Soft Tissue Tumors of the Head & Neck: What’s New?
November 24, 2021Information
November 18, 2021
Yale Pathology Grand Rounds
Jason L. Hornick, MD, PhD
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- 00:04To see you again. So.
- 00:08There are already 52 participants,
- 00:12so I'm going to go ahead
- 00:15and start introducing you.
- 00:17Uhm? So welcome everyone for
- 00:22the pathology grand rounds.
- 00:24Today's speaker is doctor Jason Hornick.
- 00:28He's a professor of pathology at
- 00:31Brigham and Women's Hospital in Boston,
- 00:35or Doctor Hornick grew up in
- 00:38California and then came up north to
- 00:43do his college at Amherst College.
- 00:47He went back to do MD PhD.
- 00:50In California,
- 00:51and then he must have missed the
- 00:54seasons because he came right
- 00:56back to Boston where he did his
- 01:00residency and stayed on and his.
- 01:05He completed his entire residency at Brigham.
- 01:09He knew exactly what he wanted.
- 01:11He did,
- 01:12and AP only residency and a fellowship,
- 01:16which was three months each in soft tissue.
- 01:20Him path,
- 01:21jiwan pathology and general
- 01:24pathology and this might seem mad.
- 01:27But all of this exposure shaped
- 01:30his academic career anyway.
- 01:32He rounded it off with one.
- 01:35Year of GI pathology.
- 01:39I'm not sure how that helped his career.
- 01:43His doctor Hartnick made his name
- 01:46as a soft tissue pathologist.
- 01:49He is an outstanding educator and
- 01:52a frequent speaker at national and
- 01:55international meetings and courses.
- 01:58He is codirector of surgical pathology
- 02:02update course at Brigham and Women's
- 02:07and of the diagnostic pathology
- 02:10update course for the US CAP.
- 02:13Doctor Hornik is very generous of his time.
- 02:16He wears many hats,
- 02:18director of Surg Path,
- 02:20medical director of Histology and
- 02:24the immunohistochemistry lab.
- 02:26His cheer of the QA committee and his
- 02:30also on several cancer focused committees
- 02:33at the Brigham and Women's Hospital.
- 02:38He nationally,
- 02:39he served on the education and committee.
- 02:43All of us cap and is currently
- 02:46on the Board of Directors.
- 02:48He's been a panelist and moderator on
- 02:52several of the educational sessions.
- 02:56His written guidelines, his chair,
- 02:59dicey committee for CAP,
- 03:01and he developed the proficiency
- 03:04testing for thousands of IFC
- 03:07labs around the country,
- 03:09our lab being one of those.
- 03:12He is involved with the agencies
- 03:16sarcoma staging and the cancer genome.
- 03:20Atlas is a sarcoma analysis working group.
- 03:25He also finds time to write board questions
- 03:28for the American Board of Pathology.
- 03:32Uhm?
- 03:32Doctor Hornick has developed and
- 03:35described many IHC markers that
- 03:39diagnose genetic abnormalities,
- 03:41and many of these are actually
- 03:45have affected our practice,
- 03:47so these are significant practice changers.
- 03:51Some of a short list would be I and
- 03:54I won that detects smart B1 genetic
- 03:58aberrations start six that detects the
- 04:03translocation in solitary fibrous tumors.
- 04:07Back story for sinonasal sarcomas.
- 04:10Panther Gabino history chemistry,
- 04:12which we use on head and neck tumors.
- 04:17This 18 it says X fusion specific
- 04:21antibody for synovial sarcomas
- 04:23that he talked about and showed
- 04:27in this morning's conference,
- 04:29and many, many, many others.
- 04:32The list is long,
- 04:34he's he's the editor in chief
- 04:37of the fifth series of if IPS,
- 04:40atlases of tumor, and non tumor pathology.
- 04:45He is an associate editor.
- 04:47For Sternberg's diagnostic
- 04:49surgical pathology,
- 04:51he is on the editorial board
- 04:54of a JSP and
- 04:56modern pathology.
- 04:58He is he has a senior leadership position
- 05:02on the editorial boards of histopathology
- 05:06advances in anatomic pathology,
- 05:10surgical pathology, clinics,
- 05:12archives of pathology and lab medicine, and.
- 05:18Not surprisingly,
- 05:19he has more than 400 original articles,
- 05:24reviews and chapters,
- 05:26and harking back to his first fellowship
- 05:30were his spent three months in
- 05:33various subspecialities his not only
- 05:36on the editorial board of these soft
- 05:39tissue and bone blue book by WHO,
- 05:43but also on the blue books.
- 05:46He's contributed to breast.
- 05:48Do you want him to rasik
- 05:51and pediatric Bluebirds?
- 05:53So in conclusion, Dr.
- 05:57Hornig still has a lot of time on his hands,
- 06:01and I'll show what else he does
- 06:04by sharing my screen here.
- 06:07Recently this year,
- 06:09Doctor Hornick with his here on the
- 06:12keyboard has cut an album for his
- 06:15band with his band up there teardowns.
- 06:19And this is available on Spotify.
- 06:22If anyone cares if anyone is
- 06:26tired of learning pathology,
- 06:28we can all go back and listen
- 06:31to his band instead.
- 06:32So with that short introduction I will.
- 06:36See the floor to Doctor Hornick.
- 06:41Thank you very much Montreux
- 06:43for that Nice introduction.
- 06:45Let me make sure this works.
- 06:48I always have a little bit of trouble.
- 06:52Can you let me know if you
- 06:54can see my full screen?
- 06:55Yep. We can. Is it in the
- 07:01presentation mode or full screen?
- 07:03Yes, it's in the presentation mode. No notes.
- 07:10Oops was that good?
- 07:12Yeah, that's the full screen mode.
- 07:14OK, perfect. So as you heard,
- 07:18I have very diverse interests.
- 07:20My main area of.
- 07:21Interest where I do most of my research
- 07:24is in soft tissue tumor pathology
- 07:27and Doctor Prasad has invited me
- 07:30today to give a lecture focusing on
- 07:32soft tissue tumors of the head neck.
- 07:34This is a a complicated area obviously
- 07:37not only for soft tissue tumors,
- 07:40but this is a an area with lots
- 07:42of vital structures and a diverse
- 07:44array of different tumor types
- 07:46that can arise in these structures.
- 07:49And I'm going to talk about some really
- 07:52dramatic changes that have come to
- 07:55head neck pathology for mesenchymal
- 07:57neoplasia in the last ten years or so.
- 08:01I have the following disclosures.
- 08:04I'm a consultant to Addie Biosciences
- 08:07and Trey Con Pharmaceuticals,
- 08:08which is not relevant to
- 08:10the discussion for today.
- 08:13I'm going to be framing my
- 08:15presentation in terms of cases.
- 08:17I think it's nice to bring them
- 08:20home to practical applications,
- 08:22and many of the findings that I'm
- 08:24going to be discussing are nicely
- 08:27illustrated by by these cases.
- 08:29I'm going to start off with a
- 08:31with a tumor type that we've known
- 08:33about for a long time, but it's a.
- 08:35It's a nice framing for the
- 08:36rest of the discussion,
- 08:38because this is a tumor that is often
- 08:40overlooked and is prone to misdiagnosis.
- 08:43At this anatomic site.
- 08:44So we're starting off with a 43 year
- 08:47old man with a left sinus mass.
- 08:50As is often the case,
- 08:51these specimens,
- 08:52these two readings often look kind of messy.
- 08:55There's a lot of hemorrhage,
- 08:57and lots of separate fragments of tissue,
- 08:59and on the low power,
- 09:00it's kind of hard to see what's going on,
- 09:02although there are some sailor foci
- 09:04in the scanning image and let's
- 09:07focus on a few of these areas.
- 09:09So now we see those one fragmente
- 09:11with some blue cells.
- 09:13Hard to know what's going on.
- 09:15Higher power another area.
- 09:17We also have these streams of blue cells,
- 09:20but certainly to make anything more
- 09:22of this will have to go closer.
