Pathology Grand Rounds: February 16, 2023 - Joseph J. Maleszewski, MD

February 18, 2023

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Matters of the Heart by Joseph J. Maleszewski, MD

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00:00Afternoon if my distinct pleasure and
00:04honour to introduce Professor Joseph.
00:08Mary Swatski, am I right?
00:12From Mayo Clinic, Gill is professor who
00:16professor of pathology and senior shows
00:19a Dean of academic affair of male Alex
00:23School of Medicine. So
00:25look at he is coming president of Society
00:29for Cardiovascular pathology and role model
00:33for cardiovascular pathologist and for
00:36that matter maybe for all pathologists.
00:40Looking at his CV is a very impressive,
00:43it's educational activity.
00:45You can see that he teach all part
00:48of cardiovascular pathology and lung
00:52pathology rate create curriculum and
00:55talking about cardiovascular pathology
00:58from congenital heart disease for neoplasm
01:02from cardiac imaging to amyloid diagnosis.
01:06And because of that he is
01:07a very frequent speaker.
01:10At national and international meetings,
01:12including Scotland, England,
01:14you're separated by yourself and then France,
01:19Chile and everywhere and
01:20make me a little bit jealous.
01:22Almost every year you gave a talk at Hawaii.
01:27And you know that January or February,
01:31think about it,
01:32you know it's very cold time at Rochester
01:35and very nice because how are you so?
01:38Other than they had about more than
01:42200 original articles and about
01:44100 book chapters and books.
01:47So very impressive,
01:48you wonder how many hours you sleep at night.
01:51Without further ado, please.
01:53He's talking about matters of
01:56the heart or matters of heart.
01:59Thank you.
02:01Well, that was a a ridiculously kind
02:04introduction. I, I have to say I I've
02:07been blown away by the the warm welcome,
02:09this amazing August institution.
02:12Obviously, Doctor Wong's introduction and
02:14his hosting have been absolutely exceptional.
02:18I do have to say it was it was kind of
02:20adorable. It extended even last night.
02:22He refused to let this Midwestern boy walk
02:24alone two blocks from the restaurant to here.
02:26It was it was like a scene right out
02:28of bodyguard. It was very impressive.
02:31So. Thank you very much.
02:33Glad to be here among friends.
02:34Doctor Dosik, of course.
02:36And I thought this was a a pretty
02:39special week for me to come here,
02:41mostly because of course,
02:43as you all know, or I hope you know it,
02:46it's the week in which we we
02:48celebrate a certain holiday.
02:50And for all of you out there
02:52who have significant others,
02:53I hope you didn't forget it.
02:55It's the week that we celebrate
02:57the Feast of Saint Valentine.
02:59And I don't know if any of you
03:00know the story of how Valentine's.
03:24Particularly well with
03:25Claudius Gothicus at the time,
03:27or Claudius the 2nd, and thus he was
03:31imprisoned and sentenced to death.
03:33And he befriended his jailer while he was
03:37an inmate, and he somehow got permission
03:40to write to his jailers daughter.
03:43And he would write her letters and
03:45he would always sign them.
03:46From your Valentine.
03:47And the jailer wasn't wild about this,
03:50but he allowed it to go on because
03:52his daughter was.
03:52She was blind, she was handicapped.
03:54And this gave her something,
03:56and she really liked it.
03:57And Valentine had told her in his letters
04:00that he was going to cure her blindness
04:03and that God would see her way through,
04:05so to speak, to a cure.
04:08And eventually her blindness did
04:11seem to improve or get better.
04:15And because of that,
04:17the the jailers family basically
04:19saw Valentine's as this miraculous
04:22individual who could work miracles.
04:25And so they saved all those letters
04:26as kind of these relic things
04:28and started passing them around.
04:29And they then started the tradition of
04:33sending loved ones these letters and notes,
04:36some of which would be adorned with symbols.
04:38And geometric symbols of which, roughly.
04:42Elevation of the heart.
04:45Everybody's familiar with
04:46the Valentine heart there,
04:47and it does bear some resemblance,
04:49obviously, to an anatomic heart as well.
04:52And so thus we continue that tradition today,
04:55and we exchange letters and poems and
04:59all kinds of little trinkets to express
05:02our love for one another in honor of
05:04Saint Valentine and what he did for Julia,
05:07the jailer's daughter when he was imprisoned.
05:11So I think it's it's appropriate in
05:14in this vein unintended of which I
05:17speak here that I I outline what I
05:20plan to talk about today in honor of
05:23Saint Valentine's by way of a poem.
05:25So here is my outline a heart themed
05:28lecture for you in three acts.
05:31We'll start with a tale of a VAX and
05:33then something new updates from The Who
05:36and will end with some amyloid plaques.
05:39So that's as good as it gets guys.
05:41So. But that doesn't entertain you.
05:43Nothing will.
05:44So alright,
05:44for those of you who are perhaps
05:47less sentimental and prefer a more
05:50classical outline, here it is.
05:52So we're gonna start off by talking
05:54a little bit about COVID-19,
05:56kind of getting our thinking back into
05:58the pandemic as if it ever really left.
06:00Then we'll talk about some of those
06:02updates from The Who that I alluded
06:04to moments ago and then discuss some
06:06new trends in cardiac amyloidosis
06:08and some newer technologies on the
06:10horizon that I think are exciting and.
06:11Certainly these topics extend beyond
06:14the realm of cardiovascular pathology
06:16into other areas of pathologic
06:18diagnostic pathology as well.
06:20So first we're going to start each
06:24of these acts with a vignette.
06:27In our first vignette is a 53 year
06:29old woman who presented with elevated
06:31troponins and New heart block without
06:34discrete lesions noted angiographically,
06:36SARS Kobe 2 testing was negative
06:39and the patient had
06:40received notably an MRA 12211273 vaccine
06:436 days prior to her presentation.
06:46And the myocardial biopsy was
06:48performed in a photomicrograph
06:49of such as shown on the right.
06:50Hand side of the slide here.
06:52What I hope you'll realize here from this
06:55relatively low power is indeed heart muscle,
06:57but it does appear to be a little
06:59bit more cellular than one might
07:01expect to see for heart muscle.
07:03Closer in, you get a sense forward.
07:05The character of that cellularity.
07:06There's a leukocytic infiltrate
07:08that's filling up the interstitium,
07:10and indeed it it's not just sitting there,
07:12but there does seem to be some
07:14behavior associated with it
07:16in the form of myocyte injury.
07:18You'll note at the top here,
07:19some of the myocytes have lost
07:21their cross striations a bit.
07:23Some of the sarcoplasmic
07:25membrane is scalloping.
07:27It's becoming a little bit Ruddy
07:29or rugged along its surface.
07:30So those leukocytes are
07:32not just simply transiting,
07:33but they're actually causing
07:35myocardial injury.
07:36This is definitionally active
07:38myocarditis at that at this
07:40point and the question becomes.
07:43What is its ideology?
07:46So let's talk a little bit about
07:49myocarditis and its etiologies.
07:50I want to,
07:51I want to rewind to a time that again,
07:53I think we would probably rather all
07:56forget about nearly three years ago now,
07:59which was the summer of 2020.
08:02That was of course our first summer
08:04where COVID was in full swing
08:07and a number of studies started
08:09coming out between June and July,
08:11primarily out of the radiology
08:14literature detailing and discussing
08:16patients who have had COVID-19 are
08:18either active or in the subacute
08:21phase that we're presenting with
08:23cardiac issues and asymptomatic
08:25cardiac patients as well that were
08:28being screened by way of cardiac
08:30MRI and CT for cardiac sequella.
08:33Of COVID-19,
08:34the results were admittedly quite alarming.
08:39The first study showed 100 patients
08:42and or exhibited 100 patients,
08:45nearly 80% of which showed some
08:48cardiac involvement by Mr.
08:50Now this involvement didn't
08:51necessarily mean that there were
08:53clinical symptoms associated with it,
08:55but rather there was delayed
08:57gadolinium enhancement meaning that
08:58there was evidence of inflammation
09:00in the myocardium irrespective
09:02of the patient symptomatology.
09:04Following those patients along
09:06after their acute phase,
09:07almost 2/3 of those patients
09:09showed some evidence of ongoing
09:11inflammation in the heart muscle.
