Pathology Grand Rounds, April 23, 2026: Miguel Reyes-Mugica, MD

Transcript

• 00:00Good afternoon,
• 00:02everyone.
• 00:03Welcome to
• 00:05Yale pathology ground runs.
• 00:09Have you ever wondered
• 00:11why children get a malignant
• 00:13tumor at such a young
• 00:14age?
• 00:15Today, you're going to hear
• 00:17from the expert,
• 00:18get some answers from him.
• 00:21So it's my great honor
• 00:24and pleasure to introduce
• 00:26today's Guam Run speaker,
• 00:28doctor
• 00:29Miguel Reyes.
• 00:31So probably doctor Reyes don't
• 00:33need a introduction.
• 00:35He's,
• 00:37you know, has friends here
• 00:38with Yale for many years,
• 00:40has a great
• 00:42friend.
• 00:43So just briefly,
• 00:45doctor Reyes is currently a
• 00:47clinical professor
• 00:50and pediatric and
• 00:51developmental
• 00:52pathology division chief
• 00:54in the department of pathology
• 00:56and laboratory medicine
• 00:58at
• 01:00University of Miami,
• 01:03Miller School of Medicine.
• 01:06Doctor. Reyes
• 01:08completed his medical education
• 01:10in National
• 01:12Autonomous
• 01:13University
• 01:14of Mexico
• 01:16in 1980s,
• 01:18followed by
• 01:19residency training and in Anatomic
• 01:22Passage
• 01:23there.
• 01:25After several years
• 01:26working as attending physician in
• 01:29National Institute
• 01:31of Pediatrics,
• 01:32he decided come to United
• 01:34States
• 01:35and to continue his medical
• 01:37careers.
• 01:39Doctor. Reyes got his pediatric
• 01:41pathology fellowship training
• 01:43in nineteen ninety four
• 01:46from Children's Memorial Hospital of
• 01:48Northwestern
• 01:49University.
• 01:51After the fellowship,
• 01:53he joined Yale
• 01:55as a faculty member in
• 01:57our department
• 01:59and
• 02:01raised his rank
• 02:03from assistant professor to full
• 02:05professors.
• 02:08So after spending fourteen years
• 02:11in
• 02:12Yale,
• 02:13he relocated
• 02:15to Pittsburgh
• 02:17to become the chief pathologist
• 02:19in Children's Hospital of Pittsburgh,
• 02:22University,
• 02:24Pittsburgh
• 02:26until twenty twenty four.
• 02:29Doctor. Reyes is world renowned
• 02:33pediatric pathologist,
• 02:35has
• 02:35make significant contribution
• 02:38to the pediatric
• 02:39pathologist communities,
• 02:41including clinical practice,
• 02:44translational
• 02:45research,
• 02:46and
• 02:47medical educations.
• 02:50He was the past president
• 02:53of International
• 02:54Pediatric Massage
• 02:56Associations
• 02:58and the Society
• 03:00of Pediatric Massage.
• 03:03Doctor. Reyes
• 03:05published
• 03:06more than three hundred peer
• 03:08review articles,
• 03:10book
• 03:11books and book chapters.
• 03:16So he is the standing
• 03:18editors
• 03:19of the WHO classification
• 03:21of tumors
• 03:22editorial board.
• 03:24And he was the
• 03:26expert
• 03:26editor
• 03:28for the newly released WHO
• 03:30classification
• 03:31of tumor
• 03:33pediatric
• 03:34tumors.
• 03:36So although, you know,
• 03:38the current WHO classification
• 03:40tumor
• 03:41already in his
• 03:43its
• 03:43fifth edition.
• 03:45The pediatric tumors
• 03:48is the first time
• 03:49WHO has including
• 03:51a separate volume
• 03:53on the pediatric tumors.
• 03:57There's no doubt this publication
• 03:59will help improving
• 04:01the standardization
• 04:03of pediatric
• 04:04tumor diagnosis
• 04:06and facilitate
• 04:08the translate
• 04:10translation of diagnostic
• 04:11research into
• 04:13practice
• 04:14worldwide.
• 04:16So without further ado,
• 04:18please join me, Wolfgang. Reyes.
• 04:28Well, thank you very much
• 04:31for being
• 04:32first for inviting me,
• 04:34then for, presenting me as
• 04:37in such a kindly manner.
• 04:40I recognize and have a
• 04:42lot of,
• 04:44fun
• 04:45to see many of my
• 04:47former trainees,
• 04:48colleagues,
• 04:49friends,
• 04:51and people that
• 04:53taught me how to become
• 04:54an academic pathologist.
• 04:56There's Costa, doctor Morrow here,
• 05:00and
• 05:01David here.
• 05:02We interacted
• 05:04the other day with here.
• 05:05We interacted with them many
• 05:07years, and,
• 05:08it has been an honor
• 05:09for me. This is really
• 05:10my academic home, so I
• 05:12am very glad to return.
• 05:16Today, I will present something
• 05:18that is different from, the
• 05:20previous conference that I presented
• 05:21here about eight years ago.
• 05:24Today, we will, talk about
• 05:26how
• 05:27looking at the slice in
• 05:28pediatric lesions
• 05:30can allow you to identify
• 05:32cancer predisposition
• 05:34syndromes. This is a topic
• 05:35that I have,
• 05:38cultivated,
• 05:39extensively in the last few
• 05:41years. How do I advance
• 05:43this?
• 05:49Oh, thank you very much.
• 05:51Didn't see that.
• 05:53So let's move on.
• 05:57I have nothing to declare,
• 05:59and, this is the outline,
• 06:03and we will go directly
• 06:04into matters.
• 06:06At the beginning of last
• 06:07year, the official's archive
• 06:09journal, the oldest journal of
• 06:11pathology in the world,
• 06:13published a special issue in
• 06:15which, my colleague from Madrid,
• 06:17Doctor. Isabel Colmenero, the chief
• 06:19pathologist at Hospital del Nino
• 06:21Jesus
• 06:22in Madrid,
• 06:24and I put together a
• 06:25collection of
• 06:26twelve papers, ten of twelve
• 06:28papers, and an editorial. We
• 06:30invited all the authors that
• 06:31contributed to this special issue
• 06:34highlighting
• 06:35the,
• 06:36challenges and novelties in pediatric
• 06:38pathology.
• 06:39I invite you to review
• 06:40the special issue because it
• 06:41contains interesting information that is
• 06:43mostly
• 06:45missed by the adult pathology,
• 06:48sphere, the adult adult pathology
• 06:50circles.
• 06:52In this
• 06:54issue,
• 06:54one of the papers
• 06:56was specifically dedicated to the
• 06:58pediatric cancer
• 06:59position syndromes in the, outside,
• 07:02of the central nervous system.
• 07:04And, I also invite you
• 07:06to read this paper because
• 07:07this will summarize
• 07:09what I am going to
• 07:10present to you today.
• 07:14Okay. It's not advancing.
• 07:16Okay. Here. So how do
• 07:17we define cancer predisposition syndromes?
• 07:21Heritable condition that increases the
• 07:23child's risk of developing cancer
• 07:25due to general mutations in
• 07:27a gene regulating
• 07:28cell growth, DNA repair, or
• 07:30genomic integrity. That's in general
• 07:32where a cancer predisposition syndrome
• 07:34is. And, of course, this
• 07:35affects not only children,
• 07:36but, adults too, but adults
• 07:39affected with these conditions bring
• 07:41these cons conditions since they
• 07:43are
• 07:44children. So we pediatric pathologists
• 07:47are at the specific point
• 07:48to identify these entities
• 07:51early, early enough to intervene
• 07:53and modify the outcomes of
• 07:55these patients.
• 07:57They are, representing,
• 08:00in inherited
• 08:01risk, usually autosomal dominant, occasionally,
• 08:05the novel,
• 08:06and the tumor often appears
• 08:08at younger ages than, general
• 08:10population. The same type of
• 08:11tumor that you see in
• 08:12adults when it appears in
• 08:14a child, it may be
• 08:15the first clue for you
• 08:16to look for a cancer
• 08:18predisposition
• 08:18syndrome.
• 08:20Multiple of these, many of
• 08:22these tumors are rare
• 08:23and, children with multiple primaries
• 08:26or unusual types are specifically
• 08:28a red flag to identify.
• 08:30The family history may show
• 08:32clustering of specific or related
• 08:34causes, but sometimes it doesn't.
• 08:37Approximately ten percent of pediatric
• 08:39cancers are due to germline
• 08:41alterations
• 08:42and early frequent recognition is
• 08:45a key,
• 08:48to, provide adequate surveillance
• 08:50therapy and family assessment.
• 08:53So
• 08:53the point that I will
• 08:55emphasize today is that frequently
• 08:57histology provides the first clue,
• 09:00but you just have to
• 09:00keep this in mind. If
• 09:02you don't, you'll miss it.
• 09:05Okay.
• 09:09The pediatric pathologist is then
• 09:11at the crossroads between what
• 09:13is the clinical observation of
• 09:14a patient, the genetics of
• 09:16this patient, and evaluating,
• 09:18the lesions that are under
• 09:20the microscope
• 09:21with the risk of increasing
• 09:23developing cancer.
• 09:25In addition
• 09:26to accurately diagnose these entities,
• 09:28we need to be familiarized
• 09:30with the implications of additional,
• 09:34seemingly
• 09:35uninteresting,
• 09:36unimportant findings that I will
• 09:38show you today.
• 09:39And clinical and or laboratory
• 09:41findings,
• 09:42that are apparently minor may
• 09:45be of various important significance.
• 09:48This is taken from the
• 09:49paper of the officials archive
• 09:50journal that I mentioned to
• 09:52you. I'm not going to
• 09:53go over every one of
• 09:55these entities. This is just
• 09:56to emphasize that I I
• 09:58would like you to, review
• 10:00the paper, read it, and
• 10:01and, send us any,
• 10:03comments, criticisms, etcetera. There are
• 10:06many,
• 10:07cancer predisposition
• 10:08syndromes listed here. Obviously, this
• 10:10is just to show you
• 10:11that the paper is long
• 10:13and,
• 10:14full of,
• 10:15information
• 10:16that I am not going
• 10:17to be able to detail
• 10:18here. But we are going
• 10:20to,
• 10:21start with one of the
• 10:22most common,
• 10:23pediatric tumors that we see
• 10:25here.
• 10:27This is Wilms' tumor also
• 10:28known as nephroblastoma.
• 10:30Nobody really knows what doctor
• 10:32Max Williams described.
• 10:35Bruce Beckwith, the late Bruce
• 10:37Beckwith, a good friend of
• 10:38mine, who was the,
• 10:40official reviewer for the children's
• 10:42oncology group for many years,
• 10:44told me several times that
• 10:46nobody really understood what Max
• 10:48Williams, described, but this is
• 10:49the entity that we recognize
• 10:51as Wim's tumor.
• 10:52A tumor that produces a
• 10:54massive
• 10:55growth
• 10:56inside the kidney with a
• 10:58claw sign on the residual
• 11:00kidney that surrounds it as
• 11:01you can see in this,
• 11:03CT scan and this is
• 11:04a classic microscopic
• 11:06appearance. I don't use the
• 11:07gross the gross term
• 11:09because it grosses me out.
• 11:11It's recommending
• 11:12it's it's recommended to get
• 11:14rid of the grossing and
• 11:15gross. But, anyway, the macroscopic
• 11:17appearance of this tumor is
• 11:19this,
• 11:20fleshy,
• 11:22relatively homogeneous, sometimes vocally hemorrhagic,
• 11:26sometimes very hemorrhagic. And then
• 11:28you can appreciate that there
• 11:29is a little rim of
• 11:31kidney that,
• 11:33is still,
• 11:34preserved there. This is Bruce
• 11:36Beckwith here visiting at Yale.
• 11:38This is me, believe it
• 11:39or not. I still didn't
• 11:41stain my beard white.
• 11:42And, this is a few
• 11:44years later, ten years later,
• 11:45when we met together in
• 11:46Tours, France.
• 11:49This Beckwith, William and syndrome
• 11:51and other syndromes such as
• 11:53Wagner, Dennis Trash,
• 11:54Simpson Golami,
• 11:56Behamel, Fraser,
• 11:58Bloom syndrome, Dyson one are
• 12:00associated
• 12:01with Wilms' tumors, and we
• 12:02will review how they look
• 12:04at,
• 12:05very briefly.
• 12:06Triphasic Wilms tumors with epithelial
• 12:09tubular components, blastema components, and
• 12:12stromal components are the rule.
• 12:14This is a blastema predominant
• 12:16component and this is a
• 12:18stromal predominant WIMS tumor. And
• 12:20sometimes you can have very
• 12:22clear muscle skeletal muscle differentiation
• 12:24that you can appreciate in
• 12:26these pictures from WIMS tumors.
• 12:28In the past, we used
• 12:29to call this territory variant
• 12:31of a WIMS tumor when
• 12:32there are components such as
• 12:34skeletal muscle,
• 12:36keratinizing
• 12:37squamous epithelium, and even osteoid
• 12:39formations.
• 12:41The war territory is not,
• 12:44recommended anymore.
• 12:46And after you make the
• 12:47diagnosis so what happens? Doctor,
• 12:51Farzana Pankaj,
• 12:53Pankar comes with you and
• 12:54tells you, Miguel,
• 12:56yesterday there was an an
• 12:57a rectomy specimen.
• 12:59Can you tell us what
• 13:00is it? Is it a
• 13:01Williams tumor? And then the
• 13:02first thing is to confirm.
• 13:03Yes. It's a woman's tumor,
• 13:05Farzana. Right? Good.
• 13:06Next question.
• 13:08What is the stage?
• 13:09Okay. And then is it
• 13:11favorable or unfavorable?
• 13:13And how do you distinguish
• 13:14that? Because that takes makes
• 13:16a difference in the treatment
• 13:17of the patient.
• 13:18And then when I respond
• 13:20these three questions,
• 13:21she goes back to her
• 13:22office to look at the
• 13:24patient and start chemotherapy.
• 13:26Is that correct?
• 13:28However,
• 13:31favorable histology is
• 13:33identified with anaplastic
• 13:36mitosis or, hyperchromatic
• 13:38nucleomegaly. You have to have
• 13:39both of them for the
• 13:41diagnosis. I listed here the
• 13:42criteria. I'm not gonna go
• 13:43over them,
• 13:45in detail
• 13:46And this is another atypical
• 13:47mitosis and, hyperchromatic nucleomegaly
• 13:50at least three times the
• 13:51size of adjacent non anaplastic
• 13:53nuclei.
• 13:55Immuno histo chemistry is irrelevant
• 13:57in the diagnosis and study
• 13:58of WIMS tumor patients, but
• 14:00I listed here what is
• 14:02important is to add the
• 14:03molecular analysis for the patients
• 14:05because there are certain loss
• 14:07of heterozygosity
• 14:08and other chromosomal abnormalities that
• 14:10may determine treatment.
• 14:12And then you have to
• 14:13examine the residual kidney, the
• 14:15non tumor kidney. And in
• 14:18that, the important thing is
• 14:19to find nephrogenic rests because
• 14:21if there are nephrogenic rests,
• 14:23the possibility of a contralateral
• 14:25synchronous or metachronous once tumor
• 14:27is high.
• 14:29And these are examples that
• 14:30Bruce Beckwith gave me. These
• 14:32are pictures from him where
• 14:33this is the nephroblastomatosis.
• 14:36That word is only used
• 14:37for cases in which the
• 14:39entire renal parenchyma
• 14:40is nephroblastic
• 14:42and not a Wilms tumor
• 14:43directly. And this is an
• 14:45example of a Wilms tumor
• 14:46with numerous
• 14:47nephrogenic rest microscopically
• 14:49easy to identify.
• 14:51Okay.
• 14:52Let me give you an
• 14:53example of one of the
• 14:54last cases that I saw
• 14:55in Pittsburgh a couple of
• 14:56years ago.
• 14:58This tumor came from a
• 14:59two year old boy with
• 15:00a left renal mass. You
• 15:01can see the microscopic external
• 15:03appearance,
• 15:04the cross, the surface,
• 15:07of the, section and the
• 15:08residual kidney is here. Everything
• 15:11fine?
• 15:12Blastema predominance,
• 15:14then there is, some perirenal
• 15:16fat, and then there is
• 15:17some residual kidney.
• 15:19So I gave the diagnosis.
• 15:21It's a woman's tumor. It's
• 15:22a favorable histology woman's tumor,
• 15:24and therefore favor,
• 15:26the chemotherapy is not as
• 15:28aggressive. And the stage is
• 15:30stage one because it hasn't
• 15:31broken through the capsule or
• 15:33the renal signs.
• 15:37And then you see, you,
• 15:38you, you, you show the
• 15:40three components
• 15:41and then you go to
• 15:42the renal
• 15:44non tumoral parenchyma.
• 15:46And this is where things
• 15:47get interesting
• 15:48because
• 15:49diagnosing one's tumor is not
• 15:51difficult.
• 15:53But looking at this
• 15:55is difficult.
• 15:57Not looking at it, but
• 15:58in understanding what you are
• 16:00seeing. What you have here
• 16:02are
• 16:03tubular structures in the medulla
• 16:04that are separated
• 16:06by a relatively mixed soy
• 16:08type
• 16:09of stroma
• 16:10that is not normal. This
• 16:12is not the normal morphology
• 16:14of the renal medulla.
• 16:16And when you see that,
• 16:19you have to diagnose it.
• 16:20So the diagnosis that I
• 16:22issued in this case is
• 16:23re is, written here. And
• 16:26then I put renal medullary
• 16:28dysplasia consistent with Beckwith Wiedemann
• 16:30syndrome, see comment and references.
• 16:34When we discuss this case
• 16:35at tumor war in Pittsburgh,
• 16:38the, director of pediatric oncology,
• 16:41the clinical director of pediatric
• 16:43oncology there,
• 16:45first I said, this patient
• 16:46has wounds tumor and this
• 16:47and this and then back
• 16:49with William and Singh. And
• 16:50there was a silence.
• 16:53Very uncomfortable, to be honest
• 16:54with you.
• 16:55And then he said, well,
• 16:58maybe.
• 17:01But, no, it's not a
• 17:02maybe. It is,
• 17:04Beckwith Wiedemann syndrome.
• 17:06I put this,
• 17:08comment in the report, and
• 17:09I mentioned a previous,
• 17:11reference that Jorge Dotto anybody
• 17:14here remembers Jorge Dotto?
