Intersection of Oncologic and Molecular Pathology

February 18, 2022

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Feb. 17, 2022

Yale Pathology Grand Rounds

Joanna Gibson, MD

ID7469

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00:00Well. While people are still
00:04logging in, we have 60, so I'll
00:08get started with the introduction.
00:13Most people don't need an introduction to
00:17Doctor Gibson, Doctor Gibson, but so my
00:20introduction is going to be very brief.
00:24Dr Gibson did her bachelor's in science
00:28from University of Minnesota and then
00:32went on to do MD PhD at the Mayo Clinic's
00:37School of Medicine. Following that,
00:40she went to Brigham and women.
00:44For a pathology residency,
00:46and she must have liked the northeast
00:51so much that she decided to pursue
00:55further career in the Northeast,
00:58finishing up with a chief residency at
01:01Brigham and Women's and then a GI Fellowship.
01:05She followed this with a brief stint
01:08back at Mayo Clinic and came right
01:11back and joined our department.
01:14In 2011, as assistant professor and
01:18now Joanna Gibson is an associate
01:22professor in GI pathology.
01:25She serves on many committees and is
01:29currently the director of Quality
01:32and Patient Safety.
01:34In Joanne's practice,
01:36she combines molecular pathology
01:39and GI pathology,
01:41and today Doctor Gibson will
01:43share her insights. Indu.
01:46Oncology and molecular pathology.
01:51A brief housekeeping notice that from today.
01:55Unfortunately,
01:56there has been a change to how
02:00CMA credit is given when you text
02:04your CMA credit number.
02:06If your CMA profile is up to date
02:10with regards to disclosure of
02:13conflicts of interest and other stuff,
02:17you would get CMA credit.
02:20Otherwise,
02:20you may.
02:22Get a message that your profile is
02:26not up to date and Susanna has now
02:30found this out just today and she sent
02:33an email to the entire department.
02:36So it's a simple fix.
02:39Just update your CMA profile.
02:42With that, I'll let Joanna take it away.
02:46Thank you Manju. Share my screen.
02:54Go to presentation mode. Hopefully you
02:56guys can see that presentation mode.
03:01Yes, great. I'm going to try
03:03to use this laser pointer.
03:05See if that works for highlighting things.
03:08So Andrew, thank you so much for
03:11the introduction and thank you so
03:13much for the opportunity to come
03:14and give Brian Rounds and in our
03:17own department it's definitely a
03:18privilege to be able to do that.
03:21So I just want to come back to my early
03:24education and pathology and sort of
03:27explain a few things that sort of.
03:30Have led to where I am today so my
03:33interested oncology started early.
03:36In my, you know when I got to the Mayo
03:38Clinic for my for my MD PhD training.
03:42You know, I started to get
03:44interested in cancer biology,
03:45and I succinctly remember a lecture
03:48that Doctor Brookhart gave when he was
03:50there at that time, and I I really,
03:52he was my first example of sort of,
03:54you know, how do you study cancer?
03:56How do you look at it?
03:57I think it triggered my interest
04:00in pathology and once I got to
04:03residency and into my fellowship,
04:05I started to sort of submit my interest
04:08specifically more in GI cancers
04:10and specifically colorectal cancer.
04:12And so yes,
04:13I kind of went back and forth the
04:15East and West Coast and just going
04:18to do one thing here and move now,
04:21I can't do it just one second here guys.
04:28The zoom window is interfering with my
04:31view of the slides and it was I didn't
04:34move it out of the way. And so I.
04:41So when I arrived at Yale,
04:42I already had a very strong
04:45interest in oncology and cancer,
04:48specifically colorectal cancer.
04:50And you know, when I got into
04:51the Yale practice, that's sort of
04:53where I focused my efforts and so.
04:56Hopefully throughout this talk you'll
04:58get to see how that intersection.
05:01Of oncology pathology molecular pathology
05:04occurred for one GI pathologists practice
05:07myself and specifically how does the
05:11intersection sort of lead to patient?
05:15Management changes and and you
05:17know how we impact patient care.
05:20So conceptually, this is how I'm going
05:22to sort of present my grand rounds.
05:25I'm going to use patient examples
05:27to highlight different biomarkers,
05:30different technologies,
05:31and different effects on patient impact.
05:35So hopefully throughout this entire talk,
05:36they'll be sort of a common theme of
05:39that progression of of data sharing.
05:43Alright,
05:43so starting with patient number one
05:46this was a 45 year old man who had
05:48his first screening colonoscopy and
05:49was diagnosed with colon cancer that
05:52you can see here on the endoscopic
05:54picture and on the Histology image,
05:58and so I'll invite the residents to
06:02use the chat if they want to and what
06:06molecular tests should be ordered and why.
06:11Open the check my other screen.
06:18And.
06:22So the answer should be MSI
06:25testing exactly excellent.
06:32Somehow something is getting stuck
06:35in my PowerPoint, I apologize.
06:39I have to quit one more time.
06:41There we go alright? So.
06:47Colon cancer remains one of
06:50the most common cancers.
06:51That's third common in both
06:53men and women after prostate,
06:55in Latin or breast and lung cancers,
06:57and it also remains a.
07:00You know high high contributor to
07:03cancer deaths in both men and women,
07:06and so it still remains a major problem in.
07:11In the United States and worldwide,
07:13and I wanted to make the patient
07:15the age at 45 because recent
07:17reports have shown that there's a
07:19rising incident saying patients,
07:21and I I really wanted to bring
07:23this into this presentation
07:24to just make everybody aware.
07:26And although we have done a
07:29really good job in decreasing
07:31cancer rates in older populations,
07:33we it had been noted that the younger
07:37patients are having increasing rates and.
07:41And the problem is,
07:43is that the young populations are not,
07:45you know,
07:45not being screened as screening age
07:48was greater than 50 for many years,
07:50and most recently because of this data,
07:52the American Cancer Society has
07:54recommended that people at age 45
07:57start undergo regular screening
07:58for colorectal cancer.
08:00And this is true for patients
08:01with average risk.
08:02Obviously,
08:02if there's any other risk factors that
08:05age of of screening might might also change.
08:09And so diagnosis in colorectal
08:12cancer is something that we do
08:14every day as GI pathologists.
08:16Here I have an example of a
08:18malignant polyp that shows a little
08:21bit of residual benign adenoma on
08:23the side of this of this tumor.
08:26But bulk of this small,
08:28malignant polyp is composed
08:30of invasive adenocarcinoma,
08:31so we recognize the Mulligan glands,
08:34but they're atypia irregularity,
08:36and it doesn't plastic stroma.
08:39And when I see a slide of cancer,
08:42I automatically just my mind
08:45comes to the molecular pathways
08:47of colorectal carcinoma and.
08:50What's exciting about colorectal personal.
08:52It's it's one of the first examples
08:56of a carcinogenesis pathway of of
08:59showing how cancer can go from benign.