09:13This is alarming and this is very concerning,
09:15especially at this time where
09:16we're all kind of in the dark,
09:17trying to feel our way through in
09:20the darkness of what this virus
09:21is going to do to the populace.
09:23A second study of relatively
09:25young competitive athletes,
09:2726 of them showed similarly an
09:29alarming numbers, with almost half,
09:3112 having some evidence by way of
09:34imaging of myocardial involvement.
09:37By inflammation.
09:39Again, terribly alarming,
09:41but important to note that all of
09:43this is contingent on imaging studies
09:45and their ability to accurately
09:47reflect what is histopathologically
09:49happening in the heart.
09:50And that's a big if.
09:52That's a big jump there.
09:54So of course the local
09:56media stations picked up on
09:58this and national media stations were far
10:02behind and they ran with these stories
10:05and they were alarmist to say the least.
10:08It wasn't just a left-leaning outsources
10:10as well, but right wing sources or right
10:14leaning sources as well discussed the
10:17potential concern for these studies
10:18or that these studies were telling
10:21us that COVID-19 really is targeting
10:23the heart muscle and in some cases.
10:25In many cases, and is going to be
10:27causing this outbreak or this epidemic,
10:29the secondary epidemic of heart
10:32disease henceforth.
10:33Well, at this time,
10:35those of us who were somewhat
10:37familiar with the imaging literature
10:39and its correlation or lack thereof
10:41with histopathology decided that it
10:43was probably prudent to put out an
10:46editorial trying to slow this down
10:47a little bit and trying to tell
10:49people to hold their horses.
10:50And really we need to better understand
10:53what's going on from a pathology standpoint.
10:55Again, kind of dragging the
10:57narrative from the radiology side,
10:59putting it back on pathology,
11:00saying there's still a role for
11:01pathology here to tell us what
11:03is going on at the tissue.
11:04Level and how the virus is interacting
11:06with the tissue and may or may not
11:08be associated with inflammation.
11:09So we basically put out this editorial
11:12in the hopes of stimulating much
11:14more research and much more focus and
11:18attention on what COVID-19 effects
11:20were from the pathologic basis.
11:22Fortunately,
11:22the Society for Cardiovascular
11:24Pathology served as an excellent
11:26conduit to Marshall an international
11:28team together that could put the
11:30initial cases of COVID-19 autopsies
11:32that they had received together.
11:34And start looking at them in
11:36a systematic and careful way.
11:38And so 21 of the initial COVID-19 autopsies,
11:42which include some of the initial
11:43autopsies that were done in Italy
11:45through the University of Patawa,
11:47characterized and evaluated these
11:49myocardial samplings,
11:50extensively sampled heart tissue
11:52for myocarditis, non myocarditis,
11:54myositis systemic injury,
11:56which is of course part and parcel
11:58to many cases of COVID-19 disease.
11:59Patients enter into respiratory failure.
12:02They obviously have all kinds of
12:04supply demand issues that can
12:05incite that type of injury,
12:07pericarditis, pericardial injury.
12:08As well as vasculitis and vascular injury.
12:12What was found was that about 17% of people
12:15did indeed have myocardial inflammation.
12:18If you carefully and
12:19extensively sampled for such.
12:21And when I say carefully and extensively,
12:23we're talking upwards of 25 to 30
12:25samples of myocardium that you're
12:27pouring over looking for these foci.
12:29And in the vast majority of these cases,
12:31about 80% of those 717%.
12:35So black,
12:36actually 2/3 of that number had
12:38very focal myocardial inflammation,
12:40so very, very spotty.
12:42Inflammation nowhere near the type
12:44that you would expect to see by way of
12:47imaging and then that was reported in
12:48those initial reports by way of CMR.
12:50So this certainly dragged those
12:52numbers down quite a bit.
12:54You had to look at a lot of
12:55myocardium to even find a little bit.
12:57And very,
12:58very few cases had striking
13:00and florid types
13:02of myocarditis. A number of other
13:05pathologies were also identified.
13:06Macrophage infiltration into the
13:08interstitium was kind of a curious
13:10finding that really was not known.
13:12To exist in other viral types of infections.
13:14So that seemed to be a
13:16somewhat unique finding.
13:17And then this other finding of small
13:19vessel thrombosis seemed to be coming
13:21up more frequently than we saw with
13:23other types of virally mediated
13:25myocarditis such as influenza,
13:26Coxsackie and adenovirus of course.
13:29So we decided to take a closer look
13:31at that small vessel thrombi issue
13:33and lo and behold, there were many,
13:36many cases of this small vessel
13:38micro occlusive disease,
13:40these small shallow thrombi,
13:41some of which were.
13:42Use of some of which were not
13:44in these cases of COVID-19 and
13:46that was elevated above all other
13:48types of viral myocarditis that we
13:49had in our registry at the time.
13:51So this did seem to be a unique
13:53feature and comported with the
13:55fact that some of the binding
13:57proteins we know to be expressed in
13:59at high levels in in endothelium.
14:02And so there was long held this
14:05idea that COVID-19 was going to be
14:08targeting the endothelium and certainly
14:10this bears that out to some extent.
14:12Now of course over the the
14:14the next few months many,
14:16many more studies would start
14:17to look at cases of myocarditis.
14:20And so here are three examples of
14:22cases that had pretty rigorous
14:24pathologic evaluation looking for
14:26myocarditis in the setting of COVID as well.
14:29And the the long and short of it is the,
14:32the,
14:32the take home message here is that
14:34when you look at all of these
14:37pathology studies in composite only
14:38about 1 to 5% show myocarditis to
14:40any appreciable degree in the vast
14:43majority of these being quite mild.
14:45As you can see 80% of these cases
14:47the myocarditis was only micro
14:49focal in the myocardium.
14:51So it's really unlikely that
14:54COVID-19 is causing this outbreak,
14:56this rash outbreak of myocarditis.
15:00As was being described originally
15:02in the media, however,
15:03with the ubiquity of COVID-19,
15:05certainly even this one to 5%
15:07number can pretty place a pretty
15:09significant burden on the healthcare
15:11system by way of myocarditis,
15:13even if 80% are mild because
15:15the denominator is so high
15:16of people being affected.
15:18So it's not an insignificant issue,
15:20it's still one we absolutely
15:21have to be mindful of.
15:24When you know, we wanted to be careful
15:26when this data was initially coming
15:28out kind of tempering those relatively
15:30low numbers with the fact that the
15:32the denominators were still high.
15:34So this mattered.
15:35And of course there were a lot
15:36of folks at the time saying
15:38that we needed to be worrisome,
15:39worried as well because the COVID-19
15:42vaccine of course was also has had
15:45also shown to have some association
15:48with myocarditis in some series.
15:50And so here are three of which that are
15:53all describing myocarditis following.
15:56COVID-19 vaccination.
15:59Fortunately the the literature has
16:01really filled out over the last few
16:03months on this vaccine related issue.
16:05And when you look at it in its totality,
16:07it shows somewhere on the order of
16:10five to 12/5 to 13 or so cases per
16:131,000,000 vaccinated individuals,
16:14a rate far lower than that that you see
16:17with COVID-19 associated myocarditis.
16:20Again, especially because of the
16:23ubiquity of COVID-19 infections,
16:25men were certainly at a higher rate
16:27in most of these series and nearly.
16:29All of these cases,
16:30this is the really important take home point,
16:32nearly all of them had complete resolution.
16:35This stands in stark contradiction to
16:37what we see with COVID-19 associated
16:39myocarditis where the Florida examples
16:42are almost invariably associated with some
16:45compromise in long term cardiac function.
16:47So these cases that have been
16:49reported related to vaccine,
16:50almost all of them are mild,
16:52almost all of them resolved and
16:54almost and virtually none of
16:56them had long term sequella.
16:58So the bottom line here.
17:00Is that it's 100 times more common
17:02to get myocarditis associated
17:04with active COVID-19 infection?
17:06And it tends to be associated with
17:08some degree of myocardial change
17:10either by way of imaging or by
17:12cardiac function about half the time.
17:14So there's really no question here when
17:17you stack up the the risk benefits of
17:21vaccine over active infection with COVID-19.