- 09:25So now you begin to see that there
- 09:27are these very large, rounded,
- 09:29slightly angulated cells embedded
- 09:32in this dense fibrous stroma.
- 09:35Even a higher power we can see this
- 09:37as a somewhat nested proliferation,
- 09:39infiltrating through the submucosal.
- 09:41We have some normal,
- 09:44normal glandular structures here.
- 09:47Higher power,
- 09:47this is a tumor that has significant
- 09:51crush artifact.
- 09:53Just the last few hypower images
- 09:55and you can see this is a small
- 09:57round blue cell tumor.
- 09:58Although the cells aren't so small,
- 10:00they're actually quite large.
- 10:01Then we come to really high power and
- 10:04you can see the primitive chromatin.
- 10:06Very large nuclei,
- 10:08very limited cytoplasm.
- 10:10So I think on morphologic grounds
- 10:13the differential diagnosis
- 10:14would certainly be broad.
- 10:16This is a young,
- 10:17not quite middle aged adults,
- 10:19so we have to think of sarcomas,
- 10:22lymphoma,
- 10:22Melanoma,
- 10:23sometimes sinonasal melanomas have
- 10:26round some morphology or given
- 10:29the the high nucleocytoplasmic
- 10:30ratio and the print
- 10:32of primitive appearance.
- 10:34We certainly could also
- 10:36consider endocrine carcinoma,
- 10:38a very wide panel of screening markers.
- 10:41Was done in this case and the first
- 10:43pass only revealed a single finding
- 10:46and that is very strong intense
- 10:48standing for Desmond in every cell.
- 10:52You can see on high power the limited
- 10:55silo plasm is nicely highlighted by the
- 10:58Desmond Stainless intermediate filament.
- 11:00Then additional confirmatory
- 11:02marker was performed.
- 11:03Actually, 2 markers MYLDE 1,
- 11:06which is positive in every nucleus,
- 11:09as is myogenin in a very strong,
- 11:12intense fashion.
- 11:12And I'm sure by now many of you in
- 11:16surgical pathology have made the diagnosis.
- 11:18This summarizes the immunity chemistry,
- 11:21all the markers that were negative,
- 11:22excluding your endocrine carcinoma,
- 11:25Melanoma, and lymphoma.
- 11:27This is alveolar Rhabdomyosarcoma.
- 11:32I don't expect you to
- 11:33follow this entire table.
- 11:35This table was included in a review
- 11:37article that I I recently wrote for
- 11:40seminars and diagnostic pathology with a
- 11:43junior colleague of mine, Michael Kaelin,
- 11:45who's a bone and soft tissue pathologist
- 11:47at the University of Maryland,
- 11:49where we focused on these new emerging
- 11:52categories of round soul sarcomas.
- 11:54But we also included this table that really
- 11:58highlights some of the conventional lineages,
- 12:00markers keratin Desmond.
- 12:01Myogenin Myo D1 that we've already mentioned,
- 12:05as well as some more,
- 12:07much more recently developed markers that
- 12:10correlate with molecular genetic alterations,
- 12:13which in some cases are really
- 12:16sufficient to make the diagnosis of
- 12:18some of these round cell sarcoma types.
- 12:22So let's talk about Rhabdomyosarcoma
- 12:24in general.
- 12:25There are four different classes of
- 12:27tumors that we consider Rhabdomyosarcoma,
- 12:29as these are all sarcomas that shows
- 12:33skeletal muscle differentiation.
- 12:35The classic embryonal and alveolar
- 12:37Rhabdomyosarcoma is typically
- 12:39affect children, adolescents,
- 12:41and young adults,
- 12:42and they do have particular anatomic
- 12:45sites where these tumors arise,
- 12:47and if you're familiar with the
- 12:49epidemiology of these classes of tumors,
- 12:52it is often possible to suggest the diagnosis
- 12:55even before you look down the microscope,
- 12:57and I always emphasize the
- 13:00demographics is critical and
- 13:02understanding some basic epidemiology.
- 13:05Of sarcomas can really help you
- 13:08dramatically toward a specific diagnosis.
- 13:10We're not going to talk about 3
- 13:13amorphic Rhabdomyosarcoma spindle
- 13:15cells sclerostin Rhabdomyosarcoma.
- 13:16We're going to come back to a little bit
- 13:19later in the session this afternoon.
- 13:22Another example of alveolar Rhabdomyosarcoma.
- 13:25This is really one of the classic
- 13:28round cell sarcomas that has
- 13:30fairly uniform nuclear morphology.
- 13:32The nuclear,
- 13:32often much larger than the nuclei
- 13:35of Ewing sarcoma,
- 13:36and if you're lucky you'll find an
- 13:38occasional reflight giant cell as you
- 13:40see in the middle of the field here.
- 13:42That's a very correct characteristic.
- 13:44Giant cell type of alveolar Rhabdomyosarcoma.
- 13:49In contrast to embryonal Rhabdomyosarcoma,
- 13:52alveolar Rhabdomyosarcoma
- 13:53typically shows very strong,
- 13:56intense diffuse staining for myogenin.
- 14:00The skeletal muscle transcription factor.
- 14:02And Brian or Rhabdomyosarcoma usually shows
- 14:06much more heterogeneity of the nuclei.
- 14:08Some small rounded cells,
- 14:10some short spindle cells,
- 14:12often embedded within a lucid
- 14:14demonised for myxoid stroma.
- 14:16And here you can see the striking
- 14:18difference in Myogenin immunoreactivity.
- 14:21And Brian or Rhabdomyosarcoma
- 14:22will show quite variable.
- 14:24My agenda and expression.
- 14:26It's often between maybe 20
- 14:28and 60 or 70% of nuclei,
- 14:30but quite different from the strong diffuse
- 14:33standing we see in alveolar Rhabdomyosarcoma,
- 14:36and in fact,
- 14:37in a limited biopsy sample,
- 14:39the extent of myogenin is very
- 14:42helpful to support the diagnosis
- 14:44of alveolar Rhabdomyosarcoma.
- 14:47These classes of sarcoma
- 14:49have distinct genetics.
- 14:50Again,
- 14:50I'm going to come back to spindle cells
- 14:53sclerostin Rhabdomyosarcoma little bit later.
- 14:55The really important thing to remember
- 14:58is alveolar Rhabdomyosarcoma's Harbor
- 15:00FOXO 1 gene fusions and this is really
- 15:03different from Brian or Rhabdomyosarcoma
- 15:06which does harbor wrasse mutations,
- 15:08but only in a small subset of cases.
- 15:12So now let's talk a little bit more
- 15:15detail about alveolar Rhabdomyosarcoma.
- 15:17Another good clinical clue to the
- 15:20diagnosis is the fact that alveolar
- 15:24Rhabdomyosarcoma often presents with
- 15:26metastasis to cervical lymph notes,
- 15:28so the presentation can be quite similar to.
- 15:33Oropharyngeal or nasopharyngeal
- 15:35carcinomas that often present with
- 15:38cervical lymph node metastases.
- 15:40The same thing goes for
- 15:43alveolar Rhabdomyosarcoma,
- 15:43so this is always important to have in
- 15:46mind in your differential diagnosis when
- 15:48you're dealing with a primitive round cell,
- 15:51malignant neoplasm.
- 15:52Alveolar Rhabdomyosarcoma has the worst
- 15:55prognosis of all of the Rhabdomyosarcoma
- 15:58types and in terms of differential
- 16:00diagnosis and one of the reasons that this.
- 16:03Class of sarcoma is often misdiagnosed
- 16:06when it arises in the sinus.
- 16:08Is is the fact that it's quite
- 16:11common for these tumors to express
- 16:15keratins and or synaptophysin,
- 16:16and there was a very nice
- 16:18paper published by Andrew.
- 16:20Folks will come back to in a minute
- 16:22that indicated the really high rate
- 16:24of standing for these markers.
- 16:26This is an example of metastatic alveolar
- 16:29Rhabdomyosarcoma in the cervical lymph node.
- 16:32You can see this is a nested tumor.