• 17:17He wrote to me this
• 17:18morning because he saw the
• 17:19announcement in Twitter,
• 17:20of this conference, and he
• 17:22said, oh, Miguel. It's nice
• 17:23that you are going back
• 17:24to Yale. Well, I'm gonna
• 17:26show your name because he
• 17:27and I
• 17:28published a case that,
• 17:31was similar to this one.
• 17:33The case from Pittsburgh
• 17:35was published
• 17:37with this group of authors,
• 17:39and one of them, Julia
• 17:40Mead, is a pediatric, you
• 17:42know, Julia Mead, Rosanna.
• 17:44She's a pediatric oncologist that
• 17:46is specialized in cancer predisposition
• 17:48syndromes. And, the following day
• 17:50of the tumor board, she
• 17:50comes to my office and
• 17:51she says, Miguel, can I
• 17:53cry with you?
• 17:55What happened?
• 17:56They you were right. They
• 17:58missed it. And the problem
• 18:00is that with, Beckwith Wiedemann
• 18:01syndrome is not an easy
• 18:02diagnosis to make even clinically,
• 18:05even to the specialist.
• 18:07I remember an autopsy here
• 18:10that one of our geneticists,
• 18:12a very highly respected geneticists
• 18:14here came to see. And
• 18:16when I
• 18:17just looked at it and
• 18:18I said, oh, it's a
• 18:19Beckwith William and syndrome.
• 18:21She looked at me like,
• 18:22what?
• 18:23And it was because it's
• 18:24not easy to diagnose it
• 18:25unless you think of it.
• 18:28So
• 18:29this patient that I show
• 18:31you was published
• 18:32and showing the medullary race,
• 18:35the medullary dysplasia,
• 18:37all the correlation with radiology,
• 18:39and then other examples in
• 18:41our,
• 18:43files
• 18:44were found with Beckwith Guilliman
• 18:46Syndrome and Guilliman's tumor. What
• 18:48is Beckwith Guilliman Syndrome? Well,
• 18:49you know, it's a combination
• 18:51of overgrowth
• 18:52affecting multiple organs described by
• 18:55Bruce Beckwith and,
• 18:57Hans Wiedemann.
• 18:58On a case report, by
• 18:59the way, and there are
• 19:00people that are very,
• 19:02upset when you say I'm
• 19:03going to do a case
• 19:04report and say what? You
• 19:06should that
• 19:07that's that's not good.
• 19:09Well, if Bruce
• 19:10of Witten or Witherman did
• 19:12not report that case,
• 19:14the field of overgrowth syndromes
• 19:16would not have started. Okay?
• 19:18So, yes,
• 19:19you may be wasting your
• 19:21time as I spoke this
• 19:22morning with doctor Ho how,
• 19:24go,
• 19:25on case reports, but you
• 19:27may not if you ask
• 19:28the interesting question. So don't
• 19:30don't don't get dissuaded to
• 19:32write cases if you think
• 19:34that they are interesting.
• 19:35These are all the genetic
• 19:36abnormalities. I'm not going to
• 19:38detail them because this is
• 19:39not the function, of this,
• 19:42conference. It's just to call
• 19:43your attention at what you
• 19:44need to look under the
• 19:46microscope or at the microscopic
• 19:48level.
• 19:50This is an example of
• 19:51a fetus with with a
• 19:53man syndrome
• 19:54that we, carried on an
• 19:56autopsy here many years ago.
• 19:59You can see the exome
• 20:00follows. This is not umbilical
• 20:02hernia, but it's a huge
• 20:04umbilical hernia hernia that contains
• 20:07all the abdominal organs, including
• 20:09the liver. And you see
• 20:10the the the two fetuses
• 20:12here with coarse features. They
• 20:14don't look
• 20:15nice. They are not cute
• 20:16babies.
• 20:17They are coarse because
• 20:19the overgrowth
• 20:20of the tissues, the soft
• 20:22tissues produces these creases
• 20:24and foldings
• 20:26that make them look not
• 20:28not cute.
• 20:30They have these creases in
• 20:31the ears as you can
• 20:32see here, these fissures and
• 20:34creases,
• 20:34and they obviously have different
• 20:36degrees of umbilical cord. And
• 20:38they can have hemihypertrophy
• 20:40or hypertrophy
• 20:41of something.
• 20:43When I invited Bruce Beckwith
• 20:44to give Grand Rounds right
• 20:46here many years ago,
• 20:48we had lunch together, and
• 20:50he told me, you know,
• 20:51the most,
• 20:54unforgettable
• 20:55case of she never said
• 20:56Beckwith Wiedemann syndrome. He said
• 20:58of BWS
• 21:00was a case that I
• 21:02saw on a man with
• 21:03a huge thumb.
• 21:05Okay? Because he doesn't hit
• 21:07the the normality, doesn't hit
• 21:08all the organs at the
• 21:10same level. Okay?
• 21:12The
• 21:14fetal cortex in the adrenal
• 21:16medulla looks like this normally.
• 21:18This is the permanent cortex
• 21:20in the process of development.
• 21:21This is a fetus or
• 21:23a baby of less than
• 21:24six months of age postnatal.
• 21:27Okay? But it can be
• 21:28a newborn. And the pancreas
• 21:30may look like this. In
• 21:32Beckwith Wiedemann syndrome cases, you
• 21:34see
• 21:35nucleomegaly
• 21:36in the fetal adrenal cortex.
• 21:38That is a sign that
• 21:40is frequently associated
• 21:42to Beckwith Wiedemann syndrome. Not
• 21:45always. Sometimes it's just a
• 21:47sign of stress, but when
• 21:48it is when it is
• 21:49so diffuse, that's another clue
• 21:51that you should not miss.
• 21:53Because even if you are
• 21:54doing an autopsy or if
• 21:55you get a nephrectomy with
• 21:57an adrenal gland that looks
• 21:58like that, you need to
• 22:00call doctor
• 22:02Farzana
• 22:03and say,
• 22:05Beckwith Wiedemann syndrome. Please check
• 22:07for that.
• 22:10The CD of blastosis is
• 22:11the process of formation of
• 22:13the islets of Langerhans. And
• 22:15in Beckwith Wiedemann syndrome, you've
• 22:16had a you have an
• 22:17increased number of islets of
• 22:19Langerhans. This is the case
• 22:21that I published with, Jorge
• 22:23Dotto. And let me tell
• 22:24you the story. When when
• 22:25this you were not part
• 22:26of the clinical team at
• 22:28that time, I think, but
• 22:29they came to the search
• 22:31pad area, and I was
• 22:32sitting with Jorge looking at
• 22:34the case.
• 22:35And when, they asked me,
• 22:36what is it? Is it
• 22:37the Wilms? And I said,
• 22:38yes. It is a one's
• 22:39tumor. Is it favorable? Yes.
• 22:40It is favorable. Thank you
• 22:41very much. Okay.
• 22:43And then when I continue
• 22:45looking at the normal
• 22:46residual kidney, it is not
• 22:49normal.
• 22:50And I I asked Jorge
• 22:51and other residents that work
• 22:53with me to walk to
• 22:54the bed of the patient.
• 22:57Our our clinical colleagues looked
• 22:59at us like, what are
• 23:00these guys doing here on
• 23:01the floor? These are pathologists.
• 23:03Right? Well, I I asked
• 23:04permission to
• 23:06check the external,
• 23:09the the clinical,
• 23:10appearance of the of the
• 23:11of the patient. He was
• 23:13a cute baby,
• 23:15about a year old,
• 23:17and,
• 23:19didn't have anything that looked
• 23:21like Benjamin syndrome. No hemihypertrophy,
• 23:23no creases, nothing, not this
• 23:25morphology. And I was very
• 23:26disappointed.
• 23:28And I said,
• 23:29can't be. I sent a
• 23:30couple of pictures to Bruce
• 23:32and he calls me and
• 23:33he says, your patient has
• 23:35PWS
• 23:36whether
• 23:37the rest of his body
• 23:38knows it or not.
• 23:40And they prove it genetically.
• 23:44So
• 23:45this is a type of
• 23:46malformation or
• 23:48abnormal
• 23:49development of the renal medulla
• 23:50that you can appreciate in
• 23:51Beckwith Wiedemann syndrome with this
• 23:53mixoid
• 23:54stroma around the tubules and
• 23:56the separation of the tubules.
• 23:58Please pay attention to that
• 24:00in those cases. You can
• 24:01also see nephrogenic rest. This
• 24:02is another example with a
• 24:04medullary ray, and these are
• 24:06the usual molecular subtypes
• 24:08of Beckwith Wiedemann syndrome. This
• 24:10is taken from the pits
• 24:12five,
• 24:13edition of the WHO,
• 24:16classification of tumors,
• 24:18and we put these pictures
• 24:19in that,
• 24:20volume.
• 24:22Other tumors may also,
• 24:25appear in patients with with
• 24:26Beckwith Wiedemann syndrome, of course.
• 24:28This is a case,
• 24:29that, had a, mesenchymal hamartoma
• 24:33associated with,
• 24:35Beckwith Wiedemann syndrome. By the
• 24:36way, the alpha fetoprotein
• 24:38in this patient was a
• 24:39million,
• 24:40above a million.
• 24:42And it was not a
• 24:43hepatoblastoma,
• 24:44which
• 24:44what would have been the
• 24:46first suspicion.
• 24:47Okay? But it's not a
• 24:49hepatoblastoma.
• 24:49I remember we sent it
• 24:51to Milton Feingold
• 24:52at Texas Children's Hospital, and
• 24:54he called me. He said,
• 24:55you're right, Miguel. He said,
• 24:58So we need to pay
• 24:59attention because the morphology of
• 25:01these lesions
• 25:02may
• 25:03give you the clue and
• 25:04the diagnosis
• 25:06of Beckwith Wiedemann syndrome. Let's
• 25:08change
• 25:11organs. I'm sure that you
• 25:13all have heard, used, and
• 25:15applied the term
• 25:17CPAM
• 25:18or CCAM.
• 25:19Right? Cystic,
• 25:22adenomatoid
• 25:23malformation of the lung or
• 25:25cystic pulmonary,
• 25:27malformation
• 25:28of the lung.
• 25:29Well,
• 25:31please don't use it anymore.
• 25:33It's
• 25:34changing. The nomenclature is being
• 25:36updated. I haven't made that
• 25:38diagnosis in about fourteen years.
• 25:40There are people that write
• 25:42and that are very nice
• 25:43and trying to please people
• 25:45that have described this. Among
• 25:47them, a good friend, Doctor.
• 25:49Tom Stalker, a retired professor
• 25:51who made all these very
• 25:54intuitive,
• 25:56beautiful,
• 25:57conceptual
• 25:58understanding
• 25:59of the development of the
• 26:01long and the cystic lesions.
• 26:02The problem is that however
• 26:04beautiful this was in types
• 26:06zero to type four,
• 26:09it's wrong.
• 26:11And, therefore, we need to
• 26:13move
• 26:13to use a more current
• 26:15classification.
• 26:17There are classically three types,
• 26:19large c's, medium sized c's,
• 26:21small c's. And then he
• 26:23said, well, this occur because
• 26:24they develop in the
• 26:26bronchi,
• 26:27terminal bronchioles, or alveoli. Well,
• 26:29no.
• 26:30She added two more types,
• 26:32etcetera.
• 26:33No.
• 26:34There are other things that
• 26:35look a little bit different
• 26:37but are part of the
• 26:38same spectrum. Congenital lower emphysema
• 26:40is one of them. This
• 26:42dilatation of the lung with
• 26:44a hyper,
• 26:47distension
• 26:48and you can see the
• 26:49microscopic appearance of this long
• 26:51parenchyma.
• 26:52And sometimes you can see
• 26:54like this under the diaphragm.
• 26:56There is a piece of
• 26:57lung that is very solid.
• 26:58This is called the Rocky
• 27:00Tanski
• 27:00lobe
• 27:01of the lung, which is
• 27:03part of the,
• 27:05spectrum of disorders
• 27:06that includes
• 27:08sequestrations,
• 27:10so called or formerly called
• 27:11CPAMs, and congenital lower emphysema.
• 27:14All of those lesions come
• 27:15to us pediatric pathologies
• 27:17very frequently. I don't know,
• 27:19Rafaela. You must receive
• 27:21about one every month
• 27:23probably or more. Right? Because
• 27:25that's more or less what
• 27:26I remember and they look
• 27:27like this.
• 27:29And we
• 27:30usually don't have a problem
• 27:31diagnosing this.
• 27:33The problem
• 27:34well, sometimes this is a
• 27:36Rocky Tanske law. See, this
• 27:37is a picture I took
• 27:38in the eighties in Mexico
• 27:40City where you see the
• 27:41two lungs and then this
• 27:43lobe with a pedicle and
• 27:44vessels. This is a typical
• 27:46sequestration,
• 27:47and we published it with
• 27:48Mark Keller. I don't know
• 27:50if anybody here remembers Mark
• 27:52Keller. He now lives in
• 27:53Miami, close to Miami, and
• 27:55he was the chief of
• 27:55radiology here, and we just
• 27:57had dinner together
• 27:58last week. It's a wonderful
• 28:00colleague.
• 28:01Well, the problem is that
• 28:02many years ago, the group
• 28:04at Harvard,
• 28:05Boston Children's, the h word
• 28:07I'm sorry, John. I remember
• 28:08that the h word is
• 28:10is is problematic here, that
• 28:12evil place of the north
• 28:13as you used to call
• 28:14it, John. But,
• 28:16when the Boston Children's describe
• 28:18this
• 28:19paper, he's
• 28:21they said bronchial atresia is
• 28:23common to extra lower sequestration,
• 28:25intra lower sequestration, and c
• 28:27cam and lower emphysema.
• 28:29So when you obstruct the
• 28:31bronchus in developing
• 28:33kid,
• 28:34that is what happens. Any
• 28:35of those lesions that I
• 28:36mentioned happens. Okay?
• 28:38And there are many papers
• 28:39supporting that. The problem is
• 28:41when you receive
• 28:43something like this.
• 28:45You receive something like this
• 28:46and then you have the
• 28:47cyst here and you say,
• 28:48well, this may be a
• 28:50bronchial atrial deformation sequence or
• 28:52so called CPAM
• 28:53and you see this and
• 28:56you have to consider that
• 28:57this may be a pleural
• 28:58pulmonary blastoma.
• 29:00This is a very aggressive
• 29:02in general tumor
• 29:04that occurs by
• 29:06with mutations of Dicer one.
• 29:08I'm sorry.
• 29:10Dicer one
• 29:12and it occurs in three
• 29:14subtypes,
• 29:15one, two, and three and
• 29:16one is called one, type
• 29:18one regressing.
• 29:20It occurs in the lungs
• 29:21and derives from the long
• 29:22missing kind. But now we
• 29:23are learning that dicer one
• 29:25mutations can produce tumors
• 29:27anywhere and everywhere.
• 29:29The first ones were described
• 29:31in the lung. Okay?
• 29:34They were described by two
• 29:35good friends, Pepper Dehner and
• 29:37Carlos Manibal,
• 29:39who taught me how to
• 29:41do an autopsy for the
• 29:42first time in nineteen eighty
• 29:44six
• 29:45or eighty four. I don't
• 29:46remember.
• 29:48These two guys in Minneapolis,
• 29:50Pepperdainer is one of the
• 29:51most prominent pediatric pathologists in
• 29:53history.
• 29:54And Carlos is a pediatric
• 29:55pathologist at heart, but he's
• 29:57a general pathologist.
• 29:58And they describe this pleural
• 30:00pulmonary blastoma
• 30:02in nineteen
• 30:03eighty eight.
• 30:04Well,
• 30:05after that,
• 30:07Ashley Hill, Jason Hor, Jason
• 30:10Jarsemboski
• 30:10and Pepper Dehner
• 30:12describe the mutations on these
• 30:14lesions
• 30:15and then,
• 30:16identify the major genetic factor
• 30:18which is Dicer one
• 30:20mutations that lead to the
• 30:22Dicer one syndrome.
• 30:24These,
• 30:25are,
• 30:26mutations that affect a key
• 30:28enzyme required to keep precursors
• 30:30of micro RNAs
• 30:32into their mature active forms.
• 30:35And when they are deleted,
• 30:37they are, very,
• 30:39severe in effects.
• 30:41The,
• 30:42germline,
• 30:43pathogenic
• 30:44Dicer one variants, they find
• 30:46these syndromes
• 30:47are always loss of function
• 30:49type
• 30:50and, like many other tumor
• 30:51suppressor genes, germline, allelic loss
• 30:54of function mutations in Dicer
• 30:55one create tumor susceptibility,
• 30:58but appear to be insufficient
• 31:00to initiate tumorogenesis.
• 31:02There are other changes required
• 31:04to develop into,
• 31:05tumorigenesis.
• 31:07Many different organs are affected.
• 31:09The first one described was
• 31:10pulopulmonary
• 31:11blastoma, but we now know
• 31:12that cystic nephroma and a
• 31:14plastic sarcoma of the kidney,
• 31:16and brianal rhabdomyosarcomas
• 31:18and cervical embryonal
• 31:20rhabdomyosarcomas
• 31:22are also associated with Dicer
• 31:23one and many other types
• 31:25of tumors including endocrine, CNS
• 31:28tumors, and ovarian tumors, gyn,
• 31:30gynandroblastoma.
• 31:32This is an example of
• 31:33a Dicer one,
• 31:35tumor.
• 31:36You can see is,
• 31:38one of the cystic types
• 31:39not as aggressive but they
• 31:41can be like this
• 31:44or like this or like
• 31:46this, pleural pulmonary blastoma cystic
• 31:48that can be very cystic.
• 31:51This is very difficult to
• 31:52diagnose as a pleural pulmonary
• 31:53blastoma because it looks completely
• 31:55benign and it behaves in
• 31:57a benign fashion.
• 31:58But you have to identify
• 32:00because the patient and the
• 32:02patient's family is at risk
• 32:04of developing
• 32:05other tumors.
• 32:08Here you have a repetition
• 32:09of what I just said.
• 32:10I'm not gonna spend more
• 32:12time here. This is how
• 32:13you pay attention to the
• 32:14stroma and diagnose it as
• 32:16a plural pleural pulmonary blastoma
• 32:18solid with rhabdomyoblastoma
• 32:21like elements
• 32:22with an aplasia, abundant cytoplasm.
• 32:25And then when you proceed
• 32:26with the genetic analysis, you
• 32:28identify the germline Dicer one
• 32:30mutations
• 32:31in,
• 32:32these,
• 32:33tissues.
• 32:34You can also use,
• 32:36immunohistochemistry,
• 32:38for
• 32:40labeling these changes.
