The Evolving Molecular Classification of Sinonasal Tumors: How to Keep Your Nose Clean

February 11, 2022

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Feb. 10, 2022

Yale Pathology Grand Rounds

Lisa M. Rooper, MD

ID7447

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00:001. Today's Grand Ronde
00:03speaker is doctor Lisa ruper.
00:06Dr Ruper graduated summa *** laude from
00:10Northwestern University in Illinois
00:12with a major in communications.
00:16She completed MD from University
00:19of Illinois in Chicago,
00:22where she won many awards,
00:25including the Alpha Omega
00:28Alpha Honor Society.
00:31Subsequently, Dr.
00:32Ruper moved to Baltimore to train
00:35in pathology at Johns Hopkins.
00:39Where her winning streak continued
00:42and she collected several awards
00:46for excellence at the institutional
00:49level and at national level.
00:52Rewards for excellence and research
00:56and posters and platform sessions
00:59at the end of her training,
01:02doctor Rupert chose to do a
01:05one year advanced speciality
01:07training in surgical pathology.
01:10Instead of a formal fellowship.
01:13There,
01:14after Doctor Ruper was recruited
01:18as assistant professor in 2017.
01:23And as circumstances called
01:25for within three months,
01:27she was appointed director
01:29of head and neck pathology.
01:32Dr Ruper rose to the challenge.
01:35Despite the departure of her
01:38mentors in head and neck pathology
01:41and in less than five years,
01:43Doctor Rupert has emerged as a
01:46star in this subspecialty field.
01:50Her research interest is in
01:53salivary and sinonasal tumors.
01:55She has published 80 origonal
01:59research articles, maybe more,
02:01but Eddie has a flask.
02:05I'm counting.
02:06Many of these articles describe
02:10new entities such as Biphenotypic,
02:13sinonasal, sarcoma deck,
02:17F2 carcinomas, AKT 1 E, 17 K,
02:23mutated, mucinous adenocarcinomas.
02:26She has worked tirelessly to redefine,
02:31characterize, and to lay down the
02:36guidelines for salivary adenocarcinomas.
02:39I find Doctor Rupert's articles
02:42very helpful in my practical in,
02:45in my practice,
02:47and I often find myself quoting
02:50her or following up my cases,
02:53working them up with Doctor
02:57Rupert's recommendations.
03:00Lisa has a knack for laying out diagnostic
03:04and differential diagnostic criteria.
03:07Not surprisingly,
03:08she has written several invited
03:11reviews and is on the editorial
03:15board of seven pathology journals,
03:18including the two top notch
03:21surgical pathology journals,
03:23American Journal of Surgical Pathology,
03:26and modern pathology.
03:30Doctor Rupert is often sought sought
03:33after for speaking engagements at
03:36national and international meetings.
03:39She has written 14 chapters in the 5th.
03:43WHO blue book on head and neck pathology,
03:46not to mention contributing to
03:50pathologyoutlines and receiving an
03:54award for Path outlined contributions.
03:57Despite this phenomenal publishing portfolio,
04:02she maintains a demanding surgical
04:05pathology and counsel practice,
04:08a busy medical student and resident
04:13teaching program and and again,
04:16not surprisingly,
04:17she has won several best
04:20teaching awards in pathology.
04:23So with that brief introduction,
04:26I'll hand the floor.
04:28Over to Lisa.
04:31Alright, thank you. Thank you so
04:32much for the lovely introduction.
04:34I am so delighted to be here today and and
04:37and be giving grand rounds for you guys.
04:39You know I just want to say we've at Hopkins
04:42have had the pleasure of working with two
04:44of your excellent residency graduates.
04:46First, Sarah Rudder and and then Ben Mazer in
04:49our surgical pathology assistantship program.
04:52Currently wait to have Ben back next year,
04:55and you know, it's just been a delight.
04:57And and I, just, you know,
04:59have the utmost respect for for your
05:01department after after working with.
05:03With such excellent, excellent people.
05:05So, so today I'm going to talk about
05:07some sinonasal evolving concepts
05:09in sinonasal tumors,
05:10which is one of my favorite
05:12topics in head and neck pathology.
05:16Nothing to disclose.
05:18And just gonna start with a
05:21little background.
05:22Of course there has been a lot
05:24that has changed in the last few
05:27years in sinonasal pathology with
05:29definition of new entities and better
05:31understanding of existing tumor types.
05:33But I would be lying if I weren't
05:35pretending that this were all you know,
05:37this were ever easy.
05:38The sender nasal tract has
05:40always been a very,
05:41very challenging diagnostic area.
05:43And that's true for several reasons.
05:45First of all,
05:46we often get samples that are small,
05:48crushed and necrotic.
05:49They try to bite off a little
05:51tissue in clinic and give us
05:53the sad pieces to diagnose.
05:55Frequently,
05:56the tumor has a small round blue
05:57cell or undifferentiated morphology,
05:59so a lot of different entities have very
06:03much overlapping histologic features.
06:05There's also a range of tumors
06:08you can have diverse tumors of
06:09multiple lineages you know,
06:10including some tumors that occur.
06:12Multiple sites that do
06:13involve the sinonasal tract,
06:15but there's obvious sinonasal
06:16specific entities as well that really
06:18don't don't occur anywhere else,
06:20and then that we need to keep up on.
06:22So in the last few years.
06:25There's really been a molecular revolution
06:27in classification of sinonasal tumors,
06:29as molecular testing has been applied to
06:32more and more entities as a result of that,
06:34I think several things have happened.
06:36First of all,
06:38we've recognized some molecularly defined
06:39entities that are known in other sites
06:41for the first time in the sinonasal tract,
06:44so that's great.
06:45We have to find new Sinonasal
06:48specific tumor types that you know.
06:50A lot of them that you hear about,
06:52and then we've also identified
06:54molecular drivers and existing
06:55tumor types and kind of.
06:56Contributed to understanding of those.
07:00Now today I'm going to go through a
07:03few of the areas in insider nasal
07:05pathology that I think are the most
07:07interesting and important areas of change,
07:09but I just want to start with
07:10a word of word of warning.
07:11I'm focusing all these cool new
07:13changes in sinonasal carcinoma
07:15is all this new classification,
07:16which I think is very interesting
07:18and really intellectually fulfilling
07:20to us as pathologists,
07:21especially as we try to figure
07:22out why the tumor
07:24on our microscope stage looks
07:25a little funny and there are
07:28large prognostic implications.
07:29Which is why I do think it's
07:31important to classify some of
07:32these new entities correctly.
07:33But the treatment utility of these
07:35carcinomas are are still emerging
07:36and a lot of these are still
07:37treated kind of in the same way,
07:39with the standard solid tumor,
07:40chemotherapy regimen and radiation therapy,
07:43surgery, etc.
07:43The most important thing for trainees
07:45to know in in Sinonasal pathology is
07:47the big thing you want to distinguish.
07:50Are tumors of different lineages,
07:51melanomas, sarcomas, lymphomas,
07:52those kind of things I'm not
07:54going to spend a lot of time
07:56talking about those today,
07:57but those are actually the things that will
07:59drive the massive differences in treatment.
08:01So if you're working up a sinonasal tumor,
08:04really the most important thing
08:06to do is make sure you have it
08:08in the appropriate language.
08:09Alright,
08:09so we could do go about this.
08:11A bunch of different ways.
08:12I've chosen chosen to focus on three
08:15key areas that really are transitioning
08:17as a result of molecular analysis,
08:20tumors with squamous differentiation.
08:22Swiss sniff,
08:23complex deficient tumors and IDH
08:252 mutant sinonasal carcinoma.
08:27So I'm gonna start out by talking
08:30about sinonasal tumors that have
08:32squamous differentiation and it is
08:34really kind of amazing that I'm
08:36sitting here talking about squamous
08:37cell carcinoma in the head and neck
08:40of being an area of great molecular
08:42change because in most headed next
08:44sites it's been considered that there's
08:47very limited pathways for squamous
08:49carcinogenesis that are that are
08:51pretty similar in different areas.