09:02Lesions to invasive lesions that impact
09:06patient health and patient mortality,
09:10and there are multiple pathways
09:12that colorectal cancer can form,
09:14and so when I'm sitting and looking
09:16at these slides of colorectal cancer,
09:19I'm always thinking is this a,
09:21you know, conventional pathways.
09:22This is the rate of pathway and for the
09:26purpose of MSI testing of why that's there,
09:28it's because we do have a familial
09:30pathway of colorectal cancer.
09:31And there's two main.
09:33Pathways,
09:33Faps and Lynch Syndrome FAP is
09:35generally fairly easy to diagnose
09:37once you get to colonoscopy.
09:39This is a phenotype that is quite dramatic.
09:43There's hundreds and hundreds of
09:45turbulent moments within the colon,
09:47and so when patients get their
09:50first colonoscopy,
09:51the diagnosis can be made relatively easily.
09:53Lynch syndrome, on the other hand,
09:55does not have a polyposis.
09:56The old name for Lynch syndrome was
09:59non polyposis colorectal carcinoma.
10:02And. And so this.
10:08So,
10:08so being able to recognize
10:09Lynch syndrome is an
10:10important component to try.
10:12You know, to try to identify whether
10:14the patients that we are seeing
10:16have a genetic predisposition,
10:17which then will impact not just
10:20that patient but also their family.
10:22And Lynch syndrome is the most common
10:25form of heritable colorectal cancer.
10:28Probably accounts up to two to
10:303% of all colorectal cancer.
10:32It has an autosomal dominant inheritance
10:34pattern and most importantly,
10:36it is associated with cancers
10:37outside of the GI tract as well,
10:39primarily in the mutual cancer,
10:41but various other ones to a lesser degree.
10:44And for many years,
10:47diagnostic criteria or based on
10:49the Amsterdam features which.
10:51Which really mostly looked at family
10:53history to be able to make a diagnosis
10:56at this particular syndrome and what
10:58happened in the 90s and into the 2000s,
11:01which is kind of when I was getting my PhD.
11:04Some of you know,
11:06some really important discoveries were made.
11:08One was that Lynch syndrome.
11:11Was.
11:13Was discovered to be related
11:16to microsatellite instability
11:18in the tumor cells and the.
11:21Set of four mismatch repair proteins
11:24were identified as the genetic cause of
11:28large syndrome and in at least one study,
11:31the most common mutation that's found
11:33in Lindstrom is MSH 2 and MLH 1 being
11:37a close second common with the other
11:39two being less frequent and just to
11:42remind everybody what are microsatellites.
11:44Microsatellites are
11:45repetitive regions of DNA.
11:48They can be found through they're
11:49found throughout the genome,
11:51including.
11:51Within exons of of important genes
11:55and they are particularly sensitive
11:57to replication errors to mismatches.
12:00So here you can see a mismatch occurred in
12:04this particular area and these proteins.
12:08These mismatch repair proteins repair
12:10that mismatch and if they are absent.
12:13If these proteins are not able to function,
12:15this mismatch is not repaired and you
12:17get you end up with variably sized
12:20alleles at that particular Microsoft like.
12:22So focus which can then be seen an
12:26old-fashioned gels which you know don't
12:29don't get done really anymore that much.
12:32So how does that you know
12:35really occur in more detail?
12:37So basically the mismatch is
12:40originally recognized by a
12:42heterodimer of MSH 2 and MSH 6.
12:45Which then recruits another
12:46heterodimer of MLH one and PMS two,
12:49and these heterodimer
12:50formations are really important.
12:51And once once this mismatch is recognized,
12:55other proteins get recruited to the
12:57site of this particular DNA mismatch,
12:59which then excised the region of the
13:02DNA that is involved and that gets re.
13:07Be synthesized and the heterodimers can be.
13:14Can be.
13:18And the reason that the heterodimers
13:21are important is because when you have
13:24a missing part of the heterodimers.
13:26So let's say there's a mutation and one
13:29of the genes that forms a heterodimer.
13:31The heterodimer is unstable and both
13:34proteins end up getting degraded.
13:37So if you have like a truncating
13:39mutation or something like that of 1,
13:41the other protein becomes unstable as well,
13:44and so we can see this.
13:46In the IHC that we do every day for
13:50four MMR proteins that we see the
13:52predominant pattern that we see
13:54is the paired loss of expression,
13:56and that's because of this biologic.
14:01Process of of the heterodimers
14:04being unstable when one is mutated.
14:07And conversely,
14:08when we see paired loss of expression,
14:10you know the other.
14:11The other header dimers usually
14:12shows preserved expression,
14:14although there are rare examples
14:15where all four might be missing.
14:18And so how does colorectal cancer
14:20develop and Lynch syndrome?
14:21There the model is an accelerated
14:25carcinogenesis model that adheres
14:27to nuisance hypothesis for the first
14:29hit is the germline mutation in one
14:32of the four at the margins and the
14:34second hit is a acquired somatic
14:37mutation of the paired MMR gene,
14:40usually within a adenoma that forms
14:43sporadically within within these
14:45patients and the thought is that.
14:47Sporadic I don't know.
14:49Must have formed an Ellis in a
14:51Lynch syndrome background.
14:53Will progress the cancer much
14:55faster than they would in a non
14:57Lynch syndrome patient.
15:01And here you can see an example of
15:02an adenoma that has lost so that
15:04knowledge one and PMS 2 not all of.
15:06Not all adenomas will show that in
15:08Lynch syndrome it's partly depends on
15:10the extent of you know of the pathway.
15:13That's that's progressed,
15:14at which time we actually see the biopsy.
15:18And so the current guidelines have been
15:22refined over the last decade or so,
15:25and now there's, you know,
15:26very strong recommendation.
15:28That there should be universal
15:30screening of all colorectal carcinomas
15:33to maximize the ability to identify
15:36patients with lips syndrome.
15:38And you know, and the mutual carcinomas
15:42are part of this recommendation.
15:44And I'm, you know,
15:44I'm going to leave it to others
15:46to talk about.
15:46End of mutual adenocarcinoma and
15:49and those you know.
15:52Special features that are
15:54associated with that tumor type.
15:58But more recently,
16:00the guidelines have also expanded
16:02the tumor types that should be
16:05included in that screening process,
16:07and that those tumors you know.
16:11Consider doing screening for
16:13other GI tractors. Small bowel,
16:16gastric pancreas, and you know, etc.
16:18And another important aspect of
16:19the new recommendations is that an
16:22infrastructure needs to be in place
16:24to handle the screening results.
16:28And the guidelines are actually interesting
16:31because they don't really come down on
16:33any particular method of screening.
16:36The two methods that are discussed in
16:38those guidelines are immunohistochemistry
16:40and the preliminary chain
16:42reaction or PCR, and you know.
16:46So both are accepted methods of
16:49screening and both have their own.
16:52Pluses and minuses in terms of what
16:55information and how sensitive they
16:57are for for capturing the patients.