17:24So we come back to our index case
17:26despite the relatively low risk of
17:30having vaccine associated myocarditis.
17:32This did appear to be an excellent
17:34example of vaccine associated myocarditis
17:36because of the strong temporal
17:39relationship between development of symptoms,
17:41the clear histopathology in this case
17:44and the temporal relationship obviously
17:47to the vaccine active myocarditis.
17:49But the good news is that the literature
17:52is quite clear on the fact that.
17:54These people do not appear to have
17:57long-term sequella associated with these,
17:59so prognostically this is a very good
18:02indication. So that's diagnosed.
18:04This case was signed out as active mixed
18:08lymphocytic escena philic myocarditis
18:10associated with the recent vaccination.
18:13All right.
18:14We're going to change gears a little
18:15bit and talk about a different topic,
18:17one of cardiac tumors,
18:19heart tumors and specifically we're
18:21going to talk about some of the
18:24changes that we've seen in the last
18:26couple of years come from the W,
18:28the New W Joe classification.
18:30To kick this off,
18:31we'll again do so by way of vignette.
18:33The case is that of a 43 year old woman
18:35who presented with recurrent ventricular
18:38tachycardia causing syncopal episodes.
18:40She was found to have a 5
18:42centimeter mass involving her.
18:43Left ventricular free wall and you
18:44can see it down there at the apex.
18:46She was subsequently referred to surgical
18:49resection for this symptomatic mass.
18:51Obviously a mass down there at the apex.
18:53Pretty well circumscribed
18:55tan white in appearance.
18:57Here it is the surgical resection
18:59cut along its short axis,
19:01somewhat homogeneous, tan,
19:03yellow in appearance.
19:05Not a lot of variability as
19:07we look through the tissue.
19:09Under the microscope, what do we see?
19:11Well, we see kind of an
19:12amalgamation of things, right.
19:13There's probably some
19:14cardiac muscle down there.
19:16There's certainly big blood
19:17vessels running through it,
19:18lots of collagen and fibrosis.
19:20So we take a closer look.
19:22What we see are these peculiar bundles
19:24of smooth muscle that inner are
19:26interposed between these very enlarged,
19:29very atypical cardiac myocytes,
19:31blood vessels,
19:31the occasional nerve running through it,
19:34just kind of a a random or
19:37motley assortment of tissue.
19:39Presenting as a mass in the free
19:41wall of the left ventricle.
19:43So anytime we see a cardiac mask,
19:45it probably behooves us to at least
19:47have in our mind what the general
19:49epidemiology of these cardiac masses.
19:50It helps us narrow our differential,
19:52helps us triage the tissue,
19:54how we're going to be handle it.
19:55And the important point here is
19:57to understand that the vast,
19:59vast, vast majority,
20:00majority of masses that arise in the heart.
20:04Are the result of progression of
20:06metastatic cancer metastatic disease.
20:08So the first question on your mind
20:10whenever presented with a heart
20:11tumor should really be what is the
20:13patient's oncologic history because
20:14that conclude you into the diagnosis
20:16of vast majority of the time.
20:18So more on the order of four to 8% of
20:21stage 4 malignancies involve the heart.
20:23That's an incredibly high percentage
20:24given the burden of high stage
20:26oncologic disease in our population.
20:28So this is something you're going to see,
20:30you're going to see metastatic disease
20:32with some regularity in all of course.
20:34Are definitionally malignant.
20:35Primary heart tumors obviously can be
20:38dichotomized into either benign or malignant.
20:41And if we were to just take a
20:42look at that sliver and ask what
20:44percentage are benign or malignant,
20:45well turns out that the benign outnumber the
20:48malignant primary cardiac tumors about 12:50.
20:50So if you have a benign cardiac tumor,
20:52you're weight primary cardiac tumor.
20:56If you have a primary heart cardiac tumor,
20:57you are more than likely
21:00to have a benign neoplasm.
21:02With that said,
21:02just because it is histologically benign
21:04does not mean that it will be clinically.
21:06Tonight the heart,
21:07as we'll see in a few slides,
21:09is an incredibly precarious
21:10location for tumors to arise,
21:12and it's an incredibly
21:13sensitive place to occupy space.
21:15It has access to the systemic blood
21:18supply so dangerous sequella can
21:20happen even from benign processes,
21:22as we'll see.
21:23The malignant tumors are obviously
21:25all problematic for their propensity
21:26to not only do all the things
21:28benign tumors can do,
21:30but they also invade and progress as they go.
21:33So with respect to the metastatic tumors,
21:35why do we see such a high burden of
21:38metastatic disease to the heart?
21:39Well,
21:39there's lots of different ways
21:41that metastatic tumors can travel
21:43to involve the heart.
21:44And the tumors that we see getting
21:46there are things that obviously,
21:48sensibly common sense actually are
21:50from epithelial tumors that arise in
21:52the neighboring structures and organs.
21:55Breast cancer, lung cancer,
21:57esophageal cancer,
21:58all the neighboring organs to the heart can
22:00potentially infiltrate in and invade the
22:02heart via a number of different mechanisms.
22:04Melanoma is a kind of a curious example,
22:06though. It takes the lion's share of tumors
22:09when we're looking at specific types,
22:11obviously, and it, for peculiar reasons,
22:14is intensely cardio atropic.
22:16About half of the metastatic lesions
22:18we see that the heart are from Melanoma
22:19and in some cases it can be a cult.
22:21It's one of the few places we can see a
22:24cult presentation of malignant Melanoma.
22:27So uveal Melanoma, subungual melanomas,
22:30even rectal melanomas have all been reported
22:32metastasizing to the heart and 1st.
22:34Showing symptoms because of their
22:36cardiac involvement because of the
22:38occult primary site.
22:39They get their via four primary ways.
22:42Those four primary routes include
22:43direct extension like this example
22:45of a lung cancer eating its way not
22:47only through the lung prank comma,
22:49but into the mediastinum,
22:50through the pericardium and into
22:52the anterior heart muscle.
22:53As you see here,
22:55hematogenous seeding can occur,
22:56obviously the hearts receiving the
22:59entire body's systemics return and
23:01then putting blood all the way
23:03out into the systemic circuit.
23:05So it's going to be seeing all the
23:06blood that runs through our body,
23:08any tumor cells that are traveling
23:09through that.
23:09But have the potential of seeding in
23:12the heart and growing there and so
23:14you can get these cannonball type
23:17lesions from hematogenous spread
23:19of epithelial malignancies.
23:21Here's another example of this case
23:23of metastatic malignant Melanoma,
23:25obvious because of the dark brown
23:27pigmentation of the numerous tumor
23:29deposits depositing not only within
23:31the endocardium,
23:32myocardium and epicardium kind
23:33of all three layers there,
23:34but also existing as tumor thrombus
23:36that you can visualize up here in
23:38the right ventricular outflow tract,
23:40obstructing outflow of the right
23:42ventricle into the pulmonary artery
23:44and mechanistically explaining this
23:46patient's death in this instance.
23:48Lymphatics are also a mechanism
23:49or a mechanistic route that tumors
23:51can use to involve the heart.
23:53The heart has a relatively extensive
23:55lymphatic lymphatic plexus that
23:57runs through the pericardium.
23:58Plugging of those lymphatics can cause
24:01profound and pronounced pericardial
24:02effusions like in this example,
24:04and you can see the lymphatic drainage
24:06on the epicardial surface or the
24:08visceral pericardial surface of the
24:10heart presenting this kind of fuzzy
24:12bordered pericardial appearance
24:13because of all the infiltration
24:15by tumor of those lymphatics.
24:18Intraluminal extension is kind of a
24:20unique way of metastatic malignancies
24:22can involve the heart muscle.
24:24Take for instance this example
24:25of renal cell carcinoma,
24:27clear cell renal cell carcinoma arising
24:29in the inferior pole of the left kidney,
24:31there coming up into the renal vein,
24:34across into the IVC,
24:35then up to involve the heart and
24:37sure enough there it exists like
24:39a serpent coming through the IVC
24:41into the right ventricle where it
24:42can then obstruct again the right
24:44ventricular outflow tract and cause
24:46what would clinically manifest.
24:48Has a large saddle and saddle
24:50pulmonary embolus.