08:53But historically the Center Newsletter
08:54Act was sort of an enigma with
08:56regard to squamous cell carcinoma.
08:58With risk factors that were
09:00really poorly understood,
09:01it didn't have nearly as strong
09:03of an association with cigarette
09:05smoking as other headed neck sites
09:06such as the oral cavity or lyrics,
09:09and it also was not associated
09:11with occupational exposures like
09:12other sinonasal tumor types like
09:14an intestinal type adenocarcinoma,
09:16sinonasal papillomas were known to
09:17be a precursor in a subset of cases,
09:20but the mechanism was unclear
09:22and etiology for a lot of cases
09:25was really unknown.
09:26Now that has changed because of
09:28emerging molecular understanding.
09:29Kind of in three areas.
09:31First of all,
09:32the role of human sinonasal
09:33squamous cell carcinoma.
09:35Second,
09:35for mutations in Santa Nasal
09:37Papillomas and finally the emergence
09:40of fusion driven carcinomas that
09:42have squamous differentiation.
09:43So I'm going to start talking about HPV,
09:45and of course we're all very familiar
09:47with HPV as an oncogenic driver and head
09:49neck squamous cell carcinoma in general,
09:51but traditionally it was recognized in the
09:53oropharynx and tonsillar and base of tongue,
09:55squamous cell carcinomas,
09:56and it's been thought of as
09:58sort of specific to that site.
09:59It does drive up to 80% of
10:02oropharyngeal squamous cell carcinoma
10:03in the United States with increasing
10:05incidents in the recent decades,
10:07but outside of that for a long
10:09time it was really thought to
10:10not play a role in other headed
10:12next sites and even still the oral cavity.
10:13Lyrics really, HPV is not a major
10:16player and as such we are only
10:18recommended to do HPV testing in the
10:20oropharynx and in neck lymph nodes.
10:23In the last few years, however,
10:25HPV has really emerged as a driver of
10:27sinonasal squamous cell carcinoma as well.
10:30And if not really regarded as a second
10:32hotspot for HPV involvement in the
10:34head and neck in most recent studies,
10:36about 20 to 25% of squamous cell
10:39carcinoma in the sinonasal tract
10:40is thought to be HPV associated,
10:42although there is a very large range
10:44in the literature and this is the
10:46highest prevalence of involvement
10:47in any non oropharyngeal site and
10:50it is now actually regarded as the
10:52most common defined risk factor for
10:54sinonasal squamous cell carcinoma.
10:56The pathogenesis of HPV driving
10:58tumors in the sinonasal tract is
11:00similar to the oropharynx and that its
11:02transcriptionally active virus you know,
11:04can be identified within the tumor
11:06cells by by RNA inside 2 hybridization
11:09or RNA sequencing,
11:10and it drives viral on proteins
11:13to push the cell proliferation.
11:16Now,
11:16one thing that's interesting that
11:18we've noticed in the last in the last
11:19couple years that the rate of HPV
11:21involved in the center nasal tract
11:22may actually have gone up over time.
11:24I say 20 to 25%.
11:26As as the the the prevalence overall,
11:28but most of those studies are
11:30actually dealing with the decades,
11:32the 90s and the early 2000s,
11:34and we noticed that there were
11:35a few recent papers that had a
11:38higher estimate of prevalence,
11:39and so we looked back at our own cases
11:42at Hopkins and actually parsed it out
11:44overtime and the prevalence of HPV
11:47and SINONASAL squamous cell carcinoma.
11:49We stained all of the.
11:52All of our cases on on tissue
11:54microarrays it went up from about
11:5610% in the 90s to about 50% now,
11:58so almost half of the squamous
11:59cell carcinomas we're seeing in the
12:01sinonasal tractor now HPV associated.
12:03So it seems to parallel.
12:04But we'll pharynx in that the
12:06involvement is increasing now.
12:07Also parallel to the oropharynx,
12:09that looks very similar,
12:10HP associated squamous cell carcinoma
12:12in the center nasal tract is non
12:14keratinizing and it tends to have this
12:16very pushing lobulated pattern of growth,
12:18often very popular as well.
12:20And these are these are very characteristic.
12:22Appearances and very recognizable.
12:25Now of course, is leads to upregulation
12:30of P-16 and P-16 overexpression,
12:32so that's consistently positive.
12:33If you do want to test for it.
12:35However,
12:35it's not as specific in the sinonasal
12:37tract as it is in the oral pharynx,
12:39because there are a lot of different
12:41sinonasal tumor types that can overexpress
12:43P 16 by non HPV related mechanisms.
12:46Therefore,
12:46if there is a reason to do HPV
12:48testing in the sinonasal tract,
12:50confirming it with specific
12:51testing such as RNA and site 2,
12:53hybridization visualized here is the
12:55way to go to confirm it really is.
12:57Involvement now the question is
13:00whether we would actually need
13:02to confirm HPV involvement or whether you
13:05know whether this is more of an academic
13:07question that explains pathogenesis
13:08but is not yet clinically relevant.
13:10And actually it does seem that HPV does lead
13:13to better prognosis than the sinonasal tract.
13:16This has actually been
13:17controversial for a while.
13:18Several single institutional studies showed
13:21either borderline significant or not
13:24significant benefit with HPV involvement,
13:26but actually looking at large
13:28National Cancer database.
13:29Studies there does seem to be a
13:33statistically significant benefit to HPV
13:35involvement in squamous cell carcinoma.
13:38I think the real question is still whether
13:41that is a clinically significant benefit.
13:43The overall survival in the sinonasal tract,
13:46even if it's HPV associated,
13:47is still in inferior to oropharyngeal
13:49squamous cell carcinoma and that will
13:51preclude some of the treatment changes
13:52that have been happening in the oropharynx,
13:54such as D escalation of chemotherapy
13:56or radiation from happening.
13:57And these are still tumors that
13:59need to be treated aggressively.
14:01So really,
14:01the clinical utility of this is unclear.
14:03We're not recommended that we
14:05routinely test yet one thing that
14:07might change that is emerging.
14:08Serum markers, the ability to track tumors,
14:11overtime and and track for recurrence
14:14by by using circulating, hpde,
14:16and this is something our clinicians
14:18have been very interested in,
14:20and we have increasingly been doing
14:22testing on tumors for that that end.
14:27It will also,
14:28as as more trials go forward
14:29with more targeted therapies.
14:31This this may become relevant in the future,
14:33but routine testing is not
14:35not yet recommended.
14:36Now of course I wouldn't be complete
14:38talking about HPV and the sinonasal tract
14:40without touching on the fact that it
14:43doesn't just cause squamous cell carcinomas.
14:45There's a very unique new entity
14:48related multi phenotypic sinonasal
14:49carcinoma that actually shows a mix of
14:52squamous and salivary differentiation,
14:54either myoepithelial or ductal combination.
14:57Care of it was originally described
14:59as HPV related carcinoma with adenoid
15:02cystic like features,
15:03but it's not an adenoid cystic carcinoma,
15:05and sometimes it doesn't look like much,
15:07much like one, they lack the
15:09characteristic fusions of adenoid cystic,
15:11and instead harbor
15:13transcriptionally active HPV.
15:15Uniquely HPV type 33,
15:16which is which is not seen a
15:19lot in squamous cell carcinoma.
15:22So this tumor you can see its resemblance
15:24stagnant cystic carcinoma here with
15:26cribriform architecture and and and
15:28ductal in my web ethereal differentiation.
15:31But other areas look more basaloid
15:33look more squamous and it even is
15:35associated with some squamous dysplasia
15:37on the surface in a large proportion
15:39of cases which really point to it
15:41probably being a tumor of surface
15:43origin that just happens to be showing
15:46some salivary differentiation.
15:47Now on stains.
15:48P40 highlights the squamous component,
15:51but it also highlights the myoepithelial
15:52component and you can see the.
