Pathology Grand Rounds: April 13, 2023 - Oluwole Fadare, MD

April 26, 2023

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Impact of Biorepository on Translational Research: The Role of the Pathologist by Oluwole Fadare, MD

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00:00It's my great pleasure to introduce
00:03Doctor Fadari for today's Who's
00:06going to Give us the grand Rounds?
00:07He's Professor of Pathology and Chief
00:10of Anatomic Pathology at University of
00:14California San Diego Health System,
00:16and he received his MD degree from
00:19Harvard University, Washington, DC,
00:21followed by residency in anatomic and
00:25clinical pathology at Yale University.
00:27He then completed his fellowship in
00:29breast and. Gynecologic pathology,
00:31also at Yale and his clinical and
00:36Consultation practice is focused
00:38on gynecologic and breast cancers.
00:41He is lectured widely on these
00:44and related topics.
00:46He has authored, coauthored,
00:48and edited over 230 papers and five books,
00:53predominantly in gynecological pathology.
00:56And he is.
00:59Serves on the editorial board of several
01:03leading prestigious pathology journals,
01:06which include Modern Pathology,
01:08Human Pathology,
01:09Archives of Pathology in Laboratory Medicine,
01:12International Journal of
01:14Gynecologic Pathology,
01:15and American Journal of Clinical Pathology.
01:18He was the 20.
01:20He was a recipient of the 2018.
01:22Arthur Purdist Out Price Without further ado,
01:27I'll hand over the floor to
01:29Doctor Fedore who will talk about
01:31Volvo's famous cell carcinoma
01:33and putative precursor lesions,
01:35historical evolution,
01:36and recent developments in the
01:38tale of stasis and progress.
01:40At the end of the lecture,
01:42please unmute yourself and ask
01:44questions or you can post it on the chat.
01:48Thank you,
01:48Doctor Fedore.
01:48I'll hand it to you.
01:51Thank you Doctor Krishnanodi
01:54for that introduction.
01:56It's really a privilege
01:58to to address y'all today.
02:00I can hardly believe it's been almost 20
02:03years since I've completed my training,
02:06but that's essentially how it goes.
02:11So this presentation is about
02:15Volvo squimmerso carcinomer.
02:16And I will talk about historical
02:19evolution of the precancerous as
02:21well as the cancerous lesions,
02:23as well as pathologic diagnosis and
02:26various other aspects of those lesions.
02:29It is often said that ***** cancer
02:33was initially described in 562AD,
02:37although if you look at works
02:40of Asus of Amida,
02:41who in his classic work to forbid with.
02:44The last one was focused on ***** cancers,
02:46and there were several considerations
02:49of excising ***** cancer and citation
02:52of previous works prior to that.
02:54In any event, for whatever reason,
02:57there was not a lot written for many,
03:00many years after that documented,
03:01I should say, for many,
03:03many years after that.
03:05Indeed, when you look at some of
03:06the earliest works in anatomic pathology,
03:08including this work by Samuel Gross,
03:10there's no mention whatsoever of.
03:12***** all causing numbers.
03:14These are all the ***** diseases
03:16that were listed in that text.
03:19However,
03:20by the end of the 19th century,
03:23certainly ***** cancer was well established.
03:26So much so that if you look at
03:28this classic text by James Zenwing,
03:30the last paragraph,
03:31let's talk about how ***** cancer
03:33usually terminates without operation,
03:36you know, within two years after
03:38discovery of the lesion,
03:39and indeed.
03:40When you look at some of the early
03:45series or the series that were
03:48published early in the last part of the
03:50last early part of the last century,
03:52you can see that the cure rates
03:54range from anywhere from 8 to 25%.
03:56It was quite dismal.
03:58Of course, things have changed.
04:00This is global gun data and it
04:03highlights the fact that number
04:04one vulval cancers are uncommon.
04:06But out of 45,000 cases you
04:08can see that 17,000 deaths.
04:10So things have certainly improved
04:12with respect to survival rates as
04:15compared to the turn of the last
04:17century in the United States.
04:18You can see that the five year
04:20relative survival for ***** cancer
04:22is around 7 to 1.1% and that has
04:25remained stable for the most part.
04:27Now the vast majority of ***** cancers
04:29are are squamous cell carcinomas
04:31more than 90% and so I would.
04:35Discussed 6 discrete things.
04:37A lot of these are controversial
04:39in some way or there's some
04:42disagreement in some way about them.
04:44And so I'll just kind of
04:47explore some of this items,
04:49including their pathology,
04:52the basic pathology,
04:54the first relates to HVV status,
04:57this meta analysis of over 8000 patients.
05:02And numerous dozens of studies show
05:05that the group prevalence of HPV
05:08positivity and all the squamous
05:11cell carcinoma is around 39.1%,
05:13those that are assessed by P16
05:17immunostochemistry that is around 34.1%.
05:20And the best data on the
05:23significance of HPV positivity
05:24also comes from a metaanalysis
05:27wherein the authors concluded
05:29that woman with HPV positive vulval cancers.
05:32Have superior survival when compared to those
05:36that are HPV negative with H R's 0.61 and
05:400.75 for five years OS&amp;DFS respectively.
05:44However, when you look at more
05:47recent studies, this is studies
05:49published in the last 10 years,
05:51the picture becomes a little bit more murky.
05:53You can see here that most studies,
05:56about 61% of studies,
05:58have not found HPV positivity.
06:00To be associated with better to be to be
06:05associated with better overall survival.
06:07And most studies have found it
06:09to be associated with better
06:10progression free survival.
06:12But even by those two measures,
06:14you can see that there's sizable minorities
06:16of studies that have found the opposite,
06:19something like 40%.
06:20At the University of California,
06:23San Diego,
06:24our data falls into that minority
06:27where HPV positive patients do
06:29much better than HPV negative case
06:32patients independent of other factors.
06:35If you synthesize everything that's
06:37been published in the literature
06:39on HPV positivity,
06:40you find out this patients are generally
06:43younger, the tumors are smaller,
06:45they associated with.
06:46Lower depths of struggle,
06:48invasion,
06:49less frequent lymph node metastasis,
06:51less frequent margin positivity.
06:52And at least three studies have
06:54found that for those patients
06:56that are treated with primary
06:58radiation or chemo radiation that
07:00there's greater responsiveness.
07:02So there seems to be greater
07:04responsiveness amongst the HPV
07:06positive group if you compare HPV
07:10positive and HPV negative cases with
07:12respect to their mutational profiles.
07:15It's just,
07:16you know.
07:1819HP V positive cases exposed to
07:20the clinical NGS panel which oped
07:23another nine institution has 397 genes
07:26and and these are just the genes
07:29that show statistically significant
07:33differences between the HPV positive
07:35and HPV negative group and are
07:37more prevalent in the HPV positive.
07:39You can see that number one
07:42even the highest mutation.
07:43Which is like 3C A it's only 28%
07:45and everything else is lower,
07:47but these are only the ones that
07:49show significant differences
07:50between them and are more common
07:52than the HPV positive group.
07:54Amongst the HPV negative group
07:56however then several genes that
07:59with high mutation of frequencies
08:01most notably CP53 and CDK and 2A
08:05as well as term P and these are
08:07seen at very high frequencies more
08:09commonly in the HPV negative group.
08:14When we look at all prior studies
08:16that have looked at the question,
08:19we did this in 2021,
08:202020 something like that.