• 32:41Let me show you a
• 32:42council that I received a
• 32:43few years ago. Came from
• 32:45Italy in a patient of
• 32:47one year old
• 32:49with,
• 32:50I'm sure all of you
• 32:50can read Italian.
• 32:52The patient had medulloepithelioma
• 32:55in the eye,
• 32:56retinoblastoma
• 32:58and,
• 32:59on the one enucleation.
• 33:01So the patient already had
• 33:03a tumor in the eye,
• 33:05retinoblastoma.
• 33:06It's a relatively common pediatric
• 33:07tumor and then the patient
• 33:09has
• 33:11a long lesion
• 33:12and this is the appearance
• 33:14of the long lesion that
• 33:15I received. These are images
• 33:16taken from that,
• 33:19that's,
• 33:19case
• 33:20and as you appreciate this
• 33:22cyst and you pay attention
• 33:23to the stroma component of
• 33:25this cyst,
• 33:26something is not right
• 33:28and then you go in
• 33:29other areas
• 33:30more cellular and then
• 33:33the diagnosis that we issued
• 33:35was this type one cystic
• 33:36pure pulmonary blastoma.
• 33:38We didn't know about the
• 33:39resection margins. We said that
• 33:41there was no involvement of
• 33:42the plural in the material
• 33:43reviewed
• 33:44and the background long parenchyma
• 33:47looked normal.
• 33:48And we made a comment
• 33:50here and referred to the
• 33:51pure, to the beats five
• 33:53edition of the pediatric
• 33:56tumors in the
• 33:58WHO. Let me show you
• 33:59another example. This is a
• 34:01two year old with a
• 34:02left pneumothorax that you can
• 34:04appreciate here
• 34:05and then
• 34:07similar lesions to the one
• 34:08that I just discussed.
• 34:10They resected these lesions. Unfortunately,
• 34:13the specimen
• 34:14perforated and it deflated.
• 34:17It was a cystic lesion
• 34:19that appears collapsed here. This
• 34:21is the ink that, our,
• 34:23residents or PAs,
• 34:25dissecting this, example
• 34:27put on to, evaluate the
• 34:28margins. And then when we
• 34:30look at the histology,
• 34:32there are areas like normal
• 34:33lung, areas with little cysts,
• 34:36but then there are areas
• 34:37like this
• 34:39and this.
• 34:40So this is not,
• 34:44as formerly referred to a
• 34:45CPAM. This is a pleural
• 34:47pulmonary blastoma,
• 34:48and you have to pay
• 34:49attention to this because
• 34:51that is what is going
• 34:52to determine
• 34:53the progression of the disease
• 34:54and the treatment necessary to
• 34:56control this entity.
• 34:58There is an aplasia in
• 34:59this stromal cells,
• 35:01very significant an aplasia in
• 35:02some areas, and we issued
• 35:04a diagnosis. Actually, this was
• 35:06the case that there was
• 35:07not mine, but it was
• 35:08in my department. And the,
• 35:10the all these cases were,
• 35:12shared with us and they
• 35:13they used to incorporate
• 35:14our opinions on the pathology
• 35:16signing this case, call it
• 35:18pluripronary blastoma type two because
• 35:20it's not the very cystic
• 35:22but not the very solid.
• 35:23It's mixed
• 35:25and then
• 35:26multiple multifocal an aplasia, a
• 35:28random myometres,
• 35:29differentiation with multifocal an aplasia,
• 35:32etcetera, etcetera, and they comment
• 35:33here.
• 35:38How about this?
• 35:40We are not in the
• 35:41lung.
• 35:42This is a cystic lesion.
• 35:45You recognize this. Right?
• 35:47The testis
• 35:48is in the paratesticular
• 35:51area.
• 35:52I put
• 35:53my cell phone under the
• 35:55glass taking the picture
• 35:57to see the transillumination
• 36:00of the cyst.
• 36:01Okay?
• 36:02And, yeah, residents laugh at
• 36:03me when I do these
• 36:04kinds of things because they
• 36:06say, why did you do
• 36:07that? Well, I want to
• 36:08see the trans illumination. Right?
• 36:10And and you just have
• 36:11to
• 36:12follow your imagination.
• 36:14And, when when I did
• 36:16this,
• 36:17the fellow that was rotating
• 36:19and doing his fellowship with
• 36:20us in Pittsburgh, doctor Louis
• 36:22Samson, a fantastic,
• 36:24fellow pediatric pathology fellow from
• 36:26Canada,
• 36:27he put this,
• 36:29pictures in the tumor board,
• 36:31and this was the final
• 36:32diagnosis.
• 36:33Cystically dilated epididymal ducts consisting
• 36:35with obstructive changes. Yes. Yes.
• 36:37Yes. And then low grade
• 36:39myxoid spin cell neoplasm
• 36:41with a comment.
• 36:42And we learned that in
• 36:43the clinical history, there was
• 36:45a history of Dicer one
• 36:47syndrome.
• 36:48So this lesion fits perfectly
• 36:50well.
• 36:51The fact that we saw
• 36:52it after the patient has
• 36:54been diagnosed with Dicer one
• 36:56is good, but it doesn't
• 36:57matter. It fits everything. And
• 36:59if you see this before
• 37:00knowing the clinical history, you
• 37:02are after it.
• 37:05Recently, group
• 37:07in,
• 37:08that evil place of the
• 37:09north,
• 37:10published this series of cases
• 37:12with Dicer one related
• 37:14WIMS like uterine
• 37:16tumor,
• 37:17with, several cases reported. And
• 37:19the the series are growing
• 37:21in adults and in pediatric
• 37:24examples of Dicer one mutations.
• 37:29Let me switch to another
• 37:31interesting
• 37:32finding.
• 37:33This is a five year
• 37:34old girl with a palpable
• 37:35or propopubic mass. This is
• 37:37a Yale case
• 37:39that, came to us with
• 37:40two independent masses. And, when
• 37:43I was looking at this
• 37:44case, I said two masses.
• 37:45And I remember doctor McNamara,
• 37:47Joe McNamara,
• 37:48one of the pediatric oncologist,
• 37:51told me, yeah, our surgeons
• 37:53think that this is a
• 37:54Williams tumor that dropped down
• 37:55a metastasis into the bladder.
• 37:57I had never seen that.
• 37:59And I have not seen
• 38:00that still now.
• 38:02So five year old with
• 38:03two tumors,
• 38:04there was, however,
• 38:07developmental
• 38:07delay in the clinical history.
• 38:10And because of that
• 38:12and facial
• 38:13dysmorphism,
• 38:15a karyotype was obtained
• 38:17at that time, and they
• 38:18found an interstitial deletion of
• 38:20nine q twenty two q
• 38:22thirty two.
• 38:24And that part of the
• 38:25clinical history made me think
• 38:27in something else.
• 38:30In addition, there was mild
• 38:31hypertrophy, hemihypertrophy,
• 38:33prominent forehead,
• 38:34hyper telerism, epicanthal folds, etcetera,
• 38:36etcetera, etcetera, all that you
• 38:38read there. These are the
• 38:39images of the kidney tumor
• 38:42with
• 38:43a epithelial
• 38:44slash,
• 38:46blastema,
• 38:47components in the Wilms tumor
• 38:49that looks a little weird,
• 38:51but it is
• 38:52a Wilms tumor.
• 38:54And these are the images
• 38:55of the bladder too.
• 38:57If you see them separately,
• 38:59you will diagnose Wim's tumor
• 39:01next, and you will diagnose
• 39:03rhabdomyosarcoma
• 39:04next.
• 39:05Here, we have stroma with
• 39:07an aplasia,
• 39:09desmin,
• 39:11myogenic expression, classic rhabdominosarcoma.
• 39:14But the patient has two
• 39:15tumors and is five years
• 39:16of age.
• 39:17If you see that in
• 39:18a sixty
• 39:19something years old patient, two
• 39:21tumors
• 39:22is very common
• 39:24in a kid?
• 39:25No.
• 39:27So when I re review
• 39:29the clinical history and I
• 39:31saw the interstitial deletion in
• 39:33chromosome nine,
• 39:34I went to my late
• 39:36wife's
• 39:37lab in the genetics department
• 39:39working with doctor Alan Bale.
• 39:42Myra was my late wife,
• 39:44and she was working in
• 39:45that laboratory. And Alan Bale
• 39:47happens to be the person
• 39:48that identify
• 39:50the patched
• 39:51gene.
• 39:52And the patched
• 39:54gene is responsible
• 39:55for Goling
• 39:57syndrome,
• 39:58which is a cancer predisposition
• 40:00syndrome,
• 40:01a very important cancer predisposition
• 40:03syndrome. You can
• 40:06advise the clinicians to pursue
• 40:07the diagnosis of Golgi syndrome
• 40:09when you receive an odontogenic
• 40:11keratocyst because they are commonly
• 40:13the first red flag to
• 40:15identify
• 40:16a Golgi syndrome in a
• 40:18child.
• 40:20Syndrome
• 40:21described by, doctor Robert Golin
• 40:23in Minneapolis
• 40:25is,
• 40:25a multi,
• 40:28tumoral,
• 40:29cancer predisposition
• 40:31syndrome,
• 40:32with, three genes
• 40:34right now that are associated
• 40:36with, with it. Patch one
• 40:38is the first one. Sufu
• 40:40is another one and then
• 40:41patch two. This is the
• 40:42one that Alan bailed and
• 40:43this is seventeen to ninety
• 40:45percent of cases are associated
• 40:46with patch one abnormalities.
• 40:49We published this page, this
• 40:50case,
• 40:51as a a combination of
• 40:53problem, my sarcoma,
• 40:55and deletion of the patching
• 40:57in syndrome
• 40:58appears in nature oncology,
• 41:00and it has been
• 41:02important,
• 41:03interesting paper in my in
• 41:05in my, personal collection because,
• 41:08it taught me a lot.
• 41:10You can see multiple basal
• 41:11cell carcinomas
• 41:12in these tumors in these
• 41:14patients, and this is how
• 41:15Robert Gordon, Bob Gordon identified
• 41:17the the the syndrome. He
• 41:19was
• 41:20on a bus
• 41:21riding in Minneapolis and saw
• 41:23a patient, and he used
• 41:25to go and say, excuse
• 41:27me. I am doctor Gordon.
• 41:28Do you mind if I
• 41:29speak with you for a
• 41:30for a minute?
• 41:32And they will be, no.
• 41:33No. Sure. And then he
• 41:35will explain that he's concerned
• 41:36with these lesions that the
• 41:37patient has in his face.
• 41:39And then he described the
• 41:42the the the the lesion.
• 41:43This is Bob Gordon.
• 41:45We invited Bob Golin to
• 41:47come to Deepgram rounds here
• 41:48many years ago, a couple
• 41:50years up, before he's dead.
• 41:52And when I invited him,
• 41:55I called his office directly,
• 41:57and, the
• 41:59secretary answered and
• 42:01said, I said, this is
• 42:02doctor Reyes from Yale University.
• 42:04May I speak with doctor
• 42:05Gorlin? I am I am
• 42:06narrating this conversation here, and
• 42:08and she goes, yes. Just
• 42:10a minute, please.
• 42:11And then she comes to
• 42:12the phone and I said,
• 42:14she says, hello? And I
• 42:15said, doctor Golin,
• 42:17si in Spanish.
• 42:19Okay? I switched to Spanish
• 42:21and I start speaking with
• 42:23him and then
• 42:25I switched back to English
• 42:26and I I invited him
• 42:28and all that. And I
• 42:28said, doctor Collin, where did
• 42:30you learn your Spanish?
• 42:34He told me that he
• 42:35was part of a CAA
• 42:37CIA
• 42:38mission
• 42:40in the Nordic countries
• 42:42and that he spent six
• 42:44weeks
• 42:45sharing
• 42:46the room
• 42:47with a Spanish
• 42:49priest
• 42:50that was part of the
• 42:51same CIA mission.
• 42:53I didn't want to know
• 42:54anything else.
• 42:57I didn't bear to ask
• 42:58anything else.
• 42:59She she was a fantastic
• 43:01individual, enormous
• 43:02guy. And when he came
• 43:04into my office, he barely
• 43:05fit. And and he's, told
• 43:07me that he had mantle
• 43:08cell lymphoma.
• 43:09He said, my spleen is
• 43:11the size of Texas.
• 43:13He died a few years
• 43:14later, but he was a
• 43:15fantastic individual.
• 43:18Another example,
• 43:20bloom syndrome. And this is
• 43:22something that I also saw
• 43:24here at Yale.
• 43:25Dan, Pat, Jane was my
• 43:27resident, was a resident at
• 43:29that time. I'm sure that
• 43:30you know who doctor Jane,
• 43:32famous doctor Dampa Jane is.
• 43:34And we saw this
• 43:38patient with a bloom syndrome
• 43:40and a Williams tumor.
• 43:42This is a syndrome that,
• 43:44involves
• 43:45repairing DNA, repairing enzymes.
• 43:48And when they are broken,
• 43:49they don't repair the DNA.
• 43:51This case had an aplasia
• 43:54as you can see here
• 43:55and
• 43:56the sister
• 43:57of this patient developed a
• 43:59hepatocellular
• 44:00carcinoma.
• 44:02Both had the same genetic
• 44:04abnormalities.
• 44:06Two children in the same
• 44:07family with two
• 44:09relatively
• 44:09infrequent lesions.
• 44:11They need to
• 44:13rise the red flag for
• 44:14you to pursue it.
• 44:16The pathologist cannot be just
• 44:17sitting in the office and
• 44:18making
• 44:19as my wife says, when
• 44:21when we are working together,
• 44:22she says, oh, you are
• 44:24just giving names to these
• 44:25animals, right, to these,
• 44:27cows. Well, no. We we
• 44:29are part of the clinical
• 44:32advisory
• 44:33team for the patient's family.
• 44:35We need to pursue
• 44:37that they follow it because
• 44:38if they if you don't
• 44:39do that, they may or
• 44:40may not realize that it
• 44:42is important.
• 44:44I don't know if I
• 44:45would,
• 44:46repeat the diagnosis of hepatocellular
• 44:48carcinoma on this particular case
• 44:49because hepatocellular carcinoma in children
• 44:52is relatively rare and is
• 44:53in a process of being
• 44:54reclassified as we speak in
• 44:54the sixth edition of the
• 44:54of the
• 45:00WHO Digestive Tumors book. But
• 45:02we published these these patients
• 45:05with bloom syndrome
• 45:06with,
• 45:07heparocellular
• 45:08and WIMS tumor in both
• 45:10of them in the same
• 45:10family. So those are clues
• 45:13you see the same family
• 45:14having two children with tumors
• 45:16as not frequent.
• 45:19Bloom syndrome
• 45:21looks like this clinically. They
• 45:22have hypersensitivity
• 45:24to the,
• 45:25sunlight, and they have multiple
• 45:27abnormal abnormalities in the karyotypes
• 45:30due to the abnormal mutations
• 45:32in the repair
• 45:33enzymes of DNA. I'm not
• 45:35gonna detail all these because
• 45:37that's we are gonna run
• 45:38out of time.
• 45:40I'm gonna probably finish with,
• 45:43this group of disorders, multiple
• 45:45endocrine neoplasia syndromes.
• 45:47These are typically seen in
• 45:48adults. We all are familiar
• 45:50with them, but you can
• 45:51also see them in children.
• 45:54This individual here
• 45:56is doctor Ivan Carney.
• 45:59I'm sure that many of
• 46:00you have heard of the
• 46:02Kearney syndrome,
• 46:04Kearney's triad,
• 46:05etcetera, etcetera. Kearney's complex.
• 46:08He described all of those.
• 46:10He is sitting with me
• 46:11in my office here at
• 46:12Yale about twenty years ago.
• 46:15I invited him twice, once
• 46:17here and once in Pittsburgh.
• 46:18He was a fantastic guy.
• 46:20Small,
• 46:21Irish
• 46:22gentleman,
• 46:23funny, and very,
• 46:25you know, combative.
• 46:27I remember
• 46:29I I remember that,
• 46:30I think Stuart Flynn, told
• 46:32me that he was presenting
• 46:34something, and then Alan Carney
• 46:35was jumping in the audience
• 46:37trying to contradict him and
• 46:39he found him, a very
• 46:40combative spirit.
• 46:42Very nice guy. And,
• 46:45we are referring to the
• 46:46Cipoll Williams Pierce,
• 46:48triad of,
• 46:49individuals that describe the multiple
• 46:51endocrine neoplasia
• 46:52syndromes where had
• 46:54a major role.
• 46:56There are many types of
• 46:57these syndromes, cancer predisposition
• 46:59syndromes.
• 47:00And what happened with,
• 47:03in in in this particular,
• 47:05group of disorders is that
• 47:06we saw two sisters
• 47:09many years ago
• 47:10that came
• 47:12at five
• 47:13years, eleven months, and three
• 47:15years and eight months,
• 47:18Both to be reviewed by
• 47:20the clinicians
• 47:22that were looking at the
• 47:23thyroid because they had
• 47:25a
• 47:26family history of thyroid carcinoma.
• 47:29And I happen to receive
• 47:30the biopsies.
• 47:31We put them together. We
• 47:33we still publish in black
• 47:34and white in
• 47:35those those years.
• 47:37And this individual
• 47:39is relatively well known, Jim
• 47:41Gill,
• 47:42whose wife is sitting right
• 47:44here. She was my resident
• 47:46also and we put together
• 47:48this paper
• 47:49and we advise
• 47:51to perform
• 47:52prophylactic
• 47:53thyroidectomy
• 47:55in young children. And, look,
• 47:57this this is an advice
• 47:58that is very
• 48:00delicate to me because you
• 48:01go to the parents and
• 48:02you say, look,
• 48:05you have to
• 48:06two daughters. One of them
• 48:07has unfortunately
• 48:09medullary carcinoma,
• 48:10but the other one has
• 48:12this change that
• 48:14seems is going to progress
• 48:16to medullary carcinoma. So, you
• 48:17need to recognize that and
• 48:19be part of that exercise
• 48:20in discussing with the patients.
• 48:22We frequently speak with patients.
• 48:24Claudia is a pediatrician, so
• 48:25she she doesn't have a
• 48:26problem with that, but I
• 48:27am not a clinician,
• 48:28But I love to speak
• 48:29with the patients and advise
• 48:30them in conjunction with our
• 48:32clinical colleagues in pediatric oncology.
• 48:35So we published this tale
• 48:36of two sisters
• 48:38with,
• 48:39Jim Gill
• 48:40and doctor Miron Janelle, who
• 48:41was a pediatric endocrinologist
• 48:43at that time directing the
• 48:45program of thyroid cancer in
• 48:47Yale University,
• 48:48and it was a fantastic
• 48:50experience.
