Pathology Grand Rounds February 29, 2024 - Bin Xu, MD, PhD

March 01, 2024

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Bin Xu, MD, PhD, Associate Attending Pathologist, Memorial Sloan Kettering Cancer Center, presents on, "Recent Advances in Thyroid Pathology: High Grade Carcinoma, Anaplastic Carcinoma and Medullary Carcinoma."

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00:02Welcome everyone. Today's Grand
00:05Round speaker is Doctor Ben Shue,
00:08A preeminent head and neck pathologist.
00:14Doctor Ben Shue graduated from medical
00:20school from McGill University in Montreal,
00:24QC, Canada, where she went on to
00:27do a pathology residence residency,
00:31and after completion,
00:32she actually applied for a head and
00:36neck fellowship here at Yale in 2014.
00:40But that was exactly the year I did not.
00:45We did not have a CGME accreditation and
00:48that was the year we did not have funding.
00:53So Doctor Shoe went to memorial to do
00:572 years of fellowship the first year
01:01as is an Oncologic Surgical Pathology
01:05fellow and the second year as a head
01:09and neck pathology fellow and made
01:13excellent use of her two years there.
01:17She went on to become attending
01:20pathologist back in Canada at Sunnybrook
01:24Health Sciences Center in Toronto
01:27and then after a couple of years she
01:31was ready to move and was recruited
01:34by Memorial Sloan Kettering Cancer
01:38Center as Assistant Attending and has
01:43recently been promoted to Associate
01:47Attending Pathology Pathologist.
01:50She practices Head and Neck pathology
01:54and Gu Pathology
01:57Doctor. Shu has won many awards during
02:01her career and award right from early
02:05years and award for Excellent student
02:09in China scholarship and for graduate
02:12student various different fellowships
02:15and awards throughout her career.
02:21The Best Resident Award as well as the
02:26Best Author Award for Pathology Outlines.
02:31Dr. Shu has contributed close to 200
02:35publications to medical literature.
02:38Her online presence is
02:41phenomenal and very significant.
02:44And among her major contributions
02:47is morphologic characterization
02:49of thyroid cancers,
02:52especially in a plastic thyroid cancers
02:55and Dicer one associated thyroid nodules.
02:59She's characterized mesenchymal
03:01tumors of head and neck as well
03:06as thyroid not midline tumors
03:08in the genital urinary system.
03:12She's also very active
03:14in risk stratification or grading
03:18of various cancers like medullary,
03:21thyroid cancer, muco, epidermoid cancer,
03:25ascenic cell carcinoma,
03:27secretory carcinoma of the thyroid
03:30and also the prognostic value of
03:34characterizing extra nodal extension
03:37for tumor positive lymph nodes.
03:41Most of these papers or publications I
03:44mentioned of practice changing publications,
03:48we have actively discussed them at our
03:51team meetings and journal club and almost
03:54immediately adopted them in our practice.
03:58So these are significant contributions.
04:01She's also a contributor of two
04:04of The Who Blue book series,
04:07one on endocrine pathology and
04:10another on pediatric pathology.
04:13So with that brief introduction,
04:15I invite Doctor Shoot to
04:17give her Grand Round talk.
04:24Thank you so much Doctor Facade
04:26for the kind introduction and for
04:29inviting me for the Grand Round.
04:31It's a pleasure to be here,
04:32although I didn't make it to
04:34the head and neck fellowship.
04:36So my talk today is on recent
04:39advances in thyroid pathology,
04:42mostly focusing on the more
04:45aggressive type including high grade
04:47carcinoma and the plastic carcinoma.
04:50And the last part I'll touch on the
04:53grieving of majorly cyrocarcinoma
04:55and the molecular associations.
04:58I have nothing to disclose so
05:00start from the a real case.
05:02So this is a 68 year old male patient
05:06with a 4.5 centimeter thyroid nodule.
05:09Have metastasis to the central compartment,
05:12lymph node to starvis.
05:14So he underwent total thyroidectomy
05:16and the central neck dissection.
05:18We already know the outcome up
05:21from now that he did develop lung
05:24and brain metastasis in one year,
05:27and he has died of his metastatic
05:29cancer in three years.
05:32So what's the thyroid tumor looks like?
05:35It's looks like a typical classic
05:38variants of papular pterocarcinoma.
05:41There are many branching papillais.
05:43There are no solid girls.
05:45They're evident nuclear feature
05:47of papular cytocarcinoma.
05:49But as you can notice point
05:51by those Red Arrows,
05:52they're focal spotty tumor necrosis and the
05:57necrosis is more evidence in the nodule,
06:00nodule metastasis,
06:01nodal metastasis at the presentation.
06:04As you can see by the red arrow.
06:07Again,
06:08even in the nodal metastasis,
06:10the tumor preserved the popular
06:13architectures and nuclear feature of PTC.
06:16So the question comes to
06:19what's the diagnosis?
06:21So before the new WHO 2020 250 edition,
06:25this can be called variably by
06:28multiple terminology including most
06:31commonly by practicing pathologists
06:34as papular sero carcinoma.
06:36But clearly that does not capture
06:39the aggressive outcome of this
06:41case as patient have the system
06:43metastasis in one year and dead
06:45of disease within three years.
06:47As we know that papular sero carcinoma
06:49overall is a very endowing cancer,
06:52they have normal life expectancy.