08:22You can see it's pretty consistent.
08:24Each bar represents a study that have
08:27looked at the issue and it's you know TP53
08:31tends to be the most common mutation.
08:34That have been identified in the HPV
08:36negative group which is in the upper graph.
08:38That's compared to the ones in the lower
08:40where it tends to be more heterogeneous,
08:43the HPV positive tumors.
08:44The mutational profile tends to be
08:47monitor genius without anyone really
08:50being overtly dominant the way P53
08:53does in the HPV negative group.
08:57The P53 being dominant in the HPV negative
09:00group also has significance clinically.
09:02You can see the green line
09:04represents the HPV positive group,
09:05patients do better.
09:07The red line represents the HPV negative
09:10group that are also P53 mutant.
09:13And you can see that there's an
09:15intermediate group where there's HPV
09:17negative or P53 wild type and those
09:20patients have intermediate prognosis.
09:23The notion that.
09:25P53 alterations is associated with
09:28***** cancer was initially reported
09:30by Pellodian colleagues in 1993
09:33and it was a small study.
09:37It was a letter to the editor,
09:39but they established that the mutations
09:41were also demonstrable and correlated with
09:44immunistic chemical staining patterns.
09:46Of course,
09:46there've been dozens,
09:47probably hundreds of studies after that.
09:50So much so now that we now have.
09:52Sort of well established staining
09:54patterns that correlate with the
09:56presence of an underlying mutation.
09:59The mutational patterns are
10:00shown on the left, on the right,
10:02and this is based on work by
10:04Tecia Klute and colleagues from
10:06the Vancouver group And you can
10:08see that you know the most common
10:11staining pattern is this parabasal
10:13diffuse over expression pattern.
10:15You could also have just staining of the
10:18basal layers or nulls or cytoplasmic.
10:20In the wild type staining patterns
10:22you have no staining of the
10:24base and some lesions we have,
10:26even though they may be staining in
10:28the middle or just scattered sporadic
10:31staining of individual cells within the nest.
10:34When that model was applied to an
10:38independent cohort of over 400
10:40HPV negative cases,
10:41the parabasal diffuse expression pattern was
10:44the most commonly observed staining pattern.
10:47When I saw the wild type, it's the
10:50scattered isolated cells being positive.
10:52So here's some images that
10:54I just took for this.
10:55You can see in the top image.
10:57On initial inspection, it may look like it's.
11:00HPV mutational type staining pattern,
11:02but in fact the basal layer is not
11:05staining so it's P53 wild type.
11:07Whereas on the bottom it looks like
11:09the central portion is not staining
11:10but the base is staining and all
11:12the cells in between are staining.
11:13So this is a mutational staining pattern.
11:17Overall HPV status is recognized
11:19to be significant,
11:21but it's not a clinical decision
11:23point at present time.
11:24The Who 5th edition does recommend.
11:27That tumors be classified based
11:29on the HPV status and the cops.
11:32Synoptic Report template,
11:33which Doctor Chris Minoli
11:36Spences and I CCR guidelines all
11:41follow The Who classification,
11:42and Figo 2021 does the same as well.
11:48The next is the question of tomorrow's
11:52subtyping in squamous cell carcinoma.
11:54Here are the various classifications
11:56over the years of the various subtypes
11:59of squamous cell carcinoma and you
12:01can see it all depends on what a
12:03particular author wants to emphasize.
12:05What The sense you do get is that,
12:07and also from my experiences,
12:09is that the same spectrum of subtypes
12:12that you see in the skin and elsewhere
12:15can also be seen in the *****.
12:17Right now, HPV positivity versus negativity
12:20is the main classification factor.
12:23And what we know is that the spindle cell
12:25and the verrucas are typically HPV negative.
12:30Everything else can be seen in either
12:33the HPV positive or HPV negative groups.
12:36The idea that subtyping relates to
12:39HPV status was initially proffered by
12:41Turkey and Kerman in the early 1990s.
12:44Where they reported that the basiloid
12:46and warty morphology were more frequently
12:49seen in the HPV positive group and the
12:51HPV the caratinizing morphology was more
12:53frequently seen in the HPV negative group.
12:57So here for example is the caratinizing
12:59squamous cell carcinoma and you can see
13:01that it's basically the three mutational
13:03type staining pattern or supposed to
13:05this one which is basiloid and it's P
13:0816 positive HPV associated or this one
13:11which is wordy and is similarly HPV.
13:14Associated however, this one,
13:16which is also which also has
13:18warty morphology, is HPV negative,
13:22P16 negative.
13:24Now I specifically illustrated this
13:26case to highlight the the notion
13:28that HPV status cannot be reliably
13:31predicted from morphologic evaluation
13:33only if for example,
13:35is the keratinize and squintin
13:36cell carcinoma and you can clearly
13:38see that it's P 16 positive.
13:40Indeed,
13:41the largest studies on the subject
13:46have found the same.
13:47This is from the Mobile vaginal
13:49study group which is only already
13:51in Natalia Brakislova,
13:53and you can see here that the
13:56HPV positive column here
14:0036.5% of cases are characterizing
14:02out of the HPV positive cases
14:04and out of the HPV negative.
14:06Smaller subset, but still.
14:08Around 5% are either basiloid or worthy,
14:12so clearly additional testing
14:14must be done to establish the HPV
14:17status if one wants to do that.
14:19Now there are various modalities
14:22for those that have been analyzed
14:24using DNA PCR for high risk HPV
14:26types and P6 animators to chemistry,
14:28there will be a discrepancy
14:30in around 10% of cases.
14:31In other words,
14:32you'll find one result using one modality
14:35and another result using another modality.
14:37As shown here,
14:40amongst those cases that are
14:42P16 positive and PCR negative,
14:44they tend to be more clinical
14:46pathologically similar to those that
14:48are positive by both modalities.
14:50In other words,
14:51they're they have background VIN 3,
14:54they are younger patients,
14:56maybe they have some warty or visible
14:58or morphology suggesting that the
15:00P16 is they are really HPV positive
15:03irrespective of what this result is showing.
15:06For those that have the reverse that
15:09have P16 negative and HPV DNA positive,
15:12it has to be more heterogeneous,
15:13but most of them actually look
15:16like P16 negative,
15:17HPV DNA negative as well.
15:20So P 16 overall is an excellent or
15:23do imperfect surrogate indicator,
15:25the discrepant rates between P16 IHC
15:29and things like RNA sexual aboritization.
15:34Are is less,
15:35it's tend to be less than 5% but
15:37there's not enough data in the
15:40***** in those particular cases.
15:43There's been some recent emphasis
15:46on these so-called double positives
15:48cases that okay if P6 N is
15:50significant and P53 is significant,
15:53well a subset of cases will
15:55be positive for both.
15:56These are peer studies that were
15:58published just within the last two months
16:00and you can see the Raka Snova found that.
16:03Two out of seven to six cases were positive
16:05and both of them were HPV positive.
16:08But Young and colleagues found
16:10that four out of 225 were positive
16:12and all of them were HPV negative.
16:14They made a big point about saying
16:16all of the cases that are double
16:18positive should be classified as HPV
16:20negative and their data supports that.
16:22But I'm not sure I quite agree
16:25with that in echo or you can see
16:28that 7% of patients that are.