- 16:34Where the differential diagnosis would
- 16:37certainly be with a Melanoma and a
- 16:40primitive poorly differentiated carcinoma.
- 16:43Obviously it's easy to confirm the
- 16:46diagnosis with Desmond or myogenic.
- 16:48And this is the paper I alluded to.
- 16:50Andrew fopen.
- 16:51Colleagues from some different
- 16:54institutions many years ago
- 16:56highlighted this potentially serious
- 16:58diagnostic pitfall of expression of
- 17:01keratins and your endocrine markers
- 17:03and alveolar Rhabdomyosarcoma.
- 17:05And in fact,
- 17:06I would estimate that maybe once
- 17:08every three or four years coming to
- 17:11our head and neck on koleji clinic,
- 17:13there will be a patient who was
- 17:15thought to have a poorly differentiated
- 17:17and render carcinoma.
- 17:18Of the sinonasal tract that turned out in,
- 17:21in retrospect,
- 17:22on RE review to be alveolar Rhabdomyosarcoma.
- 17:28OK, so that's it for alveolar rabdo.
- 17:30Now we're going to go to the second case.
- 17:33This is from a 70 year old man who
- 17:35had a lesion in the sphenoid sinus
- 17:38were starting with some sinus lesions.
- 17:41Another curettage specimen,
- 17:44not a lot going on here.
- 17:45Most of these fragments of
- 17:47tissue look pretty normal,
- 17:49but I think you'll probably notice there's
- 17:51just a few fragments that look very cellular.
- 17:54Here is one of those fragments.
- 17:56This is a spindle cell neoplasm.
- 18:00It's a pretty cellular process.
- 18:03Fascicle sheets of spindle cells
- 18:05that look fairly uniformly spaced,
- 18:08even if this intermediate magnification.
- 18:11And other fragments involved by the tumor.
- 18:13And now you could appreciate those thin,
- 18:15walled, dilated and branching blood
- 18:18vessels which we refer to as staghorn
- 18:22vessels or hemangiopericytoma like vessels,
- 18:25alluding to the tumors that we used to call
- 18:29hemangiopericytoma that now do not exist.
- 18:32Except for this tumor.
- 18:33Little higher powerview and again
- 18:35we see those thin walled dilated.
- 18:38Somewhat branching blood vessels,
- 18:40and you can begin to appreciate
- 18:43better than cytology.
- 18:44This is a uniform tumor.
- 18:46Oval to short spindle cells that are fairly
- 18:50evenly distributed and evenly spaced.
- 18:52Another nice field of that,
- 18:53the higher power with those
- 18:56classic blood vessels.
- 18:57Some areas are devoid of vessels
- 18:59and you could see some somewhat
- 19:02sharply defined cell borders,
- 19:04and then we come to very high
- 19:05power and we can see that the
- 19:08nuclear morphology is uniform.
- 19:09The chromatin is actually fairly even.
- 19:11It's not so course there's limited,
- 19:14if any mitotic activity,
- 19:16and really not any significant
- 19:19nuclear atypia.
- 19:22One more high power view again,
- 19:24you could see the even spacing
- 19:26of these uniform nuclei.
- 19:28So what's our differential
- 19:30diagnosis for this case?
- 19:32Given the anatomic sites
- 19:33and given the prior case,
- 19:35we could also think about Melanoma carcinoma,
- 19:38which would obviously be much more
- 19:40common than the tumors were talking
- 19:42about in the session this afternoon.
- 19:44Maybe monophasic synovial sarcoma?
- 19:46This is a very uniform spindle cell neoplasm.
- 19:50Although,
- 19:50as the residents discussed this
- 19:52morning in the slide seminar,
- 19:53so noville sarcoma usually has
- 19:56somewhat overlapping nuclei because
- 19:58they have such limited cytoplasm.
- 20:01In this case, the nuclear,
- 20:03the nuclear, fairly evenly spaced,
- 20:05which would argue against synovial sarcoma.
- 20:08And then finally. Possibly a gloom angio.
- 20:12Perry cytoma, whatever that is.
- 20:14This is a tumor that's also called
- 20:17sinonasal hemangiopericytoma.
- 20:21Smooth muscle actin and some areas.
- 20:23It's not so impressive,
- 20:24but on other areas there was
- 20:26quite strong staining for SMAD.
- 20:29One other stand I'm going to
- 20:30show you is beta catenin.
- 20:32This is normal tissue.
- 20:33You can see the the upper respiratory
- 20:35epithelium has beautiful membranous
- 20:38staining for beta catenin,
- 20:40whereas in the tumor we have
- 20:43this incredibly intense nuclear
- 20:45and cytoplasmic staining was in,
- 20:47which is an aberrant pattern for
- 20:50nuclear Vatican for forbidding catenin.
- 20:52The other markers that were investigated
- 20:55in this case were negative,
- 20:57and I'm sure you've already guessed
- 21:00this is William Angio Perry Cytoma.
- 21:03This is a tumor that for many
- 21:05years was called
- 21:06sinonasal hemangiopericytoma.
- 21:08This terminology has evolved a bit
- 21:10over the years, in part because the
- 21:14hemangiopericytoma term has sort of
- 21:16been abandoned and most organ systems.
- 21:17So in the head neck there's trying
- 21:19to get away from it as well.
- 21:21This is a lesion that arises most
- 21:24commonly in the ethmoid sinus.
- 21:26It's benign, although it can recur
- 21:28locally in about 1/3 of cases.
- 21:31Most patients present with a nasal
- 21:34or sinus polyp fairly small in size,
- 21:37although occasionally they can be large.
- 21:39They often have some expression
- 21:42of actin filaments.
- 21:43These are thought to be perivascular cells.
- 21:46The cells that have contractile properties,
- 21:49which is why they express
- 21:52the actin filaments.
- 21:53Are there negative for Desmond Keratins?
- 21:56But we learned in 2015 by these Nice
- 22:00papers published by two different groups,
- 22:03one of them by Florian Haller
- 22:05and Abasa Gammy, and colleagues,
- 22:07the other by Jersey Losada,
- 22:09Mark home yet,
- 22:10and and a few other colleagues
- 22:12in and head and neck pathology
- 22:14that Glow Manju Perry.
- 22:16Cytoma harbors consistent
- 22:19activating mutations in C, TNN B1,
- 22:24the genes that encodes beta catenin.
- 22:26Which leads to this incredibly
- 22:29intense nuclear and cytoplasmic
- 22:31staining for beta catenin,
- 22:33which has become a very easy
- 22:35to apply diagnostic marker.
- 22:37The only problem with beta catenin in
- 22:40head and neck spindle cell neoplasms is
- 22:43the fact that it's not entirely specific.
- 22:46My colleagues,
- 22:47Vicki Jo and Chris Fletcher,
- 22:49published this follow up paper and head
- 22:52neck pathology soon after investigating
- 22:56immunohistochemistry for beta catenin.
- 22:57In a range of different
- 23:00spindle cell neoplasms,
- 23:01and they confirmed the beautiful staining
- 23:03we find in Glen Angio Perry Cytoma.
- 23:06But at least you should be aware that
- 23:09the majority of solitary fibrous
- 23:11tumors and synovial sarcomas also
- 23:13shown aberrant nuclear beta catenin,
- 23:16but it really doesn't show
- 23:18that incredibly diffuse,
- 23:19intense staining that you see
- 23:20in Gorman Joe Perry cytoma.
- 23:25Now we go on to case three or
- 23:27still in the Sinonasal region.
- 23:29This is from a 36 year old
- 23:31man with a nasal cavity mass
- 23:33extending into the ethmoid sinus.
- 23:37This is a much larger tumor than the
- 23:40previous samples I've shown you.
- 23:42This is a really purple looking
- 23:44tumor from scanning magnification.
- 23:46Little bit higher power.
- 23:47You could also you can already
- 23:49begin to appreciate that this tumor
- 23:52has a fascicular architecture.
- 23:54Again, it has that somewhat
- 23:56purple appearance.