24:53So with respect to cardiac tumors,
24:55we've seen a number of changes
24:57over the last decade or so.
24:59The 2015 classification was a relatively
25:01truncated list of tumors that you see
25:04here that over the next six years
25:06would expand in the literature and
25:08cause The Who to update and revise,
25:11adding to a number of lesions,
25:14adding the number of lesions to this
25:16list rather as well as updating
25:18some of our understanding of the
25:20pathobiology and the treatment
25:21of the other cardiac tumors.
25:23Existed.
25:23The tumors that are shown here in green
25:26are ones that have seen such updates.
25:28There's been an important updates
25:29in terms of our diagnosis,
25:31how we make our diagnosis,
25:32some important new stains,
25:34some new nomenclature in some instances,
25:37as well as the treatment.
25:38And then the red Allegion shown in red
25:41here represent new lesions that are newly
25:44described in this 2021 classification.
25:47I'm going to take you through just a few
25:49of the updates that have been seen here.
25:51We'll start with some of the green
25:53ones and then we'll get into some
25:54of the new entities as well.
25:56One of the the lesions that have
25:58seen some important updates in our
26:00understanding is the so-called
26:02papillary fibroelastoma.
26:03This is a tumor that's long been recognized.
26:05We've first recognized these in
26:07the early 1900s.
26:08So it's no news that we're seeing them,
26:10but our understanding of them has
26:12seen some really remarkable advances
26:14over the last five and six years
26:16that have been introduced.
26:17Largely by the increasing use
26:19of digital droplet PCR,
26:21enabling us to look at very posse
26:25cellular specimens in a very detailed way.
26:28The posse cellularity of these
26:29specimens has long precluded us from
26:31understanding the molecular biology.
26:32But because of these newer technologies,
26:34we now understand that they do
26:37actually harbor oncogenic drivers
26:39and so simply aren't only explained
26:41by reactive and athelia processes
26:43that happen in the heart.
26:45We also understand because of
26:46advances in imaging that these are
26:48way more common than cardiac myxoma.
26:49So the dictum long held the cardiac
26:51myxomas where the most common primary
26:53cardiac tumor not so papillary
26:55fibroelastoma is are now recognized
26:57to be the most common as they're seen
26:59twice as commonly as cardiac myxomas.
27:02And again that that advance was
27:04made possible because of our better
27:06imaging technology and our better
27:07understanding that these two should
27:09be considered in the same neoplastic
27:11paradigm that cardiac myxomas are.
27:14They tend to arise on cardiac valves,
27:15most commonly the closing surfaces,
27:17but they're not restricted to such.
27:19They can happen on any endocardium
27:21line surface.
27:21They're typically incidental,
27:23but they can occasionally be
27:24associated with symptoms because
27:26the tumor itself can embolize.
27:27You can envision those little
27:29papillary fronds breaking off
27:30and embolizing downstream.
27:32Or there can be adherent surface
27:33thrombus like you see down here,
27:35this red tissue in its core,
27:37a little mitoses of thrombi that
27:39can come off and then embolize
27:41downstream and potentially cause.
27:43Rather devastating.
27:44Sequela,
27:45limit schemonia,
27:46CNS events, Tia or strokes,
27:48even heart attacks.
27:49In some instances they're said to have
27:52C anemone or ponpon like appearance,
27:55and a couple of examples
27:56of those are shown here.
27:57I happen to really like photographing
28:00of these particular tumors.
28:01I think they're they're incredibly
28:03photogenic, rather beautiful.
28:03They look like little flowers or little
28:06daisies in a field to me and again you.
28:08I think you can understand why
28:09they have this sea anemone type
28:10appearance or ponpon appearance.
28:12They look like little buzzy shrubs.
28:13Almost growing off of valves now,
28:15sometimes when you get these at the
28:17grossing bench or when a surgeon
28:18encounters one of these at the time
28:20of surgery that was unbeknownst
28:21to them before they went in,
28:23they'll sometimes mistake them for
28:25myxomas and the reason being is shown here.
28:28When they're taken out of an aqueous medium,
28:30they tend to collapse all on themselves
28:32and they look like little myxoid
28:34masses or little solid masses that
28:35are sitting there in the heart or
28:37sitting there on the grossing bench.
28:39The trick is to take them and put
28:41them in formal and water or alcohol.
28:42And when you do so,
28:43all those papillary fronds come
28:45out and you see the nice little
28:47pom pom like nature of these.
28:48And so it's really,
28:49that can be an incredibly helpful clue.
28:52If you get a little myxoid
28:53bulgary looking thing,
28:54you just drop it in a cup of formalin,
28:57shake it up a little bit and
28:58if you see these.
28:58Well, papillary fronds unfurl.
29:00You have the diagnosis even before
29:03you put it underneath the microscope.
29:06Now I mentioned that the heart is
29:08a precarious place for tumors to
29:09arise and nowhere is that more
29:11evident than in this slide on the
29:13left here we have an echocardiogram
29:14showing a papillary fibroelastoma
29:16arising on an aortic valve cusp.
29:18And then you can see on the right
29:20side the gross correlate to that
29:22echocardiogram that nicely shows the
29:24proximity of that papillary fibroelastoma
29:26to the right coronary ostium.
29:28It doesn't take a lot of imagination
29:30to picture piece of that tumor or a
29:32piece of adherent thrombus breaking off
29:34and then having ready access to the right.
29:36Coronary ostium,
29:37where it could embolize down and
29:38potentially cause a fatal heart attack.
29:42They do have a propensity or
29:45are commonly seen arising from
29:48damaged endocardial surfaces.
29:50This really led to the original
29:52hypothesis that these were the
29:54result of a reactive phenomenon.
29:56The two situations where we commonly
29:57will see them is in the setting of
30:00post inflammatory valvulopathy,
30:01like this example of post traumatic
30:03valve disease as shown over here
30:04on the left side of the slide.
30:06The other time we see them is when the
30:08heart has been surgically intervened upon.
30:09This example over here on the
30:11right is a younger woman.
30:12Who had undergone a subaortic septal
30:15myectomy procedure to palliate
30:17her hypertrophic cardiomyopathy.
30:18About three years after she
30:20had that procedure,
30:21she presented with aphasia
30:23and difficulty walking.
30:25An echocardiogram and scan of
30:26her brain revealed that indeed,
30:28she not only had a stroke,
30:29but also appeared to have one or
30:32more papillary fibroelastoma is
30:34growing in the region of resection
30:36along the subaortic septal myectomy.
30:38The surgeon went in to remove these out
30:41they she kept having strokes despite
30:43and TI's despite anticoagulation.
30:45When the surgeon engaged the left
30:47ventricular outflow tract and
30:48looked at the prior resection site,
30:50he said that it looked like a ****
30:52carpet in there and again you can kind
30:53of see why it looks like a flyfisherman.
30:55I spilled this tackle box onto the table.
30:5752 discrete papillary fibroelastoma
30:59were resected from the left ventricular
31:02outflow tract that day and again
31:04it was all along that previous
31:07region of damaged endocardium.
31:08All right.
31:09The next tumor is the cardiac myxoma.
31:12The prefix mixer coming from the Greek,
31:14meaning mucousy or slimy.
31:16And I can think of no better image to
31:18illustrate that than this one shown here.
31:20My daughter when she was four years old,
31:23whenever she would see this
31:24picture on my laptop,
31:24she would say daddy's looking
31:26at his heart booger again.
31:27And I think that's an incredibly
31:29appropriate and APT description
31:30of this tumor because it does.
31:32It looks mucousy or slimy,
31:33and that's why they have this name.
31:34They're benign.
31:35They are not malignant,
31:37nor do they undergo malignant degeneration.
31:38They have no malignant potential prior
31:40reports of myxomas that have undergone.
31:43Malignant degeneration,
31:44in hindsight,
31:44probably just represent denovo
31:46malignancies and myxoid sarcomas
31:48that were unrecognized at the time.
31:50They most commonly arise in
31:52the hearts left atrium,
31:53but they've been described
31:54in any Chamber of the heart.
31:56They're said to be a primitive
31:58multipotential mesenchymal origin,
31:59which is of course an incredibly fancy way,
32:00as you all know of saying we have no
32:02idea where these things are coming from.