16:32That have HPV positive tumors also
16:34have ATV53 mutation and another
16:37study from Memorial Stone Catering
16:39found that 27% of cases that are HPV
16:43positive were also at a P53 mutation.
16:46Again,
16:47these are relatively small cores,
16:49but but you know,
16:50it's not surprising that there'll
16:51be a little bit of overlap there.
16:55The third item is related
16:58to histologic grading.
17:01Most gradient of squamous cell
17:03carcinoma are based on the
17:05border system which was developed
17:07in the 1920s for oral cancer,
17:09and it talks about count determining
17:11the percentage of the tumor that
17:14have this undifferentiated cells
17:15as a way of stratifying tumors.
17:18But the contemporary application
17:20of that system is problematic
17:22because there are too many variables
17:25and everyone is applying it.
17:26In different ways.
17:27So there tends to be a lot of inter
17:31observer variability for the mountain
17:33of tumors that are in the mid of the
17:35bell curve that that is that are
17:37not extremely well differentiated
17:39or extremely poorly differentiated.
17:41And to make matters worse
17:43grading is not significant.
17:44So you know here's studies
17:47published in the last 10 years,
17:49you got 42 studies and none of those
17:53studies and when do we ever say 0.
17:56But none of those studies have
17:59found grading to be associated with
18:02overall survival and 83% of them
18:04have not found it to be associated
18:07with progression free survival.
18:09But still, you know,
18:11there are alternative forms of
18:13grading that have been attempted.
18:15You know,
18:15GOG had a very influential study
18:17from the early 1990s where they had
18:19over 600 cases and they modified
18:21broader system to basically change
18:23the percentages of the grades.
18:25And they thought that correlated
18:27better with lymph node metastasis
18:29as compared with the standardized
18:32brother criteria.
18:33But this never achieved widespread usage,
18:37mostly because I think they never
18:38published what is this specific criteria,
18:41What do you consider undifferentiated cells
18:44kind of. And so it just never took off.
18:47Then there's the so-called spray like
18:51pattern or the infiltrative pattern.
18:53And two studies found it's not
18:55associated with recurrence.
18:57But Suzanne Jeffers had a nice study
19:00from 2015 from the University of
19:02Arkansas showing that it's associated
19:05with recurrence 2 times more likely
19:07to be associated with recurrence.
19:09Then there's the Fibro mixoid
19:11stromal response,
19:12which has been shown since the early
19:151990s and subsequently confirmed by
19:16at least two different other studies.
19:19That it's associated with poor survival
19:22and more extensively metastasis
19:24and all the patient group And then
19:28finally our group reported a tumor
19:31budding that basically said Okay
19:33if you classify the level of tumor
19:35budding into three groups which
19:37has been the same system used at
19:40other other organ sites that you
19:42have clear separation between in
19:44terms of overall survival and DFS.
19:46Between the the groups independent
19:49of the factors including P53 status
19:53and HPV status.
19:55However,
19:55I think you know and this is mostly
19:59hypothesis that all of this are
20:02defining a single aggressive subset
20:05probably 1 where EMT is operational
20:08or activated or most significant.
20:11I think that's what this is.
20:14We were trying to or we tried to sort
20:17of prove that there was a too much
20:20overlap to really tell a coherent story.
20:23It's the same cases that tended to show
20:25the infiltrative pattern and fiber mixer,
20:27stroma or tumor body and
20:29infiltrative pattern or so on
20:31and so forth.
20:32There was a lot of overlap.
20:33We were able to show that each
20:34one was significant though,
20:35but there was such significant overlap.
20:38So where do we stand at present time?
20:41Well, gradient is listed as a data element.
20:44And as a result, there's a required
20:46element in the caps and optics,
20:48but I CCR are in the most recent data sets.
20:51That greeting is not a Co
20:52item and it's not recommended,
20:55whereas you know it's still not a
20:58clinical decision point at present time.
21:04The 4th and the biggest section of
21:06this presentation leads to precursor
21:08lesions and background dermatosis.
21:10Which is really a
21:13controversial area by itself.
21:15We'll start out with the more conventional.
21:18So the original carcinoma insight of skin
21:24was described by Doctor John Bowen in 1912.
21:28It took maybe 10 years for somebody
21:32to find to describe something similar
21:34in the ***** took another 20 years
21:37for somebody to describe the series.
21:40Of lesions and then ten years after that,
21:4315 years after that for the term
21:45custom inside you to be proposed.
21:47And it's kind of highlighted the glacial
21:51pace of progress in the ***** diseases
21:54during the early part of the last century.
21:58But the nomenclature disorder,
21:59as I like to call it, persistent.
22:01With different terms being used.
22:04Remember at that point it had
22:06not been associated with HPV.
22:08In the 60s and 50s it hadn't
22:12been associated with HPV.
22:13So the lesions with different clinical
22:16pathologic basis were getting called
22:18precursor lesions if they had a typia.
22:21So ultimately ISSVD International Society
22:23for the Study of Over Vaginal Diseases
22:27stepped in in 1976 and proposed the term
22:30squamous cell carcinoma inside 2:00 to.
22:32Bring everything in line with similar
22:34terminology in the skin and if you
22:37look at the various the top part of
22:39this table you can see the evolution
22:41and the terminology all the way
22:42to where we are today,
22:44which is based on last guidelines.
22:47L cell,
22:48H cell as shown here.
22:51Now of course nothing has changed about
22:54the pathology of Costnoma inside two or
22:58VIN 3 or however you want to call it.
23:00Except the morphologic spectrum
23:01has gotten expanded,
23:03so basiloid variations and are more
23:06railway recognized or worthy variations.
23:09There's a so-called Divin like pattern
23:11of H cell where in the atypia is
23:14restricted mostly to the basal regions
23:16of the epidermis until one goes down
23:18to look at it and high power it.
23:20And you'd appreciate a lot of
23:22mitotic figures in upper layers of
23:24the epidermis where this doesn't
23:26seem to be basiloid change.
23:28And that hot that that is a clue
23:30that this could be even like H sill.
23:33When you do P6 stain it lights up and
23:36P53 shows that this is a wild type
23:38staining pattern because there's no
23:40staining of the base and this is basal
23:43sparing media epithelial staining.
23:44This is a wild type staining pattern when
23:49H sill is comorbid with lichens sclerosus.
23:53If it can take on this appearance,
23:55this deviant like HCL like appearance.
23:58Here for example at the lower left
23:59you can see the conventional HCL
24:01and then the portions that are above
24:03the like in sclerosis looks almost
24:05normal and low power until you go
24:07in high magnification and appreciate
24:09some of the Ethiopia.
24:10Also more recognized over the
24:13last several decades is palliatory
24:15scatter of of HCL which can result
24:18in P16 sparing the base.
24:20And this you can see here,
24:22probably better shown here.
24:24One can also see this pattern
24:26that the peripheries of regular
24:28HCL where you know this just
24:31scattered and that is a result.
24:33P16 does a single base.
24:36And then finally we reported on a series
24:39of cases that can have such fluorid
24:41edema and inflammation in the dermis.
24:44That it looks like you know it could
24:47be mistaken until one goes on high
24:49magnification to appreciate all the
24:51atypia that's present in in the lesion.
24:55Now the incidence of HCL has increased
24:58by several thousand percentage
25:00points over the last 50 years,
25:03but the progression rate has
25:05remained relatively stable with
25:07about 9% progressing if untreated
25:10and low percentage less than 5%.