• 48:52Multiple endocrine neoplasia has many
• 48:54different expressions, histologically
• 48:56speaking. It has multiple neurofibromas,
• 48:59neuromas, etcetera and you have
• 49:01to be
• 49:02able to recognize
• 49:04the danger that exists when
• 49:05you see lesions like this
• 49:07in young children. Young children
• 49:09should not get sick and
• 49:11if they do, they usually
• 49:13get well with no help
• 49:15but when they don't, you
• 49:16need to pay attention to
• 49:18them.
• 49:20I had a few more
• 49:21examples that I am not
• 49:22going to detail because I'm
• 49:24not going to,
• 49:25spend, well, maybe,
• 49:27just to show you that
• 49:28there are several other associations
• 49:30of involving the genital syndrome.
• 49:32For example, the genital area,
• 49:34for example, Frasier syndrome where
• 49:36you can have mutations in
• 49:37WT
• 49:38one,
• 49:39gene with different types of
• 49:41mutation that can lead to
• 49:43different syndromes
• 49:44depending on the codon that
• 49:46is involved. And you can
• 49:47have abnormalities in the kidney
• 49:50and in the gonads. You
• 49:51can have gonadoglastoma
• 49:53like this. When you see
• 49:55different the differences in sex
• 49:56development like a strict gonad
• 49:58that you see here associated
• 50:00with a gonadoglastoma
• 50:02and then you pursue the
• 50:04genetics, you can
• 50:06diagnose a cancer predisposition
• 50:08syndrome.
• 50:09So
• 50:10the major non CNS pediatric
• 50:13tumor categories are, mentioned here.
• 50:15Most of them I have
• 50:16touched on, but I want
• 50:18you to,
• 50:19take home these messages.
• 50:22Ten percent of pediatric solid
• 50:24tumors represent cancer predisposition
• 50:26syndromes.
• 50:27The histopathology
• 50:28frequently gives you the sentinel
• 50:30clue
• 50:31to start working on those
• 50:33patients.
• 50:34You have to correlate genetics
• 50:35with clinical data.
• 50:38You the pathologist
• 50:39identifies
• 50:40patients at risk frequently.
• 50:42As long as you think
• 50:43of this,
• 50:44you can just pass it
• 50:46one more slide and next
• 50:48and you miss it.
• 50:49And collaboration
• 50:51with our clinical,
• 50:52genetic, oncological,
• 50:54surgical,
• 50:56pediatric specialists
• 50:57assures adequate
• 50:59precision
• 51:00diagnosis.
• 51:01Okay? So there is a
• 51:02great variety great variety of
• 51:04syndromes predisposing to cancer that
• 51:06appear in childhood,
• 51:08The pediatric pathologist,
• 51:09the first to detect suspicious
• 51:11or diagnostic findings in these
• 51:12syndromes, not infrequently.
• 51:14And the developing organism has
• 51:16highly variable ways of phenotypic
• 51:18expression
• 51:19with the pediatric pathologist,
• 51:21which with the with which
• 51:24the pediatric pathologist should be
• 51:26intimately
• 51:26familiarized. If you don't
• 51:28recognize these lesions, you miss
• 51:30an important diagnosis that will
• 51:31affect not only that patient
• 51:33but the entire family.
• 51:36And I finish with that.
• 51:40You may recognize yourself some
• 51:42of yourselves here. I couldn't
• 51:44put everyone but, you know,
• 51:46nice
• 51:47memories from Jim Gill, Marie
• 51:49Rivera,
• 51:50and,
• 51:51well, I am not going
• 51:52to name everyone because you
• 51:54know who they are. Thank
• 51:56you very much for the
• 51:57honor of, visiting Yale again.
• 52:00Thank you.
• 52:05Any questions,
• 52:06comments?
• 52:11I I know that you
• 52:12always have a question, Joe.
• 52:17You know what they did?
• 52:18You need sequencing or sequence,
• 52:20whatever, like, all it is
• 52:21is that they need all
• 52:22good secrets.
• 52:23Can you share with us
• 52:24what do you think are
• 52:25driving the depth of just
• 52:26a lot of things we
• 52:28don't recognize
• 52:29that are gonna come out
• 52:30of all that sequence?
• 52:32Yeah. It's a it's a
• 52:33very
• 52:34important
• 52:35point, John, that you raised.
• 52:36And, believe me, it's a
• 52:38very hot point of discussion
• 52:40now.
• 52:41And Jose and I exchanged
• 52:42a couple of years ago
• 52:44papers on the relevance of
• 52:46phenotype and genetic changes and
• 52:47the correlation
• 52:48of these two things. And
• 52:50right now, the WHO is
• 52:52suffering from,
• 52:54I wouldn't say attacks, but
• 52:56questioning, severe questioning from our
• 52:58clinical colleagues that say, well,
• 52:59you know, histology doesn't matter
• 53:01anymore.
• 53:02You just need to sequence.
• 53:04You just need to put
• 53:05the patient's tissue through, genetic
• 53:07analysis and identify deletion.
• 53:10And I wish that could
• 53:11be possible but it isn't
• 53:13because
• 53:16many different types of genetic
• 53:18abnormalities
• 53:19that are identifiable
• 53:21by sequencing different modalities of
• 53:23sequencing
• 53:25generate
• 53:26completely different phenotypes
• 53:28depending on a number of
• 53:29other
• 53:30things,
• 53:31epigenetics
• 53:32and environmental
• 53:34circumstances.
• 53:35The phenotype, which is what
• 53:37we pathologists see,
• 53:39macro or microscopically,
• 53:42is really the absolute
• 53:44unquestionable
• 53:45end result of the
• 53:47the genetic expression
• 53:49of an organism.
• 53:51The phenotype of a tissue
• 53:53contains the information to understand
• 53:56how the genetics
• 53:58led to that change, but
• 53:59the reverse is not true.
• 54:01If you only see the
• 54:03part of the genetics,
• 54:04you will miss certain conditions.
• 54:07So
• 54:08I hope that we are
• 54:09able to develop
• 54:10additional instruments on both sides
• 54:12of the operation, the genetic
• 54:14analysis
• 54:15and the histological
• 54:17structural, ultra structural, etcetera analysis
• 54:20to bring this
• 54:22to a uniform reality that
• 54:24can serve and guide us
• 54:26for diagnosis and treatment. This
• 54:28issue was pointed at
• 54:30in a recent paper that
• 54:32we, the editorial board of
• 54:33the WHO
• 54:35books published in the Lancet
• 54:36Oncology
• 54:37Journal a few months ago,
• 54:39last year, where we made
• 54:41the case that, yes, we
• 54:42understand that genetic analysis is
• 54:44more and more and more
• 54:46important,
• 54:46but we cannot
• 54:48eliminate
• 54:49the the role of the
• 54:51histological
• 54:51analysis because we miss the
• 54:53phenotype changes, and we miss
• 54:56the precision diagnosis.
• 54:58So I don't know if
• 54:59that is a very wishy
• 55:01washy response to you, but
• 55:06We we
• 55:08the whole career has been
• 55:09identified
• 55:10new lesions.
• 55:11Now you have a huge
• 55:13resource in the genomic database,
• 55:15and so it should be
• 55:17a pointer that
• 55:18better go back and look
• 55:19at these stations because there's
• 55:20probably something that we hadn't
• 55:22appreciated.
• 55:24Do they set the enemy's
• 55:25valuable? Because it's so fast
• 55:26and effective. It is right.
• 55:28Absolutely. And I would love
• 55:30to be in a project
• 55:31where
• 55:32we look at the genetic
• 55:33changes, and then we go
• 55:34back to the tissues and
• 55:35say, okay. How how did
• 55:37this manifest histologically?
• 55:39That is being done in
• 55:40some places, but it's still
• 55:42early to say. Mina.
• 55:49Mina.
• 55:59I'm sorry. I couldn't hear
• 56:00you. Why?
• 56:04Oh.
• 56:07That's an interesting point. I
• 56:09don't know if we know
• 56:10exactly how the,
• 56:12effect of the one
• 56:14mutation
• 56:15leads to a cystic degeneration.
• 56:17I think that this well,
• 56:18the cystic formation.
• 56:19I think that the cystic
• 56:21formation may have more to
• 56:23do
• 56:23with the specific environment histologically
• 56:26that it happens.
• 56:27In the lung, for example,
• 56:28is relatively easy to understand
• 56:30that there there is a
• 56:32flow of air around, etcetera.
• 56:34But I don't know in
• 56:35other places that are solid
• 56:36organs not exposed to these
• 56:38types of pressures. I really
• 56:39don't know. I don't know
• 56:41if anybody knows if,
• 57:14In in the kidney too.
• 57:15In the kidney, cystic nephroma
• 57:17is, by definition, cystic.
• 57:20Yes. I think of the
• 57:21design. Yes. Yes. Yes. But
• 57:22the on the
• 57:25Yeah.
• 57:29Jose? To go to go
• 57:31back to the sequence,
• 57:45Right.
• 57:48And it is clear that
• 57:49epigenetics
• 57:52is one of the major
• 57:53piece when we're sent to
• 57:56that. That means
• 57:57cancer, human enhancers,
• 57:59the whole.
• 58:16Yep.
• 58:18I
• 58:21think that your comment is
• 58:22perfectly
• 58:23correct.
• 58:24And we are pushing for
• 58:26we as humans are pushing
• 58:28for that.
• 58:29However,
• 58:30it has had
• 58:32some undesirable effects in the
• 58:34community.
• 58:36One of the examples that
• 58:37I was discussing this morning
• 58:38with Anita Hudner was that
• 58:40the p the CNS five
• 58:42edition of the WHO,
• 58:44the central nervous system tumor
• 58:46volume of the WHO incorporates
• 58:48a massive amount of sequencing
• 58:51and
• 58:51methylation, which is epigenetic
• 58:53changes
• 58:54analysis.
• 58:55And it incorporates
• 58:56them, many of them as
• 58:58essential rather than
• 59:00desirable criteria. And the problem
• 59:02with that is that
• 59:04the over ninety percent of
• 59:05the population in the world
• 59:07has no access to that.
• 59:09So, yes, we need to
• 59:11be able to develop those
• 59:13approaches, those techniques
• 59:16to identify these changes
• 59:18but we cannot demand that
• 59:20everyone
• 59:21has to be able to
• 59:22diagnose
• 59:23a tumor with not only
• 59:25sequencing, but also with methylation
• 59:27analysis or other forms of
• 59:29epigenetic analysis. But I think
• 59:31that you are absolutely correct.
• 59:32This is a direction that
• 59:33we are following.
• 59:34I don't know if we
• 59:35will get there sooner or
• 59:37later, but we will.
• 59:40The focus of the non
• 59:41coding gene, right?
• 59:43Yeah. Exactly.
• 59:44Yeah. Junk. Yes. They they
• 59:46so called junk. Yeah. They
• 59:48hit the or chromatin. Chromatin.
• 59:50Yes.
• 01:00:03Is there any progress in
• 01:00:04that? Well, I think there
• 01:00:06is progress in terms
• 01:00:10of stopping
• 01:00:11the growth development in certain
• 01:00:13examples, but not in many
• 01:00:15examples.
• 01:00:18You you cannot change the
• 01:00:19genetic composition with targeted therapy.
• 01:00:21You can invalidate
• 01:00:23or annulate the effect of
• 01:00:25a given gene in in
• 01:00:26general.
• 01:00:27There is genetic therapy
• 01:00:30that is changing the genome
• 01:00:32in certain conditions, not necessarily
• 01:00:34neoplastic,
• 01:00:35Duchenne dystrophy, for example. There
• 01:00:37are examples of genetic approaches
• 01:00:39that correct the genetic abnormality
• 01:00:42and therefore will prevent
• 01:00:44the,
• 01:00:45continuation of the disorder. But
• 01:00:47Farzana may be able to
• 01:00:48respond to that question.
• 01:00:50Yeah. So I think the
• 01:00:51at the moment, it seems
• 01:00:52like diagnosis symptoms, etcetera. There
• 01:00:54is no
• 01:00:56target with therapy. But I
• 01:00:57think the reason to diagnose
• 01:00:59them early
• 01:01:00is that we are screening
• 01:01:02algorithms and we should actually
• 01:01:04the type three, for example,
• 01:01:05PPD is the individual treat.
• 01:01:07But if you have a
• 01:01:08type one hour, you can
• 01:01:09actually resect it and go
• 01:01:11down. So I think all
• 01:01:12these screening matches that. In
• 01:01:14fact, they
• 01:02:46I think
• 01:02:48I think it will happen,
• 01:02:49but it's not happening yet.
• 01:02:51Okay?
• 01:03:03Well, thank you again to
• 01:03:05all of you, and
• 01:03:07much appreciated.
• 01:21:04Yes. The the form is
• 01:21:06still in the post, you
• 01:21:07know, the In person How
• 01:21:09you going, sir?
• 01:21:10I like it. I'm going
• 01:21:11to dinner with you. Yeah.
• 01:21:12I know. I'm looking forward
• 01:21:14to having dinner with you.
• 01:21:15That's I have a friend.
• 01:21:16We're going to O'leo's, I
• 01:21:17guess. Yeah. Yeah. I have
• 01:21:19to say hi to the
• 01:21:20other half. Hi. How are
• 01:21:21you?
• 01:21:22Hi.
• 01:21:24I don't know if I
• 01:21:24like Hi. Super good. Nice
• 01:21:26to meet you. Yeah. Yeah.
• 01:21:26Yeah. Yeah. Yeah. Yeah.
• 01:21:37Okay.
• 01:21:42I I forgot. That's that's
• 01:21:43why. Yeah. No. No. I
• 01:21:44talk about this this,
• 01:21:47as well as I'm still
• 01:21:48at
• 01:21:49I know I know. I
• 01:21:51know. I know. Yeah.
• 01:22:00Okay.
• 01:22:01Okay. I think,
• 01:22:03good afternoon,
• 01:22:05everyone.
• 01:22:06Welcome to
• 01:22:08your pathology
• 01:22:11ground runs. Have you ever
• 01:22:13wondered
• 01:22:14why children get a malignant
• 01:22:16tumor at such a young
• 01:22:17age?
• 01:22:18Today, you're going to hear
• 01:22:19from the expert,
• 01:22:21get some answers from him.
• 01:22:24So it's my great honors
• 01:22:26and pleasure to introduce today's
• 01:22:29squad run speaker,
• 01:22:31doctor
• 01:22:32Miguel Reyes.
• 01:22:34So probably doctor Reyes don't
• 01:22:36need a introduction.
• 01:22:38He's,
• 01:22:39you know, has friends here
• 01:22:41with Yale for many years,
• 01:22:43has a great
• 01:22:45friend.
• 01:22:46So just briefly,
• 01:22:48doctor Reyes
• 01:22:49is currently
• 01:22:50a clinical professor
• 01:22:52and pediatric
• 01:22:54and the developmental pathology division
• 01:22:56chief
• 01:22:57in the department of pathology
• 01:22:59and laboratory medicine
• 01:23:01at
• 01:23:03University of Miami,
• 01:23:06Miller School of Medicine.
• 01:23:08Doctor
• 01:23:09Reyes
• 01:23:10completed his medical education
• 01:23:13in National
• 01:23:14Autonomous
• 01:23:16University
• 01:23:17of Mexico
• 01:23:18in nineteen eighties,
• 01:23:21followed by residency training and
• 01:23:24in anatomic massage
• 01:23:26there.
• 01:23:27After several years
• 01:23:29working as attending physician in
• 01:23:31National Institute
• 01:23:33of Pediatrics,
• 01:23:35he decided come to United
• 01:23:37States
• 01:23:38to continue
• 01:23:39his medical careers.
• 01:23:42Doctor. Reyes got his pediatric
• 01:23:44pathology fellowship training
• 01:23:46in nineteen
• 01:23:47ninety four
• 01:23:49from Children's Memorial Hospital of
• 01:23:51Northwestern
• 01:23:52University.
• 01:23:54After the fellowship,
• 01:23:56he joined Yale
• 01:23:58as a faculty member in
• 01:24:00our department
• 01:24:02and
• 01:24:04raise his rank
• 01:24:06from assistant professor to full
• 01:24:08professors.
• 01:24:11So after spending fourteen years
• 01:24:14in
• 01:24:15Yale,
• 01:24:16he
• 01:24:17relocated to Pittsburgh
• 01:24:20to become the chief pathologist
• 01:24:22in Children's Hospital of Pittsburgh
• 01:24:26University, Pittsburgh
• 01:24:29until twenty twenty four.
• 01:24:32Doctor. Reyes is a world
• 01:24:34renowned
• 01:24:35pediatric pathologist,
• 01:24:37has
• 01:24:38made significant contribution
• 01:24:41to the pediatric pathologist communities,
• 01:24:44including clinical practice,
• 01:24:47translational
• 01:24:48research,
• 01:24:49and medical educations.
• 01:24:53He was the past president
• 01:24:56of International Pediatric Massage
• 01:24:59Associations
• 01:25:01and the Society
• 01:25:03of Pediatric Massage.
• 01:25:06Doctor. Reyes
• 01:25:07published
• 01:25:09more than three hundred peer
• 01:25:11review articles,
• 01:25:13books,
• 01:25:14books, and book chapters.
• 01:25:18So he is the standing
• 01:25:20editors
• 01:25:21of the WHO classification
• 01:25:24of tumors
• 01:25:25editorial
• 01:25:26board.
• 01:25:27And he was
• 01:25:28the expert
• 01:25:29editor
• 01:25:31for the newly released WHO
• 01:25:33classification
• 01:25:34of tumor
• 01:25:35pediatric
• 01:25:37tumors.
• 01:25:38So although, you know,
• 01:25:41the current WHO classification
• 01:25:43tumor
• 01:25:44already in his
• 01:25:45its fifth editions.
• 01:25:48The pediatric tumors
• 01:25:50is the first time
• 01:25:52WHO has including
• 01:25:54a separate volume
• 01:25:56on the pediatric tumors.
• 01:25:59There's no doubt this publication
• 01:26:02will help improving
• 01:26:04the standardization
• 01:26:06of pediatric
• 01:26:07tumor diagnosis
• 01:26:09and facilitate
• 01:26:10the translate
• 01:26:12translation of diagnostic
• 01:26:14research into
• 01:26:16practice
• 01:26:17worldwide.
• 01:26:19So without further ado,
• 01:26:21please join me, Wolfgang. Reyes.
• 01:26:31Well, thank you very much
• 01:26:33for being
• 01:26:35first for inviting me,
• 01:26:37then for,
• 01:26:38presenting me as in such
• 01:26:40a kindly manner.