15:54Septal component is negative here,
15:55which is is what you want for this.
15:58For this diagnosis to prove that it
16:00it has a biphasic differentiation or
16:03true myoepithelial differentiation.
16:04And here's our Nancy 2 hybridization
16:07we happen to have
16:09a a probe that is specific for type 33
16:11and that allows us to recognize that
16:13and in this tumor which is kind of fun.
16:16Now, this is a tumor HPV related
16:18multi phenotypic sinonasal carcinoma
16:19that's important to recognize 'cause
16:21it actually has a good prognosis,
16:23which is refreshingly different from
16:24many other center nasal tract tumors.
16:27It looks really bad, it looks high grade,
16:29but only about a third recur locally
16:31and distant metastasis, lymph node,
16:33metastasis and death from disease
16:35are all very rare,
16:36so this is 1 where HPV testing is
16:38important to make the diagnosis
16:39and helps helps point or it out to
16:42better outcomes for the patient.
16:44Alright, moving it slightly
16:45outside the HPV realm,
16:46although will return briefly as
16:48the issue of Sinonasal papillomas.
16:50Now this is another pathway of Carcino
16:52Genesis in the Sinonasal tract,
16:54and as we all know,
16:55sinonasal papillomas used
16:57to be called schneiderian.
16:58They've taken Schneider out of out of
17:00the name just to remove the eponym.
17:02Nothing unsavory associated
17:03with him like other eponyms,
17:05but inverted papillomas are the most
17:08common exophytic and oncocytic also occur,
17:11and carcinomatous transformation.
17:12Is the thing that everyone worries
17:15about with inverted papillomas.
17:17This occurs in up to 15% of
17:19inverted papillomas.
17:20It's probably a little on the
17:21higher end in terms of statistics,
17:22probably a little lower these days.
17:255% of Oncocytic papillomas and it's
17:27very rare with exophytic papillomas.
17:29And really there's no reliable histologic
17:31features to predict what will what
17:33will lead to malignant transformation.
17:34It's nothing that we can see histologically,
17:37based on how the papilloma looks,
17:38and even the number of recurrences
17:40clinically doesn't predict the
17:42development of carcinoma most.
17:44Most times we can make the diagnosis of
17:46a carcinoma ex papilloma because we do
17:48see a benign papilloma underlying and
17:51and usually the carcinomas are squamous cell.
17:54So here's just a couple slides illustrating.
17:56Here's a nice benign inverted papilloma
17:59nice rounded nests extending downward
18:01into the stroma but no cytologic atypia,
18:03whereas the squamous cell carcinoma arising
18:06X inverted papilloma shows increased atypia,
18:08infiltrative,
18:09and expanse.
18:10I'll growth and a lot of.
18:15Downward extension come on.
18:17Civic Center nasal papillomas have
18:18a different appearance.
18:20They're more glandular looking.
18:21Bilayer ****** **** epithelium with
18:24microcysts and microabscesses and then
18:28carcinoma Exxon caustic papilloma we.
18:30In this case we see colonization of
18:32an atypical squamous proliferation
18:34with that uncle cynic epithelial now.
18:38Just to go back to the HPV issue
18:40for a moment.
18:40There has been historical controversy about
18:44the role plays in Sinonasal Papillomas.
18:46This is one of these annoying topics
18:48in the literature that literally
18:49the prevalence ranges from 0%
18:51to 100% in old literature.
18:53In any role you can imagine
18:55has been proposed,
18:56does it initiate the papilloma?
18:58Is it implicated in the
18:59growth as a papilloma,
19:00or does it play a role in
19:02malignant transformation?
19:03Now there's a lot of issues when you
19:05dig through this literature and try
19:06to figure out what's actually going
19:08on here. A lot of the older studies used
19:10on PCR based testing that was very,
19:12very sensitive and detected virus
19:14at low levels. That was not
19:16necessarily biologically relevant.
19:17Some studies did not separate
19:19low risk and high risk HPV types.
19:22Some studies conflated
19:24different papilloma types,
19:25and many studies did not have
19:27central pathology review,
19:28which would particularly allow
19:30separation of papillary squamous
19:32cell carcinomas that don't truly
19:34have a papilloma component.
19:35From a true carcinoma X kapalama now.
19:40In recent years,
19:41use of of techniques like RNA and
19:43site 2 hybridization have allowed for
19:45more consensus on the role of HP exited.
19:48Papilloma is at least 25 to
19:5055% of them have low risk HPV,
19:53kind of similar to papillomas.
19:54Another headed next site, so that's great.
19:56Inverted papillomas,
19:57about 10% of them do have low
19:59risk HPV and it is possible that
20:02that is associated with a higher
20:04risk of malignant transformation.
20:06Performance,
20:06absolutely no association with
20:09and multiple studies using RNA
20:11insight to hybridization have not
20:12found transcriptionally active high
20:14risk in any papilloma subtype,
20:16so there really is not any
20:18indication for testing at any type
20:20of sinonasal papilloma at this point,
20:23so if not HPV,
20:24what's causing the sinonasal papilloma?
20:26There's been this excellent series
20:27of papers that have come out of
20:29University of Michigan premiere in
20:31Utica and Noah Brown that's really
20:32parse this out really nicely.
20:34In the past few years,
20:36it most inverted papillomas.
20:37For now.
20:38Recognized to have activating EGFR mutations,
20:42as do the associated squamous cell
20:44carcinomas and oncotic papillomas
20:46have consistent care as mutations,
20:48as do the carcinomas associated with them.
20:50So now we have a clear oncogenic
20:52driver associated with both of
20:54these types of papilloma that kind
20:56of explains their growth now.
20:59Interestingly,
20:59that is not those mutations are not
21:02enough for squamous cell carcinoma.
21:04Recently again,
21:05the same group for Michigan
21:07reported that transformation.
21:09Squamous cell carcinoma required.
21:11The accumulation of additional mutations
21:13so the squamous cell carcinoma does
21:16harbor the underlying EGFR KRAS mutation,
21:18but it gains additional TP
21:2053 or CDKN 2A alterations.
21:22In most cases when those additional
21:25alterations are not seen in matched
21:27Sinonasal papilloma and really,
21:28this mutational profile is unique among
21:30head neck squamous cell carcinoma,
21:32so it's a very unique group.
21:34Now there are some implications
21:36for treatment,
21:36although this is not yet fleshed
21:39out yet either.
21:40EGFR mutations of course broadly
21:42are potentially actionable,
21:44similar to how they're they're very
21:46commonly targeted, and lung lung cancer.
21:49Unfortunately,
21:49most of the mutations in the
21:51sinonasal papillomas are exon 20,
21:53which are often resistant to the
21:55common EGFR inhibitors compared
21:57to exon 19 deletions,
21:58but there are newer drugs that may
22:00be more robust to these alterations,
22:02so it's definitely a promising
22:04Ave for treatment in the future.
22:06Have a last squamous thing I
22:08want to talk about.
22:09Our fusion driven tumors that
22:11show squamous differentiation
22:12and this is something that has
22:15really flowered in the last few
22:17years. So first I'm going to
22:19touch briefly on nut carcinoma.
22:20This is something probably people
22:21are a lot of people are familiar
22:23with from different organ systems
22:24because this is a tumor type that
22:26arises kind of throughout the body.
22:27It used to be called nut midline
22:30carcinoma but midline of course
22:31has been removed from the name
22:33because it can occur anywhere.
22:35Approximately 35% of cases are involved,
22:38head and neck and.
22:39Most commonly in the sinonasal tract,
22:41so it really is a hot spot for this tumor
22:43to arise and defined by nut translocations,
22:46and this translation is not to
22:47play on to jenik role by blocking
22:50epithelial differentiation and meaning,
22:52maintaining the proliferation of tumor cells.
22:55Now here's a beautiful example
22:56of classic nut carcinoma.
22:58Very primitive,
22:58very high grade looking tumor.
23:00All the tumor cells are very monotonous.