32:03Probably cardiac stem cells are
32:05somewhere in in the in the heart.
32:07That's not heart muscle.
32:09About 5% of these are associated
32:12with so-called syndrome myxoma or
32:13the Carney complex and we'll talk a
32:15little bit more about that in just a moment.
32:18But they can also obstruct an embolize
32:20just like we saw with other heart tumors.
32:22Obstruction obviously is a
32:23pretty easy thing to think about.
32:24We'll talk about that in a second.
32:26Embolization can occur particularly
32:27when the myxomas have a phenotype
32:30that's more friable or crumbly.
32:32You can see this image on the bottom where
32:34it has a more villiform type architecture.
32:36You can again in envision pretty easily
32:38how that tumor is it's beating around.
32:40In the cardiac cycle could potentially
32:42break off an embolize downstream
32:44obstruction obviously comes from large
32:46myxomas or myxomas that occupy space.
32:49Here's an example of such and
32:50if you have your phone available
32:51you can point it at the QR code.
32:53This is a technology we've been
32:55working on perfecting at Mayo over
32:57the last couple of years called
32:59photogrammetry of specimens and we've
33:01taken our several 1000 cases that
33:03are in our museum collection and we
33:05we're working on scanning those into
33:07a digital database that allows you
33:08to interact with the gross specimen.
33:10In the old days,
33:11obviously you could carry buckets
33:12to conferences and everybody could
33:13Don gloves or or not in some cases
33:15and fish things out of a bucket and
33:17look at them and get a good feel
33:18for the gross pathology.
33:20That's obviously frowned on today
33:21for a whole variety of reasons.
33:23This is the next best thing though.
33:24This allows you to interact
33:25with the organ on your phone,
33:26you can spin it around,
33:27you can zoom into things and you can
33:29see in this case a large left atrial
33:32tumor and quite easily how it can fall
33:34down and ball valve over that mitral
33:36valve orifice and obstruct flow from
33:38the left atrium into the left ventricle.
33:43Underneath the microscope,
33:44the lesional cell that we're looking
33:46for to seal the diagnosis is the
33:48so-called myxoma or lipidic cell.
33:50These cells occur singly or in
33:52small clusters, small cords,
33:53a little groups or little little
33:56tumor giant cells as can be seen here.
33:58They're bland, they're often spindle shaped,
34:00they can be multi nucleated as you see there.
34:03The curious thing about these and one
34:05of the differentiating properties
34:06that you can use to separate them
34:08from fibroblasts is the fact that
34:10they tend to ring up around small
34:11intratumoral vessels like you see here.
34:14On the right sided photomicrograph,
34:16the tumor cells are all kind of holding
34:18hands around a small capillary and
34:19that's exactly what these things do.
34:20These little nascent vessels kind of
34:23form and it's unclear what role the
34:25maxima cells play in forming those,
34:27those, those, those blood vessels.
34:29Some people have hypothesized that
34:30they're part in part responsible for
34:32those intratumoral blood vessels,
34:33but they can break and hemorrhage into
34:36the tumor as the tumor is beating about
34:38in cosmics almost to start rapidly
34:40increasing in size in some instance.
34:43We mentioned that about 5% of
34:45cardiac maximas were associated
34:46with the so-called Carney complex,
34:48so named for Doctor Aiden Carney who
34:51while well into his 90s at this point
34:53is still an active pathologist who
34:55comes to work every day at Mayo Clinic.
34:57He lives in a building attached,
34:59so he's able to come no matter
35:01what the weather is and he's an
35:03absolute force of nature.
35:04He is a an inspiration to all of us I
35:07think his ability to put things together to
35:10problem solve and to kind of sort through.
35:13Puzzles,
35:13diagnostic puzzles,
35:14is unlike anybody else I've ever met.
35:16And so I always try to give him
35:18credit for the amazing work that
35:20he's done over the decades and the
35:23amazing patterns that he recognized.
35:25And one of those patterns was
35:26the Carney complex,
35:27this peculiar association of these
35:30heart tumors. Endocrinopathies.
35:31Things like Cushing syndromes,
35:33thyroid problems,
35:34things of that nature and skin.
35:36Lentigo noses on the skin.
35:39Lentigo noses are unusual in that
35:41the freckling occurs about the
35:43Vermilion border of the lips,
35:44where the lips interface with
35:46the rest of the the face.
35:49That's an unusual place to have freckling,
35:51even if you're a a freckled person.
35:53But be freckled person.
35:54And so if you see freckling of
35:55the mucus membranes are about the
35:57Vermilion border of the lips,
35:58a syndromic context should should
36:00come to mind,
36:01or should prompt you to at
36:03least consider that.
36:04Carney complex is has now been
36:06established to be the result
36:08of underlying mutations in the
36:101A regulatory subunit of the
36:12protein kinase A or PRK R1A gene.
36:15And that has played an important
36:17role diagnostically in us being able
36:19to separate out myxomas that are
36:21associated with Carney complex from
36:23those that are indeed nonsyndromic.
36:25It's important to do so because the
36:27recurrence rate is obviously higher
36:28for people who carry the syndrome,
36:30but there's also familial implications.
36:32So first degree relatives need to be
36:34screened for underlying Carney complex
36:36when an index case is identified.
36:38Another important clue to the fact that
36:40you might be dealing with the Carney
36:42complex is a non left atrial myxoma.
36:44While let Carney complex myxomas
36:46are most commonly left atrial,
36:48if you have a non left atrial myxoma it is
36:50far more likely to be in a syndromic context.
36:53So if you see a myxoma coming from
36:55anywhere other than the left atrium,
36:57you should definitely look into
36:58the patient's history and consider
37:00a diagnosis of Carney complex.
37:02Now how can we as pathologists render a
37:04diagnosis of Carney complex or suggest
37:06that tactfully other than saying look more?
37:08Carefully at your patient,
37:09look at the freckling and those
37:10type of things.
37:11Well an immunohistochemical stain has come
37:13to the fore over the last several years
37:16that really helps carry the way there.
37:19So looking for protein expression of PR KR1A,
37:22no patient with Carney complex will
37:25exhibit retained expression of PR KR1A.
37:28They all have a lesional cell loss.
37:30Fortunately because these things
37:32are clonal obviously and result
37:34from biallelic PR KR1A loss,
37:36you get nice background inflammation that.
37:38Stains with the PRK R1A protein,
37:41but the neoplastic cells themselves
37:43will be absent expression.
37:45PR KR1A loss can be seen by allelic
37:47loss can be seen in sporadic myxoma.
37:49So it's not definitive for a diagnosis
37:52of Carney complex but you can
37:54essentially exclude it if you have
37:57positive PR KR1A standard staining,
37:58you don't have to worry about
38:00Carney complex in those individuals.
38:02So that was another update to these tumors.
38:05Another tumor that was updated was that
38:08cardiac undifferentiated pleomorphic sarcoma.
38:10This is the most common cardiac sarcoma
38:13that we see arising in the heart.
38:16They tend to arise in the left atrium
38:18and are referred to in some literature
38:21as intimal sarcomas of the heart.
38:23The term intimal sarcoma itself
38:26was really basically put out there
38:28because of the relationship these
38:31have with pulmonary artery in table
38:33sarcomas in that they both are shown
38:36to exhibit MDM 2 amplification.
38:38Now of course that is not
38:40a lineage specific marker.
38:41MDM 2 amplification is seen in a host
38:44of neoplasms aside from INTIMAL.
38:46Sarcomas and these undifferentiated
38:47tumors can be seen in liposarcomas and
38:49in a whole variety of other things as well.
38:51So being that it's not lineage specific,
38:53The Who recognized that and basically
38:55lumped all of these into undifferentiated
38:58pleomorphic tumors rather than calling
39:00intimal sarcomas of the heart.
39:03Also important to note that the heart
39:05technically doesn't have an intima.
39:06It has an endocardium which while
39:09contiguous with the vascular intima
39:11is biologically distinct.
39:13The survival of this tumor,
39:14regardless of what you call it is.
39:164.
39:18Cardiac angiosarcoma,
39:19as these are also persist in The Who,
39:22they haven't seen much in the way of
39:24updates other than basically there
39:26hasn't been many updates with them.