06:54They rarely develop distant metastasis,
06:57usually in the 1 to 2% range.
07:00The other alternative to call it a
07:03Papillocera carcinoma high grade.
07:05However,
07:06there are many clinicians not
07:08used to this terminology.
07:10They may treat it as garden
07:12variety of Papillocera carcinomas
07:14and not until the publication
07:17of WHO Fixed Edition in 2022.
07:19CAP actually does not mandate
07:22us to grade papulocerrocarcinoma
07:24and we don't need to mandatory
07:27be reporting mitotic index and
07:29necrosis in papulocerrocarcinoma.
07:34It's MSK actually we call it 40 differentia
07:38cyro carcinoma based on mitosis and
07:41necrosis for the longest time since
07:462020, 2006. But this approach
07:49was not adopted outside of MSKCC.
07:52And the last thing I'm going to touch
07:55on this high grade differentiation
07:58cyrocarcinoma is a new classification
08:01terminology included in WHO 5th Edition.
08:03And this particular category of tumor is
08:06aimed to capture those tumors that I show
08:10with necrosis or elevated mitotic index,
08:14but otherwise return a differentiated
08:17psoriatic carcinoma morphology.
08:19So to touch on this new
08:21classification of tumor,
08:22I just want to briefly touch on the
08:24history of Poly deficiency cyrocarcinoma
08:27or high grade carcinoma in the thyroid.
08:30So it was first described by
08:33Doctor Rosi in 1984.
08:35At that time,
08:36it was named as insular carcinoma.
08:39Reportedly,
08:40differentiated carcinoma basically
08:42described these tumors with a
08:45fetal thyroid appearance and
08:48solid trabecular insular growth.
08:51It was not until 2004 was first
08:54included in The Who classification.
08:57Named as poorly differentiated
09:00styrocarcinoma,
09:01this was proposed to capture
09:03tumors with indetermined prognosis
09:05between papular stereo carcinoma
09:08and endoplastic stereo carcinoma.
09:10The only definition was included at the
09:14solid trabecular insular growth pattern.
09:19It's not until 2007 or 2006 that
09:24two separate study was published.
09:26Proposing criteria for Porto
09:29differentiation cyrocarcinoma.
09:31On top is a Turing proposal beat by
09:34Doctor Rosai Visa International Group
09:37that define Porto differentiation
09:40cyrocarcinoma as solid trabecular
09:42insular architecture absent of nuclear
09:45feature of popular cyrocarcinoma
09:47and at least one of the following
09:50features being collated in nuclei
09:52elevated mitosis or tumor necrosis.
09:57At about the same time MSKCC actually did
10:01a separate study and separate criteria
10:06based defining ported differentiate
10:09carcinoma based solely on mitosis
10:12and or necrosis Buried in both paper
10:16they're actually mentioning that solid
10:20Tribeca or to insular growth pattern
10:23result necrosis in the Turin Cooper
10:26does not impact survival at all.
10:29Well in the Ms.
10:30case study it's also showed that
10:32architecture does not impact survival.
10:35So despite this mentioning of
10:38architecture doesn't affect outcome,
10:42the 2017 WHO Forced Edition
10:47officially included Turing proposal
10:49which is on top as a definition of
10:52pretty differentiated carcinoma.
10:54That's basically left those tumors
10:57result solid growth pattern or with
10:59PTC nuclei but have some mitosis
11:02and necrosis behind and those
11:04tumors can be classified variably
11:07as popular Sero carcinoma,
11:10puppy Sero carcinoma high grade were in
11:13our center as 40 differential carcinoma.
11:16So that's the eventually data
11:19viewed within this two decades,
11:21these two reclassification in 2022.
11:25I'm just going to mention the
11:28classification here and then outcome
11:30in following sides to show that it's
11:33more justified to include this high
11:36grade differentiated thyroid carcinoma,
11:38morphology or classification because
11:41they do also have intermediate
11:45prognosis worse than PTC.
11:47So nowaday in the 2022 WHO they
11:51have a new classification of high
11:53grade follicular cell derived non
11:56endopathic thyroid carcinoma,
11:57a hand of mouthful of nomenclatures
12:02and that can be further divided into
12:05Poly differentiated carcinoma and high
12:09grade differentiated cyrocarcinoma.
12:11And the high grade differentiated
12:14cyrocarcinoma basically preserved
12:15for tumor meet MSKCC criteria
12:18but does not need to rain.
12:21So it's here is a summary
12:22of what it looks like.
12:24So the high grade differentiated
12:27high grade follicular derived non
12:29the past styrocarcinoma is defined
12:32by elevated mitotic count and or
12:35tumor necrosis and they don't have
12:38anaplastic morphology and under it
12:40they're two subgroup the on the left
12:43the pretty differentiated carcinoma
12:45which is defined by Turing proposal
12:48and that can be further divided into
12:51non oncocytic one and oncocytic
12:54one that have oncocytic morphology.
12:56And on the right are the high
12:59grade differentiated carcinoma.
13:00This a tumor with any architecture urine
13:03not salted or any nuclear feature.
13:06So they can re preserve the nuclear
13:08feature of popping Seracarcinoma,
13:10but they additionally have either
13:13elevated mitotic index or tumor necrosis.
13:17And from WHO 2022 ton high power
13:21fuels now switched to 2mm squares
13:25for mitotic index.