- 23:57You can see some finwall dilated
- 23:59blood vessels at the top.
- 24:01We have entrapment of these these glands.
- 24:04The glands of the sinus,
- 24:06which sometimes look a little
- 24:08bit hyperplastic.
- 24:09They look very prominent in this
- 24:12embedded within this tumor.
- 24:15Higher Power area and we can now
- 24:17appreciate the nuclear morphology.
- 24:19Very bland, fairly uniform nuclei,
- 24:23somewhat overlapping.
- 24:24Coming back to our previous comment.
- 24:27Areas are much more purple,
- 24:30uniformly fascicular we see those
- 24:33fascicles nicely at high power.
- 24:36This tumor comes all the way up to
- 24:39the surface of the sinonasal mucosa.
- 24:41And then we come again to high power
- 24:44and you can see the uniform nuclear
- 24:46morphology and we even can see some
- 24:48areas with these wiry collagen
- 24:51bundles between the tumor cells.
- 24:54So most of what I've described
- 24:56now would fit very well with
- 24:59monophasic synovial sarcoma.
- 25:00But I think given the rarity of
- 25:02that tumor in this anatomic site,
- 25:05we have to think of some of the other
- 25:07tumors we discussed this morning like
- 25:09malignant peripheral nerve sheath tumor.
- 25:11Perhaps leiomyosarcoma,
- 25:12although this tumor is not so eosinophilic,
- 25:15it's a bit more purple.
- 25:17And then biphenotypic sinonasal sarcoma.
- 25:21As I go through each of these examples,
- 25:24I'm sure even if you don't
- 25:25know what you're looking at,
- 25:27you could probably guess the diagnosis by
- 25:30how I'm framing the differential diagnosis.
- 25:33Let's look at administer chemistry.
- 25:35Smooth muscle actin was positive
- 25:37in this case.
- 25:38A fairly kind of variable.
- 25:40Not so impressive.
- 25:42Overall positive in these areas.
- 25:44There was some limited staining for Desmond,
- 25:47and there was also some limited
- 25:49staining for S100 protein,
- 25:51but this is the characteristic nuclear
- 25:54and cytoplasmic staining pattern you
- 25:56should look for to feel confident that
- 25:59you're dealing with true staining for S 100.
- 26:03TLE One was also positive.
- 26:04We didn't talk about Tilly one this morning.
- 26:07Tillie one has been developed as
- 26:09a marker for synovial sarcoma.
- 26:12It was identified by gene expression
- 26:14profiling about 15 years ago,
- 26:16but we now know that T one is
- 26:18really not so specific.
- 26:20It's only has kind of moderate specificity,
- 26:22although the sensitivity for
- 26:24synovial sarcoma is very high.
- 26:27So to summarize the immuno.
- 26:29SM Afocal Desmond S 100 TL E1.
- 26:33Whereas epithelial markers
- 26:35and socks 10 were negative.
- 26:37This is in fact,
- 26:40Biphenotypic sinonasal sarcoma.
- 26:42So what is this tumor that goes
- 26:45by this unusual descriptive name?
- 26:47Well,
- 26:47lucky for us,
- 26:48the name that we now use is a little
- 26:51bit easier to remember than the
- 26:54first descriptor of this tumor type.
- 26:56Lewis and colleagues published this
- 26:58paper almost ten years ago now where they
- 27:02first to find this interesting tumor
- 27:04that they called low grade sinonasal
- 27:07sarcoma with neural and myogenic features,
- 27:10which is a perfect description
- 27:13for this tumor type.
- 27:15This is a low grade sarcoma that seems
- 27:18to be unique to the sinonasal tract.
- 27:21It occurs in adults over a wide age range,
- 27:24slightly more common in female patients.
- 27:27It's most common in the nasal
- 27:30cavity and ethmoid sinus.
- 27:31Despite the fact that we call this a sarcoma,
- 27:34it doesn't appear to have metastatic
- 27:37potential, at least thus far.
- 27:39No metastatic cases have been
- 27:41published with molecular confirmation
- 27:42as I'll come back to in a minute.
- 27:46There have been several tumor related deaths.
- 27:49This seems to be a very rare event,
- 27:52primarily due to intracranial extension.
- 27:55Given the anatomic site,
- 27:56so these tumors can be locally aggressive,
- 27:59they seem to recur in about
- 28:0230 to 40% of cases.
- 28:05Sometimes patients experience
- 28:07multiple local recurrences.
- 28:10As we saw in our case,
- 28:11these tumors look strikingly
- 28:14similar to monophasic.
- 28:16Synovial sarcoma, including cytologic,
- 28:20uniformity, fascicular growth.
- 28:24Often somewhat WAVY nuclei and
- 28:26indistinct cytoplasm that have delicate
- 28:29stromal collagen similar to synovial
- 28:32sarcoma and solitary fibrous tumor.
- 28:35It's common to see occasional
- 28:38staghorn vessels confusingly,
- 28:40these tumors sometimes have rare rhabdom.
- 28:44I'll blast,
- 28:45which can be highlighted
- 28:46by Desmin myogenin Myo D1,
- 28:48which might lead you to consider the
- 28:51possibility of a malignant peripheral.
- 28:54Nerve sheath tumor with
- 28:56heterologous elements.
- 28:57But those tumors are almost invariably
- 28:59hygrade with a very high mitotic rates.
- 29:02Striking nuclear atypia necrosis
- 29:05or as biphenotypic sinonasal
- 29:07sarcoma is remarkably uniform.
- 29:10Rarely shows necrosis and
- 29:12has a low mitotic rate.
- 29:14The defining immunophenotypic
- 29:16features of this tumor type.
- 29:19ARCO expression of S 100 and muscle
- 29:23markers most often smooth muscle
- 29:25actin and muscle specific actin,
- 29:27but you can sometimes see Desmond
- 29:29as well and as I mentioned the small
- 29:33subset of cases with rabdo myoblasts
- 29:36have myogenin Myo D1 expression
- 29:38only in the skeletal muscle cells.
- 29:41As we saw in our case,
- 29:42TLE one can be positive which
- 29:44could lead to confusion with
- 29:46monophasic synovial sarcoma,
- 29:48and finally, socks tennis negative.
- 29:50So these are not true.
- 29:52Peripheral nerve sheath tumors.
- 29:54These are not MPNST's.
- 29:56They do not show true nerve
- 29:59sheath differentiation.
- 30:01In fact,
- 30:01we don't really know what the lineages
- 30:04of these unusual tumors but coexpression
- 30:07of S 100 and actin filaments is a
- 30:10very helpful diagnostic feature.
- 30:12Andre Oliveira and colleagues published
- 30:15this beautiful paper in Nature
- 30:17Genetics in 2014 from the Mayo Clinic,
- 30:21identifying a recurrent pack 3 mammal
- 30:243 gene fusion in biphenotypic,
- 30:28sidell nasal sarcoma and over the next
- 30:31few years several different groups
- 30:33of published cases of biphenotypic
- 30:35sinonasal sarcoma with other packs,
- 30:383 Fusion partners including FOXO One and two.
- 30:43But it seems that PAX three is
- 30:46almost always involved in the
- 30:48pathogenesis of these tumors.
- 30:50A couple of nice large series published
- 30:53since the initial descriptions.
- 30:55This was a nice paper published
- 30:58by a diverse group
- 30:59of colleagues in Virchows archives in 2018.
- 31:03A fairly large series where you
- 31:05can see the anatomic distribution,
- 31:07ethmoid cavity and nasal sinus,
- 31:09or most common,
- 31:10as we saw in the initial description.
- 31:13And in this paper, mammal three was was
- 31:16still the most common fusion partner by far.
- 31:19A small subset of cases had
- 31:22foxo one and NCO A1 fusions.
- 31:25We haven't identified
- 31:27all the fusion partners.
- 31:29A small subset of cases have as of
- 31:33yet undefined PAX 3 fusion partners.
- 31:37And then finally,
- 31:38most recently another large series
- 31:40by the French sarcoma group with a
- 31:42few other collaborators from the US.