23:02It is a translocation driven
23:04tumor but prominent nucleoli.
23:05Lots of necrosis in mitosis,
23:07very high grade, and often there's a
23:08lot of tumor infiltrating neutrophils,
23:10which we're seeing.
23:12Account.
23:12Here is what we classically
23:13think of with nut carcinoma.
23:15Unfortunately not there in every case,
23:17but when it is,
23:18it's super helpful in this abrupt
23:19keratinization where you have the
23:21primitive selves that crossover really
23:24quickly to to form keratinized cells
23:25and that can be a really helpful
23:27clue to the differential diagnosis.
23:29Now nut carcinoma.
23:30You know not only has squamous pearls,
23:33most cases have expression of
23:35squamous markers such as P40I will
23:37add that a small subset of them don't,
23:39so it is reasonable to do a nut
23:41even if you don't have.
23:43Evidence of of overt squamous differentiation
23:45that does those do exist out there,
23:47but the real clincher is
23:49often the immunostain.
23:51The nut stain for that can help
23:54confirm the diagnosis now.
23:55A couple years ago I would have said
23:57that this stain was 100% specific for
23:59nut carcinoma and it's not anymore.
24:01There's a few hybrid sarcomas that
24:03are also driven by nut translocation
24:05so that also picks up on the stage,
24:08but a subset of poroid neoplasms
24:09of the skin have also been found
24:11to have not involved in.
24:13In the translocation.
24:14So it's not not 100% specific,
24:17but in the sinonasal differential
24:19diagnosis it is really good.
24:21Now, not,
24:21of course,
24:22is important to recognize because
24:23it's a highly aggressive malignancy,
24:25median survival of less than a year.
24:27There's been some temporary success with
24:29BROMODOMAIN inhibitors in clinical trials,
24:32but they don't seem to be improving
24:34outcomes that much overall,
24:35but it is definitely something
24:36if you come across a case to to
24:39point the patients toward now
24:40adamantinoma like Ewing sarcoma is
24:42another tumor that has recently been
24:44recognized in the sinonasal tract.
24:46This is a really weird tumor.
24:48It's a rare variant of Ewing
24:50sarcoma in most cases.
24:52To date,
24:52have been reported in the head and neck.
24:55We see we found that there they
24:57seem to be more common in the
24:58salivary glands than anywhere else.
25:00But the sinonasal tract is is 1
25:01site where we do see them and it
25:03is another tumor that is defined
25:05by squamous differentiation.
25:06So it's really bizarre.
25:07It has the Ewing sarcoma fusion.
25:09It's positive for CD99 and NKX 2.2,
25:12but at the same time it shows
25:14diffuse cytokeratin expression
25:15positivity for P63 and P40 and
25:18actually forms overt keratin pearls.
25:20They're often abrupt pearls to
25:21sort of sort of like we see in.
25:23Not so.
25:23It's really weird that it's
25:24doing all the viewing things,
25:26whereas the same time staining
25:27much like a carcinoma,
25:29and it's something that you
25:30really actively have to think of,
25:31because otherwise you might not even
25:33think of doing the Ewing doing markers.
25:36So here's a classic example of an
25:39adamantinoma like Ewing kind of small
25:41nest basaloid cells very infiltrative
25:43embedded in fibromyxoid stroma.
25:45These cells also tend to be very monotonous.
25:48They're a little bit lower
25:49grade looking than not.
25:49They don't really have
25:50those prominent nucleoli,
25:51and often there's not quite as
25:53much necrosis and mitotic activity.
25:55But you do see a little bit
25:56of this abrupt keratinization.
25:58I'll say the keratinization is pretty rare.
26:01It's it's not a majority of the
26:03cases that happen, so this is,
26:05again, you know,
26:06something to to keep in mind,
26:08even if it's lacking bad feature.
26:10And here's the stains.
26:12Diffuse keratin,
26:13positive iti more than kind of the
26:15focal keratin that you can occasionally
26:17encounter in regular viewings.
26:19P40 really diffusely strongly
26:21positive CD 99 strongly positive,
26:23and again they have the WS R1 fly one
26:26fusion that we expect to see in doing
26:29so is this really a sarcoma when it's?
26:31Staining so much like a carcinoma,
26:33it's an excellent question,
26:35and it's controversial different there are.
26:37There are different opinions about
26:39this in the literature there
26:41have been some identical tumors
26:42that have been described as a
26:44carcinoma with doing like elements,
26:46and it used to be that one
26:47fly one fusion was considered
26:49pathognomonic for Ewing diagnosis.
26:50So clearly if the tumor had that fusion,
26:53we considered a Ewing I think now
26:55so many more fusions that occur
26:56in different tumors of different
26:58lineages have been recognized.
27:00You know,
27:00it might be time to question question.
27:02However, uhm.
27:03It's definitely a discrete entity,
27:05whichever whichever group you
27:06want to put it in.
27:08I'll also add that you ain't
27:09specific chemotherapy regimens,
27:10which are a little different
27:12than carcinoma regimens,
27:12have led different responses
27:13with several patients,
27:14which might argue to keep it in the circle.
27:18Alright, so the left's Klamath entity.
27:20I want to talk about is
27:21really a brand new one,
27:22which is a new group of carcinomas
27:24that have a deck aft 2 fusion.
27:27Now it's really interesting
27:28how these tumors arose.
27:29They actually were described in a case
27:32report of a patient who had a really
27:34dramatic response to immunotherapy,
27:36and they did extensive sequencing
27:38other tumor and found that they happen
27:40to have this decaf 2 fusion on that
27:42they thought.
27:42Was, you know, a neoadjuvant Neo
27:45neo antigen against which the tumor?
27:48Other that immune response was occurring,
27:50a couple more cases, though,
27:52were then reported in the pathology
27:53literature and it seemed that
27:55it was not just a random event,
27:56it was actually a recurring thing.
27:59Now, even weirder,
28:00the two genes involved in this fusion
28:03are not particularly common in Carson.
28:05No ones deck has been upregulated.
28:10It's been found to be upregulated
28:12in various cancer types,
28:14and it is rearranged with NHP
28:16214 in a subset of leukemia,
28:18but really not reported in
28:20carcinomas before and after two
28:22actually has had not previously
28:24been reported in cancer at all,
28:26although it is closely related
28:27to a family of genes which.
28:29Are implicated in leukemia,
28:30so once these came in the literature
28:32we were really curious in terms of
28:34finding more of them and and kind of
28:37figuring out what they look like.
28:38There were only a couple pictures in
28:40the in the initial papers that that.
28:45You know, just kind of describe
28:46them as as high grade,
28:47extensively infiltrative tumors,
28:48and so we were interested in finding
28:51out if there was a way we could
28:53histologically recognize them,
28:54especially if there was potential.
28:57Relevance to immunotherapy response.
28:59So we found over 3 institutions,
29:03a bunch of non criticizing sinonasal
29:05install based squamous cell carcinomas
29:07that were negative and EVV negative and
29:10these were tumors that previously were
29:12kind of put in the non keratinizing
29:14squamous cell carcinoma category.
29:17And when we ran RNA sequencing on these,
29:2013 of them,
29:21almost half had a deck Act 2 fusion.
29:23So among HPV indeed negative non keratinizing
29:26squamous cell carcinoma that are not,
29:29you know other fusion related.
29:30These are actually not that
29:32uncommon and we didn't do a full
29:34DNA sequencing as well on a few of
29:36the cases and they didn't have any
29:38other oxygenic driver alterations.
29:39So it really seems that even
29:41though they're weird jeans,
29:42Decap 2 seems to be driving
29:44the pathogenesis of this tumor.
29:47After looking at a bunch of them,
29:48we found that they really did have some
29:50some recurrent pathologic characteristics.
29:52They tend to grow in complex.
29:55Actually should point out really quick.
29:57A lot of them were called papilloma.
29:59There were three of them
30:00that were called benign,
30:01sinonasal,
30:01papillomas and three were called
30:03squamous cell carcinoma ex papilloma,
30:05so they actually in contrast with the
30:08first couple examples which were high grade.