13:27So why we propose,
13:29why we propose this classification?
13:31Is it really because they capture
13:35carcinoma of Interment prognosis?
13:37So here I'm showing to study on the left.
13:40The Kaplan mayor curve is to
13:42compare popular Sero carcinoma.
13:44Tall cell subtype or tall
13:46cell variants is a high
13:48grade differential cyrocarcinoma
13:50that also have tall cell morphology
13:54including 30% of tall cells.
13:57Those tumors are actually very rare.
14:01They account for only 5% of all
14:04tumors with tall cell morphology
14:06and characterized by elevated
14:08mitotic index or tumor necrosis
14:11and can see their disease specific
14:14survival and distant metastasis
14:17free survival drastically different.
14:19So in PTC Tal cell subtype those
14:23result elevated mitosis or necrosis.
14:26Their mortality at five years
14:29only one to 2% and their distant
14:32metastasis rate is super low at 2%.
14:35However, when you get to the high
14:37grade differentiate cyrocarcinoma
14:39or portly differentiated carcinoma,
14:42their five year disease related
14:45mortality is around 20 to 25% and
14:49the five year risk of distant
14:52metastasis is more than half.
14:54So 50 to 61% developed decent metastasis.
14:58So clearly just mitosis and
15:01necrosis allow can capture for the
15:04chemo cell derived carcinoma with
15:07this indeterminate prognosis that
15:09need additional clinical care.
15:16We additionally showed that
15:19high grade thyroid carcinoma,
15:21it's main cause of radioactive iodine
15:24refractory disease and also main cause
15:27of deaths in non endopathic thyroid
15:30for the killer cell derived carcinoma.
15:33Molecularly this group as a group
15:35high grade for the killer cell
15:38derived cyrocarcinoma also have more
15:42aggressive molecular signatures.
15:45Not sure it's maybe two,
15:48I'm not sure whether the phone is too small.
15:50So on the left are the PTCS and on
15:52the right are the high grade for the
15:54killer derived thyrocarcinoma ISO
15:56group including portate death and high
15:59grade differentiated thyrocarcinoma.
16:01You can see the driver mutation
16:04remains the same being B RAF and
16:06the Ras well The high grade for the
16:09cure derived thyrocarcinomas tend
16:11to to gain additional aggressive
16:14molecular signatures particularly third
16:17promoter mutation in 40% of cases,
16:21TP53 in 10% of cases and peak 3C AAKTM
16:26Tor pathway alterations in 11% of cases.
16:31So why don't we just lump all the
16:34tumors as a high grade for the
16:37first cell derived cyrocarcinoma.
16:39Why bother subdividing is is because
16:42poorly differential cyrocarcinoma and the
16:45high grade differential cyrocarcinoma do
16:48have molecular and clinical difference.
16:52ISO group. The poorly differential
16:54cytocarcinoma is mostly Ras driven.
16:57Their Ras mutation rate is around 45 to 50%.
17:01The urine like B Ravi sundry E mutations
17:04and they're usually more radioactive
17:08I then AB avid and responsive and the
17:12the risk of distal metastasis is much
17:16higher significant higher compared to the
17:20high grade differential cyrocarcinoma.
17:22Although the risk of this metastasis
17:25over all is still over 50% in the
17:28high grade differentiated carcinoma.
17:30On the other hand the high grade
17:33differentiated scarcity thyroid
17:34carcinoma is mostly B RAF driven.
17:36The rate of Ras mutations lower
17:38and the rate of B RAF desantry E
17:41mutations is over 50%.
17:47Looking at the molecular signature in
17:51hybrid differentiated cyrocarcinoma,
17:52hybrid follicular style divide
17:54cyrocarcinoma as a whole,
17:56it seems that B RAF is only E is associated
17:59with a proplicity for nodal metastasis
18:02and decreased risk of distant metastasis.
18:05Just as the well differentiated
18:07counterpart being popular cyrocarcinoma
18:09were follicular cyrocarcinoma.
18:11So overall RAST driven hybrid carcinoma have
18:16a higher percentage of vascular invasion,
18:19lower rate of nodal metastasis and higher
18:23frequency of distant metastasis being
18:25approaching 90% compared to B Ravi sundry
18:29E mutation mutated hybrid carcinoma.
18:32They still have a risk of distant
18:35metastasis being 1:00 and 2:00,
18:37but they have much higher risk
18:39of nodal metastasis and lower
18:41frequency of vascular invasion.
18:44Overall the disease specific deaths
18:47doesn't different between doesn't differ
18:49between the two molecular signature.
18:54So how about oncocetic partially
18:57differentiated thyroid carcinoma,
18:58those are tumor defined by
19:02over 75% of oncocetic cells,
19:05but also additionally have solid
19:09growth pattern or tumor necrosis
19:13were elevated metallic index.
19:16Those tumor as a group overall likes
19:18Ras and B RAF mutations just as the
19:23well differentiated oncocytic carcinoma.
19:25They have a very low rate of Ras
19:28mutation being 7% only no B RAF besundry
19:32mutations and overall they have a
19:35higher frequency of TP 53 then F1
19:39and P10 mutations in oncocytic party
19:43differentiate carcinoma canonically.
19:45They also behave differently from the non
19:48oncocytic party difference styrocarcinoma.