17:00Immunohistochemistry is really the
17:02preferred initial method in practice,
17:05so most labs have ability to do
17:09immunostains that so this is an expensive
17:11and it's widely available and it's
17:13fairly easy to express to assess for
17:15the expression of them are proteins the
17:18turn around time is also very quick,
17:20and and as we'll see the pattern of MMR loss.
17:24And also suggest Lynch syndrome.
17:27And.
17:31And guide any additional testing
17:33manshu I see your question.
17:37So I do not know specific associations
17:41with head and neck tumors.
17:44With Lynch syndrome specifically,
17:46but if you do, you know I'm.
17:49I'm sure there have been reports,
17:51but I'm not aware of any,
17:52and if anybody else knows,
17:54feel free to chime in.
17:59The PCR method is used mostly at
18:01least in the realm of colorectal
18:04cancer as a confirmatory method,
18:06complementary method.
18:07It's not the primary method of screening,
18:09and it does require a
18:13molecular laboratory ability,
18:14so this limits its its availability,
18:18although these days.
18:21Most academic centers have a molecular
18:23laboratory where this can be done
18:25the turn around time is a little bit
18:26longer because there is a step of
18:28DNA extraction that needs to be done
18:30and and for a long time people sort
18:32of argued in literature about which
18:34microsatellite markers are the best, etc.
18:36And you know, I'm not going to
18:38go into those kind of details,
18:41but usually at least five microsatellite
18:44markers are tested to look for instability.
18:47And, importantly,
18:48the PCR reaction will not be able
18:52to distinguish inherited forms
18:54and sporadic forms of MSI cancer.
18:56And we'll look at that a little bit more.
18:58So here's result.
18:58Number one.
18:59Here we have an add no carcinoma that
19:02shows clearly shows loss of MSH 6 at MSH.
19:062 in the tumor with preservation
19:07of MLH one and PMS 2.
19:09One important aspect of interpreting
19:13MMR stains is that you should
19:16look for intervening benign cells
19:18that have preserved staining.
19:21So in the MSH 16 that's a little bit faint,
19:25but you can see that there's some brown
19:27staining of the intervening stromal cells,
19:29mostly lymphocytes it looks like,
19:31and in the MSH 2 stain that
19:32is a little bit stronger,
19:34so there is some variability in in these.
19:38And and how you know what this
19:40looks like with results?
19:41And So what should happen next?
19:45Anybody have an idea?
19:48I'll give residents half a
19:50second to think about it.
19:57So the next step is well, so you can look
20:02for any algorithms that there's many,
20:05many algorithms that exist to help you
20:07figure out what to do with those results.
20:10So with the loss of MSH 2 and
20:13MSH 6 or isolated loss of PMS 2.
20:17The patients should be referred
20:18to cancer genetics.
20:20No additional testing is needed.
20:21They should just go to cancer,
20:22genetics and cancer.
20:23Genetics will take care of the rest.
20:25We don't need to worry about it.
20:28And we are really lucky at
20:31Yale because we do have that
20:35infrastructure in place that.
20:40That sorry, somebody is direct
20:43messaging me for the CMU code.
20:46That should be, uh, that's already
20:48been sent a couple of times.
20:50Yeah, just just ignore. Ignore, yes.
20:55And so we do have an infrastructure in place.
20:59We do have a cancer genetics
21:00and prevention program.
21:01They're located at on the SRC campus,
21:04and the one of the directors of the
21:06program is Shabbir Lor, who's endoscopist.
21:10And and so, like I said,
21:13we're lucky that we have this infrastructure,
21:15and they've actually at Yale.
21:18This infrastructure has actually
21:19changed over over the years.
21:21Initially, you know, we had universal
21:24testing for colorectal cancer for a
21:26number of years now and initially.
21:31But it was dependent on the provider,
21:34you know.
21:35So we see the biopsy of the cancer.
21:37We do the immunostains.
21:39We write a report of that,
21:41and it goes back to the endoscopist to have,
21:44you know,
21:45to have that result and then it
21:47depended on that endoscopist to be
21:49able to refer the patient to genetics.
21:51Well, this this genetics clinic
21:54decided you know what?
21:56Screw that.
21:56Let's let's see if we can get to
21:59this data a little bit more a
22:01little bit faster and so they've.
22:03They've you know,
22:05created some automated review at
22:08First pathologist review and now
22:11an automated review for colorectal
22:13cancer and and it's turned out
22:16that with this strategy where they
22:18get an automated report of all the
22:21patients that meet certain criteria
22:23with the results they've been able
22:26to identify eleven additional Lynch
22:28syndrome patients in in this time frame.
22:31And it it.
22:32Seems to be a cost effective way
22:34of doing this material and this
22:36this data had been presented at
22:39a couple of different meetings.
22:42Over the last couple of years,
22:44and so we you know,
22:46we again all we need to worry as
22:48well exists is that we report the
22:51results and those results will be
22:54automatically sent over to the
22:56genetics clinic for them to be
22:58able to reach out to the patient
23:00and to the provider of the patient
23:02to create that genetic consult.
23:05For confirmation of diagnosis.
23:09And MRI is usually pretty
23:13straightforward to interpret.
23:15There's you know it's really just as
23:17the is there standing as they're not,
23:19but there are a couple of cautious
23:23caveats that should be kept in mind.
23:25If you have a very small amount of tumor,
23:28you know,
23:29be cognizant that limited tumor samples.
23:33May have, you know,
23:35maybe under you know,
23:37maybe over called for absence of tumor
23:39staining if you're only looking at a
23:41a few glance of tumor and also some
23:44unusual patterns have been reported.
23:46Some of those are things like
23:49this dot like powder.
23:50Majority of these are associated
23:52with lots of protein.
23:53It's an abnormal expression pattern
23:55and so if if you're ever in doubt
23:58you can always order the PCR to
24:00confirm that there's presence of
24:02microsatellite stability and false
24:04negative results are pretty rare.
24:07They will occur in less than 10% of.
24:10Of patients and that can occur because
24:13depending on the mutation type,
24:15it may not be.
24:16Activity can still be preserved
24:17even though there is actual
24:18dysfunction of the protein,
24:19so it it can happen.
24:21It's a biological phenomenon that's
24:23quite possible and more recently with
24:26one of our residents not allowed.
24:28Smote. Oh, I have done a small study to
24:32look at our MMR staining here at Yale,
24:36and we looked at 150 patients who
24:39had two or more MMR IHC results.
24:42And it turns out that most of those
24:44MMR results are quite reproducible,
24:46and so it's a robust test,
24:48and we did find this coordinate MRI
24:50HC patterns and 6% of patients and.
24:56And. Those 6% primarily were
25:01independent primary tumor,
25:03so if a patient had a primary of,
25:05you know colon and a primary,
25:07you know of breast, they might show
25:09different patterns of IHC because they
25:12will arise through different mechanisms.
25:14And then I have a question from Doctor Robert
25:17about utility of them are in adenomas.
25:21And so yes, adenomas can show loss
25:26of of MMR proteins, but not always.
25:29It's, you know, if you find loss,
25:32that's great,
25:32and you can certainly use that
25:36information to suggest genetic counseling.
