report
50:52infantile fibrosarcoma with
50:53this particular gene fusion.
50:54I think that works sometimes.
50:56I think that with that in trek,
50:57rearranged spindle cell tumor.
50:59I tried that once and it backfired.
51:02So end track rearranged spindle
51:03tumor with the gab one evil fusion.
51:05You can see where that leads
51:06to a lot of confusion.
51:07How can be an entry rearranged
51:09spindle tumor but have a different
51:11fusion and so more and more?
51:13I've opted for kind of.
51:14Like kinase driven spindle salt,
51:16tumors, sarcoma with a map,
51:17one raft 1 gene fusion and written
51:20a comment that this belongs to a
51:22family of tumors that includes IFS
51:24in this provisional WHO category and
51:27and discuss with my clinical team.
51:30This is really important when we start
51:32thinking about targeted therapies,
51:34as I alluded to,
51:35each of these alterations that
51:37I've discussed has options for
51:39therapies and so discussing these
51:41in your reports and with your
51:44clinicians is of utmost importance.
51:46Some follow up from the original
51:48case I presented some some
51:49questions that raises well.
51:51What is the diagnosis?
51:52How do we predict prognosis and
51:54IFS&N track spindle cell tumors?
51:57This is still an ongoing area of research.
52:00This patient ended up being put
52:02on a targeted end track inhibitor
52:04and is still alive and currently
52:06has no evidence of disease.
52:09The lug metastases cleared,
52:10so how long should these patients
52:13be continued on ENTREC inhibitors?
52:16What does the post inhibitor
52:18pathologic response look like?
52:21Currently I have ongoing collaborations
52:23with Alex Lazar at MD Anderson and Palo
52:27de Toys in Italy we constructed a blinded
52:29central review to kind of help with
52:32his logic concordance in these tumors.
52:34That work was presented at Setos and
52:37I'm still working to look at other
52:40predictive markers by Histology in a
52:43large group of these tumors as well.
52:46And one of the say thanks for all of
52:48my collaborators on these projects,
52:51and I'm happy to take any questions.
52:57Thank you so much.
52:59Jessica was a really beautiful talk
53:02and if anybody wanna ask question
53:05you can either unmute yourself and
53:08directly ask question or put it in
53:11the in the chat and I can read it up
53:14so the forum is open for question.
53:22But why do we are waiting
53:25for somebody to think?
53:26I have one question in the
53:29classical situation of the
53:30classical infantile fibrosarcoma
53:32with economical translocation,
53:35what is will see as a going forward approach?
53:40C Steel surgery will be the main approach,
53:44or you would see as a target
53:47therapy and alternative and
53:48first line type of approach.
53:51I think it really depends on
53:53the situation for the patient.
53:56I think moving if it's receptable
53:58and it's an easy location.
54:00Yes, surgery.
54:00More and more though if it's would
54:03be more if there would be any
54:05significant morbidity to that child
54:07they are using and track inhibitors
54:10up front followed by surgery.
54:12So there is much more appetite
54:15for having a low threshold
54:17to using targeted therapies.
54:21OK Jessica, I really enjoyed your talk.
54:23I wonderful. So one question is
54:26also the different prognosis in
54:28among the patient with the same,
54:30like a translocation or the
54:32same kindness permutation.
54:34Do you see any other like a like?
54:37A molecular changes in your NGS that
54:39may explain the different outcomes.
54:42That's a really great question,
54:44so that's one of the things that we're
54:45trying, so I I right now have about
54:4860 cases and growing, and we're trying
54:50to look at if CDKN 2A alterations,
54:53which we've seen in a subset of them,
54:55is one of the alterations
54:57that may influence prognosis.
54:59We also, you know,
55:00we're trying to gather all this
55:02information is at CDKN 2A.
55:04Is it some of the nonrandom
55:06chromosomal gains?
55:06We need a pretty significant cohort
55:09and have detailed follow-up of
55:10like length of time to metastasize.
55:12Etc.
55:13To be able to risk stratify
55:15those patients so you know,
55:17could prognosis be influenced
55:19by those chromosomal games?
55:21CDKN 2A.
