William Barriss McAllister, Jr., Memorial Lecture - William D. Travis, MD.

Transcript

• 00:02Good afternoon, everyone.
• 00:04Thank you so much for
• 00:05coming.
• 00:06They're not listening to me.
• 00:08Lots of excitement around lunchtime.
• 00:15Good afternoon.
• 00:17Thank you so much for
• 00:19coming,
• 00:20today.
• 00:21It's a special event today
• 00:23for all of us.
• 00:25I have an honor to
• 00:27introduce
• 00:28our,
• 00:29recipient
• 00:30of the William Barris,
• 00:32McCallister Lectureship Award for excellent
• 00:34in excellence in surgical
• 00:36pathology, doctor William Travis.
• 00:39Doctor Travis doesn't need any
• 00:41introduction.
• 00:42Anybody who's been practicing surgical
• 00:44pathology
• 00:46know about doctor Travis, but
• 00:47I'm going to do introduction
• 00:49anyway, Bill, because it's it's
• 00:51a huge honor to have
• 00:53doctor Travis with us today.
• 00:55He started his tremendous career
• 00:58as a medical student at
• 00:59University of Florida,
• 01:01then went into a pathology
• 01:04at the Harvard
• 01:05School of Medicine,
• 01:08went to clinical pathology
• 01:10at a Mayo Clinic,
• 01:12and basically spent significant amount
• 01:14of his career or time
• 01:15of his career at NIH,
• 01:17NCI,
• 01:18and AFIP.
• 01:20And it's always shocking to
• 01:21me to know that he's
• 01:22been for twenty years at
• 01:24Memorial Sloan Kettering
• 01:26as attending,
• 01:27a pathologist
• 01:29and, as a director of
• 01:30excellent outstanding, probably the best
• 01:32thoracic
• 01:33service in the country.
• 01:35Doctor Travis,
• 01:37has over five hundred publications,
• 01:41huge impact on our field
• 01:42of thoracic pathology, but I
• 01:44would say probably the most
• 01:45important work, and this is
• 01:47my think thinking bill, is
• 01:49really in the classification of
• 01:50adenocarcinoma
• 01:52as well as neuroendocrine tumors
• 01:53of the lung.
• 01:55He really defined, I would
• 01:56say, he's the godfather of
• 01:58the modern, thoracic surgical pathology.
• 02:01He's been a recipient of
• 02:03numerous awards. I would just
• 02:05like to single out the,
• 02:08Mary Mathews Award for Excellence
• 02:10in Research from the ISLC.
• 02:13He's the founding father of
• 02:14the Pulmonary Pathology Society.
• 02:17He's been chair he was
• 02:18the chair and one of
• 02:20the founders of the pathology
• 02:22committee of the International Association
• 02:24for the Study of Lung
• 02:25Cancer.
• 02:26And he's been editor on
• 02:29four WHO books, hopefully the
• 02:31fifth one as well.
• 02:33And,
• 02:34most importantly, I think what's
• 02:36close to all of us
• 02:37who are actually, you know,
• 02:39I I grew next watching
• 02:41actually and learning from him
• 02:42and some other mentors as
• 02:44well that he's in a
• 02:45tremendous mentor
• 02:46to many, many, the list
• 02:48of, his mentees really long.
• 02:50And, as I told him
• 02:52this morning,
• 02:53he's been mentored from Gen
• 02:55z from Gen x to
• 02:56Gen z now.
• 02:58And basically, in every single
• 03:00generation, if you can name
• 03:01one outstanding pathologist, that pathologist
• 03:03is actually trained by Bill.
• 03:04So it's a great honor
• 03:06to have a Bill here
• 03:07with us, doctor Travis.
• 03:08And, but before we go
• 03:10into the,
• 03:12his lecture and kind of
• 03:13like overview overview that is
• 03:15Bill said of like past
• 03:16thirty years of his career
• 03:17and his experiences,
• 03:19I would like to say
• 03:20a few words why we
• 03:21selected, doctor Bill Travis for
• 03:23the William Barris McAllister lecture.
• 03:26So just a few words
• 03:27about Doctor. McAllister.
• 03:28He was a graduate of
• 03:30Yale College and of a
• 03:31John Hopkins Medical School and
• 03:33the Department of Pathology. He
• 03:35came actually back here to
• 03:36Yale
• 03:37and served as the Chief
• 03:38of Surgical Pathology
• 03:40for twenty five years from
• 03:41nineteen fifty three to nineteen
• 03:43seventy eight.
• 03:44He was an outstanding diagnostic
• 03:46pathologist,
• 03:47educator,
• 03:48he was included in the
• 03:49science as well as, in
• 03:51art of medicine.
• 03:52He He was an extraordinary
• 03:54mentor, advisor, and friend to
• 03:56student, residents, covert coworkers, and
• 03:58physicians from all disciplines.