• 01:26:43I recognize and have a
• 01:26:45lot of,
• 01:26:47fun
• 01:26:48to see many of my
• 01:26:49former trainees,
• 01:26:51colleagues,
• 01:26:52friends,
• 01:26:54and people that
• 01:26:55taught me how to become
• 01:26:57an academic pathologist.
• 01:26:59There's Costa, doctor Morrow here,
• 01:27:02and
• 01:27:03David here.
• 01:27:05We interacted
• 01:27:06the other day with here.
• 01:27:08We interacted with them many
• 01:27:09years, and,
• 01:27:11it has been an honor
• 01:27:12for me. This is really
• 01:27:13my academic home, so I
• 01:27:15am very glad to return.
• 01:27:18Today, I will present something
• 01:27:21that is different from, the
• 01:27:22previous conference that I presented
• 01:27:24here about eight years ago.
• 01:27:26Today, we will, talk about
• 01:27:28how
• 01:27:29looking at the slice in
• 01:27:31pediatric lesions
• 01:27:32can allow you to identify
• 01:27:35cancer predisposition
• 01:27:36syndromes. This is a topic
• 01:27:38that I have,
• 01:27:40cultivated,
• 01:27:42extensively
• 01:27:43in the last few years.
• 01:27:44How do I advance this?
• 01:27:52Oh, thank you very much.
• 01:27:54Didn't see that.
• 01:27:56So let's move on.
• 01:28:00I have nothing to declare,
• 01:28:02and, this is the outline,
• 01:28:05and we will go directly
• 01:28:07into matters.
• 01:28:09At the beginning of last
• 01:28:10year, the official's archive journal,
• 01:28:13the oldest journal of pathology
• 01:28:14in the world,
• 01:28:16published a special issue in
• 01:28:18which, my colleague from Madrid,
• 01:28:20Doctor. Isabel Colmenero, the chief
• 01:28:22pathologist at Hospital del Nino
• 01:28:24Jesus in Madrid,
• 01:28:26and I put together a
• 01:28:28collection of
• 01:28:29twelve papers, ten of twelve
• 01:28:31papers, and an editorial. We
• 01:28:33invited all the authors that
• 01:28:34contributed to this special issue
• 01:28:36highlighting
• 01:28:38the,
• 01:28:38challenges and novelties in pediatric
• 01:28:40pathology. I invite you to
• 01:28:42review the special issue because
• 01:28:44it contains interesting information that
• 01:28:46is mostly
• 01:28:47missed by the adult pathology,
• 01:28:51sphere, the adult adult pathology
• 01:28:53circles.
• 01:28:54In this
• 01:28:56issue,
• 01:28:57one of the papers
• 01:28:59was specifically dedicated to the
• 01:29:01pediatric cancer predisposition
• 01:29:02syndromes
• 01:29:03in the, outside,
• 01:29:05of the central nervous system.
• 01:29:07And, I also invite you
• 01:29:09to read this paper because
• 01:29:10this will summarize
• 01:29:11what I am going to
• 01:29:12present to you today.
• 01:29:17K. It's not advancing.
• 01:29:18Okay. Here. So how do
• 01:29:20we define cancer predisposition syndromes?
• 01:29:23Heritable condition that increases the
• 01:29:26child's risk of developing cancer
• 01:29:28due to general mutations
• 01:29:30gene regulating
• 01:29:31cell growth, DNA repair, or
• 01:29:33genomic integrity. That's in general
• 01:29:35where a cancer predisposition
• 01:29:36syndrome is. And, of course,
• 01:29:37this affects not only children,
• 01:29:39but
• 01:29:40adults too. But adults affected
• 01:29:42with these conditions bring these
• 01:29:45conditions since they are
• 01:29:47children. So we pediatric pathologists
• 01:29:49are at the specific point
• 01:29:51to identify
• 01:29:52these entities
• 01:29:54early, early enough to intervene
• 01:29:56and modify the outcomes of
• 01:29:58these patients.
• 01:30:00They are, representing,
• 01:30:02in
• 01:30:03inherited risk, usually autosomal dominant,
• 01:30:07occasionally
• 01:30:08de novo,
• 01:30:09and the tumor often appears
• 01:30:11at younger ages than, general
• 01:30:12population. The same type of
• 01:30:14tumor that you see in
• 01:30:15adults when it appears in
• 01:30:16a child, it may be
• 01:30:18the first clue for you
• 01:30:19to look for a cancer
• 01:30:20predisposition
• 01:30:21syndrome.
• 01:30:23Multiple of these, many of
• 01:30:24these tumors are rare
• 01:30:26and, children with multiple primaries
• 01:30:29or unusual types are specifically
• 01:30:31a red flag to identify.
• 01:30:33The family history may show
• 01:30:35clustering of specific or related
• 01:30:37causes, but sometimes it doesn't.
• 01:30:40Approximately ten percent of pediatric
• 01:30:42cancers are due to germline
• 01:30:44alterations
• 01:30:45and early frequent recognition
• 01:30:47is a key
• 01:30:49to,
• 01:30:51provide adequate surveillance,
• 01:30:53therapy, and family assessment.
• 01:30:55So the point that I
• 01:30:57will emphasize today is that
• 01:30:59frequently histology
• 01:31:00provides the first clue, but
• 01:31:02you just have to keep
• 01:31:03this in mind. If you
• 01:31:05don't, you'll miss it.
• 01:31:08Okay.
• 01:31:12The pediatric pathologist is then
• 01:31:14at the crossroads between what
• 01:31:16is the clinical observation of
• 01:31:17a patient, the genetics of
• 01:31:19this patient and evaluating,
• 01:31:21the lesions that are under
• 01:31:23the microscope
• 01:31:24with the risk of increasing
• 01:31:25developing cancer.
• 01:31:28In addition to accurately diagnose
• 01:31:30these entities,
• 01:31:31we need to be familiarized
• 01:31:33with the implications of additional,
• 01:31:36seemingly
• 01:31:38uninteresting,
• 01:31:39unimportant findings that I will
• 01:31:41show you today.
• 01:31:42And clinical and or laboratory
• 01:31:44findings,
• 01:31:45that are apparently minor may
• 01:31:47be of various
• 01:31:49important significance.
• 01:31:51This is taken from the
• 01:31:52paper of the officials archive
• 01:31:53journal that I mentioned to
• 01:31:55you. I'm not going to
• 01:31:56go over every one of
• 01:31:58these entities. This is just
• 01:31:59to emphasize that I I
• 01:32:01would like you to, review
• 01:32:03the paper, read it, and
• 01:32:04and,
• 01:32:05send us any, comments, criticisms,
• 01:32:08etcetera. There are many can,
• 01:32:10cancer predisposition syndromes listed here.
• 01:32:12Obviously, this is just to
• 01:32:13show you that the paper
• 01:32:15is long
• 01:32:16and,
• 01:32:17full of,
• 01:32:18information
• 01:32:19that I am not going
• 01:32:20to be able to detail
• 01:32:21here. But we are going
• 01:32:22to,
• 01:32:24start with one of the
• 01:32:25most common,
• 01:32:26pediatric tumors that we see
• 01:32:28here.
• 01:32:30This is Wilms tumor, also
• 01:32:31known as nephroblastoma.
• 01:32:33Nobody really knows what doctor
• 01:32:35Max Williams described.
• 01:32:37Bruce Beckwith, the late Bruce
• 01:32:39Beckwith, a good friend of
• 01:32:41mine, who was the,
• 01:32:43official reviewer for the children's
• 01:32:44oncology group for many years,
• 01:32:47told me several times that
• 01:32:49nobody really understood what Max
• 01:32:51Williams, described, but this is
• 01:32:52the entity that we recognize
• 01:32:54as Williams' tumor.
• 01:32:55A tumor that produces a
• 01:32:57massive
• 01:32:58growth inside the kidney with
• 01:33:00a claw sign on the
• 01:33:02residual kidney that surrounds it
• 01:33:04as you can see in
• 01:33:05this, CT scan. And this
• 01:33:07is a classic microscopic
• 01:33:09appearance. I don't use the
• 01:33:10gross the gross term because
• 01:33:12it grosses me out. It's
• 01:33:14recommending
• 01:33:15it's it's recommended to get
• 01:33:16rid of the grossing and
• 01:33:18gross. But, anyway, the microscopic
• 01:33:20appearance of this tumor is
• 01:33:22this,
• 01:33:23fleshy,
• 01:33:25relatively homogeneous, sometimes, vocally hemorrhagic,
• 01:33:29sometimes very hemorrhagic. And then
• 01:33:31you can appreciate that there
• 01:33:32is a little rim of
• 01:33:33kidney that,
• 01:33:36is still,
• 01:33:37preserved there.
• 01:33:38This is Bruce Beckwith here
• 01:33:40visiting at Yale. This is
• 01:33:41me, believe it or not.
• 01:33:42I still didn't stain my
• 01:33:44beard white.
• 01:33:45And, this is a few
• 01:33:47years later, ten years later,
• 01:33:48when we met together in
• 01:33:49Tours, France.
• 01:33:52This Beckwith William and syndrome
• 01:33:54and other syndromes such as
• 01:33:55Wagner, Dennis Trash,
• 01:33:57Simpson Golami,
• 01:33:59Behamel, Fraser,
• 01:34:01Bloom syndrome, Dyson one are
• 01:34:02associated with Wilms tumors and
• 01:34:05we will review how they
• 01:34:07look at, very briefly.
• 01:34:09Triphasic Wilms tumors with epithelial
• 01:34:12tubular components, blastema components
• 01:34:14and stromal components are the
• 01:34:16rule. This is a blastema
• 01:34:18predominant component and this is
• 01:34:20a stromal predominant
• 01:34:22WIMS tumor. And sometimes you
• 01:34:24can have very clear muscle
• 01:34:26skeletal muscle differentiation that you
• 01:34:28can appreciate in these pictures
• 01:34:29from WIMS tumors.
• 01:34:31In the past, we used
• 01:34:32to call these teratoid variant
• 01:34:34of a Wilms tumor when
• 01:34:35there are components such as
• 01:34:37skeletal muscle,
• 01:34:39keratinizing
• 01:34:40squamous epithelium, and even osteoid
• 01:34:42formation.
• 01:34:44The war territory is not,
• 01:34:47recommended anymore.
• 01:34:48And after you make the
• 01:34:50diagnosis so what happens? Doctor,
• 01:34:54for Sanapan catch
• 01:34:56Pankar comes with you and
• 01:34:57tells you, Miguel,
• 01:34:59yesterday, there was an an
• 01:35:00infractomy specimen.
• 01:35:02Can you tell us what
• 01:35:03is it? Is it a
• 01:35:04wounds tumor? And then the
• 01:35:05first thing is to confirm.
• 01:35:06Yes. It's a wounds tumor,
• 01:35:07Farzana. Right? Good.
• 01:35:09Next question.
• 01:35:11What is the stage?
• 01:35:12Okay. And then is it
• 01:35:14favorable or unfavorable? And how
• 01:35:16do you distinguish that? Because
• 01:35:17that takes makes a difference
• 01:35:19in the treatment of the
• 01:35:20patient.
• 01:35:21And then when I respond
• 01:35:22these three questions, she goes
• 01:35:24back to her office to
• 01:35:26look at the patient and
• 01:35:27start chemotherapy.
• 01:35:29Is that correct?
• 01:35:31However,
• 01:35:34favorable histology is
• 01:35:36identified with anaplastic
• 01:35:39mitosis or, hyperchromatic nucleomegaly. You
• 01:35:42have to have both of
• 01:35:42them for the diagnosis. I
• 01:35:44listed here the criteria. I'm
• 01:35:46not gonna go over them,
• 01:35:47in detail.
• 01:35:49This is another atypical mitosis
• 01:35:51and, hyperchromatic nucleomegaly
• 01:35:53at least three times the
• 01:35:54size of adjacent non anaplastic
• 01:35:56nuclei.
• 01:35:57Immuno histochemistry is irrelevant in
• 01:36:00the diagnosis and study of
• 01:36:01WIMS tumor patients, but I
• 01:36:03listed here What is important
• 01:36:05is to add the molecular
• 01:36:06analysis for the patients because
• 01:36:08there are certain loss of
• 01:36:10heterozygosity
• 01:36:11and other chromosomal abnormalities
• 01:36:13that may determine treatment.
• 01:36:15And then you have to
• 01:36:16examine the residual
• 01:36:17kidney, the non tumor kidney.
• 01:36:20And in that, the important
• 01:36:21thing is to find nephrogenic
• 01:36:23rests because if there are
• 01:36:24nephrogenic rest, the possibility of
• 01:36:27a contralateral
• 01:36:28synchronous or metachronous once tumor
• 01:36:30is high.
• 01:36:31And these are examples that
• 01:36:33Bruce Beckwith gave me. These
• 01:36:34are pictures from him where
• 01:36:36this is the nephroblastomatosis.
• 01:36:39That word is only used
• 01:36:40for cases in which the
• 01:36:41entire renal parenchyma
• 01:36:43is nephroblastic
• 01:36:44and not a Wilms tumor
• 01:36:46directly. And this is an
• 01:36:47example of a Wilms tumor
• 01:36:49with numerous
• 01:36:50nephrogenic rest microscopically
• 01:36:52easy to identify. Okay.
• 01:36:54Let me give you an
• 01:36:55example of one of the
• 01:36:56last cases that I saw
• 01:36:58in Pittsburgh a couple of
• 01:36:59years ago.
• 01:37:00This tumor came from a
• 01:37:02two year old boy with
• 01:37:03a left renal mass. You
• 01:37:04can see the microscopic
• 01:37:05external appearance,
• 01:37:07the cross the surface,
• 01:37:10of the, section and the
• 01:37:11residual kidney is here. Everything
• 01:37:13fine?
• 01:37:15Blastema predominance,
• 01:37:16then there is, some perirenal
• 01:37:19fat, and then there is
• 01:37:20some residual kidney.
• 01:37:22So I gave the diagnosis.
• 01:37:23It's a woman's tumor. It's
• 01:37:25a favorable histology woman's tumor,
• 01:37:27and therefore favor,
• 01:37:29the chemotherapy is not as
• 01:37:31aggressive. And the stage is
• 01:37:32stage one because it hasn't
• 01:37:34broken through the capsule
• 01:37:35or the renal signs.
• 01:37:39And then you see, you,
• 01:37:41you, you, you show the
• 01:37:42three components
• 01:37:44and then you go to
• 01:37:45the renal
• 01:37:46non tumoral parenchyma.
• 01:37:48And this is where things
• 01:37:50get interesting
• 01:37:51because
• 01:37:52diagnosing twins tumor is not
• 01:37:54difficult.
• 01:37:56But looking at this
• 01:37:58is difficult.
• 01:38:00Not looking at it, but
• 01:38:01in understanding
• 01:38:02what you are seeing. What
• 01:38:03you have here are
• 01:38:05tubular structures in the medulla
• 01:38:07that are separated
• 01:38:09by a relatively
• 01:38:10mixed soy type of
• 01:38:12stroma
• 01:38:13that is not normal. This
• 01:38:15is not the normal morphology
• 01:38:17of the renal medulla.
• 01:38:19And when you see that,
• 01:38:21you have to diagnose it.
• 01:38:23So the diagnosis that I
• 01:38:25issued in this case is
• 01:38:26re is, written here. And
• 01:38:28then I put renal medullary
• 01:38:31dysplasia, consistent with Beckwith Wiedemann
• 01:38:33syndrome, see comment and references.
• 01:38:37When we discuss this case
• 01:38:38at tumor war in Pittsburgh,
• 01:38:41the, director of pediatric oncology,
• 01:38:44the clinical director of pediatric
• 01:38:46oncology
• 01:38:46there,
• 01:38:48first I said this patient
• 01:38:49has Wilms tumor and this
• 01:38:50and this and then back
• 01:38:51with William and Cindy. And
• 01:38:53there was a silence.
• 01:38:55Very uncomfortable to be honest
• 01:38:57with you.
• 01:38:58And then he said, well,
• 01:39:01maybe.
• 01:39:04But, no, it's not a
• 01:39:05maybe. It is,
• 01:39:07Beckwith Wiedemann syndrome. I put
• 01:39:10this,
• 01:39:10comment in the report and
• 01:39:12I mentioned a previous,
• 01:39:14reference that Jorge Dotto,
• 01:39:17anybody here remembers Jorge Dotto?
• 01:39:19He wrote to me this
• 01:39:20morning because he saw the
• 01:39:21announcement in Twitter,
• 01:39:23of this conference, and he
• 01:39:24said, oh, Miguel. It's nice
• 01:39:26that you are going back
• 01:39:27to Yale. Well, I'm gonna
• 01:39:28show your name because he
• 01:39:30and I
• 01:39:31published a case that,
• 01:39:34was similar to this one.
• 01:39:36The case from Pittsburgh
• 01:39:38was published
• 01:39:40with this group of authors,
• 01:39:42and one of them, Julia
• 01:39:43Mead, is a pediatric, you
• 01:39:45know, Julia Mead, Rosanna.
• 01:39:47She's a pediatric oncologist that
• 01:39:48is specialized in cancer predisposition
• 01:39:50syndromes. And,
• 01:39:52the following day of the
• 01:39:53tumor board, she comes to
• 01:39:54my office and she says,
• 01:39:55Miguel, can I cry with
• 01:39:56you?
• 01:39:57What happened?
• 01:39:59They you were right. They
• 01:40:00missed it.
• 01:40:02And the problem is that
• 01:40:03with, Beckwith Wiedemann syndrome is
• 01:40:05not an easy diagnosis to
• 01:40:06make even clinically, even to
• 01:40:08the specialist.
• 01:40:10I remember an autopsy here
• 01:40:13that one of our geneticists,
• 01:40:14a very highly respected geneticists
• 01:40:17here came to see. And
• 01:40:19when I
• 01:40:20just looked at it and
• 01:40:21I said, oh, it's a
• 01:40:22Beckwith Wiedemann syndrome.
• 01:40:23She looked at me like,
• 01:40:24what?
• 01:40:25And it was because
• 01:40:27it's not easy to diagnose
• 01:40:28it unless you think of
• 01:40:29it.
• 01:40:30So
• 01:40:32this patient that I show
• 01:40:33you was published
• 01:40:35and showing the medullary race,
• 01:40:38the medullary dysplasia,
• 01:40:39all the correlation with radiology,
• 01:40:42and then other examples in
• 01:40:44our,
• 01:40:46files were found with Beckwith
• 01:40:48Williamann syndrome and Wilf's tumor.