- 31:45This was another large series where
- 31:48packs 3 mammal free fusions were found
- 31:51in 37 out of 41 molecularly confirmed cases.
- 31:56They identified another fusion
- 31:57partner in the form of WW T R1 and
- 32:01we have those same fusion partners
- 32:03we saw in the previous case.
- 32:07And again, my colleague Vicki Jo,
- 32:09with some other collaborators
- 32:11in my department,
- 32:12published a study with us a few years
- 32:14ago where we we looked at using packs
- 32:173 administer chemistry as a surrogate
- 32:20for biphenotypic sinonasal sarcoma.
- 32:22This worked very well.
- 32:24We had a uniform staining in all 15 cases.
- 32:28We investigated many of these cases.
- 32:30We confirm by fish as you
- 32:32see in the lower left image,
- 32:34we have the break apart using.
- 32:37Pax three directed probes and the
- 32:39tumors we might consider in the
- 32:41differential diagnosis are almost
- 32:43always negative for PAX three.
- 32:45This is a very easy to apply marker.
- 32:48We have a very nice nuclear staining in
- 32:51a characteristic case of biphenotypic
- 32:54sinonasal sarcoma and one other
- 32:56example where you see it just
- 32:58underneath the surface epithelium.
- 33:02All right, we have a few
- 33:03more cases to go through.
- 33:04A few more different topics.
- 33:06Case four is from a 56 year old
- 33:10woman who presented with dyspnea,
- 33:12and she was found to have a large,
- 33:14soft palate tumor.
- 33:15So we're now moving away from the
- 33:18sinus is down into the palace.
- 33:20This was from the resection.
- 33:22It was actually kind of a debulking because
- 33:25this patient was having breathing difficulty.
- 33:27They recognized his tumor and they did
- 33:30surgery urgently so that she could.
- 33:32They could make sure they
- 33:33could maintain an airway.
- 33:35We have this very large,
- 33:37highly cellular purple tumor.
- 33:39Which had higher power.
- 33:40We can now begin to appreciate
- 33:43the Fascicular architecture.
- 33:45The primitive nuclear
- 33:47morphology and other areas.
- 33:49We have a slightly nested or cordlike
- 33:51architecture with this somewhat
- 33:54prominent collagenous stroma.
- 33:56In other areas we have much more
- 34:00uniformly fascicular architecture.
- 34:01Primitive nuclear morphology.
- 34:03This somewhat coarse chromatin.
- 34:06Higher power in the first
- 34:07area as I showed you,
- 34:08we have the nests and cords of
- 34:11primitive cells within this very dense.
- 34:14Collagen rich stroma.
- 34:17In some areas in the stroma,
- 34:19rich foci.
- 34:20These nests almost look like they're
- 34:24forming these cleft like or pseudo
- 34:27vascular spaces a little bit LV.
- 34:29Older in.
- 34:30In cytology this is another classic
- 34:33appearance to this type of sarcoma.
- 34:37And finally we look at high power
- 34:39and we see the primitive chromatin.
- 34:41Course very limited cytoplasm in these
- 34:45nests within this collagenous matrix.
- 34:48So what about differential diagnosis?
- 34:50If you notice the vascular appearance
- 34:52or you the pseudo vascular parents,
- 34:55perhaps you might consider angiosarcoma.
- 34:58If you thought the funny stroma
- 34:59looked a bit like bone matrix,
- 35:02osteoid that hadn't quite calcified.
- 35:05You might consider extra stone lost,
- 35:07you Sir coma.
- 35:08This morning we saw an example of
- 35:11sclerosing epithelioid fibrosarcoma,
- 35:13so you might consider that
- 35:15as a possible diagnosis,
- 35:17given the very dense expression.
- 35:21Excuse me at deposition of collagen.
- 35:25Sclerosing Rhabdomyosarcoma, perhaps?
- 35:27Synovial sarcoma,
- 35:29given the uniformity of
- 35:31the nucleo morphology?
- 35:34So let's look at a minister
- 35:35chemistry on this case.
- 35:36Desman is very strongly positive
- 35:39and pretty much every cell.
- 35:41And mild D1 is also strongly
- 35:43positive even in the scanning image.
- 35:45You can appreciate that every nucleus
- 35:48has strong expression of my OG.
- 35:50One high power.
- 35:51We confirm that impression from low power.
- 35:54In contrast, if you look at myogenin,
- 35:57it's only a very small subset
- 36:00of nuclei that are positive.
- 36:03So in summary,
- 36:04we have skeletal muscle marker expression.
- 36:06We have negative staining for EMA.
- 36:09The vascular transcription factor ERG
- 36:13and the sclerosing epithelioid fibrous
- 36:15sarcoma marker mark for all negative.
- 36:18And you've guessed it,
- 36:21this is sclerostin Rhabdomyosarcoma.
- 36:24So at the beginning of the session this
- 36:26afternoon I mentioned I was going to
- 36:28come back to this topic of spindle cell,
- 36:30sclerosing revenue mile sarcoma.
- 36:32This is the most recent addition
- 36:35to these sarcomas that shows
- 36:38skeletal muscle differentiation.
- 36:40Spindle cell sclerostin Rhabdomyosarcoma
- 36:41is occur most often in the head and neck,
- 36:45although you can see them in the extremities
- 36:48and trunk or in parrot testicular locations.
- 36:51Paratesticular tumors are almost
- 36:54only seen in infants,
- 36:57male infants,
- 36:58and young boys as they'll
- 37:00come back to in a minute.
- 37:01These tumors often have my old
- 37:05one trans activating mutations.
- 37:07There is a slight female
- 37:09predominant for that.
- 37:10Group of tumors.
- 37:12These tumors,
- 37:12as we saw in our clinical case,
- 37:14often present as a rapidly growing mass.
- 37:18And symptoms are related to local
- 37:21compression because of their very
- 37:23characteristic anatomic sites of
- 37:26presentation in the head neck.
- 37:28There are another group of spindle
- 37:32cells thrusting rhabdomyosarcoma's
- 37:33that do not have mild you.
- 37:35One mutations that instead have gene
- 37:38fusions as they'll come back to in a minute.
- 37:40Those tumors have a very good prognosis.
- 37:42Those are almost only seen
- 37:44in very young infants,
- 37:46sometimes with congenital presentation.
- 37:49In contrast,
- 37:50the miod one mutant spindle cell
- 37:54speros in rhabdomyosarcoma's really
- 37:56have a dismal prognosis with a
- 37:58less than 20% five year survival.
- 38:03At one end of the spectrum,
- 38:04these tumors look very similar to
- 38:08leiomyosarcoma's with intersecting
- 38:10fascicles of elongated spindle cells
- 38:13with abundant bright pink seidel plasm.
- 38:16Some cases you'll appreciate us
- 38:19true skeletal muscle differentiation
- 38:21at the HD level.
- 38:23We have these occasional polygonal
- 38:25or strap like cells that have really
- 38:28intense somewhat orange or red or cytoplasm.
- 38:32Other examples have a much more
- 38:35primitive fibrosarcoma like
- 38:37appearance with coarse chromatin,
- 38:39a high mitotic rate and limited
- 38:42set up plastic differentiation at
- 38:45the other end of the spectrum.
- 38:46We have these incredibly densely
- 38:49hyalinized sclerosing tumors where
- 38:52we have this osteoid matrix like
- 38:56deposition of hyalinized collagen.
- 39:00And other cases kind of sit somewhere
- 39:02in the middle as we saw in our case,
- 39:04in our clinical case for this discussion.
- 39:07I think this this example has
- 39:09some fascicular architecture,
- 39:11but you could still appreciate in the
- 39:14background the dense collagenous stroma.
- 39:17Desmond is diffusely positive,
- 39:19similar to many rhabdomyosarcoma's
- 39:21the best skeletal muscle
- 39:23transcription factor to used for
- 39:26this tumor is miod want.
- 39:27Some cases are entirely
- 39:29negative for myogenic,
- 39:31so if you only run myogenin,
- 39:33you may get confused and think
- 39:36you're not dealing with this
- 39:38distinctive form of Rhabdomyosarcoma.