25:14Of cases we identified are called
25:17cancer in the resection specimen.
25:19That said though,
25:21there still remains this big
25:24disconnect wherein in most insight
25:27to lesions are HPV associated,
25:29but most invasive lesions are
25:32HPV independent and in the 70s.
25:34That caused a look back to a study
25:36that was originally published
25:38in 1961 by It Built and Goslin.
25:41And they talked about three
25:43types of intrepidated costs,
25:44new line including of the simplex
25:46type of course of the bonus type
25:47is what we now refer to as HCL
25:49and the pygas type we refer to
25:51as extra mammary pygas disease.
25:53But the simplex type is what they really,
25:57you know,
25:58were initially introducing
25:59at that point And it was,
26:01it was I like to highlight this study
26:03because especially for the trainees
26:05and the audience it highlights
26:07the significance of making basic.
26:09Clinical pathologic observations,
26:11because everything they've
26:12ever said really held's true.
26:14If you look and read that paper,
26:17they talked about its association
26:19with leukoplicy vilitis,
26:20which is like in sclerosis.
26:22They talked about how it has
26:24a short insight to face.
26:25They talked about how it's
26:27frequently present on the margins.
26:29All of those have remained true.
26:32And when you focus on the
26:33lower portion of this table,
26:35you can see the evolution in the terminology.
26:37We started with ISSV D's hypertrophic
26:40dystrophy and V IM3 of the differentiated
26:42type to where we are today,
26:45which is differentiated
26:47for ventricular pleasure.
26:49D event is generally seen
26:51in an older age group.
26:53There's a school of thought
26:55that's emerging that D event can
26:56be seen in the younger and it's
26:58increasing in the younger age group,
27:00which is probably related to that
27:02second peak like in sclerosis which
27:05occurs in teenagers and younger than 10.
27:08So those patients probably when they're 30th,
27:10so may develop the event.
27:12In any event,
27:13most patients are postmenopausal age group.
27:16The event is generally a centrally
27:18located disease or current inhaler skin
27:21areas without keratinized and epithelium.
27:23But of course it can get big and
27:26extend upward outwards to the
27:27Libya majora and elsewhere as well.
27:31Most events are diagnosed
27:33concurrent with the invasive cancer.
27:36But cases that are diagnosed in
27:38isolation are often difficult to diagnose.
27:40Indeed,
27:41when you have patients with cancer
27:43and you go back and look at their
27:45ostensibly prior lichen sclerosis biopsies,
27:47a lot of those lichen sclerosis
27:50biopsies had different in them.
27:54In terms of the percentage of the events
27:57that found to have cancer follow up,
27:59it ranges from 32.8% to what I consider
28:02a little bit of an outlier study.
28:05They found 85.7% at follow up.
28:08This is from the Vancouver group
28:10and but I think what everyone would
28:12agree on is the time to progression
28:14to look at the far right column is
28:16that everyone agrees that there's
28:18a short median time to progression
28:20between the diagnosis of the Devon.
28:24By itself, in a biopsy and the subsequent
28:27diagnosis of a carcinoma can range widely,
28:30but the median time is relatively short.
28:34There's a cumulative risk of
28:36cancer for defend.
28:37If you look at 10 years,
28:39regular HCL at 10 years,
28:41like I said before, it's only about
28:4210% and look at how flat the curve is.
28:45On the other hand,
28:45when you look at Devin at 10 years,
28:47the cumulative risk is close to 50% and
28:50the curve is really bumping upwards.
28:54However, the diagnosis remains problematic.
28:58Here's just a recent
29:00study got 4 pathologists,
29:02including a gynecological pathologist.
29:03The Scala was that gynecological pathologist.
29:06He's got 2 dermatopathologist
29:08and one general pathologist.
29:11And this is not even about
29:13diagnosis of divine per se,
29:14or what relative value each observer assigns
29:17to each of these individual features.
29:20It was just are these features
29:23present or not?
29:24And even that resulted in not entirely
29:28reassuring Kappa values in terms
29:31of its observer reproducibility.
29:33But I think what most would agree
29:36on is that basically tepia.
29:39Is a requirement for the diagnosis
29:41of Divin and recently ISSVD had a a
29:46consensus document in which they made
29:48that point that the diagnostic features
29:51of Divin would be Basilatipia and they
29:53defined that which I should talk about,
29:56Yeah,
29:56the case also needs to be P16 negative,
29:59P53 kind of wild type or
30:01mutational type staining,
30:02they mentioned that their supportive
30:05features.
30:06You know,
30:07all of which are sort of well recognized,
30:09but they have to do with most of
30:12the keratinized and subtypes into
30:15cellular breakdown into cellular
30:17vacuoles and prematural maturation.
30:19So if we consider the supportive
30:21features first here you can
30:23see that there's basal etipia.
30:26Focal And then there's what they
30:28refer to in the ***** context
30:31that this keratosis or premature
30:33meteoration which terms that may
30:35be used differently in Dermpa,
30:37but that's how they've been
30:39used traditionally in *****.
30:41And you can see that the the epidermis
30:45turns pink immediately after the
30:47basal layer and then there was this
30:50splengiosis like degenerative changes
30:52and vacuous that are present within it.
30:54Regarding the main thing though,
30:57which is a typia,
30:59they listed criteria including
31:01chromatin problems, hypochromasia,
31:02nuclear enlargement,
31:03something three times the size of a
31:06lymphocyte or that's obviously different
31:08than background or some pleomorphism.
31:10We talk about common features
31:12and less common appearances,
31:14so of course something like this.
31:16We can all probably agree that this is given.
31:18This is click up based on the Typia,
31:20it has two features,
31:22hyperchromasia and nuclear enlargement.
31:24And so everyone would agree
31:26that that's basilatipia.
31:27It's pretty true.
31:28Maturation loss of a granular layer and
31:31this is the so-called hypertrophic variant.
31:34And this is another hypertrophic variant.
31:36The basilatipia is more subtle,
31:38but clearly still present.
31:39At the tip of this arrows you can see some
31:43nuclear enlargement and hypochronesia.
31:44Here's one where the granular
31:46layer is preserved, but still.
31:48We can appreciate at the tip of
31:49this iris that there's a nuclear
31:52enlargement and hypochromesure,
31:53and also notice the background
31:55of Michael sclerosis that's
31:57seen in this particular area.
31:59Here's more of the conventional book
32:01where there's irregularly irregular
32:03what they call basal disarray and
32:05announced the most Inritti and basal.
32:08The tip here of course,
32:09and degenerative changes as shown here.
32:12This is species the three I HC.
32:16There's one where the basaltipia
32:18is getting more and more subtle,
32:20but a high magnification then one can
32:22still get to differentiated then,
32:24especially if you focus on.
32:25For example, look at the tip of
32:26the arrow in the lower left,
32:28you can appreciate some basaltipia that's
32:30currently present in these lesions.
32:32On the other hand,
32:33something like this,
32:34which to my eye does not have
32:36basaltipia but low and behold
32:38turns out to be a P53 abnormal,
32:41the so-called subtle variant of DV.
32:46Which you know,
32:47sometimes you can sort of your
32:49yourself way out of being able
32:51to diagnose the whole thing.
32:52But in anyway my to my eye this is not
32:54quite diagnostic at the morphologic level,
32:57but it is the event and so the so-called
33:00sort of variant and there are other variants.