19:51The oncocytic party difference
19:53Styrocarcinoma is less a REI avid
19:56just like the oncocytic carcinomas
19:58and the reason of nodal metastasis
20:01is prognosis on the other hand does
20:04not differ between the two group.
20:10So taking everything together also
20:13combined this evidence we know from the
20:16well differentiated thyroid carcinoma.
20:19We now know that thyroid follicular
20:22cell derived carcinoma can be basically
20:25divide divide into three subgroup.
20:28The Ras like tumor urely at
20:31the follicular pattern lesion
20:32including follicular carcinoma.
20:35The PTC encapsulated follicular events.
20:38When they progress,
20:39they progress to pretty
20:42differentiated thyroid carcinoma,
20:43the non oncocytic type.
20:46In the middle are the oncocytic tumors.
20:49This tumors as shown by our group
20:52and the group from Harvard Lakes
20:54B Ravi Sundry E and the Ras,
20:57they already have widespread chromosome
21:00loss and mitochondria DNA mutation which
21:03allow them to accumulate this oncocytic
21:06cytoplasm that we see on Histology.
21:09When they progress,
21:11they progress to poorly differentiated
21:13cyber carcinoma but the oncocytic type.
21:16Lastly at the B RAF driven tumor that would
21:20be include PTC papular sero carcinoma,
21:23classic type papular sero carcinoma,
21:25tall cell subtype or virus and the
21:28infiltrated for the coronary virus
21:30of papular sero carcinoma and they
21:33typically progress to high grade
21:36differentiated cyrocarcinoma.
21:37And when this tumor progressed the
21:40additionally can other molecular
21:43changes including turn promoter
21:45mutations and TP53 mutations.
21:50So that's pretty much the new calcification
21:53for the high grade carcinoma and I'm
21:56going to switch deer to anapacic thyroid
21:59carcinoma which is the most deadly
22:02thyroid carcinoma in the human body.
22:05So by WHO definitions is a highly
22:09aggressive you're the fatal Cyril malignancy
22:14composed of undifferentiated cells.
22:17The undifferentiated morphology can be
22:19manifest by Histology that you no longer
22:23recognize a physical cell origins or
22:26by immunohasal chemistry when they lost
22:29expression of thyroid specific markers
22:32such as TTF 1 Seroglobulus tax eight
22:36our lowest pathologist not only to make
22:39right diagnosis but this day we're
22:42required to provide some prognosis,
22:44prognostic and predictive values for
22:47from our specimen including actionable
22:50molecular targets such as Birafi,
22:53Sandra E this we touched a little
22:57bit during our science seminar this
23:00morning and the passive sero carcinoma
23:02can look like many things.
23:04The most common morphology are
23:07the spindle phenotype,
23:08and among spindle morphology
23:11they have various morphology.
23:13They can be cellular spindle,
23:16they can be posicellular and spindle,
23:18so-called the posicellular variants,
23:20and they can focally have mixed ways,
23:22stroma, redemptal and mixo fibrosarcoma.
23:27They can be prunomorphic with
23:30tumor gene cells.
23:31They can be squamous that have two
23:34keratin pros and keratinizations where
23:36they can be epicidioid or epicidio in
23:40which they return the expression of
23:43keratin but no longer appreciable as
23:46a follicular cell derived carcinoma
23:48based on Histology and immunohistochemistry.
23:52Other rare phenotype including rapidoid
23:56with prominent eccentric cytoplasm
23:59inclusions all still class Gen.
24:02cell rich subtype which we covered
24:042 case during the size seminar and
24:07rarely you can see heterogeneous
24:10component in these tumors as well-being
24:13chondrosarcomatoid or osteosarcomatoid.
24:18There is a question in the morning
24:21seminar saying whether this
24:22histological feature matters.
24:24We have shown that from a corpora
24:27of 360 anaplastic pterocarcinoma as
24:31a combined combined effort from us
24:35and from Sydney all this nuclear
24:38all this histological features
24:40does not impact outcome.
24:43So it's really for us to recognize
24:46the histological spectrum to
24:48make the right diagnosis.
24:50But histological feature per
24:52SE does not impact prognosis.
24:55They are case report of positive
24:57cellular variants of antopathy.
24:59Steroid carcinoma can have slow
25:02progression and improve survival,
25:04but the evidence is only based
25:07on case report and it's not
25:09very conclusive as of now.
25:15The only histological contribution of
25:22anapasi steroid carcinoma is recently based
25:25on molecular findings and prognostic data.
25:28The pure, the so-called thyroid
25:31squamous cell carcinoma is now debunked
25:35and taken out of WHO 5th edition.
25:39So thyroid squamous cell carcinoma
25:42was initially defined as a separate
25:45entity in The Who 4th edition.
25:48It's defined by tumor comprised entirely of
25:52tumor cells with squamous differentiations.
25:55And there's no evidence of other type
25:58of thyroid carcinoma being most commonly
26:01papulosario carcinoma tall cell variants.
26:04However, recent study especially those
26:06from our group have shown that this
26:09tumor this is a squamous phenotype have
26:12a higher frequency of B Ravi sundry
26:15E mutations just like Papulocerio
26:18carcinoma and the outcome is similar
26:21between this pure squamous phenotype
26:24and the other endopathic styrocarcinoma.
26:27The medium overall survival is 14 months
26:30in your study compared to all the other
26:34tumor that was medium survival of 10 months.