- 39:41So as I mentioned, these tumors
- 39:43most often have my O D1 mutations.
- 39:46There were three proper papers published
- 39:49the same year by Marc Ladanyi,
- 39:52Pockrus Hogendoorn and Christina Senescu.
- 39:55These really nice papers in nature Genetics,
- 39:58Journal of pathology and genes
- 40:00chromosomes and cancer identifying this
- 40:03very common recurrent trans activating
- 40:05mutation in my O D1 which leads to
- 40:08very strong expression of the mild D1.
- 40:11Protein, as I showed you in
- 40:14the last few slides.
- 40:15But we've learned over time that these tumors
- 40:19do not always show my OG one mutations.
- 40:22Some of these tumors have gene fusions
- 40:25with a variety of fusion partners and
- 40:28this nice paper published two years
- 40:30ago by the Group of Memorial Narse.
- 40:33Agaram was the first author.
- 40:35He's one of the bone and soft
- 40:37tissue pathologists at memorial in
- 40:39New York with Cristina Antonescu.
- 40:41And they're suggesting that you really
- 40:44should think of these as different
- 40:47risk groups depending on what the
- 40:51underlying molecular pathogenesis is.
- 40:53The mild you want mutant tumors,
- 40:55which are pretty much
- 40:56all the tumors in adults,
- 40:58have mild you one mutations.
- 41:00I have a really poor prognosis,
- 41:03whereas the tumors that present in
- 41:06very young infants have various gene
- 41:09fusions and have a very good prognosis.
- 41:12If you don't find miodowa mutations,
- 41:14those tumors also have a fairly
- 41:17good prognosis.
- 41:18There are some second hits that have been
- 41:21identified as you see from this study,
- 41:23but really the thing to remember
- 41:25is the my OG one mutations.
- 41:29All right, we are back to the nasal cavity.
- 41:31The last case I'm going to discuss
- 41:34this afternoon is from a young woman
- 41:36who was found to have a right nasal
- 41:39cavity mass when she presented to
- 41:41her primary care physician with
- 41:43a unremitting nasal congestion.
- 41:46Another very cellular tumor.
- 41:49This is the excision specimen,
- 41:51another tumor with a purple
- 41:53appearance from low power.
- 41:54But when you begin to look
- 41:56at a little bit higher power,
- 41:57you begin to see that these tumor
- 42:00cells have abundant eosinophilic
- 42:02granular cytoplasm.
- 42:05And in the background you see this
- 42:07very delicate capillary vascular
- 42:09network that compartmentalizes the
- 42:12tumor into these delicate bundles,
- 42:15or nests higher power.
- 42:17You can see the central nucleoli quite
- 42:21uniform appearance to the nuclei,
- 42:23although there are some very slight
- 42:26nuclear contour irregularities.
- 42:28Some of the cells have a little
- 42:30bit more optically clear cytoplasm,
- 42:32but most of the cells have this granular.
- 42:35Eosinophilic appearance and now
- 42:36in this image these images you
- 42:39can nicely see that delicate.
- 42:41Capillary vascular network.
- 42:43Looking very similar to the vascular
- 42:47pattern of clear cell renal cell carcinoma.
- 42:51High power you can nicely see those nucleoli.
- 42:54Occasional cells are multinucleated
- 42:56with slightly more nuclear atypia.
- 43:00Finally,
- 43:01high power we now begin to
- 43:03appreciate the mitotic activity.
- 43:05We found some scattered mitotic figures.
- 43:07I think it was up to maybe two or three
- 43:11and 10 high power fields in this case.
- 43:14So what is our differential diagnosis?
- 43:16I mentioned metastatic renal cell carcinoma,
- 43:19but we have to think about the
- 43:21other tumor types that also present
- 43:24with a similar nested architecture
- 43:26and a similar vascular pattern.
- 43:28So obviously today's session
- 43:30is on soft tissue tumors,
- 43:32so it can't be renal cell carcinoma.
- 43:34This is a this is a good testing strategy.
- 43:37Alveolar soft part sarcoma perhaps
- 43:40clear cell sarcoma malignant pecoma.
- 43:43Maybe we should consider a
- 43:45these tumors possibly.
- 43:46So let's look at a minister.
- 43:49Chemistry TFE 3 is very strongly
- 43:52and intensely positive,
- 43:54so that could suggest several of
- 43:57the possibilities I mentioned.
- 43:59The only other marker that
- 44:01was positive was HMB 45.
- 44:03That marker of melanocytic differentiation
- 44:05and it was not so impressive,
- 44:08but it did show that really
- 44:10distinctive granular subtle plasmic
- 44:12pattern of staining which we look
- 44:15for for tumors that have melanosomes.
- 44:18So to summarize, the immunophenotype.
- 44:21Muscle markers were negative.
- 44:23As well as Melanie.
- 44:25If you're thinking of Melanoma S
- 44:28100 stocks tender negative,
- 44:29those are also uniformly positive
- 44:32and clear cell sarcoma.
- 44:34And finally,
- 44:35thinking about renal cell carcinoma
- 44:37characins were also negative.
- 44:39This is a malignant pecoma.
- 44:43So Pecoma is this very mysterious tumor.
- 44:46That has a very unusual definition.
- 44:49Tacomas are said to be composed of
- 44:54perivascular epithelioid cells which
- 44:57are distinctive epithelioid cells
- 44:59that are often closely associated
- 45:01with blood vessel walls and that
- 45:04often Co Express Millen, acidic,
- 45:06and smooth muscle markers.
- 45:09We think of Petco misses being
- 45:11a family of tumors that include
- 45:14the much more common and better
- 45:16known family member,
- 45:17Angiomyolipoma,
- 45:18which usually presents in the kidney.
- 45:21But this morning we talked about tumors
- 45:23in the liver that are also often
- 45:27called angiomyolipomas that are in
- 45:29fact just pecoma's of the of the liver.
- 45:32We have a rare rare disorder called Lam
- 45:36Lymphangioleiomyomatosis that mostly
- 45:37occurs in the lungs and lymph nodes.
- 45:40And the tumor we're talking about today.
- 45:43A group of distinctive tumors that have
- 45:45been called pecoma not otherwise specified,
- 45:48or simply pecoma All these tumors share
- 45:52this distinctive magical cell type that we
- 45:55call the perivascular epithelioid cell,
- 45:58which has no known normal
- 46:01cellular counterpart,
- 46:02so this isn't really a known cell type,
- 46:05but it's a concept that was invented
- 46:07by a group from Italy from Verona
- 46:09more than 20 years ago now,
- 46:11and this concept has stuck and
- 46:14we use it to describe pecoma.
- 46:18The first large series of soft tissue,
- 46:20Petco Miss,
- 46:21was published by Andrew Phillip Thomas,
- 46:23Mensal Sharon Weiss and colleagues and
- 46:262005 when they first proposed criteria
- 46:29for malignancy based on the small series.
- 46:33We now know that Petco massacre at a
- 46:35very broad range of anatomic sites.
- 46:37You can see them primarily presenting
- 46:40is very small skin tumors.
- 46:42They are relatively common in
- 46:44the gastrointestinal tract.
- 46:46I promised the GI pathology faculty earlier
- 46:48today that I would allude to the GI tract,
- 46:52even though today I'm talking about
- 46:54soft tissue tumors of the head neck.
- 46:56Because I am also a GI pathologist.
- 46:59So pack owners are much more
- 47:02common in women than men.
- 47:04They usually present in adults and unlike
- 47:09angiomyolipoma and lymphangioleiomyomatosis,
- 47:12pecoma unspecified the tumors
- 47:14in the soft tissue.
- 47:16GI Tracting uterus are rarely associated
- 47:19with the cancer predisposition syndrome,
- 47:22TSC, the tubers sclerosis complex.
- 47:26You can find them in the extremities,
- 47:28trunk wall and skin,
- 47:30but those are a small minority
- 47:31of all pecoma's.