25:39But if you find preserved IHC,
25:42it does not rule out the
25:44possibility of Lynch syndrome.
25:46In that case,
25:47I don't have a slide specifically
25:48addressing this question.
25:52Alright, so here is another result,
25:54so this is another possible outcome.
25:56Here we have a mucinous adenocarcinoma.
26:00You can see a lot of you know mucin
26:02production with the malignant lens
26:04here and we see loss of MLH one and
26:06PMS two and again we always want
26:08to look for positive staining in
26:11the intervening normal cells that
26:13are present within the around.
26:15The tumor within the tumor.
26:17And we have preservation of MSH 2 and MSH 6.
26:19So what's the?
26:21Next step here anybody.
26:29So I'll just move on to that,
26:31let's see. There you go.
26:34So the answer is that we should
26:36go to MLH 1 methylation and the
26:38reason why we need to do that is
26:40because we need to distinguish.
26:42Tumors that occur in the setting of Lynch
26:44syndrome from those that occur sporadically.
26:46So here is our algorithm and
26:48so now we have lots of MLH,
26:50one with or without loss of PMS
26:53two this should trigger.
26:56Ordering MLH 1 metalation PCR to
27:00determine what happens and the MLH 1
27:03methylation specific PCR is performed
27:05in our Yale Molecular Diagnostics Lab,
27:08so it's pretty easy to to do that
27:12ordering and depending on what the MLH
27:161 methylation results show you would
27:21you would refer the patient to genetics,
27:24so if no methylation is seen.
27:27Of MLH one, then the patient should
27:29be referred to cancer genetics,
27:32and so that's the reason.
27:33Why is because there's two pathways
27:35to MSI and colorectal cancer,
27:37and they're actually both quite different.
27:38So we've talked at length about Lynch
27:41syndrome and I wish I see your answer.
27:44I I, you know, I, I didn't.
27:47I didn't see it fast enough to read
27:49it as I started to explain the answer.
27:52But you're absolutely correct,
27:54methylation.
27:55So the Lynch syndrome we've already
27:57talked about.
27:57We talked about how patients have
28:00germline mutations and they get a
28:02second hit in their adenoma which can
28:05then lead to deficient mismatch repair.
28:08Ultimately,
28:09microsatellite stability and
28:10with microsatellite stability
28:12come secondary mutations and a
28:14variety of coding microsatellites.
28:16And it can lead to and all
28:18of that leads to cancer.
28:20Sporadic MSI cancers are quite different,
28:24although the end result is very similar
28:27meaning that they do end up with
28:29the same deficient mismatch repair.
28:31But the mechanism and the process is
28:34very different and so MSI high sporadic.
28:39Cancers occur through the serrated pathway
28:42of carcinogenesis and in this pathway,
28:45sessile strated polyps are
28:47thoughts develop a intermediate,
28:50dysplastic steps.
28:51Most SSPS will.
28:53This will have beer after 600 imitation,
28:57so these tumors also very commonly
29:00have fee 600 mutations and then
29:03what happens and you know.
29:05It's it's really unclear how
29:07this starts or why you know what
29:09is it within an SSP that allows
29:12for this mechanism to occur.
29:14But what is that to happen is
29:16that the MLH 1 gene is silenced
29:19in an epigenetic fashion through
29:22methylation of the promoter of MLH one.
29:24So here's all of these CPG islands
29:26that end up getting methylated,
29:28and once it is methylated the chromatin
29:32closes up and is inaccessible to being.
29:36Transcribed and the protein
29:38can no longer be expressed.
29:40So virtually all cases of sporadic.
29:47MSI high cancers will have
29:49MLH 1 promoter methylation,
29:51which we can test for and the result
29:55is that patients get MSI high cancers.
29:59These tend to be poorly differentiated
30:02or mucinous in nature.
30:04They also have other associations such as
30:06more commonly being found on the right side,
30:08more commonly being found in older
30:11patients and female patients.
30:13They do tend to have a good prognosis and
30:15there are some specific. Therapeutic?
30:20Options for these patients. And so.
30:26Going back to our paradigm,
30:29this is where we would determine
30:31if if a patient needed referral
30:33to genetics or if they have a
30:35sporadic form of MSI high cancer
30:37when it comes to loss of MLH 1.
30:47And so moving out patient two patient
30:50two is a 50 year old woman she had.
30:53She was diagnosed with a right sided add no
30:56carcinoma and we already had testing done.
30:59She had MLH one and PMS two loss.
31:02So you can see those there.
31:04She was positive for MLH 1 methylation.
31:08So we think it's sporadic.
31:11It's a sporadic I'm.
31:12It's like I can't, Sir,
31:13but the note was that she had
31:16greater than 50 polyps in her colon.
31:19So what is a possible diagnosis and
31:21the hint is that she ended up with a.
31:26Total colectomy and majority of
31:28her polyps versus ulcerated polyps.
31:33And if any of the residents
31:36have an idea of. Of a diagnosis.
31:45Alright, so the possible diagnosis is
31:47that the patient has severe polyposis
31:49syndrome and this continues to be an
31:52underrecognized colorectal predisposition
31:54polyposis syndrome that is specifically
31:57associated with MSI high MLH one loss
32:01and MLH 1 methylated carcinomas, and.
32:07Men and women tend to get this equally.
32:10This can be seen at any age.
32:12And it's usually diagnosed unexpectedly
32:15at screening colonoscopy or or at.
32:18Or colectomy, there's two main variants.
32:22Type one and Type 2,
32:23based on sort of the location and
32:25number of polyps that are found in
32:27and these sort of correlate with
32:29The Who criteria for SPS diagnosis,
32:34so criterion one is, you know,
32:36more than five strated polyps proximal
32:38to the ****** and they have to be,
32:39you know, greater than 5 millimeters and
32:41two of them have to be greater than one.
32:43I mean that gets a little bit wordy.
32:45Where's the Criterion 2 is,
32:46you know greater than.
32:4923 polyps anywhere in the colon with no
32:52particular size criteria and you know,
32:55even though this is a fairly
32:58distinct polyposis syndrome,
33:00genetics are not understood, not known.
33:05Have not been, you know,
33:06specific Gene has not been discovered.
33:08That sort of explains
33:10majority of these cases,
33:11although some some have been proposed.
33:14At the Scopic Lee,
33:15these patients just have multiple polyps
33:17and they tend to have this characteristic
33:19mucus cap so so they can be recognized,
33:21and the scopic Lee somewhat.
33:23If there is ability to do
33:25confocal laser endoscopy,
33:26which you know most places
33:28don't have that ability,
33:29there are some unique features
33:32that can be that can be detected,
33:35such as these thin branching.
33:37***** and dystrophic goblet cells.
33:40When you look at the specimens grossly again,
33:42there's no distinctive features.