55:21We haven't seen too many other recurrent
55:23molecular alterations outside of that,
55:25so we have pretty good DNA and RNA
55:30sequencing for most of our cohort,
55:31so we haven't seen you know P53
55:33or other secondary hits out
55:35outside of CDKN
55:362A IC and also thank God it's more
55:39fun like a practice point view.
55:41A lot of times when.
55:42Something looks like IMT and
55:44dogs or rice positive or so.
55:47Do you just go like a further
55:49two like a proof there's
55:51really like a mutation in this,
55:53like a protein or jeans?
55:56Sorry, can you repeat that?
55:57Yeah, so typically when we sign out
55:59you know I am T like you mentioned.
56:01I'm like sometimes this untracked
56:03tumors can morphologically
56:05resemble a lot of things.
56:06So if you say something like IMT
56:09and all positive are you done there
56:11or do you go to NGS or whatever
56:13mutational panel you have?
56:16So I mean I I still have a morphologist
56:18at heart, so I start with morphology
56:21and and also the clinical presentation.
56:24So do you know?
56:25Obviously they're still IMT.
56:27They're just imt's they look beautiful,
56:28I imds, and so in this blinded review,
56:31for example, that I did with Alex and
56:34Paolo that were these entrec tumors,
56:36where some of them I EMTs.
56:37Yes. So I think a subset of
56:40imt's can harbor and track.
56:42So I start with the morphology and then.
56:44And yes, I also use.
56:45I use pound track and elk and
56:48other IHC pretty liberally.
56:50But I have a low threshold
56:53to send for sequencing.
56:54Thank you Yep.
57:00There is a commentary on the Charter,
57:03but I will read up visits from George
57:06Massage and he suggested maybe it's
57:09time to resurrect the term fibrosarcoma
57:12and that Gato molecular to avoid
57:14the way nomenklatura limitations.
57:21I like this suggestion.
57:22I think that there would be some
57:25backlash from adult BST pathologists.
57:27There's there's,
57:28so there's been this systematic desire
57:30to rid our world of fibrosarcoma.
57:34At least the adult fibrosarcoma
57:35for more precise nomenclature,
57:37but I understand the desire to to to want
57:40to do that at the same point in time.
57:43I think it's really hard,
57:44you know, for many years we tried
57:46to get rid of you went from.
57:48To UPS to try to to rid
57:51the world of fibrosarcoma.
57:53I think the nomenclature
57:54is just very confusing.
57:55You know, in an adult I I do.
57:57Adult bonus as you two,
57:58we've really fibrosarcoma,
58:00is so strictly reserved now for
58:02fibrosarcoma arising in DFS,
58:04and so the term fibrosarcoma
58:06itself is just so confusing,
58:08and we've kind of created a mess
58:09of our own nomenclature sometimes,
58:11and it's it's hard to explain it.
58:14I often joke that it's created just to
58:17torture pathology residents and clinicians.
58:20So so yes,
58:21we do need to refine our
58:22nomenclature and in a better way.
58:31Without going too much into detail,
58:33very specific engines use.
58:40So yes and yes or no,
58:44I think with NGS you have to be
58:47very careful because not all created
58:49equal and and not just. You know,
58:52I often see people bigger is better,
58:55and I don't think bigger is better.
58:57You need to be mindful of what genes you
58:59have and what the the sequencing capacity is.
59:02So I'm fortunate that my institution is
59:05affiliated with the night Diagnostic lab.
59:07If you guys are familiar, it's a large.
59:09Molecular Reference lab and so
59:11you know for sake of simplicity.
59:13And because it's a good lab,
59:14I often send my sequencing to
59:17the night diagnostic lab.
59:18They were founded by Chris
59:20Corliss and Brian Druker.
59:22If you guys are familiar with Brian Druker,
59:24he was influential in and you
59:26know the development of GLEEVEC.
59:28So I come from an institution
59:29that has a long line of succession
59:31of targeted therapeutics and
59:33identification of tyrosine kinases,
59:34so it really benefits my my work and
59:37partly why I came here so covering.
59:39Chinese alterations is not a
59:41problem for my sequencing.