26:37So based on this prognostic
26:39data and molecular data,
26:41it's it is now believed that thyroid
26:44squamous cell carcinoma is a
26:46subtype of anaplastic sero carcinoma
26:48rather than a separate entity.
26:53So in term of the immuno profile,
26:55I'm only going to touch quickly you already
26:59because they underwent the differentiation,
27:02so they start to lose expression of
27:05cyber physical cell markers and keratins.
27:08So generally this tumor should be
27:11seroglobulin negative if it's positive,
27:14it's only really focal and it is
27:16transition between a differentiated
27:18sero carcinoma and antopathic carcinoma.
27:21About 1/3 is TTF 1 positive and packs
27:258 depending on the conality 50% to
27:2970% of packs 8 positive keratin.
27:33In practice we actually use a spectrum.
27:36Overall 75% of the endopathy
27:39pterocarcinoma are keratin positive,
27:42but there are some viabilities in
27:45term of pan keratins and the high
27:49mild cure rate keratins.
27:51We also use mutation driven protein.
27:54Your diagnosis friend plastic
27:57pterocarcinoma including a Baron
28:00P15P53 expression in about 60%
28:02of cases by immunohistochemistry.
28:04We use specific marker for B RAF
28:08V sundry E by immunohistochemistry
28:11that it's positively about 40% of
28:14antipathy Styrocarcinoma Ras Q61R
28:18detect H Ras N Ras and K Ras Q61 are
28:24mutation only and that is positively
28:28about 15% of the cases.
28:30So in practice and the KSE 7
28:33it's usually high.
28:34However,
28:35there's a caviar that some of
28:37the anaplastic sero carcinoma,
28:39especially the squamous one.
28:41Because of the highest Dromo content,
28:44the KSE 7 May be lower,
28:46ranging from 10% to 100%.
28:50So in practice,
28:52In our practice,
28:53we're actually using a combination of
28:56differentiation marker and mutation
28:58marker to diagnose anaplastic styrocarcinoma.
29:02The differential diagnosis is
29:03extensively covered this morning
29:05in the science seminar,
29:06so I won't touch on it now.
29:09I only going to quickly mention one
29:13paper because it's one of my rear
29:17collaboration with a Yale pathologist.
29:21So basically we established that
29:24primary sarcoma of the thyroid gun
29:27can occur is a comfort license 1%
29:30of all thyroid malignancies and we
29:34report a single case of he coma
29:37that was never reported in the
29:41thyroid literature that have RBM
29:4310 and TFE 3 translocation and Dr.
29:47Sinai and Doctor Wu can be helped
29:50for this project.
29:51So moving on to the molecular of
29:55endoplastic thyroid carcinoma,
29:58once again endopathic thyroid
30:00carcinoma because it's for the
30:02cure cell derived,
30:03they returned the early driver
30:06mutations being B RAC with
30:08sundry E and the Ras mutations.
30:10The frequency is being 638% and
30:1527% compared to differentiated,
30:18well differentiated and poor
30:20high grade thyrocarcinoma.
30:22The accumulate even more mutations,
30:26the TP 53 mutation for example,
30:29becoming highly prevalent,
30:31accounting for 63% of anaplastic
30:34thyrocarcinoma and the frequency of
30:36turtle motor mutation is also higher,
30:39being 50%.
30:40They also additionally have peak
30:433C AAQTM tour pathway alterations,
30:46swift sniff complex alterations and
30:50mismatch mismatch Repair alterations.
30:56Anapastic SERO carcinoma,
30:57the B RAF Nissundry E and the
31:00Ras no longer designate the
31:03route of spread and survival.
31:05At this stage is really the Anapaci
31:08stereo carcinoma morphology or
31:11diagnosis that designate outcome.
31:13The B Ravi sundry E mutated or Ras
31:16mutated endopathy stereo carcinoma have
31:18a similar rate of nodal metastasis,
31:21distant metastasis and mortality
31:24being in the range of 60 to 70%.
31:301 thing as a pathologist we know commonly
31:34being asked to do as B RAF is only E testing.
31:38The reason is that this new adjuvant that
31:42Bafinib which is AB RAF inhibitors and
31:46Trabafinib which is a Berk inhibitors,
31:48they have a fabulous response
31:51in B RAF V certainly E mutated
31:54antopathy steroid carcinoma.
31:56Data from MB Anderson showed
31:59that they lead to feasibility of
32:02complete surgical resection and
32:04durable local regional controls.
32:07Based on this data,
32:10FDA actually approved combined
32:13that Bafnib and tribetanib as a
32:15standard first line treatment for B
32:19RAF eccentric E mutated endopathy
32:21cyrocarcinoma and this is included
32:24in endopathic in ATA guideline to
32:28treating endopathy cyrocarcinoma.
32:31Here is an example actually of
32:33a real case we recently see.
32:35You can see on the left the PET
32:38showing a large thyroid base PET
32:41Avid mass emitting the trachea
32:44and after only three cycles of
32:47Dypathinib and tribadinib the tumor
32:49shrink down significantly and the
32:52path avidity is decreased.
32:54And here is the case after surgical
32:57resection on the left of the
33:00pre treatment sample showing a
33:03hypercellular endopathy pterocarcinoma.