33:02This is atrophic variant to shown
33:04on the left is more acantalytic
33:05that's shown on the far right is the
33:08apotrophic examples of which have shown.
33:10And here's the intermediate.
33:12Invariant,
33:12the one that looks sort of halfway in
33:15between something that's completely mature,
33:18premature maturation and all that and
33:20something that's visible looking.
33:22And this is a so-called intermediate variant.
33:25Most of them are non keratinizing,
33:27but they're also keratinizing variants.
33:29So here's an intermediate keratinizing.
33:32You can see it's clinically a
33:34discrete lesion between the blue
33:36Marks and a high magnification.
33:38It looks like it's not
33:39quite mature in in well.
33:41It's very minimal base
33:43of the tippy eye to see.
33:45To my eye, MP53 lights up that whole area.
33:51Just like there is a divin like
33:54pattern of H cell as shown here,
33:57there is there is also H
34:00cell like pattern of divin,
34:02the so-called basaloid divin
34:04wherein the epidermis is entirely
34:07basiloid and immature looking.
34:10But then you do P53 lights up,
34:13P16 is negative.
34:14I have not had the misfortune of
34:17identifying a basil or divine in a biopsy.
34:20Every case of saying has been
34:22adjacent to her invasive cancer,
34:24which of course helps with the diagnosis.
34:27With respect to immunos,
34:29to chemistry,
34:32the main point of controversy
34:34is whether or not there is a
34:37thing as a P53 wild type divine.
34:40The literature suggests that
34:42there is because any up to 35% of
34:46cases of reported cases of Divin
34:48in the literature, P53 wild type.
34:50But of course there's a little
34:52bit of circularity there,
34:53you know it's called Divin
34:55even though it's P53 wild type.
34:58Divin is difficult to diagnose
35:00by morphology alone, you know.
35:01So there's a there's a little bit
35:03of circularity in that event.
35:04That's what the literature indicates,
35:06that you can't have P 53 Watt type
35:09and ISSVD certainly supports that.
35:11And I and I also know from my personal
35:15experience that I've seen cases that
35:17are classical Divin with clear cut
35:20bisalitipia that are P53 wildfires.
35:22So I know it occurs
35:26with respect to interpretation.
35:27The same study that I cited earlier,
35:30Trisi and Clute also talked
35:33about the side two patterns.
35:35Including staining of the base that
35:37extends upward the so-called part
35:39of basil diffuse pattern or basil
35:41only staining just the base only,
35:44not extending upwards.
35:45A subset of these are
35:47associated with a P53 mutation,
35:49but it's a nonspecific staining pattern
35:52and you get the null in the cytoplasmic.
35:55The mid epithelia of basal sparing.
35:56I showed images before when there's no
35:58staining at the base even though the
36:01epithelium itself is strongly staining.
36:02These are wild type staining pattern,
36:04but the more common wild type staining
36:06pattern is when you have sporadic
36:07staining as shown in the left image.
36:11Now of course in real life
36:14it's never perfect.
36:17Everyone can recognize the clay
36:19cut wild type staining patterns.
36:21And then there's some cases that it
36:22looks like it's extending upwards,
36:23but it's in a discrete area
36:26without a morphological correlate.
36:28In other words,
36:29that area is not atypical at all.
36:31Or when you have strong staining that
36:34doesn't extend upwards and it's like okay.
36:37What do we do with that?
36:40Seems stronger than expected.
36:43And again,
36:44like I said,
36:44that has been associated with
36:46the presence of a P53 mutation.
36:48But you can also see them when
36:50P53 mutation is absent,
36:51as in like in sclerosis or liking
36:54simplex chronicles or other even
36:56spongeotic dermatitis cases you can
36:58you can see that pattern as well.
37:00Or when the standing of the
37:02base and it extends upwards,
37:04but in a kind of a wimpy way.
37:06Slightly and then like what to do with that.
37:09So in these scenarios it would be
37:11nice to have additional markers to
37:13assist with the diagnosis of Divin.
37:15Unfortunately these markers are not great.
37:19All the markers that have been
37:21proffered and listed here that
37:22are aware of 1 P CK13CK17 sorts 2.
37:26They're just not ideal.
37:28They each have their own problems.
37:30For the main differential,
37:32we don't really care about Divin versus H,
37:34so per se.
37:36We care mostly about D Vin versus Lycos,
37:41non putative non neoplastic lesions,
37:44inflammatory disorders,
37:45that's really what the issue is.
37:48The one that does show the
37:50most promise is got a three.
37:52Got a three was initially reported by
37:54Dean Yang from the Cleveland Clinic a
37:56couple of years ago as being lost in
37:58the basal and para basal layers of D Vin.
38:01Got a three is normally expressed in
38:04the epidermis expressed in H cell.
38:05Difusely, but in Divin,
38:07apparently it's lost in the basal layer
38:11and the parabasal layers as well.
38:14So we examined this and we found
38:17it to be useful.
38:19You know,
38:19this is 19 out of 25 cases showed
38:22greater than 75% of cells lost in
38:25the basal and parabasal regions,
38:27but that still is 2 out of the 25
38:31cases that had no loss whatsoever.
38:33We also found a lot of the VIN threes
38:37showed some loss in a partial or complete.
38:40But what is useful is that a lot
38:42of dermatosis like in sclerosis
38:44like in Simplex Chronicus and a
38:46variety of others did not show loss.
38:48We had a rare case that we were
38:50convinced does not have Divin.
38:52These are all P53 wall type by the way
38:55and P16 negative we were convinced,
38:58not sure divin but still short
39:00loss of of of this markers.
39:03So the overall problems can be
39:05summarized as in sometimes you
39:07have weak expression throughout the
39:09epidemics and so you can't tell
39:11whether there's loss in the base.
39:13And like I said,
39:14about 10% of cases show normal expression
39:16or defiant cases show normal expression.
39:19And then there's this
39:19question of partial loss.
39:20What is partial indeed the,
39:22you know, we use this numbers
39:2425 to 75% what is you know,
39:26I hate any sort of.
39:28Markers that need to be interpreted
39:31with numbers in that way and so it
39:33just you know it it's it's a problem
39:35but at least it's the one that
39:37shows the most promise Any marker
39:39really has to be combined with P50
39:41degree or and P16 really also in
39:46this space are these lesions they
39:48are controversial by the by the
39:50very nature especially recently or
39:52that are HP3 independent and P53
39:55wild type as I alluded to before.
39:58Most cases of devane are diagnosed
40:01concurrent with invasive carcinoma,
40:03and when that happens,
40:05the P53 mutational status of the
40:07invasive and inside 2 lesions match
40:10each other about 78% of the time,
40:13and then the remaining 21% of
40:15the time there's a mismatch.
40:17And that invariably,
40:19according to one large study,
40:22is because the invasive cancer
40:24is P53 abnormal.
40:25Whereas the lesion adjacent is P53 wild type.
40:31Now that tells me two things in
40:32an excision if I see an insight
40:34to lesion that's at the margin.
40:36The fact that the P53 is different
40:38between the excision and the and the
40:41putative precursor lesion doesn't mean
40:43I should ignore the precursor lesion.
40:45I would argue that you know that
40:47could still be very significant,
40:49but more importantly at this P53
40:51wild type insight to lesions that
40:53are adjacent invasive cancer.
40:55And what are they? Can they be recognized?
40:57What is the mutation that's happening
41:00with them of these lesions?