30:11A lot of these had a more low
30:13grade appearance and again,
30:14as I as I'm getting too they seem
30:16to be pretty recognizable,
30:17so a lot of them show kind of
30:20complex anastomosing lobules kind
30:22of downward growth tend to have a
30:24deep pushing pattern of invasion,
30:25but have a rounded border.
30:26Often that can mimic a benign process.
30:30They do show some more confluent
30:32growth and we expect to see in a
30:34papilloma as opposed to the Nice
30:36separated lobules we see in papilloma.
30:38And one thing that seems to be
30:40pretty helpful for for and pretty
30:42specific is that they have these
30:43central areas of this cohesion,
30:45whether they're tumor cells
30:46just fall apart from each other,
30:47and that always makes me think
30:50of the diagnosis.
30:51They do tend to have very bland technology.
30:53The first examples were on the
30:55higher grade end of the spectrum,
30:56but the vast majority that we found
30:58actually were lower grade appearing
31:00and kind of like not carcinoma.
31:03They have a lot of tumor
31:05infiltrating neutrophils,
31:05and that also shows overlap
31:07with sinonasal papillomas,
31:08which can also have tumor
31:09infiltrating neutrophils.
31:10So lots of things kind of kind
31:12of leading to red herrings in
31:14terms of classification.
31:15Occasionally they have squamous pearls,
31:17but most of them are non keratinizing
31:19and they show immunohistochemical
31:21evidence of squamous differentiation.
31:24So interestingly as as we kind
31:26of characterize these,
31:27we notice that they looked a lot
31:29like a group of other tumors that
31:31had been described in the literature
31:32as low grade papillary schneiderian
31:34carcinoma about 14 in the
31:35literature also had complex papillary
31:38architecture and frequent low grade
31:40psychology also mimics sinonasal papillomas.
31:42We suggested this when we wrote up our paper
31:45and almost simultaneously another group.
31:47Included some of the original tumors reported
31:49under that other name and found that
31:51they were also had deck asked to fusion,
31:53so this is all thought to be part of
31:56the deck aft 2 carcinoma special.
31:58So do we care clinically?
32:01Well, although they're low grade,
32:02they can't actually behave
32:04pretty aggressively.
32:04A lot of them occur,
32:05and a significant subset metastasized
32:07and even lead to death from disease,
32:10so it's something to recognize is not
32:11just a very, very low grade tumor,
32:13certainly not just a papilloma
32:15and the real question.
32:17Raised by the the first recognition of it is,
32:19is this a new target for immunotherapy?
32:22Of course there was one patient who
32:23did really well on immunotherapy.
32:25We actually had two in our
32:26series who happened to be treated
32:28for immunotherapy as well.
32:29One responded at first,
32:30although they later recurred and
32:32unfortunately died of a disease
32:33and one patient did not respond.
32:35So it doesn't seem to be a slam dunk.
32:37But overall,
32:38it's an interesting addition to the
32:41squamous neoplasia in the sinonasal tract,
32:44so in the 5th Edition 8 WHO classification,
32:46which hopefully should be coming
32:48out this year,
32:49several of these entities have been
32:51recognized squamous cell carcinoma
32:53in general is still split into
32:55keratinizing and non keratinizing types,
32:56but associated squamous cell carcinoma
32:58and deck after carcinomas are
33:01going to be recognized as subtypes.
33:03With multi phenotypic carcinoma
33:04and nut carcinoma are recognized as
33:07separate entities and adamantinoma
33:08like Ewing sarcoma is you know,
33:11a subtype of Ewing sarcoma.
33:13There's no special recognition
33:15for carcinomas X kapalama,
33:16but that pathogenesis is also reflected.
33:20Alright,
33:20so going on to another interesting area
33:22of Swiss sniff complex deficient tumors.
33:25Now the sweets sniff complex met
33:27stands for switched sucrose,
33:28non fermenting belicza,
33:30chromatin remodeling,
33:30complex 15 protein subunits that
33:33are coded for by up to 29 jeans.
33:36And there's lots of these that
33:38are very important.
33:39The ones we in pathology here about a
33:41lot are smart be one hour I and I-1
33:43on smarca 4 or BR G1 and these are
33:45the ones that have become important
33:47to pathogenesis in the sinonasal tract.
33:50They play an important role
33:52in remodeling nucleosomes and
33:53regulating the accessibility of DNA,
33:54which can,
33:55you know have a huge role in cancer and
33:58mutations in at least one of the subunits.
34:00And of course there's a bunch of subunits,
34:02so lots of opportunities but can be
34:04seen in up to 25% of human cancer,
34:06so they really seem to play a
34:08very important role arid 1A,
34:10which is of course seen in a lot
34:11of a lot of gynecological cancers,
34:13is the most common implicated in cancer.
34:16But it's really across the board
34:18and we have tumors,
34:19some of them that are defined by
34:21the presence of Swiss knife.
34:22Alterations some that frequently
34:24have these alterations,
34:25although they're not exclusive and and
34:27some tumors that kind of have these
34:30alterations at the secondary or tertiary
34:32that as part of of differentiation.
34:34So the tumors we want the complex
34:37numbers we want to talk about today
34:39are smart B1 and Smart K4 smart,
34:41B1 deficient tumors.
34:41We're very familiar with many of these
34:44that are defined by loss of smart V1
34:46rhabdoid tumor, atypical teratoid,
34:48rhabdoid tumor, epithelioid sarcoma,
34:50renal medullary carcinoma, very common.
34:53Smacking 4 deficient tumors,
34:54the most common one defined by that
34:56is ovarian small cell carcinoma,
34:58hypercalcemic type,
34:59but it's also seen in undifferentiated
35:02uterine and thoracic Neoplan Now in the
35:05past decade it has been recognized as an
35:08important player in the sinonasal tract.
35:10Smarcb 1 deficient sinonasal carcinomas
35:13are a unique and newly recognized
35:15sinonasal specific malignancy.
35:18It is defined by recurrence
35:20Mark B1 inactivation,
35:21and they don't have any other
35:24recurrent oncogenic mutations,
35:25and they have a very
35:27variable immunophenotype,
35:28so they have lots of smart view
35:30on one by immunohistochemistry.
35:32Some of them are positive for P63 and
35:34P40 and have to be kind of considered in
35:36your squamous differential diagnosis.
35:37Some of them have synaptophysin positive
35:39ITI so it can be really heterogeneous
35:41and it really is that smart B1
35:43that is central to classification.
35:45As a result of this,
35:46they were initially reclassified
35:48from several categories.
35:50We think of these as being pulled
35:52out of the sinonasal undifferentiated
35:53carcinoma category, and most of them were,
35:56but others were called squamous cell
35:58carcinoma, myoepithelial carcinoma,
35:59even adenocarcinoma.
36:00So they came from different areas.
36:02Here's a beautiful example,
36:03most of them kind of show nests
36:05and lobules of basaloid cells
36:07with intermixed cells.
36:08That sort of have a rhabdoid
36:10in plasmacytoid appearance,
36:11and that rhabdoid appearance can
36:12really make you think of this
36:14diagnosis if you happen to find them.
36:16I have seen cases unfortunately
36:19that don't have that helpful clue.
36:21Here is some cytoplasmic maculation
36:23which is a very frequent finding in
36:26these tumors and some some of the
36:29tumors are more uniformly composed
36:30of the plasmoid or rhabdoid cells.
36:34And this, again,
36:35is one of these tumors with a
36:36recurrent genetic abnormality that
36:38even though it's high grade it
36:40hasn't across in a lot of mitosis
36:41the cells still seem to look pretty,
36:43but not as they were all kind
36:45of cut out of the same cloth.
36:46And here is beautiful loss of smart
36:48be one with retained staining in
36:51endothelial cells as a control,
36:53which again other than the other
36:55immune profile, is heterogeneous.
36:56But this is the key to the diagnosis.