39:27Recurrent molecular genetic findings
39:29had not been seen.
39:30They remained the most common
39:32cardiac sarcoma that exhibits some
39:34specific lineage of differentiation,
39:35specifically that of endothelium.
39:38It consists of malignant endothelial cells.
39:41Obviously it takes on all the
39:42morphologies that we can see arising.
39:44In extra cardiovascular places,
39:46we can see epithelioid angiosarcoma.
39:48Spindle cell angiosarcoma as
39:50the whole diagnostic range.
39:52Bright contrast is seen on imaging,
39:54which often helps our imaging
39:56colleagues to identify and diagnose
39:58these prior to tissue being taken.
40:00They tend to occur in many young men.
40:02Dramatic presentations can occur.
40:03One of the more unfortunate cases
40:06I've seen over the years was on a
40:08Christmas Eve 26 year old expected
40:10father presented with a single
40:12bad syncopal episode and was found
40:14to have a hemorrhagic pericardial
40:16effusion that harbored angiosarcoma.
40:19Cells in it.
40:19It was just a awful and devastating
40:21story because these affect
40:22young people in their prime.
40:24They're incredibly sad.
40:25There's very little that
40:26can be done for them.
40:27Cardiac transplant is obviously
40:29difficult because immunosuppression in
40:30the face of an aggressive malignancy
40:32is never an optimal solution.
40:34And radiotherapy is virtually off the
40:36table because of how sensitive the
40:39heart is to external beam radiation.
40:41A number of molecular genetic findings
40:44have been described in Angiosarcoma's today,
40:46but important as I mentioned up top,
40:48none are recurrent and none are diagnostic.
40:51None have really been shown to
40:52have much in the way of prognostic
40:54significance other than the fact
40:55that some trisomies have shown
40:57some increased survival,
40:58but we're talking on the
40:59order of weeks there,
41:00which aren't clinically
41:02a significant finding.
41:05Conduction system hamartoma represents
41:06another update that The Who has provided.
41:09This is an update to the condition
41:11that has been formally referred
41:12to as histiocytic cardiomyopathy.
41:13These are hamartomatous proliferations of
41:16Purkinje cells or the cells conduction
41:18or the hearts conduction apparatus.
41:20The proliferation of those Purkinje
41:22cells which are located in the
41:24endocardium can make the heart
41:26have a hyper trabeculated or non
41:28compacted type of appearance.
41:29They can grow all through the
41:30heart muscle and even up and onto
41:32the surface of the valves.
41:34These are recognized to be associated with.
41:36NU FB.
41:3611 mutations and the name was changed
41:38from CARDIOMYOPATHIES because they
41:40aren't in fact a cardiomyopathy,
41:42but rather a clonal proliferation
41:45of these Purkinje cells.
41:47Most individuals with these
41:49are present in childhood.
41:51Unfortunately,
41:51about a fifth of them present with
41:53sudden infant Death syndrome,
41:54which again highlights the importance
41:57for investigative work and autopsy work.
41:59In looking at these cases of
42:01sudden infant death syndrome,
42:03identifying germline FDU FB11 mutations
42:06is obviously a critical thing.
42:09Another new and new entity that
42:11was described and entered into
42:13The Who as the so-called hamartoma
42:15of mature cardiac myocytes.
42:17These are somewhat curious lesions that
42:20present as somewhat poorly circumscribed
42:22yellow tan lesions in the myocardium.
42:25They can make the myocardium
42:26look asymmetrically thick and so
42:28they're often the lesion is often
42:30confused with other conditions
42:31that cause asymmetric thickening,
42:33like genetic heart muscle disease
42:35or hypertrophic cardiomyopathy.
42:37The lesions themselves consist of a kind of.
42:39Unusual collection of cardiac
42:41myocytes that are absolutely huge.
42:43How huge you might ask?
42:44Well, these were taken at
42:46the same magnification.
42:47One on the bottom is the normal
42:48myocardium that's adjacent to
42:49this lesion and the heart muscle.
42:51Myocytes that are taken within the
42:52lesion are shown above and you can
42:54see that they can be 10 to 15 times
42:56the size of normal cardiac myosin.
42:58It's like elephant myocardium
42:59occurring in the heart muscle.
43:01It is not electrically contiguous
43:02with the rest of the heart.
43:04So these do appear to be somewhat
43:06tumoral in nature and can obstruct and
43:08cause all kinds of nasty complications.
43:10There are a few other hammer
43:12Tomas that we're also mentioned,
43:13the so-called lipomatous hamartoma
43:14at the AV valves,
43:15fat fatty deposits or like Puma
43:17like lesions in the AV valves.
43:19And then the so-called mesenchymal hammer,
43:21cardiac hammer Toma which consists
43:22of an amalgamation of different
43:24tissues occurring in the heart,
43:26namely fat, collagen, blood vessels,
43:29nerves and bundles of smooth muscle.
43:32Does that sound familiar?
43:33Well,
43:34those are the things we saw at the
43:35top in our index case or our vignette.
43:37So this case, act two was indeed a case of.
43:41Amazonka, Amal. Cardiac hamartoma.
43:44All right, we've reached the third act.
43:47Cardiac amyloidosis.
43:48Our vignette to lead us into this
43:50final topic is a 73 year old woman
43:52with symptomatic aortic valve
43:54stenosis and chronic A-fib was
43:56undergoing aortic valve replacement.
43:57At the same time she underwent
43:59amputation of her left atrial
44:01appendage to prevent thrombosis and
44:03for appropriate bypass cannulation.
44:05Underneath the microscope we see a
44:07pretty normal appearing myocardium,
44:08but the interstitium does seem
44:09to be a little bit expanded.
44:10There's some acellular substance
44:11there in the interstitium.
44:13It's a little bit pale looking,
44:15could be collagen,
44:16could be something else special stain
44:18sulfated lesion Blues tends to stain.
44:20The Mucopolysaccharide matrix of amyloid,
44:22a seafoam green color certainly
44:24indicates that we might be
44:26dealing with cardiac amyloidosis.
44:28What is cardiac amyloidosis?
44:29Well,
44:30the term amylum amyloid itself comes
44:32from the Latin meaning starch amylum.
44:35It consists of a misfolded
44:37extracellular protein.
44:38When I say that it's misfolded,
44:39it's depositing as anti parallel
44:41beta pleated sheets in the cardiac
44:43interstitium in the extracellular
44:45space of any tissue,
44:46as it were ultra structurally
44:48those fibrils are somewhere on the
44:50order of 7 1/2 to 10 nanometers
44:51in size and are non branching,
44:53helping to separate them
44:54from collagen fibers.
44:56Importantly,
44:56because of that secondary structure
44:57of the beta pleated sheets,
44:59they can bind the intercalating
45:01dye Congo red,
45:03and when they do so they can buy refrige.
45:05With an apple green birefringence platter
45:07and as we'll see in a few moments.
45:09Likewise cross beta diffraction
45:10can be seen on X-ray diffraction
45:13spectroscopy and this is not
45:15a protein specific disease.
45:16In fact us humans make 31 proteins that
45:19are recognized to have a myogenic potential.
45:22All you need for a protein to have a myogenic
45:25potential is have that protein have the
45:27propensity to form these beta pleated sheets.
45:30So that can happen because of an
45:32intrinsic property of the protein,
45:33the proteins amino acid constituency.
45:35Naturally makes it want to do that.
45:37And in which case we can see the disease
45:39manifest with aging or when the proteins
45:41in high concentrations it can be the
45:43result of an underlying genetic mutation
45:44that changes the amino acid structure
45:46and makes it more amyloidogenic.
45:48And then of course we can have proteolytic
45:50remodeling of the precursor protein.
45:52So a post transcriptional process that
45:54makes the protein more likely to deposit
45:57in these beta pleated sheet configurations.
45:59Of the 31 types we recognized in humans,
46:0113 of them have been described
46:03as occurring in the heart.
46:05Despite that these top 2A TR&amp;L
46:08type transthyretin and light chain
46:10amyloid take the lion share.
46:1298% of cardiac amyloid is accounted
46:14for by these two protein types.
46:16It was long thought that light
46:18chain amyloid was the most common
46:19type that we see in the heart.