41:03Mutation of cancer fraction analysis,
41:05which as we all know has problems,
41:07but still have shown that perhaps
41:10the 53 is not the initiating event
41:13in this cremence across knowns that
41:16mutations in a NOx signaling pathway,
41:183rd and some others may come first.
41:22And then they acquire P53 later.
41:24The question is what is the
41:26morphology of those cases that don't
41:28have P53 but have other mutations?
41:30Does it just look like P53 rod type even?
41:33Does it look like something else?
41:35Does it look normal?
41:37And so that is the question and it's
41:39not a trivial 1 because like I said,
41:42a subset of ***** cancers are
41:44HPV negative and P53 rod type.
41:46What is the precursor for those
41:49lesions and those lesions
41:50represent? Intermediate They
41:52have intermediate prognosis and
41:54represent 15% of all Volvo cancers.
41:59This HPV negative P53 wild time cases.
42:02So the question is what is the precursor
42:06lesion for this subset of cases and can
42:09that lesion be diagnosed by pathologists?
42:13There have been attempts to do so.
42:15The first lesion that fits this bill.
42:17Was was reported on almost 20 years ago as
42:21low vikentosis with altered differentiation,
42:24which would be negative P53 well typed
42:27by definition a subset associated with
42:29like in sclerosis and by morphology.
42:32They have the Russiform architecture,
42:34they have stacked pyrokeratosis
42:37and the whole spinosum seems
42:43pale this pink appearance.
42:46Again, they don't have
42:48the features of the event,
42:49No basal etsypia to speak of.
42:52Not all cases are vertical recifonts.
42:54Some cases are more on the
42:56flattened end of stance,
42:57but clearly these cases are oftentimes admix.
42:59You can notice the stacked para characters
43:02in these cases and no basal etsypia, so the.
43:06The first inclination is to dismiss
43:09these lesions you know but you know
43:12they studies that have looked at it
43:14have shown that they do have some
43:16driver type mutations within them.
43:18You can see you know subset of cases have
43:21large one Itras mutations and as well.
43:25And there's a related lesion,
43:27the so-called differentiated exophytic
43:29***** and trepidal lesion which is defined
43:32simply very similarly to to to VAD,
43:35except you know this is more prominently
43:38a canthotic in the rusi form uniformly
43:44that it doesn't have the paleness that
43:48we spoke of previously and a smaller
43:50subset associated with lichen sclerosis.
43:53So that's the so-called devil.
43:55And then finally there's the the Russiform,
43:58like in Simplex Chronicus.
44:01So you know,
44:02this is a controversial lesion
44:05in which you know,
44:06you could argue it one way or the other.
44:08I took this image directly from
44:11a paper by Roy and colleagues.
44:14I see a Simon Roy that's part
44:16of our audience.
44:18So maybe it's the same Roy in any event.
44:21This is a this is this paper is
44:23there is from Lycos and Chronicles.
44:25We've all seen some iteration of this
44:28lesion is defined by papulometosis,
44:31prominent hyperglynylosis and
44:33hyperkinetosis where the subset
44:35associated with like and sclerosis.
44:37Over time devil and that started
44:40getting lumped together because their
44:42morphological features were so similar
44:44and they started being considered as
44:48precancerous lesions because the same.
44:50A spectrum of mutations were found
44:52to be present in both the devil and
44:55costnoma irrespective of whether
44:57or not the costnoma was diagnosed
45:00synchronously or metachronously.
45:02And also we had a subset of cases
45:05where diagnosis of of of devil of
45:08that was made and then it recurred
45:10as an invasive costnoma.
45:12And I certainly have a personal
45:14experience with those as well.
45:17And and then there's this study from
45:20again Roy et all that had 27 cases.
45:26And so then essentially the
45:27largest study to date and look at
45:30the progression rates to squamous
45:31cell carcinoma in this courts,
45:33it was 46% for that.
45:3640% for Devil and about 20 percent,
45:3827% for the Russeform and let's see
45:41with 37% overall for the whole court.
45:44So you know they,
45:45they take the position that all of
45:48these were part of the same spectrum
45:50of lesions and ISSVD has taken the
45:53same position prior they took that
45:55position one year before that paper,
45:58what they call that these lesions,
46:00whether it's bad Devil or whatnot.
46:03Should all be under the same umbrella
46:06called ***** aberrant maturation.
46:07And today you find ***** aberrant
46:11maturation as essentially HPV independent
46:14lesions that combined aberrant maturation,
46:18that big hyperkeratosis or parakeratosis
46:22and echanthosis and irregular
46:25Richie with minimal nucleotipia.
46:28Also the the lesion needs to be P16
46:32negative and in in P53 wild type.
46:36So here's a lesion which doesn't
46:40seem to be remarkable except
46:42everything looks uncommonly pink.
46:44Thick other keratosis,
46:46Galilei is preserved.
46:48This was signed out descriptively
46:49a couple of years ago.
46:51He came back twice before he was immediately
46:55before he was ultimately excised.
46:57In this excites with negative margins,
47:00but the point is you know
47:02when it was being biopsied,
47:03the idea was they were taking out most of it.
47:05There were tiny lesions to get out but
47:08this is what was there microscopically.
47:10And so this is an example of the
47:12so-called ***** after in maturation.
47:14It is more of a russiform morphology
47:17but you know it was a 24 millimeter
47:21sessile carpet lesion in the right *****.
47:24And so all of it was taken out.
47:25So we don't know what would have happened
47:27to this lesion if it had not been taken out.
47:30And here's a lesion that I'm showing
47:32because I know that this lesion
47:34which was signed out descriptively
47:36initially several years ago,
47:37decades ago,
47:39actually came back as an invasive cancer,
47:43whether that's related or not,
47:44it came back as an invasive cancer at
47:46the exact site that this was removed.
47:49So you know,
47:5111 can sort of make up that one one wishes.
47:55Now there's been a move that says that you
47:58know that van terminology is not ideal,
48:01that perhaps a neo name should be used,
48:07the so-called the russoformic anthrotic
48:10***** Interpitelian neoplasia,
48:11but then that this more closely reflects the
48:15pathogenesis and the morphologic features.
48:17This was published last year
48:21and the features are basically.
48:23Devil Van Mythology.
48:25No. Basility.
48:26BIA.
48:26You know,
48:27anything that you know can probably
48:29meet criteria for the rules from
48:31like in Saint Brooks Chronicles.
48:33In other words,
48:34no specific popular monstroses
48:36and acantosis and the like.
48:38So you know,
48:39whether or not this name takes and
48:42we end up using Van versus Van Van,
48:45it's not clear that it's still fresh.
48:47Again,
48:47that's why the point of controversy
48:49that's worth discussing.
48:51But I think what matters at the end
48:52of the day is that to highlight that
48:54this is not a typical lesion whose
48:56clinical pathologic significance
48:57is not known, not entirely known,
49:00but you know,
49:02certainly should be removed or
49:05ablated inside one way or the other.
49:08But what it's worth, you know,
49:12in our serious cases that were
49:14called VAM of a bin.
49:15They also in a significant subset
49:18showed aberrant stain for Gala 3.
49:20They said this reduced or loss
49:22of expression in various subsets
49:24suggesting that this is not a way
49:27to separate those lesions out.
49:30Now clearly high risk HPV is
49:32what pursues the diagnosis of
49:36HCL&amp;D van. There's usually talk
49:38about inflammatory dermatosis is the
49:40background in which this happens.