36:59Now smart B1 loss has also been
37:01recently reported in adenocarcinomas.
37:03These can actually mimic yolk SAC tumors,
37:05and it's likely that things reported
37:07as yolk SAC tumors in the sinonasal
37:09tractor also are all probably
37:10smart B1 deficient adenocarcinomas.
37:12They even have gotten 3 and sell
37:15for positivity,
37:16and it's not likely that they
37:17behave any different than
37:19other smart B1 deficient cancers,
37:20but they actually do make glands
37:23and they still do have loss of
37:25a smart V1 and then smarca 4,
37:27you know another switched across non
37:29fermentable complex member has also recently
37:31been implicated in sinonasal cancers.
37:34Now this seems to be rarer than
37:35the smart B1 deficient tumors.
37:37There's only about 20 cases reported to date,
37:40and in contrast, they tend to have a
37:43neuroendocrine phenotype kind of patchy
37:44week positivity for synaptophysin,
37:46less expression of P. 40.
37:48Most of them were previously classified
37:51as neuroendocrine carcinomas.
37:53Here's a nice example.
37:54Most of them have this very high
37:57grade undifferentiated basaloid
37:59small cell or large cell morphology,
38:02but a few of them look substantially
38:04more rhabdoid,
38:04kind of similar to the smart
38:06P1 deficient carcinoma.
38:11And here is the smart Smarca 4,
38:15which is nicely lost with it
38:18retained internal control.
38:19So clinically, these are important
38:21to recognize because they're really
38:23aggressive tumors that really there's
38:25a few patients who had good outcomes,
38:27had aggressive multimodality therapy.
38:28But the five year disease
38:30free survival is very poor.
38:32Hopefully they'll eventually become
38:33relevant to treatment as well.
38:35There's various potential,
38:36like small molecule inhibitors, which.
38:4110 player role in various Swiss
38:44sniff mutated tumors that are under
38:47investigation and hopefully will
38:49provide new directions in the future.
38:51Now really quick.
38:51I wanna touch base on an unexpected
38:54addition to the Swiss Family Center
38:58nasal treto carcinosarcoma excuse me.
39:02Isn't aggressive neoplasm unique to
39:04the sinonasal tract and it has been
39:06kind of an enigma for years it is
39:09defined by three intermixed components
39:11and neuro epithelial, epithelial,
39:14and mesenchymal all mixed together,
39:16which we look at some pictures
39:18of and despite its name,
39:19it really doesn't have a
39:21conventional germ cell component,
39:22but because it has such diverse Histology,
39:24it's very difficult to diagnose
39:26on small biopsy specimens.
39:27So here's a beautiful example of
39:30a classic torretto carcinosarcoma
39:32with all of these different
39:34elements mixed together.
39:35No no no no no.
39:36Let me just explain component that had
39:39kind of a fetal clear cell of appearance.
39:43So I'm more glandular looking area
39:45which kind of produces some music.
39:50Part of the epithelial elements
39:52here is a spindle component that
39:54tends to be hypercellular kind
39:56of nondescript spindle cells.
39:57Sometimes it makes matrix either chondroid
40:01or osteoid matrix here and then.
40:03Here's a neuroectodermal component.
40:05Primitive cells with some
40:07neuropil formation and rosettes,
40:10and all of these things are mixed together,
40:12and because this is such a
40:14histologically diverse tumor,
40:15it's historically been controversial
40:16as to how it should be classified
40:18and where it originates.
40:20Is it truly a germ cell tumor?
40:21Does it originate from some sort
40:23of a pluripotent stem cell,
40:25or is it some sort of divergent
40:27differentiation and it's historically not
40:29well characterized on a molecular level?
40:31Now we looked at this not because we
40:33thought it was going to have any sort
40:35of sweet sniff related mutations,
40:37but actually because we'd written another
40:39paper recently about thyroid teratomas,
40:42totally different tumor,
40:43but also had multilineage differentiation,
40:45and we'd found dyster mutations
40:47in those that was fun and we just
40:49wondered if they were there as
40:50well as enterado carcinosarcoma.
40:52And I only bring that up to
40:54highlight to trainees.
40:55Sometimes the best research comes when
40:57you're absolutely wrong and we were
40:58totally wrong about our hypothesis.
41:00But we found something else cool instead.
41:03When we ran one case just to test it,
41:05we found lots of smart 4.
41:08And we expanded that ended up
41:10staining 18 of them and found
41:13immunohistochemical lost in 82% of
41:16them and we did sequencing on three
41:18of them to start out with and all of
41:21them had biolex market for inactivation.
41:24So it seems like Toretto
41:26Carcinosarcoma does fit into this.
41:28We sniff of deficient complex,
41:31and that's interesting,
41:32mostly in terms of classification
41:34of these tumors,
41:36because it suggests that they're on
41:37a spectrum with a smart K4 deficient.
41:38Sinonasal carcinoma,
41:39as opposed to being a germ cell tumor,
41:42and that it's a stool for
41:44for identifying them.
41:46Immunohistochemically when
41:47the diagnosis is difficult.
41:49Of course, that is not the entire story.
41:51With these tumors,
41:51there's another report in the
41:53literature of one with beta catenin
41:55mutation and and several other
41:56cases in our series actually did
41:58not have smart K four loss.
41:59So since then we haven't published this yet,
42:02but we've sequenced a bunch more of them.
42:0514 cases of them,
42:07and with known immunohistochemical
42:09expression of smart.
42:10Or or loss.
42:11And we did find that most of them
42:14had either smart K4 mutations or
42:16ctne B1 beta catenin mutations,
42:18although there were other genes implicated.
42:22I'm in a cluster together,
42:23tumors that had some market for
42:25lost by amino Histochemistry had
42:27smart K4 inactivation or beta
42:29catenin mutations and then other
42:31molecular alterations were seen in
42:33other tumors and this actually kind
42:35of just expands the link between
42:37Toretto carcinosarcoma and and
42:38sinonasal carcinomas because all of
42:40the mutations seen here have been
42:43reported in sinonasal neuroendocrine
42:45neoplasms and it also beta catenin
42:47provides another helpful tool for diagnosis.
42:51However,
42:51it's important to emphasize.
42:52Try to partner sarcoma is
42:54a morphologic diagnosis.
42:55You're looking out for all of these
42:57elements together and it is not yet
42:59defined by Swiss snapgene involvement.
43:01So in the next edition,
43:02WHO sinonasal carcinoma,
43:03there's a new category for Swiss sniff.
43:06Complex deficient sinonasal carcinomas that
43:08includes this mark B1 deficient carcinoma,
43:10and adenocarcinoma,
43:11as well as the smart K4 deficient
43:13carcinoma and Toretto carcinoma
43:15is lumped under the Toretto.
43:17Carcinosarcoma is lumped under
43:18the sinonasal carcinoma category.
43:20But it is not formally defined as
43:22a Swiss sniff deficient neoplasm.
43:25Alright, just a few more minutes.
43:28I really wanna hit something
43:29quick at the end.
43:31Definitely new and emerging
43:33story in sinonasal carcinomas,
43:35and that's tumors with IDH 2 mutations.
43:38Now we've talked about a lot of tumor
43:40types that have been reclassified,
43:42and a lot of these have been
43:43reclassified out of the sinonasal
43:45undifferentiated carcinoma category.
43:46It's been a shrinking category
43:48in the last few years.
43:49It's a hybrid carcinoma and has
43:51always kind of been regarded
43:52as a diagnosis of exclusion.
43:54No squamous differentiation,
43:56no glandular differentiation.
43:58Usually no neuroendocrine differentiation.
43:59I'm going to get back to that.
44:01It's been controversial, but formally,
44:03according to the guidelines,
44:04not and rule out all of these other
44:07tumor types. Smart one smart.
44:08Or not all of the good stuff
44:10once you rule everything out and
44:11you have a high grade carcinoma,
44:13you can call it a sinonasal
44:15undifferentiated carcinoma.