• 01:40:50What is Beckwith Wiedemann syndrome?
• 01:40:52Well, you know, it's a
• 01:40:53combination of overgrowth,
• 01:40:55affecting multiple organs described by
• 01:40:58Bruce Beckwith and,
• 01:40:59Hans Wiedemann,
• 01:41:01on a case report, by
• 01:41:02the way. And there are
• 01:41:03people that are very,
• 01:41:05upset when you say I'm
• 01:41:06going to do a case
• 01:41:07report and say what? You
• 01:41:09should that that's that's not
• 01:41:11good. Well,
• 01:41:12if Bruce of Witten or
• 01:41:14Witherman did not report that
• 01:41:15case,
• 01:41:16the field of overgrowth syndromes
• 01:41:19would not have started. Okay?
• 01:41:21So, yes,
• 01:41:22you may be wasting your
• 01:41:23time as I spoke this
• 01:41:25morning with doctor Ho how,
• 01:41:27go,
• 01:41:28on case reports, but you
• 01:41:30may not if you ask
• 01:41:31the interesting question. So don't
• 01:41:33don't don't get dissuaded to
• 01:41:35write cases if you think
• 01:41:36that they are interesting.
• 01:41:38These are all the genetic
• 01:41:39abnormalities. I'm not going to
• 01:41:41detail them because this is
• 01:41:42not the function, of this,
• 01:41:44conference. It's just to call
• 01:41:46your attention at why you
• 01:41:47need to look under the
• 01:41:48microscope or at the microscopic
• 01:41:50level.
• 01:41:52This is an example of
• 01:41:54a fetus with with the
• 01:41:55syndrome
• 01:41:57that we, carried on an
• 01:41:59autopsy here many years ago.
• 01:42:02You can see the exome
• 01:42:03follows. This is not umbilical
• 01:42:05hernia, but it's a huge
• 01:42:06umbilical hernia hernia that contains
• 01:42:10all the abdominal organs including
• 01:42:11the liver. And you see
• 01:42:13the the the two fetuses
• 01:42:14here with coarse features. They
• 01:42:17don't look
• 01:42:18nice. They are not cute
• 01:42:19babies.
• 01:42:20They are coarse because
• 01:42:22the overgrowth
• 01:42:23of the tissues,
• 01:42:24the soft tissues produces these
• 01:42:26creases
• 01:42:27and foldings
• 01:42:29that make them look not
• 01:42:31not cute.
• 01:42:32They have these creases in
• 01:42:34the ears as you can
• 01:42:35see here, these fissures and
• 01:42:36creases,
• 01:42:37and they obviously have different
• 01:42:39degrees of umbilical cord. And
• 01:42:41they can have hemihypertrophy
• 01:42:43or hypertrophy
• 01:42:44of something.
• 01:42:45When I invited Bruce Beckwith
• 01:42:47to give Grand Rounds right
• 01:42:48here many years ago,
• 01:42:50we had lunch together and
• 01:42:53he told me, you know,
• 01:42:54the most,
• 01:42:56unforgettable
• 01:42:57case of he never said
• 01:42:59Beckwith Wiedemann syndrome. He said
• 01:43:01of BWS
• 01:43:03was a case that I
• 01:43:04saw on a man with
• 01:43:06a huge thumb.
• 01:43:07Okay? Because he doesn't hit
• 01:43:10the the normality doesn't hit
• 01:43:11all the organs at the
• 01:43:13same level.
• 01:43:16Okay? The fetal cortex in
• 01:43:18the adrenal medulla looks like
• 01:43:20this normally. This is the
• 01:43:22permanent cortex in the process
• 01:43:23of development. This is a
• 01:43:25fetus or a baby of
• 01:43:26less than six months of
• 01:43:28age postnatal.
• 01:43:29Okay? But it can be
• 01:43:31a newborn. And the pancreas
• 01:43:33may look like this. In
• 01:43:35Beckwith Wiedemann syndrome cases, you
• 01:43:36see
• 01:43:38nucleomegaly
• 01:43:39in the fetal adrenal cortex.
• 01:43:41That is a sign that
• 01:43:43is frequently associated
• 01:43:45to Beckwith Wiedemann syndrome. Not
• 01:43:48always. Sometimes it's just a
• 01:43:50sign of stress, but when
• 01:43:51it is when it is
• 01:43:52so diffuse, that's another clue
• 01:43:54that you should not miss.
• 01:43:56Because even if you are
• 01:43:57doing an autopsy or if
• 01:43:58you get a nephrectomy with
• 01:44:00an adrenal gland that looks
• 01:44:01like that, you need to
• 01:44:02call
• 01:44:04doctor Farzana and say,
• 01:44:07Beckwith Wiedemann syndrome. Please check
• 01:44:09for that.
• 01:44:13The CD of blastosis
• 01:44:14is the process of formation
• 01:44:15of the islets of Langerhans.
• 01:44:17And in Beckwith Wiedemann syndrome,
• 01:44:19you've had you have an
• 01:44:20increased number of islets of
• 01:44:22Langerhans.
• 01:44:23This is a case that
• 01:44:24I published with, Jorge Dotto.
• 01:44:26And let me tell you
• 01:44:27the story. When when this
• 01:44:28you were not part of
• 01:44:29the clinical team at that
• 01:44:31time, I think, but they
• 01:44:32came to the search part
• 01:44:34area, and I was sitting
• 01:44:35with Jorge looking at the
• 01:44:37case.
• 01:44:37And when, they asked me,
• 01:44:39what is it? Is it
• 01:44:40the Wilms? And I said,
• 01:44:41yes. It is a Wilms
• 01:44:42tumor. Is it favorable? Yes.
• 01:44:43It is favorable. Thank you
• 01:44:44very much. Okay.
• 01:44:45And then when I continue
• 01:44:47looking at the normal
• 01:44:49residual kidney, it is not
• 01:44:51normal.
• 01:44:52And I I asked Jorge
• 01:44:54and all the residents that
• 01:44:55were with me to walk
• 01:44:57to the bed of the
• 01:44:58patient.
• 01:44:59Our our clinical colleagues looked
• 01:45:02at us like, what are
• 01:45:03these guys doing here on
• 01:45:04the floor? These are pathologists.
• 01:45:06Right? Well, I I asked
• 01:45:07permission to
• 01:45:09check the external,
• 01:45:11the the clinical,
• 01:45:13appearance of the of the
• 01:45:14of the patient. It was
• 01:45:15a cute baby,
• 01:45:18about a year old
• 01:45:20and
• 01:45:22didn't have anything that looked
• 01:45:23like Bagel Guillain Man syndrome.
• 01:45:25No hemihypertrophy,
• 01:45:26no creases, nothing, not dysmorphology.
• 01:45:28And I was very disappointed.
• 01:45:30And I said,
• 01:45:32can't be. I sent a
• 01:45:33couple of pictures to Bruce
• 01:45:35and he calls me and
• 01:45:36he says, your patient has
• 01:45:38PWS
• 01:45:40whether the rest of his
• 01:45:41body knows it or not.
• 01:45:43And they prove it genetically.
• 01:45:46So
• 01:45:47this is a type of
• 01:45:49malformation or,
• 01:45:50abnormal
• 01:45:51development of the renal medulla
• 01:45:53that you can appreciate in
• 01:45:54Beckwith Wiedemann syndrome with this
• 01:45:56mixedoid
• 01:45:57stroma around the tubules and
• 01:45:59the separation of the tubules.
• 01:46:01Please pay attention to that
• 01:46:02in those cases. You can
• 01:46:03also see nephrogenic rest. This
• 01:46:05is another example with a
• 01:46:07medullary ray, and these are
• 01:46:08the usual molecular subtypes
• 01:46:11of Beckwith Wiedemann syndrome. This
• 01:46:13is taken from the PETES
• 01:46:15five,
• 01:46:16edition of the WHO
• 01:46:19classification of tumors,
• 01:46:20and we put these pictures
• 01:46:22in that,
• 01:46:23volume.
• 01:46:24Other tumors may also,
• 01:46:27appear in patients with Beckwith
• 01:46:29Wiedemann syndrome, of course. This
• 01:46:31is a case,
• 01:46:32that,
• 01:46:33had a, mesenchymal
• 01:46:35hamartoma
• 01:46:36associated with,
• 01:46:37Beckwith Guiedemann syndrome. By the
• 01:46:39way, the alpha fetoprotein in
• 01:46:41this patient was a million
• 01:46:43above a million,
• 01:46:44and it was not a
• 01:46:45hepatoblastoma,
• 01:46:46which what would have been
• 01:46:48the first suspicion.
• 01:46:50Okay? But it's not a
• 01:46:51hepatoblastoma.
• 01:46:52I remember we sent it
• 01:46:53to Milton Feingold
• 01:46:55at Texas Children's Hospital and
• 01:46:57he called me. He said,
• 01:46:58you're right, Miguel. He said,
• 01:46:59mesenchymal
• 01:47:00glaucoma. So we need to
• 01:47:02pay attention because the morphology
• 01:47:03of these lesions
• 01:47:05may
• 01:47:06give you the clue and
• 01:47:07the diagnosis,
• 01:47:09of Beckwith Wiedemann syndrome. Let's
• 01:47:11change organs.
• 01:47:15I'm sure that you all
• 01:47:16have heard, used, and applied
• 01:47:19the term
• 01:47:20CPAM
• 01:47:21or CCAM.
• 01:47:22Right? Cystic,
• 01:47:25adenomatoid
• 01:47:26malformation of the lung
• 01:47:28or cystic pulmonary,
• 01:47:30malformation of the lung.
• 01:47:32Well,
• 01:47:34please don't use it anymore.
• 01:47:36It's
• 01:47:37changing. The nomenclature is being
• 01:47:39updated. I haven't made that
• 01:47:41diagnosis in about fourteen years.
• 01:47:43There are people that write
• 01:47:45and that are very nice
• 01:47:46and trying to please people
• 01:47:48that have described this. Among
• 01:47:50them, a good friend, Doctor.
• 01:47:52Tom Stalker,
• 01:47:53a retired professor who made
• 01:47:55all these
• 01:47:56very
• 01:47:57intuitive,
• 01:47:59beautiful,
• 01:48:00conceptual
• 01:48:01understanding
• 01:48:02of the development of the
• 01:48:04lung and the cystic lesions.
• 01:48:05The problem is that however
• 01:48:07beautiful this was in types
• 01:48:09zero to type four,
• 01:48:11it's wrong.
• 01:48:14And, therefore, we need to
• 01:48:15move
• 01:48:16to use a more current
• 01:48:18classification.
• 01:48:19There are classically three types,
• 01:48:22large c's, medium sized c's,
• 01:48:24small c's, and then he
• 01:48:25said, well, this occurred because
• 01:48:27they develop in the
• 01:48:29bronchi,
• 01:48:30terminal bronchioles or alveoli. Well,
• 01:48:32no.
• 01:48:33She added two more types,
• 01:48:35etcetera. No.
• 01:48:37There are other things that
• 01:48:38look a little bit different
• 01:48:40but are part of the
• 01:48:41same spectrum. Congenital lower emphysema
• 01:48:43is one of them. This
• 01:48:44dilatation of the lung with
• 01:48:47a hyper,
• 01:48:50distension
• 01:48:51and you can see the
• 01:48:52microscopic appearance of this long
• 01:48:54parenchyma
• 01:48:55and sometimes you can see
• 01:48:56like this under the diaphragm.
• 01:48:59There is a piece of
• 01:49:00lung that is very solid.
• 01:49:01This is called the Rocky
• 01:49:02Tanski
• 01:49:03lobe
• 01:49:04of the lung, which is
• 01:49:06part of the,
• 01:49:07spectrum of disorders
• 01:49:09that includes
• 01:49:10sequestrations,
• 01:49:12so called or formerly called
• 01:49:14CPAMs, and congenital lower emphysema.
• 01:49:16All of those lesions come
• 01:49:18to us pediatric pathologies
• 01:49:20very frequently. I don't know,
• 01:49:22Rafaela, you must receive about
• 01:49:24one every month
• 01:49:25probably or more. Right? Because
• 01:49:28that's more or less what
• 01:49:29I remember and they look
• 01:49:30like this.
• 01:49:31And we
• 01:49:33usually don't have a problem
• 01:49:34diagnosing this.
• 01:49:36The problem
• 01:49:37well, sometimes this is a
• 01:49:38Rocky Tanske lob. See, this
• 01:49:40is a picture I took
• 01:49:41in the eighties in Mexico
• 01:49:42City where you see the
• 01:49:44two lungs and then this
• 01:49:45lobe with a pedicle and
• 01:49:47vessels. This is a typical
• 01:49:49sequestration, and we published it
• 01:49:51with Mark Keller. I don't
• 01:49:52know if anybody here remembers
• 01:49:54Mark Keller. He now lives
• 01:49:55in Miami, close to Miami,
• 01:49:57and he was the chief
• 01:49:58of radiology here, and we
• 01:49:59just had dinner together last
• 01:50:01week. It's a wonderful colleague.
• 01:50:04Well, the problem is that
• 01:50:05many years ago, the group
• 01:50:07at Harvard,
• 01:50:08Boston Children's, the h word
• 01:50:10I'm sorry, John. I remember
• 01:50:11that the h word is,
• 01:50:12is is problematic here, that
• 01:50:14evil place of the north
• 01:50:15as you used to call
• 01:50:17it, John. But,
• 01:50:19when the Boston Children's describe
• 01:50:21this
• 01:50:22paper, he's they said bronchial
• 01:50:25atresia is common to extra
• 01:50:27lower sequestration, intra lower sequestration,
• 01:50:29and c cam and lower
• 01:50:31emphysema.
• 01:50:32So when you obstruct the
• 01:50:33bronchus in a developing kid,
• 01:50:36that is what happens. Any
• 01:50:38of those lesions that I
• 01:50:39mentioned happens. Okay.
• 01:50:41And there are many papers
• 01:50:42supporting that. The problem is
• 01:50:44when you receive
• 01:50:46something like this.
• 01:50:47You receive something like this
• 01:50:49and then you have the
• 01:50:50cyst here and you say,
• 01:50:51well, this may be a
• 01:50:52bronchial atresia deformation sequence or
• 01:50:54so called CPAM
• 01:50:56and you see this and
• 01:50:58you have to consider that
• 01:51:00this may be a pleural
• 01:51:01pulmonary blastoma.
• 01:51:03This is a very aggressive
• 01:51:05in general tumor
• 01:51:07that occurs by
• 01:51:08with mutations of Dicer one.
• 01:51:10I'm sorry.
• 01:51:13Dicer one. And it occurs
• 01:51:16in three
• 01:51:17subtypes, one, two, and three,
• 01:51:19and one is called one,
• 01:51:21type one regressing.
• 01:51:22It occurs in the lungs
• 01:51:23and derives from the long
• 01:51:25missing kind. But now we
• 01:51:26are learning that dicer one
• 01:51:28mutations can produce tumors
• 01:51:30anywhere and everywhere.
• 01:51:32The first ones were described
• 01:51:34in the lung. Okay?
• 01:51:37They were described by two
• 01:51:38good friends, Pepper Dehner and
• 01:51:40Carlos Manibal,
• 01:51:42who taught me how to
• 01:51:43do an autopsy for the
• 01:51:45first time in nineteen eighty
• 01:51:47six
• 01:51:48or eighty four. I don't
• 01:51:49remember.
• 01:51:50These two guys in Minneapolis,
• 01:51:52Pepperdainer is one of the
• 01:51:53most prominent pediatric pathologists in
• 01:51:56history. And Carlos is a
• 01:51:57pediatric pathologist at heart, but
• 01:51:59he's a general pathologist.
• 01:52:01And they describe this pleural
• 01:52:03pulmonary blastoma
• 01:52:05in nineteen eighty eight.
• 01:52:07Well,
• 01:52:08after that,
• 01:52:10Ashley Hill, Jason
• 01:52:12Jason Jarsimboski,
• 01:52:13and Pepper Dehner describe the
• 01:52:15mutations on these lesions.
• 01:52:18And then,
• 01:52:19identify the major genetic factor
• 01:52:21which is Dicer one
• 01:52:23mutations that lead to the
• 01:52:25Dicer one syndrome.
• 01:52:27These,
• 01:52:28are,
• 01:52:29mutations that affect a key
• 01:52:31enzyme required to keep precursors
• 01:52:33of micro RNAs
• 01:52:35into their mature active forms.
• 01:52:37And when they are deleted,
• 01:52:40they are, very,
• 01:52:42severe in effects.
• 01:52:44The, germline,
• 01:52:46pathogenic
• 01:52:47Dicer one variants, they find
• 01:52:48these syndromes
• 01:52:49are always loss of function
• 01:52:51type
• 01:52:52and, like many other tumor
• 01:52:54suppressor genes, germline, a loss
• 01:52:57of function mutations in Dicer
• 01:52:58one create tumor
• 01:53:00susceptibility
• 01:53:01but appear to be insufficient
• 01:53:03to initiate tumorigenesis.
• 01:53:04There are other changes required
• 01:53:06to develop into,
• 01:53:08tumorigenesis.
• 01:53:09Many different organs are affected.
• 01:53:12The first one described was
• 01:53:13pluripulmonary blastoma, but we now
• 01:53:15know that cystic nephroma
• 01:53:17and aplastic sarcoma of the
• 01:53:18kidney, embryonal rhabdomyosarcomas,
• 01:53:21and cervical embryonal
• 01:53:23rhabdomyosarcomas sarcomas are also associated
• 01:53:26with Dicer
• 01:53:26one and many other types
• 01:53:28of tumors including endocrine,
• 01:53:30CNS tumors, and ovarian tumors,
• 01:53:32gyn, gynandroblastoma.
• 01:53:35This is an example of
• 01:53:36a Dicer one,
• 01:53:38tumor.
• 01:53:39You can see is,
• 01:53:40one of the cystic types
• 01:53:42not as aggressive but they
• 01:53:44can be like this
• 01:53:46or like this or like
• 01:53:48this. Plural pulmonary blastoma cystic
• 01:53:51that can be very cystic.
• 01:53:53This is very difficult to
• 01:53:55diagnose as a pleural pulmonary
• 01:53:56blastoma because it looks completely
• 01:53:58benign and it behaves in
• 01:54:00a benign fashion.
• 01:54:01But you have to identify
• 01:54:03because the patient and the
• 01:54:05patient's family is at risk
• 01:54:07of developing
• 01:54:08other tumors.
• 01:54:11Here you have a repetition
• 01:54:12of what I just said.