- 47:32Most of the time you'll find them in
- 47:36central body cavity or visceral locations.
- 47:38This is a nice resection that was
- 47:42performed in our hospital of a
- 47:44primary pecoma of the pancreas.
- 47:47This was such a nice gross photograph
- 47:49that I included in The Who the last
- 47:51two times the 4th and 5th series.
- 47:54It looks kind of similar to
- 47:56the pancreatic parenchyma.
- 47:57It's very sharply demarcated
- 47:58from the pancreas,
- 48:00but this is a pecoma that looks really
- 48:03similar to the angiomyolipoma of the liver.
- 48:06They were reviewed in the
- 48:08slide seminar this morning.
- 48:10And here you can see a very
- 48:12interesting accentuation around
- 48:14the blood vessel in the middle.
- 48:16We have these blood vessels that
- 48:18seem to have the tumor cells just
- 48:22underneath the endothelial lining.
- 48:25Sometimes these tumors have very striking,
- 48:28clear cell morphology and a
- 48:30beautiful nested appearance,
- 48:32making them almost indistinguishable
- 48:34from clear cell renal cell carcinoma.
- 48:37Some of them have trabeculae
- 48:39are architecture.
- 48:40This example also arose in the nasal cavity
- 48:44and then also had a TFE 3 gene fusion.
- 48:48Other examples look much more
- 48:51similar to leiomyosarcoma's with
- 48:54fascicular spindle cell morphology,
- 48:56but in contrast to true smooth muscle tumors,
- 48:59which typically show very
- 49:01dense core cytoplasm.
- 49:03The cytoplasmic quality of pecoma,
- 49:05as is almost always this delicate
- 49:08granular eosinophilic to clear cytoplasm.
- 49:13There is a distinctive sclerosing variant
- 49:16of pecoma that has a marked predilection
- 49:20for the pararenal retroperitoneum.
- 49:23As you see in these two images on this slide,
- 49:27we again have that orientation under
- 49:29the endothelium of the blood vessel,
- 49:32and these cords of somewhat
- 49:34clear cells within a very dense
- 49:37hyalinized collagenous stroma.
- 49:39As I mentioned, we define these
- 49:41tumors as showing a mixed Milan,
- 49:44acidic and myogenic phenotype.
- 49:46They're nearly always positive for HMB 45.
- 49:50That's the best marker for pecoma.
- 49:52Smooth muscle actin is the most
- 49:54sensitive of the muscle markers.
- 49:56However,
- 49:57it's important to be aware of the
- 50:00fact that in particular the clear cell
- 50:03examples that harbor TFE 3 fusions
- 50:06are sometimes entirely negative.
- 50:09For smooth muscle actin and desmin.
- 50:13You can find focal S 100 in
- 50:15a subset of cases,
- 50:16but it's usually unimpressive
- 50:19and predominantly cytoplasmic,
- 50:21which helps distinguish them
- 50:23in a phenotype from Melanoma.
- 50:26In addition,
- 50:26socks 10 that marker we think of as
- 50:29being very strongly expressed in close
- 50:31to 100% of melanomas is negative and pecoma.
- 50:36And in correlating with the presence
- 50:39of the gene fusions TFE 3 protein
- 50:42is expressed at high levels in
- 50:45about 10 to 15% of cases.
- 50:47And that's a good surrogate by
- 50:49administer chemistry for the
- 50:51presence of the gene rearrangement.
- 50:54This is a,
- 50:55uh,
- 50:55some examples of smooth muscle
- 50:57actin and desmin staining.
- 50:59This was actually from the case
- 51:00in the pancreas.
- 51:01I showed you a few minutes ago
- 51:03and these were are nice examples
- 51:06of the variability of staining
- 51:08for HMB 5:45 and Melanie.
- 51:10And in fact,
- 51:12in order to support the diagnosis,
- 51:14I usually run all four markers
- 51:17SMAD and Desmond.
- 51:18HMB 45 MLN A and if you do that,
- 51:21usually you'll get a hit,
- 51:22at least with one of the muscle markers,
- 51:24and one of them will anesthetic markers.
- 51:27We don't really have very good
- 51:29criteria for malignancy in pecoma.
- 51:31As I mentioned Andrew folks first
- 51:35suggested criteria but we don't
- 51:36have a lot of cases to go on.
- 51:38We know that features associated with
- 51:41malignant behavior include large tumor size,
- 51:43mitotic activity and atypia pleomorphism.
- 51:47So in my practice I really use
- 51:50the combination of essentially
- 51:51any mitotic activity with atypia
- 51:54pleomorphism the support the diagnosis.
- 51:57Of malignancy this is a malignant
- 51:59pecoma of the colon,
- 52:01a large fleshy sarcoma like lesion.
- 52:05These tumors can look very similar
- 52:08to metastatic Melanoma.
- 52:09With macro nucleoli striking pleomorphism
- 52:13and eosinophilic or amphiphilic cytoplasm,
- 52:16whereas in other cases they have much
- 52:18more of a clear cell appearance,
- 52:20looking very similar to metastatic
- 52:23clear cell renal cell carcinoma,
- 52:25this is obviously a metastasis to the liver.
- 52:29We again see those macronuclei,
- 52:32plia, morphic,
- 52:33and multinucleated tumor cells.
- 52:36Pete Argani from Hopkins with
- 52:38Sharon Weiss first presented
- 52:40this series of tumors with TFE 3
- 52:43gene fusions about 10 years ago.
- 52:46This was the case.
- 52:47I mentioned that I had just
- 52:48a couple of years ago from the sinus that
- 52:51trabeculae are tumor with fairly clear
- 52:55cytoplasm that had a TFE 3 gene fusion.
- 52:58A and RC Agram and Christina TSQ published
- 53:01this beautiful paper six years ago in the
- 53:04American Journal of Surgical Pathology,
- 53:06highlighting what we understand about
- 53:09the molecular genetics of Pecoma TSC.
- 53:112 mutations are found in the majority of
- 53:15cases and we also have trends locations in
- 53:18a range of of pecoma TFE 3 being the most
- 53:23common gene involved in translocations.
- 53:28Because of the alterations of TSC 2 in the
- 53:32majority of Tacomas and visceral locations,
- 53:34including in tumors that
- 53:36pursue an aggressive course.
- 53:38The malignant examples we can use
- 53:42mtor inhibitors to effectively treat
- 53:45patients with this tumor type.
- 53:48These are some sort of case reports
- 53:50and small series published almost
- 53:52ten years ago now showing that M
- 53:54Tor inhibitors such as Sorolla,
- 53:56Miss or quite effective in treating
- 53:59patients with malignant pecoma's.
- 54:01This is an example of a patient treated
- 54:04in our hospital at the Dana Farber Cancer
- 54:06Institute by my colleague Andy Wagner,
- 54:08who's he's really the world expert in
- 54:11treating patients with malignant pecoma.
- 54:13He's treated on the order of about
- 54:1570 patients with this sarcoma type.
- 54:17Over the last ten years or so,
- 54:19and you can see this very dramatic
- 54:22clinical benefit to serralles therapy
- 54:24with a marked decrease in size of
- 54:27these multiple metastatic lesions
- 54:29in the abdominal cavity and pelvis.
- 54:32Very recently,
- 54:32this is a paper that was just
- 54:34published online a few weeks ago.
- 54:36There is now a modified albumin
- 54:39conjugated version of sirolimus
- 54:41that is also really effective in
- 54:44patients with malignant pecoma,
- 54:46especially patients that have TSC 2
- 54:50mutations thus far in this series,
- 54:52all the patients whose tumors
- 54:54were confirmed to harbor TSC.
- 54:562 alterations were are alive either
- 54:59without disease or with disease.
- 55:02And you can see from that plot
- 55:04in the lower left,
- 55:05the striking clinical benefit in the
- 55:08majority of patients with malignant pecoma
- 55:11treated with this seromas conjugate.
- 55:16So for my final slide of
- 55:18summary of practice points,
- 55:20don't forget that head and neck location
- 55:22is very common for both alveolar
- 55:25Rhabdomyosarcoma and spindle cells.