44:16And here's an example of 1
44:18sheets of high grade cells,
44:20lots of necrosis,
44:21and these cells are a little
44:23bit more polymorphic than the
44:24ones that we see in other.
44:26Some of the translocations
44:28driven sinonasal tumors,
44:29often very prominent nucleoli
44:31kind of more nuclear atypia.
44:33Now, interestingly,
44:35a lot of the residual category of
44:38snuck that has not been reclassified
44:40was recently found to have IDH 2
44:42mutation anywhere between 50 and 88%
44:45of residual tumors in that category.
44:47Had IDH 2 hot spot mutations and
44:50what's interesting is that it's
44:52actually recognizable via mutation
44:53specific immunohistochemistry,
44:55which provides a confirmatory marker,
44:57so it kind of moves snuck out of the
45:00category of a diagnosis of exclusion,
45:02and lets us actually actively
45:04prove what it is.
45:05So here's a beautiful example of the stain.
45:07It picks up the mutant protein,
45:09so you are looking for positive
45:10expression in the cytoplasm of the cell.
45:12So that's really cool.
45:14Now the question of neuroendocrine
45:16differentiation and stuck has
45:17minimal controversial overtime.
45:18It actually originally was defined
45:21as having some neuroendocrine
45:23differentiation despite its name,
45:24and although most pathologic guidelines
45:26do not technically allow this,
45:28it has been a source of persistent
45:30confusion because of distinctions
45:31with other high grade tumors that
45:33have neuroendocrine differentiation.
45:35Large cell neuron during carcinoma
45:37has been particularly challenging,
45:39mostly because it shows substantial
45:41histologic overlap.
45:42So here's a large cell neural
45:44endocrine carcinoma.
45:45Nest the cells pleomorphism prominent nuclei.
45:48A lot of cytoplasm,
45:49very similar to what we're seeing
45:51in this knock up,
45:52but it shows substantial
45:54neuroendocrine differentiation.
45:55Here's one nuclear positivity kind
45:57of at a level that currently we
45:59wouldn't accept and snack. Well.
46:01Large scale Neurontin carcinomas have
46:03also recently been found to have IDH 2
46:06mutations up to 83% of them show mutation,
46:09which suggests that,
46:11as their morphology suggests,
46:12they probably actually are on
46:14us on a spectrum with sinonasal
46:16undifferentiated carcinoma.
46:17And here's an example of, again,
46:19nice IDH 2 mutant immunohistochemistry in
46:21the largest cell neuron during carcinoma.
46:24Nicely positive,
46:25now beyond morphology and
46:27immunohistochemistry and molecular
46:29methylation profiling is something that's
46:32starting to emerge in the literature
46:34to be used for sinonasal tumors,
46:36and there's lots of different tumor
46:38types that have very distinctive
46:41clustered methylation profiles.
46:42So regardless of Histology,
46:44IDH 2 mutant snuck and large cell
46:46neuroendocrine carcinoma do cluster
46:48together on this methylation.
46:50Profiling with a global
46:52hypermethylation pattern,
46:53which is actually very characteristic
46:55of multiple tumor types that have died.
46:562 mutation and this kind of further
46:59validates that they are similar and
47:01probably belong in the same group.
47:03Now, does this matter clinically?
47:05This also has significant prognostic
47:07implications because regardless of Histology,
47:10either large cell neuroendocrine
47:12carcinoma or knock,
47:13they have better prognosis than snakes
47:15that don't have known mutations as well as
47:17smart B1 deficient sinonasal carcinomas.
47:19So it's helpful now.
47:21Prognostically in terms of treatment.
47:23Of course.
47:23I DH two as well as one encodes
47:27isocitrate dehydrogenase.
47:28Which is the enzyme that plays an
47:30important role in the Krebs cycle.
47:31So we were actually seeing real
47:33live significance of the Kreb
47:35cycle here and mutations lead to
47:38Uncle metabolites which cause.
47:41Cancer and it's pretty common
47:42in different tumor types.
47:44Leukemia glioma chondrosarcoma are
47:45all very well known for having IDH,
47:47one or two mutations.
47:50Fortunately,
47:50inhibitors have been developed that
47:52can kind of induce differentiation
47:54and lead to treatment response,
47:56and it's a potential target
47:58for treating these IDH mutant
47:59sinonasal tumors in the future.
48:01So 5th edition,
48:03WHO classification sinonasal
48:04undifferentiated carcinoma large
48:05cell neuron endocrine carcinoma
48:07are actually still separately
48:09classified and it's mentioned.
48:11Under in both disease chapters that IDH
48:132 mutations are seen but it's not yet.
48:16The classification driver will see
48:18how this holds forth in the future.
48:20Alright, so just to finish up,
48:22a molecular testing has had a huge
48:24impact over the last decade in
48:26sinonasal tumors with definition and
48:28recognition of multiple new diagnosis
48:30understanding the pathogenesis of
48:32existing tumor types as well as
48:34clarifying relationships between
48:35entities that were previously
48:37regarded as entirely separate.
48:39Now,
48:39right now the practical implications of this,
48:41I think,
48:42are sort of at a precipice we like to learn.
48:44Data is sort of partially
48:45integrated into the new WHL.
48:46Of course,
48:47some of these molecularly
48:48defined categories are there.
48:50This, we sniff deficient tumors,
48:52nut carcinoma, etc, etc.
48:53So those are written into the literature,
48:55but not all of it has crossed over over yet.
48:58In terms of shaping the classification,
49:01what's fortunate at this point
49:02is that most relevant molecular
49:04findings are identifiable through
49:06surrogate immunohistochemical or
49:07insight 2 hybridization markers.
49:09So we can do a nut immunostain.
49:10We can do an IDH 2 immunostain and
49:12we don't necessarily have to do
49:14comprehensive sequencing and therefore
49:16we don't usually comprehensive
49:18molecular analysis is not performed.
49:20A standard of care and usually it's
49:23only used around here when they're
49:25they're searching actively for
49:27for end stage treatment options.
49:29So you know it's not quite in the mainstream,
49:33and it's certainly not impacting
49:35on standard of care treatment yet.
49:37Now is further molecular classification
49:39coming?
49:40I mean, we kind of all watch
49:41other other areas of pathology.
49:43I think neuropathology,
49:44right now is is the main one.
49:46Switch over to an entirely molecular
49:48driven classification system.
49:50There's actually this very week in ABCP.
49:52There was a proposal for a molecular
49:55based subclassification of sinonasal
49:57squamous cell carcinoma, and you know?
49:59In some ways this is great.
50:00If it gives us more information,
50:02but in other ways we we risk making
50:03what is already a challenging
50:05classification really inaccessible.
50:07For many pathologists,
50:07if it if it is driven only
50:09by molecular testing,
50:10and we also are struggling to get
50:13insurers and even Medicare to pay
50:15for molecular testing, so you know,
50:16do we really wanna hinge everything on
50:18on testing that we potentially can't even do?
50:21A can't even bill for,
50:22so it's a question.
50:23I think it's gonna need to be resolved
50:25on multiple levels going forward.
50:27And of course new categories still
50:28may be coming down the pipeline.
50:30So that still will be kind of evolving.
50:32Evolving changes as we go forward.
50:34Alright, thank you so much.
50:36I'm happy to take any questions.
50:40Thank you so much Lisa.
50:42So if you have a question,
50:45please unmute yourself and ask.
50:48I don't see any questions in chat.
50:57Hi Lisa. It's a really great talk,
51:01so I have one question so I'm not.
51:02I'm the molecular pathology.
51:04So here we do the the UN command tests
51:08for the for the oncologist and occasion.
51:11As I understand that.
51:12And the smart smart CP1,
51:15smart safe for deficiency.
51:18So carcinoma is measured based on the
51:20morphology and the immunostaining
51:21confirmation. Yeah, but occasionally we
51:24see the molecular result,
51:25which is a hint. There's some smart
51:28CP one and smart C4 deficiency,
51:30but morphology doesn't quite fit
51:32the the what describes how do we
51:36explain for this excellent question?