46:21But we now recognize because of better
46:23imaging modalities that assess for
46:25transthyretin amyloidosis more awareness of
46:27the condition and some detailed studies,
46:30some of which we've been working on
46:32at Mayo of older non selected autopsy
46:34material that a TTR amyloid is is
46:37actually far more common than the
46:39light chain variety and it increases as
46:41you get older in fact an individuals
46:44over 90 nearly or little more.
46:46And 1/3 of individuals will have
46:49cardiac amyloidosis.
46:51They'll have TTR amyloid within their heart.
46:55This obviously the the the other
46:57dictum that is been held over the
46:59years is that this was exclusively
47:01a disease among men,
47:02largely because our our screening
47:04bias has been toward the symptoms
47:06men exhibit with this type of heart
47:08disease and has ignored the symptoms
47:10women present with with this disease.
47:12When you carefully look for at
47:14the myocardium 4 amyloidosis,
47:16what you find is that there actually is not.
47:18This is not exclusively a disease of men,
47:21but women too are affected by this disease.
47:24Certainly there is a male.
47:25That election for the disease usually
47:272 to one when you look between
47:2970 and 90 for instance.
47:31But women do still get this
47:33disease and not insignificantly
47:34given how common the disease is,
47:36like we mentioned before.
47:38The properties of amyloid,
47:40as I discussed with the residents at
47:42our teaching conference this morning,
47:43do allow you to to at least get
47:45hints at it by light microscopy
47:47before you do special staining.
47:49Differentiating it from collagen
47:51can be difficult,
47:52but some of the differentiating features
47:53are that collagen tends to be more
47:56fibrillar and amyloid tends to crack.
47:57It creates linear cracks all through that
48:00homogeneous or glassy extracellular protein.
48:04Course special staining with Congo
48:06red intercalates that beta pleated
48:08sheet structure stains the tissue
48:09red and then when you put it between
48:11cross polarized light it will tend
48:13to manifest with a birefringent
48:14pattern that is often apple green
48:17or yellow green in colour.
48:18Other stains can be employed here.
48:20Congo red can be a technically
48:22challenging stand to do things like
48:23methyl Violet and sulfated El Shablu
48:25which we've already talked about can
48:26be very helpful in the heart because
48:28the amyloid protein stands out in such
48:31stark differential to the surrounding
48:32myocardium these stains are less.
48:34Hopeful in the kidney and the lung where
48:37there are the mucopolysaccharide that
48:38hangs around with amyloid is present as
48:41well normally and so you can get some
48:43loss of your specificity in those organs.
48:47None of the histologic patterns that
48:49we see with amyloid are sufficient to
48:51type them by way of light microscopy.
48:53Lots of different typing strategies have
48:55been employed over the years to figure
48:57out what protein is causal in these patients.
48:59Things like looking at the patient
49:00serum to get an understanding of
49:02whether or not they have free light
49:05chains has been employed, for instance.
49:06These are indirect measures of
49:08figuring out what the amyloid is.
49:09But because of the commonality of monoclonal
49:12gammopathy of undetermined significance,
49:14these do not always correlate
49:15with the amyloid type that we see.
49:17Lots of people out there who are in
49:19their 90s who have a gammopathy that's
49:22seemingly completely idiosyncratic and
49:24unrelated to the fact that they have
49:28potentially TTR amyloid underneath.
49:30Immunostains have long been used.
49:33Anybody who's tried to do immunostains
49:35to type amyloid can attest to
49:37the difficulty in doing so.
49:38Obviously on the pro side,
49:40we're all familiar with Immunostains
49:42from a diagnostic standpoint
49:43and as a rapid turnaround,
49:45we all have the equipment to do
49:46immunostains and most of our clinical labs.
49:48The problem is that if you're
49:49going to get really type specific,
49:51you kind of need large antibody
49:52panels for those rare cases,
49:54high,
49:54high background staining which causes
49:55you to look at a bunch of different
49:57stains and kind of say, well,
49:58I think this one might be staining more,
50:00not really sure.
50:01It's it's tough,
50:02and oftentimes there's kind of
50:03a wigi board involved in the
50:06interpretation of these things.
50:07So lots of papers out there that
50:09attest to how difficult this is.
50:11Enter mass spectrometry.
50:12This was a technology that was really
50:15pioneered by Mayo about a decade and 1/2 ago.
50:17Now it has the strength of being reliable
50:19and it's a direct measure of the protein.
50:21And so we can micro dissect out the tissue,
50:23send it through the mass spectrometer
50:25and get a very detailed report
50:27on the protein constituency of
50:29those laser microdissected areas.
50:30The problems, of course,
50:32is that it has limited availability.
50:33Really we're the,
50:34there's only two or three labs
50:36in the country that do this.
50:38And it has a higher cost obviously than any
50:40most chemistry or those types of things.
50:42The cost has been bending down now it's
50:44now well under $1000 in the turn around
50:46time is usually around a week or so.
50:48The way it's done is you look for areas of
50:50Congo red tissue on a plastic embedded slide,
50:53you micro dissector color in where
50:55all the Congo red tissue is.
50:56You tell the computer to fire a laser at it,
50:59the laser gets fired,
51:00the tissue that's Congo red positive melts,
51:02gets dropped into a dye that dies then
51:05proteolytically digested putting an
51:06spectrometer and you get a proteomic.
51:08Spectrum, that's compared to
51:09the Swiss Pro database,
51:10which tells you the proteins in
51:12highest abundance in that sample,
51:14one that's amyloidogenic that's in
51:16highest abundance is the causal protein.
51:18It's pretty simple in that regard.
51:19There's there is an art of
51:21course to the interpretation,
51:22but it's a pretty straightforward
51:25from a conceptual standpoint assay.
51:28On the horizon,
51:29digital pathology offers some new
51:31avenues for us to explore here.
51:33Take for instance,
51:34this technology of discrete frequency
51:36infrared spectroscopy that we've
51:37been playing with a lot as of late.
51:39This is a digital image analysis of an
51:42unstained section of tissue that we had,
51:45that we then assess using this discrete
51:48frequency infrared spectroscopy.
51:50The spectral shifts that are seen
51:51in different areas of the tissue
51:53allow the computer to very accurately
51:54predict the type of tissue that
51:55it's looking at in different areas.
51:57And in fact,
51:57we can tell the computer to do
51:58all kinds of things.
51:59That information,
52:00take for instance this deep faked HD
52:02that the computer has generated in
52:04relation to the spectral fingerprint
52:06that it got from that unstained section.
52:08We could do the same thing with
52:10immunohistochemical markers and we're
52:11trying to do the same thing with amyloid,
52:13for instance.
52:13Take for instance those areas in
52:15in the boxes there that actually
52:17have amyloid in them.
52:19We've shown now that those areas do
52:20have a different spectral property than
52:22collagen and other extracellular proteins.
52:25And so with a very high degree of accuracy,
52:27we can distinguish amyloid.
52:28From other types of tissue that
52:31are in the heart and make a
52:33diagnosis of amyloidosis based
52:35off of those spectral shifts.
52:37More to the point,
52:38we think that the technology has the
52:40potential to be so specific that
52:41can even speciate the protein that's
52:43present in the tissue there between
52:45the different types of amyloidogenic
52:47proteins and may afford us a new Ave.
52:49beyond mass spectrometry by which
52:51we can type amyloid.
52:53Amyloid deposits in the tissue and
52:55lots of different ways can deposit
52:57in big clumps and nodular aggregates
52:58like you see there in between the
53:00cells where it kind of strangles
53:01the myocytes,
53:02you can understand why it has the
53:04effect that it does on hard on
53:06heart filling and then in a vascular
53:07sense as well it can fill up the
53:09blood vessels and cause a schematic
53:11microvascular disease as well.
53:12The problem is all different types
53:13of amyloid can have all of these
53:15patterns and so again that histologic
53:17pattern is just not enough for us to
53:19usually get to a type specific diagnosis.
53:21There is however one.
53:23Notable exception and that's the
53:25type of amyloid that results
53:27from atrial natriuretic factor,
53:29the protein that the atrial
53:31myocytes naturally produce.
53:32It produces an amyloid that is
53:35morphologically distinct from
53:37run-of-the-mill TRL Amala.