59:43That being said,
59:43I do a lot of content work and I
59:46just recently actually got a console
59:48for just not nodular fasciitis,
59:50but they're like, oh,
59:51we did the sequencing panel of 500 genes.
59:54But ironically,
59:54USP 6 wasn't actually included on that.
59:57So just a word to the wise,
59:58make sure that you understand which
60:00genes are covered and the limitations.
01:00:02So USP 6, for example,
01:00:03is often an alteration of promoter swapping.
01:00:06So next generation sequencing
01:00:08often won't actually detect.
01:00:09USP 6 gene alterations.
01:00:12So just understanding the tests they
01:00:15are ordering is really important and
01:00:17why it might fail. I always you know.
01:00:20Again,
01:00:20tell my trainees a test is a test and
01:00:23every test has its limitations and
01:00:25even within my lab who I think is terrific,
01:00:28I recently had an IMT and they didn't
01:00:31detect an out gene rearrangement
01:00:33and Chris Corliss who's an amazing
01:00:35molecular pathologist. He was like.
01:00:37Are you sure if your diagnosis
01:00:39and I said yes?
01:00:40And then we did fish and it was
01:00:42fish positive and so he went back
01:00:43and manually read the sequencing
01:00:45reads and found the ALK gene fusion.
01:00:47So you know,
01:00:48every every test has its limitations.
01:00:56I can read it up for you by Rita Brad.
01:01:00What do you think about pan track?
01:01:02A minister chemistry in epithelial tumor?
01:01:05Do you have any issue with specificity?
01:01:10Again, great question.
01:01:11Thank you, I I. As a pediatric,
01:01:15components of tissue pathologists,
01:01:16I don't use it regularly
01:01:17in epithelial tumors.
01:01:18With a few exceptions,
01:01:19so I've used it a few times in
01:01:22thyroid for Pediatrics and I've
01:01:23used it for secretory carcinomas,
01:01:26both in salivary glands and breast
01:01:28and some pediatric patients,
01:01:29and it works well.
01:01:33Can I am very particular in how
01:01:35I titrate my Pantech ihcc so I
01:01:37validate it on a on tumor which is
01:01:41different than most institutions,
01:01:43so I have it titrated very low so I
01:01:45don't get so much background staining.
01:01:48It does mean that I am very aware
01:01:51that I can miss some check 3 fusions
01:01:55so I I would say don't have very many
01:01:58issues with specificity because I've
01:02:01purposely titrated my stain that way.
01:02:04And so if it is,
01:02:05it is very blazingly positive.
01:02:07I know it's positive but I do know that
01:02:09I have the risk of missing some Trek 3.
01:02:11So if it's negative and I have a high
01:02:13level of suspicion, I send it for NGS.
01:02:16I don't.
01:02:17I and there was a really
01:02:19great paper by Jason Hornet.
01:02:21Go about, you know,
01:02:22kind of benefit of doing this for screening
01:02:25for colorectal cancers or other cancers,
01:02:28and the number of cases you would
01:02:30need to screen to see the benefit and
01:02:32basically the the summary of the paper is.
01:02:35It's not really worth it,
01:02:38so I encourage you to read that for
01:02:40other kind of adult carcinoma screening.
01:02:42I haven't personally done that.
01:02:44'cause I don't do that in
01:02:46my practice as much so.
01:02:47I think there would be
01:02:49some limitations there.
01:02:49I think that as the sort
01:02:51of path director here,
01:02:53I advocate for just for like lung cancers.
01:02:55We have a nice lung cancer
01:02:57molecular panel and it covers
01:02:59all the lung cancer alterations
01:03:01including track out care as etc.
01:03:03And I think that that is a better utility,
01:03:06cost effectiveness and tissue
01:03:07saving just to to be able to get
01:03:10everything done for that patient.
01:03:19Well, any other question. Otherwise we
01:03:22will let Jessica finish up her coffee.
01:03:27I'm happy to stay on for questions or
01:03:29people can email me if they have questions.
01:03:34Uh, I don't see anything more in the chat,
01:03:37so Jessica was really pleasure.
01:03:40And thank you so much.
01:03:42Thank you all.