49:44And and and but really the main
49:47inflammatory dermatosis that we're
49:48talking about is lichen sclerosis
49:50because no one that showed a consistent
49:52association between any of the others
49:54and and and deviant or cancer in general.
49:57So lichen sclerosis is the big player here.
50:00A smaller subset of the cases of VAM of a
50:03van also have background lichen sclerosis
50:06about 30% lichen sclerosis is of course.
50:10Stats as an intermediate dermatitis,
50:13kind of a thing that progresses to more
50:17distinctive sclerosis and oxidative stress
50:22and alterations in gene expression profiles,
50:26and ultimately neoplasia in
50:29a small subset of patients.
50:31Now the association between lichen sclerosis,
50:36which was previously called
50:38the complicative bulbitis.
50:39And cancer has been recognized since
50:42at least the mid to late 1800s,
50:47including this favorite court of mind
50:49that that association was thought to be
50:51closer than that of any pathologic lesion,
50:53with the exception of the modern
50:56X-ray dermatitis.
50:57Now it's not uncommon in resection
51:00specimens for ***** squamous cell
51:02carcinoma to observe D van like and
51:05sclerosis and invasive carcinoma
51:07within the same specimen.
51:09And in biopsies of DV only you have
51:12concurrent lycan sclerosis in almost
51:1590% of cases and for squamous cell
51:17cost numerous that are HPV negative.
51:20If you look hard enough you'll find
51:21like in sclerosis in the background
51:23in up to 88% of cases.
51:26Basis of Lycos sclerosis in biopsies have
51:28been associated with an increased risk
51:31of ***** cancer with an Sir of over 33.
51:35So you have a 33 fold higher than expected
51:39frequency of cancers in women with
51:42Lycos sclerosis as compared with controls.
51:44Another way of looking at it is
51:46to look at what happens when you
51:49mix Lycos sclerosis with HCL.
51:51So here's the 10 year accumulated
51:53incidence of cancer from H cell,
51:55which as we alluded to before
51:57is only about 10%.
51:59You had lichen sclerosis to regulate
52:02HPV associated H cell and all of a
52:04sudden the risk moves on to close
52:06to 40% or 10 years.
52:08And also the rate of movement of
52:10this curve is is, is is much higher.
52:15And and another way to look at
52:17it again were on the significance
52:19of the background is to look at
52:21what happens with the recurrences.
52:23That's a work by Cigarette Regal I
52:25thought it's such a nice elegant study
52:28that looked at HPV negative *****
52:30squad and cell carcinomas and 71%
52:34of them were P53 wild type were P 53
52:38Newton sorry in the invasive cancer
52:40the primary site when they recurred though.
52:44Only 88% of them were P53 mutant,
52:46so you could argue that 12% of cases
52:49were neo cancers that are rising.
52:51In this background you can flip
52:53it the other way as well.
52:54Those cases were initially P50 very
52:57well type significant majority of them,
52:5957% of them when they recurred
53:02had a P53 mutation.
53:03Again, we could argue some
53:05progression in the subset,
53:06but it also argues that a significant
53:08subset of these cases are neo cancers
53:11that are happening in this background.
53:13Of inflammatory dermatosis that may
53:16be permissive for the development
53:18also bolstering the argument that
53:21these are independent cancers is that
53:24when you have the same patient with
53:26multiple D vents and you look at the
53:29the mutational profiles for P53,
53:32they have different P53 mutation within
53:35different events in the same patient
53:38in a subset of patients and also when this.
53:42Invasive squamous cell cause normals recur.
53:46A significant subset of those
53:49recurrences have a set of mutations
53:51that are not present in the original,
53:54not just more complicated mutations
53:57that suggest progression.
53:58They have mutations that are new and
54:01they don't then that are completely
54:04absent from the invasive cancer as well.
54:07So for example you know the primary site.
54:11May have a P53 mutation and and
54:14maybe one or two others.
54:16The the recurrence would not have a
54:18P53 mutation and would have a different
54:20set of other genes that are mutated.
54:24So Justin again that these are
54:26independent cancers in a subset of
54:29recurrences that occur in this setting.
54:32And so when we have this H between
54:35negative cancers 1 hopes and you have two
54:39different defense associated with it.
54:41When an invasive cancer arises from it,
54:431 hopes that you know this lesion,
54:48this separate D van is clinically
54:50evident enough for the surgeon to see.
54:53It's pathologically evident enough
54:55for the pathologist to see.
54:57And if we do see it,
54:58that is P53 mutation type to
55:01facilitate the diagnosis because it
55:03really determines exactly what kind
55:05of an excision the patient will get.
55:08And that goes to the issue of.
55:11The margins,
55:12How much of margins should should be
55:14obtained given all this activity that
55:16are happening around the invasive cancer,
55:18the D van,
55:20the almost the events that are happening now.
55:23The professional organizations
55:24recommend that in clearance of around
55:27a minimum of 1010 millimeters be be be
55:29be done with a histologic clearance
55:31for around 8 millimeters to account
55:33for shrinkage that #8 millimeters.
55:37Comes from studies that have shown
55:41in the 1990s,
55:42just the three-year old studies,
55:44that that number is the is the sweet spot.
55:46Anything that 8 millimeters or
55:48more has to have less frequency of
55:51recurrences in this particular setting.
55:54However, studies published in the
55:56last 10 years have shown that the
55:58issue is much more complicated.
56:00And indeed, most studies have not
56:04found that 8 millimeter cut off to be
56:07associated with progression free survival.
56:09In fact, some of the others of the
56:11original study have now essentially
56:14recanted because additional data
56:16have shown that you know it.
56:19It did not influence risk,
56:20that that's more free margin
56:21distance whether you use an 8,
56:23five or three millimeters.
56:25What does influence recurrences?
56:28Is finding deviant and lichen
56:30sclerosis at the margin.
56:32Finding deviant by itself at the margin
56:35are the one are the things that affect
56:37recurrences in patient revolving cancer.
56:39Lichen sclerosis by itself
56:42did not affect recurrences,
56:44but recognizing the abnormality around this
56:47invasive cancer continues to be problematic.
56:50So we look at this little ditzel
56:52of an excision that we received,
56:54which is typical.
56:55And there's abnormal area adjacent
56:56to it that we can all recognize.
56:59And then there's what looks like
57:00normal skin adjacent to it.
57:01It looked normal to the surgeon.
57:03They thought they were getting the margin.
57:04It looked normal to the gross prosector,
57:07but microscopically it was not.
57:09It was full of differentiated Vin and
57:12indeed when having a saying the P53 on
57:15all blocks of all margins around their
57:20P53 null LOVA squamous cell cancer.
57:22Four out of 13 cases became positive
57:24margins and those that were more
57:27focally positive before became
57:28more extensively possible for DVN.
57:30And the DVN that were in this newly
57:33identified margins tended to be very subtle.
57:34And this was recently confirmed
57:36earlier this year by the Vancouver
57:38group showing that when they did
57:40P53I EC just on the closest margin
57:42that 29% additional cases of DVN
57:46or at least P53 abnormal insight
57:48to lesions were identified and.
57:51These lesions were so subtle the
57:53more you move away from the invasive
57:55cancer that they thought they were
57:58morphologically occult could not be
58:00identified by morphology unknown.