- 55:27Grossing revenue miles sarcomas.
- 55:29Beware of keratin and
- 55:32neuroendocrine marker expression,
- 55:33so you don't go down the tubes and make a
- 55:37misdiagnosis of alveolar Rhabdomyosarcoma.
- 55:39I've now shown you lots of examples
- 55:42of biphenotypic sinonasal sarcoma.
- 55:44This distinctive pack three
- 55:46translocation associated low
- 55:48grade sarcoma that Co expresses.
- 55:51Muscle markers and neural markers
- 55:53and finally Pecoma Harbor either TSC,
- 55:572 deletions, or TFE 3 fusions.
- 56:02So I'm going to close there and I
- 56:04want to thank you very much to the
- 56:06department into Manju Prasad for
- 56:08inviting me to visit your department today.
- 56:10I'm sorry that it had to be
- 56:12converted to a virtual visit,
- 56:15but I always have to now advertise
- 56:17for my rock band the teardowns.
- 56:19As you heard,
- 56:20we released our first album that's
- 56:22available on all streaming services
- 56:24and after a very long delay we're
- 56:25beginning to play some shows
- 56:27around town where we're playing in
- 56:29Summerville coming up next month and
- 56:31then in Jamaica Plain in Boston.
- 56:33In January,
- 56:34I doubt that we're ever going to
- 56:36travel outside of the Boston area.
- 56:38Since this is a hobby for all of
- 56:40us who have different careers,
- 56:42and honestly,
- 56:43we're not good enough to make
- 56:45this our our our full time job.
- 56:48And I'm happy to answer any questions,
- 56:50thank you.
- 56:57That was wonderful, Jason.
- 57:00I'm sure you're good enough to.
- 57:03Play for us at one of
- 57:07our departmental events.
- 57:08Uhm, there was a comment.
- 57:11My computer crashed.
- 57:15All the way through your presentation.
- 57:18So I lost all the comments in chat and
- 57:22I know that singing Pan had a comment,
- 57:25so singing can you unmute yourself and?
- 57:30And say your comments.
- 57:35I think it was about alveolar
- 57:39Rhabdomyosarcoma metastatic to lymph nodes.
- 57:42Can you hear me yes?
- 57:44Hi, so thank you for the
- 57:46wonderful presentation. So
- 57:47I just want to make a quick comment
- 57:50so I haven't seen. Like if you cases
- 57:52of metastatic tremors. Psycho Martin.
- 57:56If notes showing us purely sinusoidal
- 57:59pattern with polymer cells.
- 58:02And the tumor cells
- 58:04he feels in a positive for CD56 and
- 58:07AWK. So one case was misdiagnosed
- 58:10as a hog positive and approximately
- 58:1470 former by our third pathologists.
- 58:17So just beware.
- 58:19Both types of randomized sarcoma
- 58:22may have expression that thank you.
- 58:26No thank you. That's that's a great point.
- 58:28I think alveolar Rhabdomyosarcoma is a
- 58:30very good mimicker of many different
- 58:32tumor types because of these very
- 58:34strange appearances of expression
- 58:36and alk is quite commonly positive,
- 58:39and that's a very interesting.
- 58:41Interesting problem,
- 58:42thank you and all 56 as well. So yes.
- 58:47Oh, I always wondered why we had both
- 58:52my D1 and myogenin so clearly it has.
- 58:56Prove to be useful both these stains
- 59:00and why both might should be or might
- 59:04be ordered and can be useful. Yeah,
- 59:07I think that's a very good point,
- 59:08and in fact, before we recognize
- 59:11spindle cell and sclerostin rabdo,
- 59:13I don't think we really needed
- 59:14my OD one and for many years the
- 59:17antibodies available were pretty bad.
- 59:19They often showed a lot of
- 59:21subtle plasmic staining.
- 59:21The new clones are much better.
- 59:23They actually worked beautifully and
- 59:25they're really helpful for this class of.
- 59:27Of Rhabdomyosarcoma.
- 59:30Yeah, and I brought my my journey into our
- 59:34lab and I stopped using my D1 altogether,
- 59:38but clearly we'll have to look at our clones.
- 59:43The other thing I wanted to ask
- 59:45Jason is many of these antibodies.
- 59:48This newer antibodies that affusion
- 59:51specific or gene aberration specific.
- 59:55Do you offer them as test only
- 59:59like like the other labs?
- 01:00:01Yeah, unfortunately we don't
- 01:00:03because we just don't have the
- 01:00:04staffing to be a reference lab.
- 01:00:06At this point we can barely keep
- 01:00:09up with our volume in House.
- 01:00:10We we have about.
- 01:00:13650 to 700 a day not counting him path,
- 01:00:17so it's just it's it's impossible,
- 01:00:19so we for now we're only doing it
- 01:00:22as part of diagnostic consults.
- 01:00:23I think in a couple of years
- 01:00:26some of you might have heard our
- 01:00:29institutions are probably going to
- 01:00:30be forming a central lab for all of
- 01:00:32the mass General Brigham Hospital.
- 01:00:34So at that point, maybe will do.
- 01:00:37Reference lab work,
- 01:00:37but at this point we can't.
- 01:00:41Thank you. Any other
- 01:00:44questions from anyone else?
- 01:00:46I see that I see Don Pot had a
- 01:00:48comment that I'm a very good cook.
- 01:00:50If I want to thank you for that.
- 01:00:51I I only really started cooking
- 01:00:53full force after we had started the
- 01:00:55lock down with the pandemic and
- 01:00:57now I'm really obsessed with it and
- 01:00:59I love taking photographs during
- 01:01:00the process as dog pot as seen.
- 01:01:02So it's a it's a new hobby and I I love
- 01:01:06cooking very different ethnic groups.
- 01:01:08I love like Thai and and and
- 01:01:11various other types of food.
- 01:01:13And dump, as other question had to do with.
- 01:01:16Fusion detection we haven't.
- 01:01:18We haven't brought on one of the the RNA
- 01:01:22based NGS fusion panels yet in our lab.
- 01:01:26We have really only been reserving
- 01:01:30molecular confirmation for the
- 01:01:31cases that we struggle with,
- 01:01:33which because we have so many antibodies
- 01:01:35that I bring on and I enjoy doing as my
- 01:01:38kind of translational research effort,
- 01:01:40we don't do a lot of genetics,
- 01:01:41but we've mostly been using
- 01:01:43fish at this point.
- 01:01:44Really old school conventional fish.
- 01:01:46On occasion we'll do Archer,
- 01:01:49one of the fusion panels,
- 01:01:51but it's at MGH or Children's Hospital.
- 01:01:54We don't.
- 01:01:55We don't do it right now in our lab.
- 01:01:57I think that.
- 01:01:59Especially for round cell sarcomas,
- 01:02:01it's really valuable to
- 01:02:03have that method because.
- 01:02:05If it isn't Ewing sarcoma, it is very hard.
- 01:02:10To confirm the diagnosis of the
- 01:02:14other so-called undifferentiated
- 01:02:16round soul circles.
- 01:02:19Thank you.
- 01:02:20Yeah,
- 01:02:20in the head and neck area,
- 01:02:22this sarcoma is extremely baffling
- 01:02:24because that's not the first
- 01:02:27thing that comes to our mind.
- 01:02:30Fortunately for me, I also sign out
- 01:02:33on the bone and soft tissue service,
- 01:02:36so sometimes it strikes me
- 01:02:38it's not a head and neck tumor,
- 01:02:40but a soft tissue tumor.
- 01:02:43But they can be very challenging and we
- 01:02:46are trying to validate the orchard fusion,
- 01:02:49Plex version three,
- 01:02:50and we can't wait to get it started.
- 01:02:58If there are no other questions then.
- 01:03:02I'd like to thank Doctor Hornick profusely.
- 01:03:06For his generous time and for these
- 01:03:10very lucid discussions. Thank you, thank
- 01:03:14you again thanks everyone. Have a great day.