33:43The polyps tend to be sessile,
33:45and you know,
33:46so if you notice one of these types of
33:48phenomena in the in the colon cancers
33:51that you gross sampling of multiple
33:53polyps is crucial for the deduction of SPS,
33:56and the reason why is,
33:57if you have a partial colectomy and a
33:59patient has serrated polyposis syndrome,
34:01it might be that they are,
34:03you know, continues to be a high
34:04risk for developing cancer,
34:06and their remaining colon.
34:07That they have and in one small
34:10study that had done a few years ago,
34:13we found in a cohort of 22 patients who had
34:16colectomy and were found to have polyposis,
34:19we actually found SPS as the cause of
34:22the polyposis in about 1/4 of them.
34:25And furthermore,
34:26in a separate study,
34:28we looked at a population of
34:31over 2000 patients who had at
34:34least one pseudopolyps diognosed.
34:36And we found that one point 4% or 32
34:40patients met criteria for serrated
34:43polyps syndrome and these patients
34:46had a variety of polyp types.
34:49Many of them had advanced neoplastic
34:52features, so they either had,
34:53you know,
34:54dysplasia within their serrated polyp,
34:56or frank invasive carcinoma and
34:58what's interesting is that these
35:01carcinomas actually had a variety
35:03of augmentations within them.
35:04So even though the prevalent thought is
35:07that these. Cancers all lead to you know,
35:09one type of MSI high tumor
35:11with direct mutations.
35:13We actually did find that there's you
35:14know one with a key reputation among
35:16these and some did not have the reputation,
35:18so it's sort of an interesting
35:20question still.
35:22And so all of this together,
35:26you know we can put together a
35:28basic molecular classification
35:29of colorectal cancer.
35:33OK, so now kind of going to shift
35:35gears and start talking a little
35:37bit more about mutation testing.
35:39So here's another patient.
35:41Newly diagnosed metastatic
35:43colorectal cancer to the liver.
35:46Prior testing showed microsatellite stable
35:50tumor and what should you order next?
35:58And so in order to, you know.
36:00So this is where we come back to the
36:03NCCN guidelines and sort of start
36:05to understand how is information
36:06used and what sort of information
36:08is needed for continued treatment,
36:11and so patients who have metastatic
36:13colorectal cancer should have
36:15genotyping forreston draft mutations.
36:18And the reason for that is
36:21is because there is a.
36:23Antibody that's frequently used as part
36:26of chemotherapy for colorectal cancer.
36:29The targets. The rest raft pathway,
36:31and so in order for this antibody to work,
36:35rest, and draft have to be wild type.
36:40And so this is where this is
36:42where this pathway comes in.
36:44So here we have EGFR, which then
36:49signals downstream into grass and RAF.
36:52RAF happens to be the most mutated
36:55gene in colorectal cancers.
36:57Approximately, you know,
36:58up to even 50% of colorectal
37:01cancers will have RASK mutations,
37:03and they're in order to use setx map as
37:07a component of the chemotherapeutic.
37:10Regimen.
37:12We have to rule out mutations in the
37:15tumor because this this antibody will
37:18have no efficacy of downstream of that
37:22of of of EGFR is an activating mutation.
37:27But you can see that we also have,
37:29you know there's mutations in
37:31various other genes as well,
37:32some of which may be targetable
37:34and others are not.
37:35So how do we test for driver
37:39driver for forreston ref?
37:41Mutations in colorectal cancer.
37:43This has evolved overtime.
37:45You know,
37:46ten years ago would have
37:48been PCR of some sort.
37:50And you know,
37:52but that has evolved quickly through.
37:56Into real time PCR and now primarily
37:59next generation sequencing being the
38:01standard for doing this type of testing.
38:04And so I so after coming to Yale,
38:06I got interested in colorectal
38:09molecular testing at Yale,
38:10and I, you know,
38:13sort of.
38:14Intersected with with our molecular
38:16labs and try to find out like what
38:18is going on and so we have two main
38:21labs that do CRC molecular testing
38:23and they don't overlap too much
38:26with each other in terms of the
38:28the specific test that they do.
38:30So the molecular diagnostics
38:31lab does a lot of PCR.
38:34For MSI and also single gene
38:36testing like graph 4K Ras,
38:39they also performed the MLH fund
38:41methylation and I'm here just focusing
38:43on the role of this lab and CRC testing.
38:45I'm not at all going to talk about,
38:47you know all the other wonderful
38:49things that that lab does and has
38:52developed in recent years and
38:53then we have the tumor profiling
38:56laboratory and the tumor profiling
38:58laboratory primarily uses next
39:00generation sequencing as a method for
39:02detecting mutations and tumor cells.
39:04And I'll talk in a lot more
39:06detail about that lab, so.
39:08You know when I first arrived
39:10at Yale in 2011,
39:12this was our GI Group back then and
39:14I was primarily doing GI pathology,
39:17but I I really wanted to expand my
39:21clinical practice and I started
39:23thinking about maybe I I could join the,
39:26you know,
39:27one of the molecular labs and
39:29after discussing
39:30with various people I got support from.
39:39There we go. I got support from Doctor
39:43Walter and the tumor profiling lab
39:45and with doctor Marrows and Doctor so
39:48Nards and Doctor James support as well.
39:51I was able to join the tumor profiling
39:54laboratory as a faculty member.
39:56And you know, how did I do this?
39:59I mean, this was not something
40:01that happened overnight.
40:02I joined the laboratories
40:04Case Review conference.
40:05Just sort of a consensus
40:08conference type review of cases.
40:11I went to the precision Medicine
40:14tumor board for, you know,
40:16a while before then joining the roster of
40:18people who present at that tumor board,
40:20I shadowed the faculty at that time in the
40:23German profiling lab and then finally.
40:26I was able to get a block of six
40:29weeks to be able to do a rotation
40:31sort of identical to what a fellow
40:34would do and learned all the different
40:37aspects of the tumor profiling lab.
40:40And so primarily next generation
40:44sequencing is the platform that is
40:45used by the tumor profiling lab and
40:47this is an ultra high throughput,
40:49scalable, fast method of sequencing DNA,
40:52and it's, you know.
40:54I I fit the whole sequence of events
40:57of how next generation sequencing
40:59works on one slide,
41:00but it's it's it's a very busy slide
41:03and so there's there's different
41:04steps that have to be done.
41:06First sample has to be prepared,
41:08DNA has to be extracted.
41:10Library preparation and templating
41:12has to occur.
41:14Sequencing has to occur in the
41:16sequencing is sort of a bit of a
41:18magical step where it's actually, you know.
41:22It's a.
41:25Electric, you know it's a.
41:26It's a electronic signaling
41:28or electronic sequencing.
41:30Basically that that occurs and
41:32it generates a ton of information
41:35by informatics is a big big
41:37step and we have several people
41:39working on that who actually.
41:42Go through all of these steps and
41:44give us the annotated mutations that
41:46are found in a particular tumor,
41:48and then we have to interpret
41:50those those variants and we use
41:53different types of databases to to
41:55do that and just to sort of make
41:57sure that everyone sort of knows
41:59most of the stuff happens in the
42:01Department of Laboratory Medicine.
42:03The variant interpretation
42:04is what the faculty do,
42:06and we do that and and it's the
42:10pathology faculty who do that.