58:01And it's not like P53 signature
58:04where it's like whatever this one is
58:07actually associated with a threefold
58:10increased risk of recurrence finding
58:13AP53 abnormality at the margin
58:15even though there's no morphologic
58:18correlate for that P53 abnormality.
58:21And that goes to the what has happened when,
58:24what has,
58:25what has happened with respect
58:26to how patients are treated.
58:28So prior to 1995,
58:30surgeries were more draconian,
58:32you know lot of radical valvectomies
58:34for small lesions and the like.
58:37And so there was no difference between
58:39HPV positive and HPV negative.
58:41But those differences emerged after we
58:43moved to more conservative surgeries.
58:46So what tended to happen prior to
58:481995 was that they were taking
58:49out the invasive cancer as well
58:51as everything in the background.
58:52And that's again that's speculative,
58:53but that's probably what was happening
58:55that they were taking out the invasive
58:58cancer and everything else around it.
59:00So it it behaved more like an in
59:02positive case where you're taking
59:04the discrete lesion in the duct,
59:06but that has changed.
59:07So what really matters now is identifying
59:09whether or not those cases but even
59:12surgical excision is appropriate.
59:14For all those lesions adjacent,
59:17whether or not once you think about more
59:20aggressive ablation insight to insight
59:22to for for those lesions after the
59:25main invasive cancer has been removed.
59:28I'll end by by showing this to explain
59:32the title of my of this presentation
59:34we just talked about a stay a tale of
59:37stasis and this is the survival rate.
59:40Is the upper curve talks about,
59:42you know, new Volvo cancer cases
59:45that have been diagnosed based on
59:47Co data going back to 1975 and look
59:50at the flat death rate associated
59:52with it over the last 50 years.
59:54Despite all of those progress,
59:57all the advances prognosis
59:59remains roughly just bad.
01:00:01There's been no significant
01:00:03improvement overall in, in,
01:00:05in in the survival rates for Volvo
01:00:07cancer over the last half century.
01:00:10But there is also a tale of progress.
01:00:12RFS has improved to some
01:00:15extent and so recurrences,
01:00:16which is really the main thing
01:00:19to some extent has improved.
01:00:22But there are clearly a
01:00:23lot of work to be done.
01:00:25And the question is for pathology
01:00:27really it's about what is the true
01:00:29morphologic spectrum for Devin,
01:00:31as well as this HBV negative
01:00:33P53 raw type precursor regions,
01:00:35the biomarkers for Devin.
01:00:38Urgently needed.
01:00:39And then what to do with the three
01:00:42mutations and the margins and
01:00:43exactly how do we handle that?
01:00:45And of course identifying the
01:00:48aggressive subset using the mythology
01:00:51essentially is so much great.
01:00:53So thanks again for the privilege and
01:00:56I will be happy to make any questions.
01:01:00Thank you Doctor Fedori
01:01:01for a wonderful lecture,
01:01:02particularly focusing on the
01:01:05challenging HPV independent.
01:01:07Volvo in Preptelian lesions,
01:01:08in the interest of time,
01:01:10I'll hand it open it up for please
01:01:14unmute yourself and ask questions.
01:01:19Hi. Hi, this is, this is Pale Lou.
01:01:21You can hear me. Yes, I can, I think.
01:01:24Thank you for bringing this
01:01:27timely update in this ground.
01:01:29But the vova cancer in the precursor lesions.
01:01:32There's lots of details,
01:01:35interesting discoveries in recent decades,
01:01:37so I do have a question.
01:01:40We'll see. What do you think?
01:01:41Do you think the diving as a
01:01:44whole is a single kernel event
01:01:47of any dealing associated?
01:01:49Squints are customized.
01:01:50This could be a field effect,
01:01:55I think. Because of Divin of course,
01:01:58like I said, it's the subset of them
01:02:00are diagnosed by themselves and are
01:02:02never actually diagnosed with squamous
01:02:04cell carcinoma that clearly and in
01:02:07those cases do have you know the
01:02:10expected mutation of profile of PCC3,
01:02:13PIC, 3C, A HRAS and the like that
01:02:18number one it can occur by itself.
01:02:21We have enough data for that
01:02:22when we see Divin.
01:02:25Associated with invasive
01:02:27squamous cell carcinoma,
01:02:29most of those deviant lesions have
01:02:33a similar mutation or profile,
01:02:36at least based on the limited NGS panels
01:02:38that have been used as the squamous
01:02:41cell carcinoma that are adjacent to them.
01:02:44So I think what's probably
01:02:47happening is that multiple factors,
01:02:50some of them are independent
01:02:52new lesions that are entirely
01:02:54unrelated to the invasive cancer,
01:02:56but I think a subset are indeed field
01:02:59effect that are happening that are sort of
01:03:02related to the invasive cancer as well.
01:03:04So with that,
01:03:05so have you seen or read the articles,
01:03:08investigations where you show?
01:03:10Different patches of divings,
01:03:12they have different P53 mutations.
01:03:14Or have you seen a diving or
01:03:18revovactum of diving where you see
01:03:21different P53 staining patterns?
01:03:23Like you you have focally diffuse
01:03:26positive and the other focus will
01:03:28be now or the others possibly
01:03:31cytoplasmic P53 alteration?
01:03:32I don't know.
01:03:33Have you read it or have you
01:03:35seen such a case?
01:03:35I don't think there is.
01:03:37I don't think that has
01:03:38been reported I I I I must.
01:03:40I'm familiar with just by everything
01:03:43that's written in the space.
01:03:45The the first question that
01:03:47you know the same devins with
01:03:50different patterns has been shown.
01:03:53You know if you read the the small
01:03:56case series by Pinto had one was
01:03:59nonsense the other one was missense,
01:04:03different devins in the same patient.
01:04:07Mutations and so they had
01:04:08different staining patterns.
01:04:09One was null and the other one
01:04:11was null for expression and so,
01:04:13so we know that that happens.
01:04:15I for one have not seen a case where
01:04:19you know in a resection specimen
01:04:22there are multiple devins associated
01:04:24with an invasive cancer and they
01:04:26have different staining patterns.
01:04:27The devins have different staining patterns
01:04:31and I don't think, I don't think
01:04:33it's been documented elsewhere.
01:04:46On a slightly different note,
01:04:48what are your thoughts and this
01:04:50new method of depth of invasion
01:04:52on HPV independent cancers?
01:04:56Well, I guess time would tell.
01:04:59I think time would tell whether or not
01:05:04I always like new things like that,
01:05:06especially if it improves.
01:05:09Prognostication or stratification
01:05:11of patients. I think once it's
01:05:14introduced then we'll analyze it,
01:05:16we'll do a lot of you know review
01:05:20of it and see whether or not it
01:05:22actually performs as indicated.
01:05:24I think it's easy to do.
01:05:25We currently doing the study right now
01:05:28on that same subject we'll we'll we'll
01:05:31see what what it shows ultimately.
01:05:34So I I without judgment until
01:05:35we see that either.
01:05:39So thank you again for a wonderful talk.
01:05:43It's a shame you couldn't be in person,
01:05:44but we understand. So hopefully.
01:05:49Well, thanks again. It's again,
01:05:50it's an absolute pleasure and it's
01:05:52good to to see faces of friends,
01:05:56colleagues and mentors.
01:05:58And so thanks again for the
01:06:01invitation and you'll have a
01:06:03great rest of your day. Thank you.