• 01:54:13I'm not gonna spend more
• 01:54:14time here. This is how
• 01:54:16you pay attention to the
• 01:54:17stroma and diagnose it as
• 01:54:19a plural pleural pulmonary blastoma
• 01:54:21solid with rhabdomyoblastoma
• 01:54:24like elements with an aplasia,
• 01:54:26abundant cytoplasm.
• 01:54:28And then when you proceed
• 01:54:29with the genetic analysis, you
• 01:54:30identify the germline Dicer one
• 01:54:32mutations
• 01:54:33in, these,
• 01:54:36tissues.
• 01:54:37You can also use,
• 01:54:39immunohistochemistry,
• 01:54:41for
• 01:54:42labeling these changes.
• 01:54:44Let me show you a
• 01:54:45council that I received a
• 01:54:46few years ago. Came from
• 01:54:48Italy in a patient of
• 01:54:49one year old
• 01:54:51with,
• 01:54:52I'm sure all of you
• 01:54:53can read Italian.
• 01:54:55The patient had medulo epithelioma
• 01:54:58in the eye,
• 01:54:59retinoblastoma,
• 01:55:01and,
• 01:55:02on the one enucleation.
• 01:55:04So the the patient already
• 01:55:05had a tumor in the
• 01:55:06eye,
• 01:55:07retinolblastoma.
• 01:55:08It's a relatively common pediatric
• 01:55:10tumor and then the patient
• 01:55:12has
• 01:55:13a long lesion
• 01:55:15and this is the appearance
• 01:55:16of the long lesion that
• 01:55:18I received. These are images
• 01:55:19taken from that,
• 01:55:21that's, case.
• 01:55:23And as you appreciate this
• 01:55:24cyst and you pay attention
• 01:55:26to this trauma component of
• 01:55:27this cyst,
• 01:55:29something is not right and
• 01:55:31then you go in other
• 01:55:32areas,
• 01:55:33more cellular and then
• 01:55:36the diagnosis that we issued
• 01:55:37was this type one cystic
• 01:55:39pure pulmonary blastoma. We didn't
• 01:55:41know about the resection margins.
• 01:55:43We said that there was
• 01:55:44no involvement of the plural
• 01:55:45in the material reviewed
• 01:55:47and the background long parenchyma
• 01:55:49looked normal.
• 01:55:51And we made a comment
• 01:55:53here and referred to the
• 01:55:54pure, to the beats five
• 01:55:56edition of the,
• 01:55:58pediatric tumors in the WHO.
• 01:56:01Let me show you another
• 01:56:02example. This is a two
• 01:56:04year old with a left
• 01:56:05pneumothorax that you can appreciate
• 01:56:07here.
• 01:56:08And then
• 01:56:09similar lesions to the one
• 01:56:11that I just discussed,
• 01:56:13they resected these lesions. Unfortunately,
• 01:56:16the specimen perforated and it
• 01:56:19deflated.
• 01:56:20It was a cystic lesion
• 01:56:21that appears collapsed here. This
• 01:56:24is the ink that, our,
• 01:56:26residents or PAs,
• 01:56:28dissecting this, example
• 01:56:30put on to, evaluate the
• 01:56:31margins. And then when we
• 01:56:33look at the histology,
• 01:56:34there are areas like normal
• 01:56:36lung, areas with little cysts,
• 01:56:38but then there are areas
• 01:56:40like this
• 01:56:42and this.
• 01:56:43So this is not,
• 01:56:46as formerly referred to a
• 01:56:48CPAM. This is a pleural
• 01:56:50pulmonary blastoma, and you have
• 01:56:51to pay attention to this
• 01:56:53because that is what is
• 01:56:54going to determine the progression
• 01:56:56of the disease and the
• 01:56:58treatment necessary to control this
• 01:57:00entity. There is an aplasia
• 01:57:02in this stromal cells, very
• 01:57:04significant an aplasia in some
• 01:57:05areas, and we issued a
• 01:57:07diagnosis. Actually, this was a
• 01:57:09case that there was not
• 01:57:10mine, but it was in
• 01:57:11my department. And the,
• 01:57:13the all these cases were
• 01:57:15shared with us, and they
• 01:57:16they used to
• 01:57:17incorporate our opinions on the
• 01:57:18pathology signing this case, call
• 01:57:20it pluripotent blastoma type two
• 01:57:22because it's not the very
• 01:57:24cystic
• 01:57:25but not the very solid.
• 01:57:26It's mixed
• 01:57:27and then multiple multifocal an
• 01:57:30aplasia, a drabdomyomatous
• 01:57:32differentiation with multifocal an aplasia,
• 01:57:34etcetera, etcetera, and they comment
• 01:57:36here.
• 01:57:41How about this?
• 01:57:42We are not in the
• 01:57:43lung.
• 01:57:44This is a cystic lesion.
• 01:57:47You recognize this. Right?
• 01:57:50The testis
• 01:57:51is in the paratesticular
• 01:57:53area.
• 01:57:55I put my
• 01:57:56cell phone under the glass
• 01:57:58taking the picture
• 01:58:00to see the trans illumination
• 01:58:02of the cyst.
• 01:58:04Okay?
• 01:58:05And, yeah, residents laugh at
• 01:58:06me when I do these
• 01:58:07kinds of things
• 01:58:08because they say, why did
• 01:58:09you do that? Well, I
• 01:58:11want to see the trans
• 01:58:12illumination. Right? And and you
• 01:58:13just have to
• 01:58:15follow your imagination. And,
• 01:58:17when when I did this,
• 01:58:20the fellow that was rotating
• 01:58:22and doing his fellowship with
• 01:58:23us in Pittsburgh, doctor Louis
• 01:58:25Samson, a fantastic,
• 01:58:27fellow, pediatric pathology fellow from
• 01:58:29Canada, he put this,
• 01:58:32pictures in the tumor board,
• 01:58:33and this was the final
• 01:58:34diagnosis.
• 01:58:35Cystically dilated epididymal ducts consisting
• 01:58:38with obstructive changes. Yes. Yes.
• 01:58:40Yes. And then low grade
• 01:58:41myxoid spindle cell neoplasm
• 01:58:43with a comment. And we
• 01:58:45learned that in the clinical
• 01:58:47history there was a history
• 01:58:49of Dicer one syndrome. So
• 01:58:51this lesion fits perfectly well.
• 01:58:54The fact that we saw
• 01:58:55it after the patient has
• 01:58:56been diagnosed with Dicer one
• 01:58:59is good, but it doesn't
• 01:59:00matter. It fits everything. And
• 01:59:02if you see this before
• 01:59:03knowing the clinical history, you
• 01:59:05are after it.
• 01:59:08Recently, Estero Olivas group in,
• 01:59:11that evil place of the
• 01:59:12north,
• 01:59:13published these series of cases
• 01:59:15with Dicer one related
• 01:59:17WIMS
• 01:59:18like uterine
• 01:59:19tumor,
• 01:59:20with, several cases reported. And
• 01:59:22the the series are growing
• 01:59:24in adults and in pediatric
• 01:59:26examples of dysent one mutations.
• 01:59:32Let me switch to another
• 01:59:34interesting
• 01:59:34finding.
• 01:59:35This is a five year
• 01:59:36old girl with a palpable
• 01:59:38suprapubic mass. This is a
• 01:59:39Yale case
• 01:59:41that, came to us with
• 01:59:43two independent masses. And, when
• 01:59:45I was looking at this
• 01:59:46case, I said two masses.
• 01:59:48And I remember doctor McNamara,
• 01:59:50Joe McNamara, one of the
• 01:59:52pediatric oncologists,
• 01:59:54told me, yeah. Our surgeons
• 01:59:55think that this is a
• 01:59:57one's tumor that dropped down
• 01:59:58and metastasis into the bladder.
• 02:00:00I had never seen that
• 02:00:01and I have not seen
• 02:00:03that still now.
• 02:00:05So five year old with
• 02:00:06two tumors, there was, however,
• 02:00:09developmental delay in the clinical
• 02:00:11history.
• 02:00:12And because of that
• 02:00:14and facial deep dysmorphism,
• 02:00:17a karyotype was obtained
• 02:00:19at that time. And they
• 02:00:21found an interstitial deletion of
• 02:00:23nine q twenty two q
• 02:00:24thirty two.
• 02:00:26And that part of the
• 02:00:28clinical history made me think
• 02:00:30in something else.
• 02:00:32In addition, there was mild
• 02:00:34hypertrophy, hemihypertrophy,
• 02:00:35prominent forehead,
• 02:00:37hypertilarism,
• 02:00:38epicanthal folds, etcetera, etcetera, etcetera,
• 02:00:40all that you read there.
• 02:00:41These are the images of
• 02:00:43the kidney tumor
• 02:00:45with
• 02:00:46a epithelial
• 02:00:48slash,
• 02:00:49blastema,
• 02:00:50components in the Wilms tumor
• 02:00:52that looks a little weird,
• 02:00:53but it is
• 02:00:55a Wilms tumor.
• 02:00:57And these are the images
• 02:00:58of the bladder too.
• 02:01:00If you see them separately,
• 02:01:02you will diagnose one's tumor
• 02:01:04next, and you will diagnose
• 02:01:05rhabdomyosarcoma
• 02:01:07next.
• 02:01:08Here, we have stroma with
• 02:01:10an aplasia,
• 02:01:12desmin, myogenic
• 02:01:14expression,
• 02:01:15classic rhabdominosarcoma.
• 02:01:16But the patient has two
• 02:01:17tumors and is five years
• 02:01:19of age.
• 02:01:20If you see that in
• 02:01:21a sixty
• 02:01:22something years old patient, two
• 02:01:24tumors
• 02:01:25is very common
• 02:01:27in a kid.
• 02:01:28No.
• 02:01:30So when I rereview the
• 02:01:32clinical history and I saw
• 02:01:34the interstitial deletion in chromosome
• 02:01:36nine, I went to my
• 02:01:38late wife's
• 02:01:39lab in the genetics department
• 02:01:42working with doctor Alan Bale.
• 02:01:44Myra was my late wife,
• 02:01:47and she was working in
• 02:01:48that laboratory. And Alan Bale
• 02:01:50happens to be the person
• 02:01:51that identify
• 02:01:52the patched
• 02:01:54gene.
• 02:01:55And the patched gene is
• 02:01:57responsible
• 02:01:58for
• 02:01:59Goling
• 02:02:00syndrome,
• 02:02:01which is a cancer predisposition
• 02:02:03syndrome,
• 02:02:04a very important cancer predisposition
• 02:02:06syndrome. You can
• 02:02:08advise the clinicians to pursue
• 02:02:10the diagnosis of Golgi syndrome
• 02:02:12when you receive an odontogenic
• 02:02:13keratocyst because they are commonly
• 02:02:16the first red flag to
• 02:02:18identify
• 02:02:19a Golgi syndrome in a
• 02:02:20child.
• 02:02:22Syndrome
• 02:02:23described by, doctor Robert Golin
• 02:02:26in Minneapolis
• 02:02:27is, a multi,
• 02:02:31tumoral,
• 02:02:32cancer predisposition syndrome,
• 02:02:35with, three genes
• 02:02:37right now that are associated
• 02:02:38with, with it. Patch one
• 02:02:40is the first one. Sufu
• 02:02:43is another one and then
• 02:02:44patch two. This is the
• 02:02:45one that Alan Bale, and
• 02:02:46this is seventeen to ninety
• 02:02:47percent of cases are associated
• 02:02:49with patch one abnormalities.
• 02:02:51We published this space this
• 02:02:53case,
• 02:02:54as a combination of randomized
• 02:02:57sarcoma, windstorm, and deletion of
• 02:02:59the patching in syndrome
• 02:03:01appears in nature oncology,
• 02:03:03and it has been,
• 02:03:05important,
• 02:03:06interesting paper in my in
• 02:03:08in my, personal collection because,
• 02:03:11it taught me a lot.
• 02:03:13You can see multiple basal
• 02:03:14cell carcinomas
• 02:03:15in these tumors in these
• 02:03:16patients, and this is how
• 02:03:18Robert Gordon, Bob Gordon identified
• 02:03:20the the syndrome. He was
• 02:03:22on a bus
• 02:03:24riding in Minneapolis and saw
• 02:03:26a patient, and he used
• 02:03:28to go and say, excuse
• 02:03:30me. I am doctor Gordon.
• 02:03:31Do you mind if I
• 02:03:32speak with you for a
• 02:03:33for a minute?
• 02:03:35They will be, no. No.
• 02:03:36Sure.
• 02:03:37And then he will explain
• 02:03:38that he's concerned with these
• 02:03:39lesions that the patient has
• 02:03:41in his face.
• 02:03:42And then he described the
• 02:03:44the the the deletion. This
• 02:03:46is Bob Golin.
• 02:03:47We invited Bob Golin to
• 02:03:49come to give Grand Rounds
• 02:03:51here many years ago, a
• 02:03:52couple years up, before he
• 02:03:54said.
• 02:03:55And when I invited him,
• 02:03:58I called his office directly,
• 02:04:00and, the secretary
• 02:04:02answered and said and I
• 02:04:04said, this is doctor Reyes
• 02:04:06from Yale University. May I
• 02:04:07speak with doctor Gorin? I
• 02:04:08am I am narrating this
• 02:04:10conversation here. And and she
• 02:04:12goes, yes. Just a minute,
• 02:04:13please.
• 02:04:14And then she comes to
• 02:04:15the phone and I said,
• 02:04:16she says,
• 02:04:17hello? And I said, doctor
• 02:04:19Gorlin,
• 02:04:20si
• 02:04:21in Spanish.
• 02:04:22Okay? I switched to Spanish
• 02:04:24and I start speaking with
• 02:04:26him
• 02:04:26and then
• 02:04:28I switched back to English,
• 02:04:29and I I invited him
• 02:04:30and all that. And I
• 02:04:31said, doctor Corin, where did
• 02:04:32you learn your Spanish?
• 02:04:36He told me that he
• 02:04:37was part of a CIA
• 02:04:40CIA mission
• 02:04:42in the Nordic countries
• 02:04:45and that he spent six
• 02:04:47weeks
• 02:04:48sharing
• 02:04:49the room with a Spanish
• 02:04:52priest
• 02:04:53that was part of the
• 02:04:54same CIA mission.
• 02:04:56I didn't want to know
• 02:04:57anything else.
• 02:04:59I didn't bear to ask
• 02:05:01anything else.
• 02:05:02She she was a fantastic
• 02:05:04individual, enormous guy. And when
• 02:05:06he came into my office,
• 02:05:07he barely fit. And, he's,
• 02:05:10told me that he had
• 02:05:11mantle cell lymphoma. He said,
• 02:05:13my spleen is the size
• 02:05:15of Texas.
• 02:05:16He died a few years
• 02:05:17later, but he was a
• 02:05:18fantastic individual.
• 02:05:21Another example,
• 02:05:23bloom syndrome. And this is
• 02:05:24something that I also saw
• 02:05:26here at Yale.
• 02:05:28Dan, Pat, Jane was my
• 02:05:30resident, was a resident at
• 02:05:32that time. I'm sure that
• 02:05:33you know who doctor Jane,
• 02:05:35famous doctor Dampa Jane is.
• 02:05:37And we saw this
• 02:05:41patient with a bloom syndrome
• 02:05:43and a Williams tumor.
• 02:05:45This is a syndrome that,
• 02:05:47involves
• 02:05:48repairing DNA, repairing enzymes.
• 02:05:51And when they are broken,
• 02:05:52they don't repair the DNA.
• 02:05:54This case had an aplasia
• 02:05:56as you can see here
• 02:05:58and
• 02:05:59the sister
• 02:06:00of this patient
• 02:06:01developed a hepatocellular
• 02:06:03carcinoma.
• 02:06:05Both had the same genetic
• 02:06:07abnormalities.
• 02:06:08Two children in the same
• 02:06:10family with two
• 02:06:11relatively
• 02:06:12infrequent lesions.
• 02:06:14They need to
• 02:06:15rise the red flag for
• 02:06:17you to pursue it. The
• 02:06:19pathologist cannot be just sitting
• 02:06:20in the office and making,
• 02:06:22as my wife says, when
• 02:06:24when we are working together,
• 02:06:25she says, oh, you are
• 02:06:26just giving names to these
• 02:06:28animals, right, to these,
• 02:06:30cows. Well, no. We we
• 02:06:32are part of the clinical
• 02:06:35advisory
• 02:06:36team for the patient's family.
• 02:06:38We need to pursue that
• 02:06:40they follow it because if
• 02:06:41they if you don't do
• 02:06:42that, they may or may
• 02:06:43not realize that it is
• 02:06:45important.
• 02:06:47I don't know if I
• 02:06:48would,
• 02:06:49repeat the diagnosis of hepatocellular
• 02:06:51carcinoma on this particular case
• 02:06:52because hepatocellular carcinoma in children
• 02:06:54is relatively rare and is
• 02:06:56in a process of being
• 02:06:58reclassified
• 02:06:59as we speak in the
• 02:07:01sixth edition of the of
• 02:07:02the WHO Digestive Tumors book.
• 02:07:05But we published these these
• 02:07:06patients
• 02:07:07with bloom syndrome
• 02:07:09with,
• 02:07:10heparocellular
• 02:07:11and WIMS tumor in both
• 02:07:12of them in the same
• 02:07:13family. So those are clues
• 02:07:15you see the same family
• 02:07:17having two children with tumors.
• 02:07:19That's not frequent.
• 02:07:22Bloom syndrome looks like this
• 02:07:24clinically. They have hypersensitivity
• 02:07:27to the,
• 02:07:28sunlight,
• 02:07:29and they have multiple abnormal
• 02:07:31abnormalities in the karyotypes
• 02:07:33due to the abnormal mutations
• 02:07:35in the repair enzymes of
• 02:07:37DNA. I'm not gonna detail
• 02:07:38all these because
• 02:07:40as we are gonna run
• 02:07:41out of time.
• 02:07:43I'm gonna probably finish with,
• 02:07:45this group of disorders, multiple
• 02:07:47endocrine neoplasia syndromes.
• 02:07:49These are typically seen in
• 02:07:51adults. We all are familiar
• 02:07:52with them but you can
• 02:07:53also see them in children.
• 02:07:57This individual here
• 02:07:59is doctor Aiden Carney.
• 02:08:02I'm sure that many of
• 02:08:03you have heard of the
• 02:08:05Kearney syndrome,
• 02:08:06Kearney's triad,
• 02:08:08etcetera, etcetera. Kearney's complex.
• 02:08:11He described all of those.
• 02:08:13He is sitting with me
• 02:08:14in my office here at
• 02:08:15Yale about twenty years ago.