33:05We supported morphic slash
33:08spindomorphology on the on the
33:10right a basically the post treatment
33:13sample of the thyroid dectomy we
33:16received and the entire tumor,
33:18nearly the entire tumor is wiped out
33:21as this fibrosis and information and
33:23that there are only one small focus
33:26of endopathy styroid carcinoma in
33:28the middle top and at high power.
33:32You can see that endopathy
33:34styrocarcinoma is only manifest as
33:36this scattered hyperchlomatic for
33:38neomorphic cells embedded in the
33:41sea of macrophages and lymphocytes.
33:44In our experience,
33:46we have more than 50 case now the
33:49response rate but it's variable
33:51but many of them have a complete
33:54response in the surgical specimen,
33:57some of them does not have
33:59a significant response.
34:01The residual difference is Ptero
34:04carcinoma surprisingly was urinary
34:06not touched by this combined
34:09therapies and it will be left behind
34:12in the thyroidectomy specimen.
34:14Because of this combined therapies,
34:18we are now asked by our clinician,
34:21medical oncologist to have rapid
34:23B rapid sundry E on every single
34:27case of endopathy styrocarcinoma.
34:29In our hand we found B RAF
34:32Lisandre immunohistochemistry.
34:33It's a highly sensitive and specific
34:36marker to screening for B RAF Lisandre E
34:40mutations endoplastic steroid carcinoma.
34:42The sensitivity is about 95%.
34:45So there are first negative cases
34:47but the specificity is 100% showing
34:51on the right three cases,
34:54one is squeamoid anoplastic,
34:56one is osteocarps John cell rich and
34:59one is raptoroid and all three cases
35:01are positive for B RAC Nissundre E
35:04So basically even our patient of
35:06anopathy sero carcinoma walk into our door.
35:09The first thing our medical oncologist
35:11asked is a rapid B RAC nissundre
35:14E you know histochemistry and then
35:16we can get it turn around.
35:17We seen a day to put patient that
35:20on that bacfinib and trabechium and
35:23that will be followed by some form
35:26of molecular confirmation either by
35:29PCR based ISA such as E dialog or
35:33next generation sequencing which can
35:36take two weeks or more to get the results.
35:40So in this graph I already
35:43showed the differentiated well
35:45differential cyrocarcinoma,
35:47the high grade cyrocarcinoma and
35:50I'm now just adding the last
35:54line of the progression which is
35:57anaplasic psoriatic carcinoma.
35:58So overall now we think thyroid
36:02have a style wise progression
36:04from well differentiated to high
36:06grade to anaplasic cirrocarcinoma.
36:08Well, the driver mutations remains the same.
36:13They can additional molecular aggressive
36:17molecular signatures when they progress.
36:21And the Ras like tumor are the
36:23foamicular pattern lesions,
36:24the B RAF like tumor are the classic
36:27and talso papular sero carcinoma,
36:29well oncocytic carcinoma,
36:31it's by them by their own characterized
36:34by widespread chromosome loss
36:36and mitochondria mutations.
36:40So that's basically summarize the
36:43fordicular cell derived new pattern part.
36:46So now we're moving towards a combined
36:51molecular histological classifications
36:54in which Ras tumor is really the RASP,
36:58the fordicular pattern lesion when they go,
37:01they when they spread the spread decently
37:04that would be include fordicular adenoma.
37:07The NIFPS, the portly differential
37:09carcinoma and the forticular carcinoma were
37:13invasive encapsulated follicular events.
37:16But the B RAF like tumors are the
37:18infiltrative 1, they're tall cells,
37:21Casa infiltrative particular subtype
37:24or infiltrative solid subtype.
37:27When they progress a progress to high
37:29grade differentiation center carcinoma,
37:31then we have the non B RAF,
37:33non Ras oncostatic tumor.
37:37Eventually all of them can
37:40lead to the development of
37:42endopathic thyroid carcinoma.
37:44So we're going to switch here
37:46and use the last 10 minutes or so
37:49in major or thyroid carcinoma.
37:53So major or thyroid carcinoma was
37:55first described by Doctor Hazard,
37:57Doctor Kovka and Doctor Creel in 1959.
38:02Since it's publications have
38:04already been more than six decades,
38:08the prognostic factor identified
38:10the imaginary steroid carcinoma age,
38:12sex, PMN staging serum,
38:16calcitonin, serum CA calcitonin,
38:19doubling time, type of red mutations,
38:23sporadic versus hereditary
38:24disease and so on or so forth.
38:27But notice that there's no not
38:30a single pathological parameters
38:33in this prognostic factor list.
38:36It's not until 2020 that a
38:39greeting system was developed for
38:42modular stereo carcinoma.
38:44Well the pulmonary and pancreatic
38:47pancreatic neuroendocrine carcinoma
38:49have their neoplasm have their well
38:52accepted well established prognostic
38:55relevant histological greeting system.
38:58So in 2020 there are two parallel
39:01study published a few months apart.
39:05One by us using A2 tier grading system
39:07using you only mitosis and necrosis
39:10and the other by a Sydney group
39:13from Doctor Gill using a three tier
39:16grading system using mitosis necrosis
39:18and Kia 67 proliferation index.
39:24We included 144 cases of my joint stereo
39:27carcinoma and we use the same cut off as
39:30as 40 different stereo carcinoma being 5
39:34mitosis per 2mm squares and tumor necrosis.
