The Evolving Molecular Classification of Sinonasal Tumors: How to Keep Your Nose Clean
February 11, 2022Information
Feb. 10, 2022
Yale Pathology Grand Rounds
Lisa M. Rooper, MD
ID7447
To CiteDCA Citation Guide
- 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.