• 02:08:17I invited him twice. Once
• 02:08:19here and once in Pittsburgh.
• 02:08:21He was a fantastic guy.
• 02:08:23Small,
• 02:08:24Irish gentleman,
• 02:08:26funny, and very,
• 02:08:28you know, combative.
• 02:08:30I remember
• 02:08:31I I remember that,
• 02:08:33I think Stuart Flynn,
• 02:08:35told me that he was
• 02:08:36presenting something, and then Alan
• 02:08:38Carney was jumping in the
• 02:08:39audience trying to contradict him
• 02:08:41and he found him, a
• 02:08:42very combative spirit.
• 02:08:45Very nice guy. And,
• 02:08:47we are referring to the
• 02:08:49Sippel Williams Pierce,
• 02:08:50triad of,
• 02:08:52individuals that describe the multiple
• 02:08:54endocrine neoplasia syndromes where had
• 02:08:57a major role.
• 02:08:59There are many types of
• 02:09:00these syndromes, cancer predisposition syndromes.
• 02:09:03And what happened with,
• 02:09:06in in in this particular,
• 02:09:07group of disorders is that
• 02:09:09we saw two sisters
• 02:09:11many years ago
• 02:09:13that came
• 02:09:14at five
• 02:09:16years, eleven months, and three
• 02:09:18years and eight months,
• 02:09:21Both to be reviewed
• 02:09:23by the clinicians
• 02:09:24that were looking at the
• 02:09:25thyroid because they had
• 02:09:28a
• 02:09:29family history of thyroid carcinoma.
• 02:09:31And I happen to receive
• 02:09:33the biopsies.
• 02:09:34We put them together. We
• 02:09:36we still publish in black
• 02:09:37and white in
• 02:09:38those those years and this
• 02:09:40individual
• 02:09:42is relatively well known, Jim
• 02:09:44Gill,
• 02:09:45whose wife is sitting right
• 02:09:46here.
• 02:09:47She was my resident also,
• 02:09:50and we put together this
• 02:09:51paper
• 02:09:52and we advise
• 02:09:54to perform
• 02:09:55prophylactic
• 02:09:56thyroidectomy
• 02:09:57in young
• 02:09:58children. And, look, this this
• 02:10:00is an advice that is
• 02:10:01very
• 02:10:03delicate to me because you
• 02:10:04go to the parents and
• 02:10:05you say, look,
• 02:10:08you have to
• 02:10:09do daughters. One of them
• 02:10:10has unfortunately medullary carcinoma,
• 02:10:13but the other one has
• 02:10:14this change that
• 02:10:17food seems is going to
• 02:10:18progress to medullary carcinoma. So
• 02:10:20you need to recognize that
• 02:10:21and be part of that
• 02:10:23exercise in discussing with the
• 02:10:24patients. We frequently speak with
• 02:10:26patients. Claudia is a pediatrician,
• 02:10:27so she she doesn't have
• 02:10:28a problem with that, but
• 02:10:29I am not a clinician.
• 02:10:31But I love to speak
• 02:10:32with the patients and advise
• 02:10:33them in conjunction with our
• 02:10:35clinical colleagues in pediatric oncology.
• 02:10:37So we published this tale
• 02:10:39of two sisters
• 02:10:41with,
• 02:10:42Jim Gill
• 02:10:43and doctor Miron Janelle, who
• 02:10:44was a pediatric endocrinologist
• 02:10:46at that time directing the
• 02:10:48program of thyroid cancer in
• 02:10:50Yale University,
• 02:10:51and it was a fantastic
• 02:10:53experience.
• 02:10:55Multiple endocrine neoplasia has many
• 02:10:57different expressions, histologically
• 02:10:59speaking. It has multiple neurofibromas,
• 02:11:02neuromas, etcetera and you have
• 02:11:04to be
• 02:11:05able to recognize
• 02:11:06the danger that exists when
• 02:11:08you see lesions like this
• 02:11:10in young children.
• 02:11:11Young children should not get
• 02:11:13sick and if they do,
• 02:11:15they usually get well with
• 02:11:16no help
• 02:11:18but when they don't, you
• 02:11:19need to pay attention to
• 02:11:21them.
• 02:11:22I had a few more
• 02:11:24examples that I am not
• 02:11:25going to detail because I'm
• 02:11:26not going to,
• 02:11:28spend, well, maybe,
• 02:11:29just to show you that
• 02:11:30there are several other associations
• 02:11:33of involving the genital syndrome.
• 02:11:35For example, the genital area,
• 02:11:37for example, Fraser syndrome where
• 02:11:39you can have mutations in
• 02:11:40WT
• 02:11:41one,
• 02:11:42gene with different types of
• 02:11:44mutation that can lead to
• 02:11:46different syndromes
• 02:11:47depending on the codon that
• 02:11:49is involved and you can
• 02:11:50have abnormalities in the kidney
• 02:11:53and in the gonads. You
• 02:11:54can have gonadoblastoma
• 02:11:56like this. When you see
• 02:11:58different the differences in sex
• 02:11:59development like a strict gonad
• 02:12:01that you see here associated
• 02:12:03with a gonadoblastoma
• 02:12:05and then you pursue the
• 02:12:06genetics, you can,
• 02:12:08diagnose a cancer predisposition syndrome.
• 02:12:12So
• 02:12:13the major non CNS pediatric
• 02:12:15tumor categories are, mentioned here.
• 02:12:18Most of them I have
• 02:12:19touched on but I want
• 02:12:21you to,
• 02:12:22take home these messages.
• 02:12:25Ten percent of pediatric solid
• 02:12:27tumors represent cancer predisposition syndromes.
• 02:12:30The histopathology
• 02:12:31frequently gives you the sentinel
• 02:12:33clue
• 02:12:34to start working on those
• 02:12:35patients.
• 02:12:37You have to correlate genetics
• 02:12:38with clinical data.
• 02:12:40You, the pathologist
• 02:12:42identifies patients at risk frequently
• 02:12:45as long as you think
• 02:12:46of this.
• 02:12:47You can just pass it
• 02:12:49one more slide and next
• 02:12:50and you miss it.
• 02:12:52And collaboration
• 02:12:54with our clinical,
• 02:12:55genetic, oncological,
• 02:12:57surgical,
• 02:12:58pediatric specialists
• 02:13:00assures
• 02:13:01adequate
• 02:13:02precision diagnosis.
• 02:13:04Okay? So there is a
• 02:13:05great variety great variety of
• 02:13:07syndromes predisposing to cancer that
• 02:13:09appear in childhood, the pediatric
• 02:13:11pathologist,
• 02:13:12the first to detect suspicious
• 02:13:14or diagnostic findings in these
• 02:13:15syndromes, not infrequently,
• 02:13:17And the developing organism has
• 02:13:19highly variable ways of anotypic
• 02:13:21expression with the pediatric pathologist,
• 02:13:24which with
• 02:13:25the with which the pediatric
• 02:13:27pathologist should be intimately
• 02:13:29familiarized. If you don't recognize
• 02:13:31these lesions, you miss an
• 02:13:33important diagnosis that will affect
• 02:13:35not only that patient, but
• 02:13:36the entire family.
• 02:13:38And I finish with that.
• 02:13:43You may recognize yourself, some
• 02:13:44of yourselves here. I couldn't
• 02:13:46put everyone but, you know,
• 02:13:49nice
• 02:13:50memories from Jim Gill, Marie
• 02:13:52Robert,
• 02:13:53and,
• 02:13:54well, I am not going
• 02:13:55to name everyone because you
• 02:13:57know who they are.
• 02:13:58Thank you very much for
• 02:14:00the honor of, visiting Yale
• 02:14:01again.
• 02:14:02Thank you.
• 02:14:07Any questions,
• 02:14:09comments?
• 02:14:14I I know that you
• 02:14:15always have a question.
• 02:14:20You know what they do?
• 02:14:21You need sequencing or sequence,
• 02:14:22whatever, like, all it is
• 02:14:24is that they need to
• 02:14:25walk in sequence. Can you
• 02:14:27share with us what do
• 02:14:27you think are driving the
• 02:14:28next just a lot of
• 02:14:30things we don't have recognized
• 02:14:32that are gonna come out
• 02:14:33of all that sequence?
• 02:14:35Yeah.
• 02:14:35It's a it's a very
• 02:14:37important point, John, that you
• 02:14:39raised. And, believe me, it's
• 02:14:40a very hot point of
• 02:14:42discussion now.
• 02:14:44And Jose and I exchanged
• 02:14:45a couple of years ago
• 02:14:46papers on the relevance of
• 02:14:48phenotype and genetic changes and
• 02:14:50the correlation
• 02:14:51of these two things. And
• 02:14:53right now, the WHO is
• 02:14:54suffering from,
• 02:14:57I wouldn't say attacks, but
• 02:14:59questioning, severe questioning from our
• 02:15:00clinical colleagues that say, well,
• 02:15:02you know, histology doesn't matter
• 02:15:04anymore.
• 02:15:05You just need to sequence.
• 02:15:07You just need to put
• 02:15:08the patient's tissue through, genetic
• 02:15:10analysis and identify deletion.
• 02:15:13And I wish that could
• 02:15:14be possible but it isn't
• 02:15:16because
• 02:15:19many different types of genetic
• 02:15:21abnormalities
• 02:15:22that are identifiable
• 02:15:24by sequencing different modalities of
• 02:15:26sequencing
• 02:15:28generate
• 02:15:29completely different phenotypes
• 02:15:31depending on a number of
• 02:15:32other
• 02:15:34things, epigenetics
• 02:15:35and environmental
• 02:15:37circumstances.
• 02:15:38The phenotype, which is what
• 02:15:40we pathologists see
• 02:15:42macro or microscopically,
• 02:15:45is really the
• 02:15:47unquestionable
• 02:15:48end result of the genetic
• 02:15:50expression
• 02:15:51of an organism.
• 02:15:53The phenotype of a tissue
• 02:15:56contains the information to
• 02:15:58understand how the genetics
• 02:16:00led to that change, but
• 02:16:02the reverse is not true.
• 02:16:04If you only see the
• 02:16:05part of the genetics,
• 02:16:07you will miss certain conditions.
• 02:16:09So
• 02:16:10I hope that we are
• 02:16:12able to develop
• 02:16:13additional instruments on both sides
• 02:16:15of the operation, the genetic
• 02:16:17analysis
• 02:16:18and the histological
• 02:16:20structural, ultra structural, etcetera analysis
• 02:16:23to bring this to a
• 02:16:25uniform reality that can serve
• 02:16:27and guide us for diagnosis
• 02:16:29and treatment. This issue was
• 02:16:31pointed at
• 02:16:33in a recent paper that
• 02:16:34we, the editorial board of
• 02:16:36the WHO
• 02:16:37books
• 02:16:38published in the Lancet Oncology
• 02:16:40Journal a few months ago,
• 02:16:42last year,
• 02:16:43where we made the case
• 02:16:44that, yes, we understand that
• 02:16:46genetic analysis is more and
• 02:16:48more and more important,
• 02:16:49but we cannot
• 02:16:51eliminate
• 02:16:52the the role of the
• 02:16:53histological analysis because we miss
• 02:16:56the phenotype changes and we
• 02:16:58miss the precision diagnosis.
• 02:17:01So I don't know if
• 02:17:02that is a very wishy
• 02:17:04washy response to you, but
• 02:17:08We
• 02:17:09we
• 02:17:11whole career has been identifying
• 02:17:13new lesions.
• 02:17:14Now you have a huge
• 02:17:15resource in the genomic database,
• 02:17:18and so it should be
• 02:17:20a pointer.
• 02:17:21But we have to look
• 02:17:22at these stations because there's
• 02:17:23probably something that we haven't
• 02:17:25really appreciated.
• 02:17:26Should they send to them,
• 02:17:27I mean, it's valuable because
• 02:17:28it's so cost effective. They
• 02:17:30just buy it. Absolutely. And
• 02:17:32I would love to be
• 02:17:33in a project where
• 02:17:35we look at the genetic
• 02:17:36changes and then we go
• 02:17:37back to the tissues and
• 02:17:38say, okay. How how did
• 02:17:39this manifest histologically?
• 02:17:42That is being done in
• 02:17:43some places, but it's still
• 02:17:45early to say. Mina.
• 02:17:52Mina.
• 02:18:02I'm sorry. I couldn't hear
• 02:18:03you. Why?
• 02:18:07Oh.
• 02:18:10That's an interesting point. I
• 02:18:11don't know if we know
• 02:18:13exactly how the,
• 02:18:15effect of the diCircle one
• 02:18:17mutation leads to a cystic
• 02:18:19degeneration. I think that this
• 02:18:20well, the cystic formation.
• 02:18:22I think that the cystic
• 02:18:23formation may have more to
• 02:18:25do with the specific environment
• 02:18:28histologically
• 02:18:29that it happens
• 02:18:30In the lung, for example,
• 02:18:31is relatively easy to understand
• 02:18:33that there there is a
• 02:18:35flow of air around, etcetera.
• 02:18:37But I don't know in
• 02:18:37other places that are solid
• 02:18:39organs not exposed to these
• 02:18:41types of pressures. I really
• 02:18:42don't know. I don't know
• 02:18:43if anybody knows if,
• 02:18:58solid.
• 02:19:17In in the kidney too.
• 02:19:18In the kidney, cystic nephrona
• 02:19:20is, by definition, cystic.
• 02:19:23Yes. I think of the
• 02:19:24benign Yes. Yes. Yes.
• 02:19:41Express
• 02:19:43What,
• 02:19:44when, what time do you
• 02:19:45express
• 02:19:46a number of proteins?
• 02:19:48Right.
• 02:19:50And
• 02:19:50it is weird
• 02:19:52that epigenetics
• 02:20:11not just the sequence, but
• 02:20:13also some Epigenetics.
• 02:20:15Sequence,
• 02:20:16like,
• 02:20:18upon,
• 02:20:19you know, that's Yep.
• 02:20:23I think that your comment
• 02:20:25is perfectly
• 02:20:26correct.
• 02:20:27And we are pushing for
• 02:20:29we as humans are pushing
• 02:20:31for that.
• 02:20:32However,
• 02:20:33it has had
• 02:20:34some
• 02:20:35undesirable effects in the community.
• 02:20:38One of the examples that
• 02:20:40I was discussing this morning
• 02:20:41with Anita Hudner was that
• 02:20:43the p, the CNS5
• 02:20:45edition of the WHO,
• 02:20:47the central nervous system tumor
• 02:20:48volume of the WHO incorporates
• 02:20:51a massive amount of sequencing
• 02:20:53and
• 02:20:54methylation, which is epigenetic changes,
• 02:20:57analysis.
• 02:20:58And it incorporates them, many
• 02:21:00of them as essential rather
• 02:21:02than
• 02:21:03desirable criteria. And the problem
• 02:21:04with that is that
• 02:21:07the over ninety percent of
• 02:21:08the population in the world
• 02:21:09has no access to that.
• 02:21:11So, yes, we need to
• 02:21:14be able
• 02:21:15to develop those approaches, those
• 02:21:17techniques
• 02:21:18to identify these changes
• 02:21:21but we cannot demand that
• 02:21:23everyone
• 02:21:24has to be able to
• 02:21:25diagnose
• 02:21:26a tumor with not only
• 02:21:28sequencing, but also with methylation
• 02:21:30analysis or other forms of
• 02:21:32epigenetic analysis. But I think
• 02:21:34that you are absolutely correct.
• 02:21:35This is a direction that
• 02:21:36we are following.
• 02:21:37I don't know if we
• 02:21:38will get there sooner or
• 02:21:40later, but we will.
• 02:21:42What is the focus of
• 02:21:43the non coding Jew? Right?
• 02:21:45Yeah. Exactly.
• 02:21:47Yeah. Junk. Yes. They they
• 02:21:49so called junk. Yeah. They
• 02:21:51hit the of chromaffin chromatin.
• 02:21:53Yes.
• 02:21:54Is it really a best
• 02:21:55in targeted
• 02:21:57therapy, you know, to prevent
• 02:21:58the tumor from alright. Once
• 02:22:00we know the nicer or
• 02:22:01then whatever genies that that
• 02:22:03we targeted to avoid the
• 02:22:05tumor
• 02:22:08Well, I think there is
• 02:22:09progress in terms
• 02:22:12of stopping
• 02:22:14the growth development in certain
• 02:22:16examples, but not in many
• 02:22:18examples. You
• 02:22:20you
• 02:22:20cannot change the genetic composition
• 02:22:22with targeted therapy. You can
• 02:22:24invalidate
• 02:22:25or annulate the effect of
• 02:22:27a given gene in in
• 02:22:29general.
• 02:22:30There is genetic therapy
• 02:22:32that is changing the genome
• 02:22:35in certain conditions, not necessarily
• 02:22:37neoplastic,
• 02:22:38Duchenne dystrophy, for example. There
• 02:22:40are examples of genetic approaches
• 02:22:42that correct the genetic abnormality
• 02:22:45and therefore will prevent
• 02:22:47the, continuation of the disorder.
• 02:22:49But Farzana may be able
• 02:22:51to respond to that question.
• 02:22:53Yeah. So I think the
• 02:22:54at the moment, these, like,
• 02:22:55diagnosis symptoms, etcetera, there is
• 02:22:57no
• 02:22:59talk with therapy. But I
• 02:23:00think the reason to diagnose
• 02:23:01them early
• 02:23:03is that we are screening.
• 02:23:05And we can actually
• 02:23:07the type three, for example,
• 02:23:08PPD is the individual treat.
• 02:23:10But if you have a
• 02:23:11type one heart, you can
• 02:23:12actually resect it and you're
• 02:23:14done. So I think early
• 02:23:15screening matches that. In fact,
• 02:23:17they
• 02:23:19were in in in in
• 02:23:20where the mother I mean,
• 02:23:22I just tell you an
• 02:23:23example of how screening helps.
• 02:23:24The mother had saw on
• 02:23:27CNN
• 02:23:28that if you have a
• 02:23:29sex
• 02:24:49I think
• 02:24:50I think it will happen,
• 02:24:52but it's not happening yet.
• 02:24:54Okay?
• 02:25:06Well, thank you again to
• 02:25:08all of you, and
• 02:25:10much appreciated.
• 02:26:27My
• 02:26:28computer.
• 02:26:33Okay. Can I leave now?
• 02:27:51Okay. Thank you. Thank you.
• 02:27:52Thank you. Okay. I am
• 02:27:54Rosie. Nice to meet you.
• 02:27:55Rosie, very nice to meet
• 02:27:56you. I'm Sarah.