39:38Well Sydney grade is more resemble AGI
39:42pancreatic biliary grading system with added
39:45that cause necrosis as a served parameters.
39:50So basically a present of necrosis will
39:53boost will make the grade to be one
39:56year or higher regardless of either
39:59grading system that was proposed.
40:01In details we you can see on the right
40:04that either grading system is highly
40:08prognostically relevant and predict disease
40:11specific survival and overall survival.
40:16So the next year, in 2022,
40:19we decide to sit 2021-2022,
40:22we decide to sit together
40:24and recruiting more center.
40:26The aim is really to develop a
40:30universal grading system using a
40:32consensus cut off so that it can be
40:36easily applied throughout the world.
40:39In practice we recruited 327 patients
40:43from 5 center across Europe,
40:45Australia and the US.
40:49The features we use of peritotic count,
40:53PS67 necrosis,
40:54and the mitotic count we followed
40:56the basically gastrointestinal sash,
40:59pancreatal biliary neuron,
41:01The tumor criteria we counted hotspot
41:04per 2mm squares and we mandate
41:07counting of 500 to 2000 cells.
41:11Necosis is just classified as
41:14present or absent. A high grade.
41:17Major or serial carcinoma is defined by
41:20at least one of the following features,
41:22A mitotic index of five or
41:25more per 2mm squares,
41:27A KIC 7 proliferation index of 5% or more,
41:32or tumor necrosis.
41:34We did try other cut offs similar to
41:36long or pancreatic biliary in our study,
41:39but none of them work because
41:43major or pterocarcinoma generally
41:45like very high mitotic index
41:48or KSC 7 proliferation index.
41:50So this is a consensus grading
41:54system we came up to and what we've
41:57shown here is that they're really
42:00highly predictive of outcome.
42:02They independently predict outcome
42:04of major or thyroid carcinomas
42:09in including overall survival,
42:13disease specific survival,
42:14local regional recurrence,
42:16free survival and distant
42:18metastasis free survival.
42:20The low grade macular thyroid carcinoma
42:22have a 10 year disease specific
42:25survival of 97% while the in the high
42:28grade tumors it's decreased to 53%.
42:31Same thing for the distant metastasis
42:34free survivals is 84% in low grade
42:37tumors and 31% in high grade tumors.
42:42So week based on this study the grading
42:47scheme that is now included in The
42:50Who 50 editions and we subsequently
42:53conduct a separate study looking at
42:56the molecular profile of these tumors.
42:59We take most of our tumors with
43:02tissues and we recruit one more
43:05center with being Emory University's.
43:08So a total of 290 cases of primary
43:12resected major serial carcinoma.
43:14And what we found is that right red
43:18somatic mutation create this grade.
43:20So there is a much higher percentage
43:23of right somatic mutations in
43:26high grade tumor compared.
43:30On the other hand,
43:31we also found the right somatic mutation
43:33was associated with larger tumor size,
43:37higher prognostic group slash
43:40stage and vascular invasion.
43:43RED M918T which is an aggressive
43:47form of RED mutations was also
43:50associated with a worst clinical
43:53pathological features being younger age,
43:57higher stage vascular invasion,
43:59extra thyroid extension positive margins.
44:03But surprisingly it doesn't correlate
44:05with the grade in our study.
44:09I mean you look at the outcome based
44:12on molecular signature along we found
44:14that the red somatic mutations or
44:17germline mutation is associated with a
44:20decreased distant metastasis or that's
44:23a type of distant metastasis free
44:26survivals imagine or thyroid carcinoma.
44:28On the other hand,
44:30the Ras mutation have improved over
44:33survival but only a trend it was not
44:37significant and M9118T does not make it
44:42so it was not prognostically significant.
44:45However,
44:46all this molecular signatures when
44:49you do macular analysis together with
44:52grade and group and grade and stage,
44:55the prognostic relevance of a
44:57red and RICE mutation was lost.
45:01So in the end is really the grade
45:03and this stage trumped the molecular
45:07signature imaginary sero carcinoma
45:09in predicting outcome.
45:11So that's another prove that the grade works.
45:16One interesting molecular signature
45:18we found is TP 53.
45:21It's occurring very low frequency in
45:24major steroid carcinoma being 4%,
45:26but it was associated with decreased
45:29survivals including overall survival,
45:31disease,
45:32specific survivals and distant metastasis.
45:35Free survivals since publication
45:39are grade consensus grading paper.
45:43There are multiple studies,
45:45including one from Yeo last year,
45:48validate that the grade group works.
45:52It's it's an independent predictor of
45:56survival for vaginal pterocarcinoma.
46:02We also did some subsequent small
46:06study showing that the grid can
46:10be reproducible between academic
46:12pathologist that was lead by just
46:16Doctor Balada from Brigham TA 67
46:20Imaginal sero carcinoma can be
46:23accurately assessed by eyeballing
46:25imaging analysis or AI based platform
46:28that is from Emory group and our group
46:34AE Tiny group. Other further also
46:37further support our observation that
46:40the red somatic mutation is associated
46:43with high grade tumor and outcome.
46:46And lastly, we just recently published
46:50A prognostic nomogram developed
46:53using our multi center core and the
46:57normal Grammy including mitosis,
46:59tic 7 and tumor necrosis and this
47:02study was lead by the Australia group.
47:06So that's pretty much the talk.