51:37I don't. I don't know if we've
51:39answered that question yet, I think.
51:43The way this tumor was defined, I you know,
51:46I'm saying I'm using molecular loosely as
51:48in kind of molecular related findings,
51:50but it really was defined based on the
51:52immunohistochemistry and kind of the
51:54functional like loss of that of that protein.
51:56So you know it's really a great
51:58question in terms of what to
52:00do with a tumor that doesn't.
52:02Doesn't fit into into that category,
52:05not apparently, but has has the loss.
52:07I've had a couple of those cases
52:09that I've had some some apparent.
52:12In you know Histochemical findings or
52:14molecular findings and end up end up
52:16signing it out descriptively, but I don't.
52:18I'm not certain yet.
52:19I think those are those.
52:21It's not entirely clear what to
52:22do with those and and probably
52:24won't be until we have more clear,
52:26you know,
52:26treatment implications for for
52:28what we do with them.
52:30So my
52:30second question is
52:31regarding your presentation
52:33and also there's some experts also
52:35speculate that the AI D18 losses
52:38also should be in that category,
52:41but so far nobody has discovered any
52:44case yet, at least in the literature.
52:46And So what do you think?
52:48So that's interesting,
52:49so I think there's a couple cases
52:51that have error 1A mutations in
52:54sinonasal neuroendocrine carcinomas.
52:55I think there was a paper from out of
52:58MSK a couple years ago that sequenced
53:01some neuroendocrine carcinomas.
53:02And I think there may have been
53:04one or two mutations in that there.
53:07I know we have some emerging data.
53:09There's some weird neuro epithelial
53:10tumors that I didn't get into here
53:12that are kind of overlap between
53:14olfactory neuroblastoma and carcinoma.
53:15And we have at least one of those that have.
53:17I have an error with 1A mutation 2,
53:19so I think there's probably more more of a
53:21role for the other partners coming forward.
53:23I think. I think it's probably I mean,
53:24for whatever reason,
53:25smart B1 is the most common here,
53:26so that's that's what we figured out,
53:28but I think I think there's going to be
53:30more kind of figured out going forward.
53:32I think it's it's definitely
53:33floating around there.
53:35OK, thank you.
53:37Oh Lisa, do you mind on sharing your
53:42screen so I can see if there are
53:44any hands that are OK? Thank you.
53:47I don't see any hands up right now,
53:51so I'll go ahead and ask my question.
53:55You said that 83% of Sinonasal
53:59Lascelles Newland, Ukraine,
54:00cold snow Mars turned out
54:02to have IDH 2 mutation.
54:04What about the LC next of the lung?
54:07Do they have the same?
54:08They don't. Come early.
54:13Yeah, at least most of them don't.
54:14I mean, largest owner,
54:15different person over the lung.
54:16To my you know somewhat novice
54:18understanding of it is kind
54:20of three different pathways,
54:21and it's probably similar
54:22in the head and neck.
54:23Honestly, it's kind of an
54:25amalgamation of different things.
54:26Some of them are more like small cells
54:28and small cells than most most sites
54:30not in not in the center nasal tract.
54:32Interestingly,
54:32but most other sites have P53RB mutations,
54:35some of them some of large
54:37hereunder in the lung do have the
54:39same mutations adenocarcinoma,
54:41so you might actually find a few with with.
54:43Smarca 4 there because that's actually,
54:45you know,
54:46reasonably common in lung adenocarcinoma,
54:48Stew and then summer like carcinoids.
54:50So I think it's probably analogous in
54:52the head and neck that large scale
54:55neuroendocrine with some of them
54:57are kind of like snuck some of them.
55:00I didn't get into that now.
55:03Some of them also have HPV as
55:05well as small cell carcinomas.
55:07That's fairly commonly seen in sinonasal
55:09neuroendocrine carcinomas as well,
55:10so.
55:12Probably mixed bag.
55:14The other question I have is
55:17as of today in your practice,
55:20how do you pick this deck?
55:22F2 carcinomas because
55:24Histology is not enough.
55:26You would suspect it based on the Histology.
55:29Where do you send it out to confirm,
55:32and what tests do you request?
55:35So it's it's super frustrating right
55:36now because it's not widely available.
55:38Testing it is not available
55:40on our fusion panel here yet.
55:42There is a fish that is now
55:44available at PROPATH in Dallas,
55:46TX and and that is is is one
55:49place I have have sent one thing.
55:52I have heard rumors that there
55:54is an immunostain and we might
55:56be hearing about it at uscap
55:57that that there's a forthcoming
55:59immunostain that picks up after two,
56:01and I think that that hopefully will help
56:04us recognize these more in the future
56:06since it doesn't have treatment implications.
56:08At this point I have been mostly
56:10signing these out descriptively,
56:11unless the clinicians really want to know,
56:13and kind of say it has morphologic
56:16features suggestive of decaf too.
56:19And and we can kind of pursue
56:20the testing if necessary,
56:22but I think we're a
56:23little ahead of ourselves.
56:23I think in terms of recognizing these these
56:26fusions on research based sequencing,
56:28but not necessarily being able
56:30to find them clinically yet.
56:31But hopefully they will.
56:32Again,
56:33there will be a stain coming coming shortly.
56:36The third question I have is do you order
56:40CD 99 on all non keratinizing carcinoma
56:44as I do no scared after your talks? Yes
56:48I'm always worried about missing adamantine
56:51oma like Ewing because that will be a
56:53big treatment change I I think they
56:55do tend to air here on on doing chemo.
56:58For that you know. Again,
56:59it's controversial whether that's right
57:01or that's wrong but but I at least
57:04want that to be in the discussion.
57:06So if I do have a non Karen Ising carcinoma
57:09that chose squamous differentiation I
57:12or another undifferentiated tumor that
57:13I'm having a hard time classifying,
57:15I will do a CD 99 for trainees.
57:20At the end, you know NKX 2.2 is
57:22also a great great Ewing marker,
57:24but there's a lot more overlap with
57:26other entities in the sinonasal tract,
57:28so NTX 2.2 tends to stain a lot of things
57:31with neuroendocrine differentiation,
57:33and you see it in a lot of
57:34olfactory neuroblastomas,
57:35so I tend to air on CD 99 for that reason.
57:39It's a good good learning. Call message
57:45is there another question in
57:47the chat? Uh, something cropped
57:51up, yeah? How do you assess
57:54global DNA methylation?
57:55In your talk, there were a number of
57:58entities that seemed to show distinctive
58:01patterns of global methylation.
58:03How widely have you applied
58:06this test in tumors?
58:08Does it provide classification
58:11information that is substantially
58:14different than RNA seek?
58:17That is an excellent question.
58:19We have not used it widely widely at
58:21all at that point that that that chart
58:23that I was presenting was actually
58:25from from from MSK who did it.
58:27Some generally speaking,
58:28the methylation analysis.
58:30It's beginning to be used
58:32widely in neuropathology,
58:32but it's not widely available
58:34as a test on my understanding,
58:36in any neuropathologists can can chime in.
58:38Here are neuropathologists,
58:39as with I think multiple institutions in the
58:42country send it all to the NIH to get done,
58:45so it's not a test at all.
58:47That is, is widely available.
58:49And I think it's,
58:50and I think it provides
58:51interesting information.
58:52You know it's an interesting Lee.
58:53Different way to classify it,
58:55and if we're able to do it more,
58:57I think it will definitely
58:58be great to see you know.
58:59Does it add benefits to to classification
59:01to answer answer challenging
59:02questions or or you know is is RNA
59:04C giving us everything we need?
59:06I think that's a that's a great
59:08question and still a very early in
59:10the emergence of that technology.
59:14OK, thank you so much Lisa.
59:16I don't see any other hands up.
59:19This was really very very educational
59:22for us head and neck with Ologist
59:25and I hope others also enjoyed it.
59:29Thank you so much for having me. Thank you.