42:11And so.
42:12How is NGS actually used,
42:15and what are the advantages
42:17of it so you know,
42:18with NGS you can sequence
42:21really any area that you know.
42:24Almost any area that is of interest
42:27and the advantages that multiple
42:29areas can be sequenced all at once,
42:32like massively,
42:32and so you know when you look at crass.
42:36Yes,
42:36there are some common hotspots
42:38that are really interesting
42:40and recur quite frequently,
42:41like a code on 12 or 13,
42:43but there's a lot of other smaller
42:45hotspots at 146 at 1:17 at 61,
42:48and so with NGS we're able to sequence
42:51all of the hot spots at once,
42:53and so we have one panel.
42:55For.
42:58That looks at 50 different hotspots
43:00or I should say looks at 50 genes
43:03at various hotspots and this is the
43:07panel that's used for diagnosing.
43:10Metastatic colorectal cancer and how
43:14does the entry of data come back to us?
43:17It's actually.
43:19Comes back in an Excel style
43:22spreadsheet which can be somewhere
43:24you know this is a simple.
43:26Summary of that result.
43:27So here we have, you know, for example,
43:31TP 53 has a C DNA mutation that
43:35replaces G2AG to an A at nucleotide 818,
43:40which then leads to a change in the
43:44protein of arginine to 73 to a histidine.
43:47And what's also important is that
43:50this particular position was.
43:54Stop.
43:54It was read almost 2000 times,
43:58so this position was was found in 2000.
44:03Let's look was seen at least 2000 times,
44:05and 20% of those reads showed this variant,
44:10and so here you can see what that
44:13looks like in in the I GB program.
44:17So this is the genomics viewer that we
44:19used to look at the actual mutation.
44:21So here we have the K rest gene.
44:23With this particular mutation,
44:25and there's each of these bars
44:28represents one of these reads
44:31that forms the coverage and.
44:33That she represents the change at
44:36that particular meeting, and we have.
44:38And they're color coded for
44:40reverse sent forward reads.
44:44And so this is what a cancer mutation
44:48hotspot panel result looks like.
44:50There's an add no carcinoma
44:52estimated 30% malignant cells and
44:56we have a BRAF V600E mutation.
45:01And our other pathology records
45:03show that this was an MSS cancer,
45:07and so this brings up an interesting
45:10subject of the reputation in MSS.
45:13Colorectal cancers.
45:13And this is an interesting subtype of
45:16cancer that does not neatly fit into
45:18our current models of personal genesis.
45:21These tumor types are.
45:25Relatively rare on the order of,
45:27you know, maybe 5-4 to 7% depending
45:30on what study you read, and you know.
45:34Unlike other tumor types,
45:36that kind of neatly fit into our
45:39knowledge of of precursor lesions, etc.
45:41We don't really know how these tumors
45:44arise and what is the what is the primary
45:46sort of starting point for those.
45:49But the most interesting thing is that
45:51they do now have a therapeutic option,
45:54and so recognizing these tumors.
45:56Is important and I'm working
45:59with our current fellow Dr each,
46:02as well as some others and looking at.
46:08MSS CRC's. Looking at some of those
46:10molecular features to add to this knowledge,
46:12and this is this is the most recent.
46:19This is that this is a study that
46:22described that tablet therapy,
46:23the doublet therapy includes
46:26this EGFR targeted treatment,
46:28such as a tax map,
46:30combined with a BYREF inhibitor.
46:32Initially, this was also had a
46:34component of a MEK inhibitor,
46:36but within a few months of
46:39this paper being published,
46:41they've they've decided that
46:43the doublet has just as much
46:45efficacy as the triplet therapy.
46:47And so this is now becoming a
46:50standard of of care for BRAF.
46:55Mutated by MSS tumors.
46:59Alright, so moving on to a different patient.
47:01This was a patient #4 who had a combined
47:04hepatocellular cholangiocarcinoma.
47:06It was MSS and now his
47:09progressive disease and.
47:10As a pathologist, do you order anything?
47:13The answer is no, you don't.
47:16It's kind of a trick question.
47:18It's the oncologist who may order
47:20a comprehensive NGS panel and
47:22that panel at Yale is on combine.
47:25And so the anchor mine is
47:27a much bigger panel.
47:29It sequences 87 jeans at various hotspots.
47:34There's also 48 genes
47:36that are fully sequenced.
47:38These are mostly the tumor supressors.
47:41We were also able to look at
47:43amplification of a number of genes
47:45as well as a number of gene fusions
47:47and so the anchor mine panel is
47:49used primarily in patients who
47:52have stage four disease and have.
47:54Failed conventional chemotherapy and
47:56it's really to identify mutations that
47:59may be therapeutic therapeutically.
48:02Targetable in a specific manner,
48:04or may may have implications
48:07for clinical trials as well,
48:10and we what what's unique about the
48:12Yale practices that we use a germ
48:15line control to determine the somatic
48:17status versus hereditary status
48:18of any variance that we identify.
48:21And so,
48:22so this was actually two patients
48:24with in this example, and.
48:26And we ended up publishing
48:28this short case series.
48:31With a former fellow at Yale,
48:34so one of the patients was at 59 year
48:36old woman and she had a combined
48:40cholangio carcinoma carcinoma.
48:41You can see that HTC component here.
48:44The collector component there.
48:46She had a personal history of
48:48breast cancer in the past and
48:50the thyroid cancer as well,
48:52and then she had a fairly extensive
48:54family history of cancer of various
48:56cancers and then patient #2,
48:58excuse me is a 62 year old man
49:00and he didn't have prior cancers.
49:03But he did have a sister who had
49:05both breast and uterine cancers,
49:06who had died of those cancers.
49:10And these are the alkaline results
49:12for those two patients.
49:14Both patients ended up having
49:16a bracket 2 mutation.
49:20And.
49:22Patient one has this
49:25pathogenic nonsense mutation,
49:26so it's premature leads to premature
49:28termination of the protein,
49:30and this was found to be both in the
49:33germline and in the tumor and patient.
49:35Two had two Broadcom mutations.
49:38One of these mutations is a
49:40pathogenic splice site mutation and
49:42this was found to be again in the
49:44patients germline sample as well
49:46as the tumor sample and then there
49:47was a second somatic mutation in
49:49bracket two as well and so based
49:51on these results a diagnosis of
49:53heritage Terry breast cancer.
49:55In a variant,
49:56syndrome can be made in both
49:59patients and you know it's it's one
50:01of these situations where I'm like,
50:03well, you know people,
50:04could you know maybe the patient
50:05with breast cancer should have been,
50:06you know, found to have this previously.
50:08I don't know. Not really sure.
50:11You know what, you know.
50:13When patients get screened for
50:15breast cancer exactly.
50:17For the syndrome, but looking at you
50:20know malignancy risks and patients
50:22with this particular syndrome
50:25combined cholangiocarcinoma HCC or
50:27is not really anywhere on that list.
