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

Transcript

• 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&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&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.