53:38Take for instance this example
53:40where we had two different amyloids.
53:43He's an A&amp;F type amyloid on the right
53:45in the same part and you can start to
53:47appreciate some of the morphologic
53:49dissimilarities between them.
53:51The NF type amyloid is tends
53:53to be darker staining.
53:54Is to be more force,
53:55a little bit more cordlike and
53:57fibrillar than the A TTR amyloid.
53:59So NF type amyloid fortunately
54:01is something that we think we
54:03can pick up on just by its light
54:05microscopic appearance.
54:06And that's good because it turns out
54:08that the finding of ANF type amyloid
54:10does not come with the prognostic
54:12implications that other types of amyloid do.
54:14While it's more common in women,
54:15more common with older age,
54:17and more common in the setting
54:19of atrial fibrillation,
54:20it does not portend any difference
54:22in survival,
54:23any degree of disease.
54:24Recurrence in the form of Afib recurrence,
54:26any form of heart failure or
54:28anything like that.
54:28So if we see a NF type amyloid in the heart,
54:31we can basically write that
54:33off and not worry about it.
54:34And so not having the mass spec all of those,
54:36given how common this is seen in
54:38about half of atrial appendages,
54:39it's good that there's a feature
54:41that allows us to to pick that
54:42up and basically skirt it off to
54:44the side without incurring great
54:45costs on all of these cases.
54:47So back to our index case,
54:50this was the case again
54:51from the atrial appendage.
54:52I hope you'll note now that it
54:53has a bit of that course darkly
54:55staining character to it.
54:56And this is very indicative
54:57of a NF type amyloid.
54:59So given that morphologic appearance,
55:01we can make the diagnosis of isolated
55:04atrial amyloidosis of the A and appetite.
55:07So we've covered a lot of ground,
55:09a lot of disparate ground,
55:10lots of different topics this morning,
55:12all kind of with our common
55:14thread around heart disease,
55:15I guess more generically in our
55:17Valentine's Day theme, as it were.
55:19We talked about the cardiovascular
55:22implications of COVID-19,
55:23specifically from infection and
55:25vaccination and why the case for
55:27vaccination can clearly be made
55:29by the pathologic and imaging
55:31data that's out there.
55:32The new updates to the classification
55:34system for cardiac tumors as described
55:36by The Who and then some newer trends
55:39in the diagnosis of cardiac amyloid.
55:41I thank you all for this wonderful
55:43invitation and your very kind
55:45attention during this topic,
55:47which I recognize maybe foreign to
55:48many of you.
55:49So thank you very much.
55:54I would be remiss if I didn't also
55:57mention back at home my team of wonderful
55:59cardiovascular pathologists that I
56:01work with kind of a subdivision of
56:04a thoracic pathology at Mayo Clinic.
56:05These five individuals all
56:07do cardiac pathology with me,
56:08doctor Christine Aubrey, Andrew Lehman,
56:10Melanie Boys and in Chino.
56:12And without them none of what I talked
56:14about today would even be possible.
56:15So they are an amazing team of not just
56:18colleagues, but very, very close friends.
56:20And I love each and every one of them.
56:22They all have my hearts.
56:23As it were.
56:24So thank you.
56:32I have a question.
56:33Can you just stand for the BRK to
56:36engage the violent loss in intra?
56:38You show us a fruitful picture, correct.
56:40I have tried twice in the press
56:42and it's very hard to intervene.
56:44So how can you tell us more
56:46about your experience with
56:47intracardiac so mad that I
56:48see. Yeah. The the titration for
56:50that antibody was challenging,
56:52very challenging.
56:52We spent a lot of time on the titration
56:55and we do recognize that in some organs,
56:58the breast is one of them.
56:59The skin has been another.
57:01Challenging place.
57:01We sometimes have to modify the
57:04titration characteristics until
57:05we get good background standing,
57:07solid background staining
57:08that we're comfortable with.
57:09So yeah, it it really is about
57:11antibody titration there.
57:16Joe, I asked questions with the
57:18new schema. Yeah, So what do we
57:21know about how we use don't use.
57:26Very little, very little has
57:27been known or studied about them.
57:29It's definitely a topic that
57:30needs to be looked into.
57:32Yeah. It's interesting.
57:33A lot of cardiac tumors tend
57:35to take on a myxoid character.
57:37And the hypothesis behind that has long
57:40been that basically cardiac tumors,
57:43more so than most tumors,
57:44are subject to constant mechanical
57:47and hemodynamic injury, right.
57:49They're basically in washing
57:50machines all day long.
57:51They're getting battered about.
57:52They're in an aqueous medium.
57:54They're serum elements that are
57:55transiting in and out of the tumor
57:57as these things are beaten around.
57:59And so people have attributed
58:01the myxoid nature of cardiac.
58:03Numbers to that effect.
58:04Whether that plays a role,
58:05I don't know,
58:06or whether it's the myxoma cells
58:08elaborating that music on their own.
58:10All good questions.
58:13It's very hard,
58:14very
58:15difficult identify that
58:16subnormal counter problem.
58:19Indeed. Yeah. There's nothing,
58:20nothing like that that's
58:21normally in the heart.
58:22You're exactly right.
58:24It's real challenge. Yeah.
58:27When you spoke about the changes that
58:30they saw imaging on probably right.
58:32So the prevalence that of positive
58:35cases by imaging and their
58:37cases of positive myocarditis,
58:40they are not the same amount, correct.
58:43So any idea on what were they looking,
58:46what are they seeing?
58:47That's a great question.
58:48So imaging diagnosis relating to
58:50myocarditis are largely contingent upon
58:52something called the Lake Louise criteria,
58:54which in part related to delayed.
58:57We'll get a line enhanced and host of things.
58:59What they're saying on imaging
59:01is that there's something in the
59:03heart beyond just the normal.
59:05Heart muscle that can be edema,
59:08that can be inflammation,
59:09that can be all kinds of different
59:11things that are in that we don't have
59:13biopsy correlates to all of those.
59:15Those are studies that shockingly
59:17have never been done.
59:18There's a few correlative studies.
59:20They represent really small series,
59:22usually less than 10 cases where they
59:24correlate imaging findings and biopsy.
59:26But the the the take home
59:28point there is there.
59:30Could potentially be something
59:31in that interstitium that
59:33explains the imaging findings.
59:35That simply isn't myocarditis.
59:36It's something else that they're
59:38detecting and attributing to
59:39myocarditis just because of a lack
59:41of knowing what on Earth it is.
59:42We really lack those radiologic,
59:45pathologic correlative studies that
59:46would allow us to answer that.
59:48It's something that's desperately needed.
59:52Get to work on.
59:55I guess the hard part is to
59:57actually get somebody to be willing
59:59to undergo a biopsy after they,
01:00:02correct? Correct. Yeah.
01:00:03I mean, the other way that you could
01:00:06potentially approach that is by much
01:00:08more rigorous autopsy recruitment
01:00:09of individuals at the end stage
01:00:11of life who exhibit most energy
01:00:12findings that you then look at.
01:00:14That would be another way
01:00:15of doing it because I agree.
01:00:16I think it's a hard sell to tell
01:00:18people that you're going to engage
01:00:19the jugular vein and go into their
01:00:21heart potentially caused by customer
01:00:22regurgitation and a host of other things.
01:00:24Just because you want to study this,
01:00:26yeah, it's a hard sell.
01:00:27So we gotta find other ways of doing.
01:00:29Certainly as imaging gets better,
01:00:31there's, there's animal models that
01:00:32we could potentially engage there.
01:00:34There there's other ways at this,
01:00:35but it's hard.
01:00:40You
01:00:43could have a international, yeah, in 2026.
01:00:49Call up that is the was cardiac
01:00:53it was only three or four. Yeah.
01:00:56And that and again, none of them were,
01:00:59none of them were what I would
01:01:02call cardiac cause of death per se.
01:01:05You know, mechanistically,
01:01:06the heart may have been the final
01:01:08nail in the coffin, so to speak,
01:01:10but from a causal standpoint,
01:01:12they're all COVID-19.
01:01:15Right. All of them.
01:01:19Very good question. Thank you.
01:01:24Thank you.
01:01:32Yes.