50:30So you know, maybe they're related,
50:31you know, pancreatic.
50:32You know it's a biliary type cancer.
50:35Maybe that that that might be a
50:37hint that that could be part of it.
50:39So here's an example where we can
50:43really impact patient results,
50:46patient families by detecting mutations.
50:52And you know what?
50:53The risks that are associated
50:55with them in tumors that are not
50:58necessarily expected for that syndrome.
51:00And in addition to that,
51:03this also leads to the possibility
51:05of a specific type of therapy,
51:08and so in brocco mutated tumors,
51:10the use of carp inhibitors is.
51:14Is a possibility where you know.
51:19Where you know if you Park is an
51:22enzyme that is involved in DNA repair
51:26and if you include if you add up our
51:29PIN hitter and hit this enzyme in
51:32tumors that have a mutated BRACA.
51:342 homologous recombination cannot
51:36be done and these patients undergo.
51:40You know these tumors undergo cell death
51:43and something called synthetic lethality.
51:45And there are now a lot of
51:47carpet hitters that are.
51:48Clinical use primarily for
51:50ovarian and breast cancers,
51:52but they definitely would be an
51:54option for both of these patients
51:56if if they should recur.
51:58For their tumor, and this is another example.
52:01That was a different publication
52:03that was also interesting,
52:04and this was a 63 year old man who
52:07had a gallbladder respected and
52:08this was initially seen else not at
52:11not centrally Yale and the initial
52:13diagnosis that was made was Edna carcinoma.
52:15Several, you know months later.
52:18The page you know,
52:21the clinician oncologist ordered,
52:23and she S testing and MSI testing,
52:26and it came to us.
52:28For assessment and between the morphology
52:32and the results from the oncoming testing,
52:37the diagnosis was revised to Miso,
52:39thi Lio Ma,
52:40and that's because this particular tumor,
52:43one of the reasons was that this
52:45particular tumor showed about 1 mutation,
52:47and again there's two of them.
52:49There's one mutation that was seen both
52:50in the tumor and in the patient's blood,
52:53and a second back,
52:54one mutation that was found
52:55in just the tumor.
52:56So here's an example of somebody again.
52:59Has a germline first hit and that one
53:01and the tumor there's a second hit in
53:05in the in the second allele of BAP one.
53:12Doctor Shelper I see your question.
53:14I can come back to it a little bit later
53:16and so for this particular patient we
53:18can make a diagnosis of Bab 1 trimmer
53:21for Disposition syndrome and you know,
53:23looking at this patient pedigree,
53:24there was actually quite a lot of
53:26cancer in this patient syndrome.
53:28And you know, again,
53:29you know we can sort of allow this
53:31family to be able to be tested for it
53:34and and now they can start potentially
53:36screening for some of these cancers, etc.
53:41And and so.
53:43You know the concept of being able
53:45to do genetic findings that are
53:48discovered through online testing.
53:50Is is something that we are working
53:53on in collaboration again with our
53:55genetics clinic and we looked at 123
53:59patients who had a known pathogenic
54:02variant and you know 2/3 of them.
54:08We're not known prior to the testing
54:10with alkaline that that that they
54:12had in pathogenic mutation in their
54:14germ line that will impact either
54:18their family members or options for
54:20therapy and then doctor Shelper.
54:22You mentioned that in this case the
54:25germ line was it is a little bit low.
54:28It would be expected to be at.
54:3040% or 50% if it was a heterozygous
54:33germline variant,
54:34it's within range of what we see with.
54:39With.
54:40With MGS testing,
54:42so sometimes there can be a little
54:45bit of skewing that happens with NGS
54:47and you may not get a perfect number,
54:50but we we typically accept these results.
54:57And Doctor Robert asked another question.
54:59The diagnosis of change from the
55:01adenocarcinoma to miso, thi Lio Ma?
55:03It was based by both.
55:05Really it was based on both.
55:07So when they add note when this
55:10gallbladder came over we were able to.
55:13So I'll say this was all Doctor Ilkay who
55:16initially raised alarm about the diagnosis.
55:19She she thought it was an odd looking add,
55:21no carcinoma, quote, UN quote,
55:23and so she ordered additional
55:25immunostains to check.
55:26And and at the same time NGS was
55:29being done with anchor mine.
55:31So basically,
55:32when all of those results came out,
55:35you know it was coordinated
55:38and the change was made.
55:40So sort of a combination.
55:41It was not one or the other.
55:46OK, so in the last three minutes last
55:49patient, so this was a patient who
55:51had a new diagnosis of metastatic
55:54non different carcinoma and the
55:56question is what do you order?
55:57And really again it's a tricky question
56:00because NGS does not really have a
56:03huge role in the diagnosis of any
56:06neuroendocrine tumors or neoplasms.
56:08Neurocrine tumors tend to be
56:10diagnosed by morphology as either well
56:12differentiated or poorly differentiated.
56:14And you know, poorly differentiated
56:17ones tend to have a lot of P53RB
56:21mutations or CDKN 2A mutations,
56:23whereas the mtor pathway tends to
56:26be altered in the wild if tumors,
56:28and so NGS that targeted therapy does
56:31not really have a huge role in this.
56:33Nevertheless,
56:34on combine was ordered for this patient.
56:37And so this is from the hepatitis
56:40specimen and we estimated 90% malignant
56:42cells within this tumor sample and over
56:46150 mutations right outside in this tumor.
56:49And you know, this is something that,
56:51like when we get one of these results
56:54on the tumor profiling lab service.
56:56We just like want to start crying because how
56:59do you assess 150 importations in one tumor?
57:03And you know you've got like 20 other
57:06tumors to look at, so you kind of.
57:08You know you sort of gain experience
57:10and you figure things out anyway,
57:13so we had 15 mutations there.
57:16That were, you know,
57:17sort of significant.
57:18There's 140 others that were maybe
57:21like a little bit more vus types,
57:24and so basically this is a tumor that's
57:27consistent with hypermutation and.
57:30How does hyper mutation occur in cancer?
57:33There's multiple causes of it.
57:35MSI is one of those we've already spoken
57:38about MSI quite a bit and others could
57:41be mutations and pull or pull D and
57:44Neurocrine tumors are not commonly.
57:49Do not commonly show MSI high status.
57:52Maybe only a handful of those cases.
57:55And maturity of.
57:58You know MSI high tumors are
58:00sporadic in nature,
58:01so you know we want to execute lynchings.
58:03M in this patient and
58:05thankfully none of these.
58:06None of these mutations were germ
58:08line in this particular patient and
58:10just looking deeper into literature
58:14you know what do we know about
58:16hypermutation and nerve tumors you
58:18know and does MSI contribute to that?
58:20And at least then one study there seems
58:22to be a contribution of them aside,
58:24hypermutation in our consumers and
58:26another study also found a fairly
58:29high number. Tumors that had.
58:33Mr.
58:33That was unstable but not a
58:36lot of detail about it,
58:38and the point is that maybe it doesn't
58:41really matter what the cause of the MSI
58:43in this patient is, but now we know that.