47:10So the take home message is really
47:13in the thyroid pathologies there is a
47:16shift towards a classification scheme
47:19based on prognostically relevant
47:21histological features and molecular
47:25pathogenesis because Mitos I hope I
47:28showed here mitosis and necosis matters
47:30in both C cell derived carcinomas
47:33and funicar cell derived carcinoma.
47:36And because of that is our part of our
47:39job to search for elevated mitotic
47:43the index and necrosis in this tumor
47:46in order to accurately classify this
47:49tumor grading this tumor and provide
47:52prognostic relevant data to the clinicians.
47:56So that's pretty much the talk.
47:58Thank you very much and I'm open
48:01to questions.
48:05Oh yeah, just a second. I was
48:07told I have to turn this on. OK,
48:12good talk. I like it's the value
48:13of necrosis and Mectotis most of
48:15the things not they got EFNI and
48:17we can have ischemic necrosis,
48:19attractive proliferation. Yeah.
48:20Are you using this criteria?
48:23We are not over calling this group.
48:26We exclude I think in all of our study
48:28we exclude Fla related degenerative
48:31necrosis and tumor necrosis.
48:34So I have to be true tumor necrosis,
48:36the imaginary cereal carcinoma for example,
48:39the specifically mentioned here
48:41FOA related necrosis or degenerated
48:44necrosis is not tumor necrosis.
48:46So you need 2 tumor necrosis. Yeah,
48:53other question where where has a
48:59so-called lumner cell carcinoma that
49:04always had you can type necrosis and
49:08add like colonic carcinoma like here
49:13where in the cell could
49:15it be high grade if you have necrosis
49:17or elevated mitosis will be high grade
49:20differentiated cell carcinoma. So
49:23you do not recommend columns?
49:28No. But we do see cases
49:31resolved necrosis and mitosis.
49:33So common cell variants do occur,
49:35but only those resolved mitosis and necrosis
49:38will be called papulosariocarcinoma,
49:41coloner cell subtype or rare.
49:45But many of those as it was classified
49:47as one aggressive variance, right.
49:50But I think really because they're high
49:52grade, so there should belongs to the
49:55high grade category rather than PTC,
49:58popular serial carcinoma,
50:00common cell variants.
50:02But we see common cell variants
50:04without mitosis, we do see rarely.
50:06We do see them.
50:07Yeah, I haven't seen
50:10it also it seems like we have.
50:12I'll see would be extremely helpful
50:16and diagnosing and positive carcinomas
50:19that may experience carcinomas.
50:22You anyone know what the incidence
50:25of the inevitation is in Gordon?
50:28The like is when as carcinomas
50:31of the they are, they are
50:37low frequency of my kinase passing
50:41alterations in hidden neck,
50:43mucosal base, squamous cell carcinoma.
50:46I don't have the exact percentage in my I
50:50think all together is less than 10% and
50:53it can be rough and B rough so B rough.
50:57This entry per SE should be really low,
51:01around 1 to 2% maximum. Yeah.
51:09Sorry. Thank you for coming across
51:12ATC's that have fusion signatures
51:14like PTP 6 or rather, yeah, yeah,
51:18we do. Actually in our 360 core
51:20we have a few fusion driven
51:23tumor including red PC1 OP and
51:27one in track three I believe.
51:30Yeah, so it happens kind of
51:35just like all the other issues, it's
51:36just as all the other ATC.
51:38So by the end when they transform
51:41to antipathy stereocarcinoma,
51:43it's really the tumor type
51:45that Disney the outcome. Yeah,
51:51yeah, very nice thought.
51:52Thank you. Thank you.
51:54I'm understanding correctly
51:56the however the carcinomas in
51:58an aggressive category, so you
52:02put re rapture from juniors as well.
52:05And my question is the presence of
52:08target therapy by rewrap with neck,
52:11has that altered the spiral of the
52:16patients or is that that or not
52:20yet anaplasic styrocarcinoma.
52:22They do have improved survival
52:24because they becoming some of them
52:27becoming surgically managed both
52:29disease if it's local and the plastic
52:33styrocarcinoma and even in decent
52:36metastasis they do control them
52:38better because in general the the
52:41average survival for endopathy cereal
52:43carcinoma is only a few months.
52:45And we do have patient Barack and
52:49Merck survive one year, two years,
52:52but the data is still early
52:55because it's a recent change.
52:57Would you expect that survival benefit
52:59to be carried into the general,
53:03no, like unfortunately no birac,
53:06Merc or birac inhibitor by itself in
53:10treating differential cyrocarcinoma.
53:12Our experience is quite disappointing.
53:14They're not touching them,
53:15they only, they basically only
53:18treating the anapacic component.
53:20That's the case.
53:21I show the differentiated component was
53:23not touched by the combined therapy.
53:25It's there. Yeah, thank you.
53:28Actually the general carcinomas patients
53:31by or natural causes not from cancers.
53:36So we have therapy it's known for.
53:40So they don't have cancer
53:44but I I was not thinking that
53:46there was an aggressive it was
53:49more aggressive but it's not.
53:52No. So the way very few of
53:56the general kind of once they.
54:11Yeah. Yeah exactly. So the rash German
54:14tumor are you already REI sensitive.
54:17Yeah. So they they you already try REI
54:19first for distant metastasis and distant
54:22metastasis in different shapes are
54:24carcinoma is mostly rash driven. Yeah.