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

April 26, 2023## Information

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.