58:46Or the hypermutation.
58:47But now we know that there's a
58:49response to PD one inhibition.
58:50That's an option for him,
58:52and this is an example of a
58:55patient who responded to Pembroke.
58:59You know who had a MSI High Nordic rent
59:03tumor and this is something that's,
59:06you know this.
59:07This expanding utility for using MSI to
59:10predict response to PD one is
59:14a relatively recent finding.
59:16And we can also think about MSI.
59:21As measured by NGS,
59:22this is an emerging by informatics tools.
59:24There are numerous computational methods
59:26that can be used for NGS detection
59:28and just in the interest of time I'm
59:30going to skip through some of these.
59:32We did look at.
59:33We did look at one of these methods to be
59:36able to tell NGS with our former fellow,
59:40and we did find that this is a
59:42specific but non sensitive method,
59:44at least using the oncoming NGS data and so.
59:48In this particular patient,
59:50although the mantis was negative for MSI,
59:52you know we still have questions
59:55about you know what might have
59:57been the cause of this patience.
59:59Anyway, I'm going to skip the next couple
01:00:01of slides here and just get to the end.
01:00:03If any of you are interested in
01:00:04in more of these types of cases,
01:00:06please come to the precision Medicine
01:00:08tumor board where we review all kinds
01:00:10of tumors with all sorts of findings,
01:00:13both germline and somatic,
01:00:14and determine what best causes are.
01:00:17So, in summary,
01:00:18I hope you guys have seen how I've
01:00:20gone through this mandering path
01:00:22of being a GI and liver surgical
01:00:25pathologist into incorporating molecular
01:00:27pathology into my practice and into my.
01:00:31Research and focusing on
01:00:33patients results and.
01:00:36And outcomes,
01:00:37and hopefully in the future
01:00:40we can coordinate some of this
01:00:42information more seamlessly and
01:00:44have an integrated practice where.
01:00:47This information flow happens easily
01:00:50and accessibly to everyone and so.
01:00:54I'd like to thank everyone I you know, AM.
01:00:58Moving on to some new new things
01:01:01in the department as the Director
01:01:03of Quality and Patient Safety cell
01:01:05be leaving behind some of this,
01:01:07some of this research that I'm doing here,
01:01:09but I'm sticking around and I'm looking for.
01:01:15You know collaboration with everybody,
01:01:18and in this new endeavor.
01:01:21And that's it.
01:01:22That's yeah,
01:01:22I'm sorry for going over a little bit,
01:01:25but I'm happy to take some
01:01:27additional questions at this time.
01:01:30So we have about 84 people logged in
01:01:33and we are well over the time limit,
01:01:38but maybe a quick one or two questions.
01:01:42Please unmute yourself and ask.
01:01:47So I can start with Joanne, you know?
01:01:50Joanne, thank you for this.
01:01:52Very interesting you know seminar.
01:01:55I think this is you as your last set.
01:01:57So I point out this is exactly
01:01:59probably the future direction of
01:02:01future practice of our pathologies.
01:02:04So my question to you is if we are from from
01:02:06your personal experience and do you feel?
01:02:09I mean if whatever you can share with us,
01:02:13some of your personal experience,
01:02:14you know when you are not about
01:02:16certain that you did not.
01:02:17Through the Molecular Pathology
01:02:19fellowship you are just, you know,
01:02:21surgical pathologists and then decided to.
01:02:24You know to practice molecular
01:02:25pathology what you know.
01:02:27What's your experience you think is doable?
01:02:29I mean certainly it's doable.
01:02:30You prove it.
01:02:31But what I'm saying and it obviously
01:02:32you know and it hurdles any sort of
01:02:35insights you may have for other sort
01:02:37of aspiring surgical pathologies that
01:02:40may thinking that goes through the,
01:02:42you know, the way you have guns.
01:02:44Yeah, yeah, absolutely.
01:02:45I mean, I hope other pathologists
01:02:47can join me in in this way as well.
01:02:50I I think challenge is that
01:02:52there is more molecular work.
01:02:54Then there are molecular
01:02:56trained molecular pathologists,
01:02:58so there is need for you know additional
01:03:01expertise in this area and I think
01:03:04in addition the world of molecular
01:03:07pathology I think is changing rapidly
01:03:10more rapidly than the fellowship
01:03:12training can sort of keep up with
01:03:16and you know a lot of these end results.
01:03:19You know this is all in the last five years.
01:03:22Fellowships can change fast
01:03:23enough to sort of incorporate.
01:03:25That aspect, and.
01:03:29And you know, I you know,
01:03:31I personally had a strong interest in cancer.
01:03:33That I, you know, goes back to you,
01:03:35know my PhD days.
01:03:37So I was sort of primed to
01:03:40learn this material quickly.
01:03:42But it can be done, I think with.
01:03:46You know what?
01:03:47So one thing that I did I I always like
01:03:49to think I always like to say that I
01:03:51actually did exactly what a fellow does.
01:03:53I did a six week rotation at TPL at that's
01:03:56what a fellow in molecular pathology does.
01:03:58They do a six week rotation in
01:04:00TPL and I'm focusing on just that
01:04:03aspect of molecular pathology.
01:04:04I'm not, you know,
01:04:06I I let others worry about you,
01:04:08know the fish.
01:04:09The MLH 1 methylation the PCR,
01:04:12you know, I, I trust the you know
01:04:15other labs to do their part so I'm.
01:04:17You know,
01:04:18with a narrow focus like that,
01:04:20I think it's quite possible for many
01:04:22pathologists sort of interact with this,
01:04:24and I think in addition,
01:04:26we really need to expand our teaching
01:04:28so that everybody can sort of chip in
01:04:32small things in in this in this endeavor.
01:04:36So just by increasing our,
01:04:38you know our ability to teach the future
01:04:41generations some of this material.
01:04:43I think it's just it's a.
01:04:44It's a rapidly evolving field.
01:04:47And and I think we need to be.
01:04:51Creative and how we approach all the
01:04:54work that this field is generating.
01:04:58Thank you.
01:05:08Well, if there are no questions. I'll let.
01:05:14It was a great shock Joanna I I think
01:05:17as a surgical pathologist,
01:05:19I really appreciate the bringing in
01:05:21of integration with molecular and I.
01:05:24I think we would all welcome
01:05:26that integrated report and
01:05:28the learning that we can gain
01:05:30from you and your colleagues.
01:05:32So I I think that we will be
01:05:35very supportive of this and
01:05:36I want to thank you for giving
01:05:38such an interesting talk.
01:05:39So patient focused. That I think,
01:05:43makes it quite clear that the time is now
01:05:46to do this, yes, so you and I will
01:05:48have to talk about the colon cancer,
01:05:51integrated reports and how we can
01:05:52bring that to our service for sure.
01:05:57And we also want to talk
01:06:00about integrated report.
01:06:01In reports in head and neck cancers,
01:06:04absolutely all of them.
01:06:06Thank you so much.
01:06:10Alright, thank you everybody,
01:06:13thank you. Thank you.