• 04:00And I think doctor Travis
• 04:02is more than deserving this,
• 04:03lectureship award. So Bill, thank
• 04:05you so much for coming
• 04:07to us today. It's really
• 04:08my pleasure
• 04:10to give you a little
• 04:11talking of appreciation.
• 04:13Just to view.
• 04:29Thank you so much, Sonia.
• 04:30It's a real pleasure to
• 04:31be here and
• 04:33to talk about a subject
• 04:35that is very, near and
• 04:36dear to me and has
• 04:37been really
• 04:39a major focus of my
• 04:40career.
• 04:41I,
• 04:43must say
• 04:45let me try to keep
• 04:46track of time here.
• 04:52The topic is historical classification
• 04:54of lung cancer and interstitial
• 04:56lung disease.
• 04:57And to get invited to
• 04:59come to Yale to talk
• 05:00about thoracic pathology,
• 05:02I was
• 05:03really amazed going through the
• 05:05historical
• 05:06leaders of thoracic pathology that
• 05:08have been
• 05:09in this department.
• 05:10And,
• 05:11it's a real honor and
• 05:13privilege to be able to
• 05:15sort of follow in in
• 05:16these,
• 05:17footsteps. And, of course, doctor
• 05:19Homer
• 05:20and Daisik are the current,
• 05:22primary leaders, and I'm sure
• 05:24there'll be many more in
• 05:25the future.
• 05:27I had the privilege of,
• 05:29writing this lifetime achievement award
• 05:31article,
• 05:33in honor of doctor Yesner.
• 05:35Most of you look like
• 05:36you're probably too young to
• 05:38have known doctor Yesner, but
• 05:39I had the privilege to
• 05:40overlap with him a little
• 05:41bit.
• 05:43And, you can read this
• 05:44if you would like. He
• 05:45certainly had a huge impact,
• 05:48on thoracic pathology, lung cancer
• 05:50in particular, and the WHO
• 05:53classification.
• 05:54And currently, you have a
• 05:56wonderful
• 05:59lung pathology research team here,
• 06:01in the department, and,
• 06:03I've had the privilege of
• 06:04working,
• 06:06side by side with,
• 06:08most of these individuals,
• 06:10particularly,
• 06:12Kurt, David, Katarina, who overlapped
• 06:15a little bit when,
• 06:16she was still at MSK
• 06:18and I had just arrived.
• 06:20And then, Frank Detterbeck has
• 06:22been a
• 06:23very,
• 06:24close friend over many years
• 06:26and a collaborator on many
• 06:28important,
• 06:28projects, particularly lung cancer staging.
• 06:32So the outline of the
• 06:33talk is to talk about
• 06:34the history and approach to,
• 06:36WHO lung cancer classification.
• 06:40But the focus of this
• 06:41will be the sort of
• 06:43inner workings and logistics of
• 06:45the two thousand eleven lung
• 06:46adenocarcinoma
• 06:47classification where we address,
• 06:51both advanced lung cancers and
• 06:53resected adenocarcinomas.
• 06:55And then I've also been
• 06:57privileged to be involved with
• 06:58classifications of interstitial lung disease.
• 07:02So I highlighted some of
• 07:04the individuals who've been key
• 07:06members and, Sonia, you wanna
• 07:08see your picture here.
• 07:12So,
• 07:13as as
• 07:15a Yale,
• 07:16pathologist who I've been very
• 07:17involved with over the years
• 07:19in classification
• 07:20of,
• 07:22lung cancer,
• 07:24My career started
• 07:25with classification of neuroendocrine lung
• 07:28tumors, and then as,
• 07:30doctor Dasik mentioned, being involved
• 07:32with the last four WHO
• 07:34classifications
• 07:35of lung, pleural, and thymic
• 07:37tumors.
• 07:39And then,
• 07:41the adenocarcinoma
• 07:42classification, I would say, is
• 07:44probably
• 07:45one of the most,
• 07:48amazing experiences that I have
• 07:49been involved with as a
• 07:51professional
• 07:52from the classification standpoint, and
• 07:54and we'll get into that.
• 07:56So what is the WHO
• 07:57classification? It's a pathologic and
• 07:59genetic classification
• 08:01and grading of human tumors
• 08:03designed to be accepted and
• 08:05used worldwide.
• 08:06It provides
• 08:08standard criteria for, pathology diagnosis
• 08:11and clinical practice,
• 08:13cancer registration,
• 08:14epidemiologic
• 08:15studies,
• 08:16and clinical trials and research.
• 08:21So since the first WHO,
• 08:24was published in nineteen sixty
• 08:26seven,
• 08:27where it was basically based
• 08:28on H and E, stains,
• 08:31we've had increasing complexity adding
• 08:33mucin stains, electron microscopy, then
• 08:36immunohistochemistry,
• 08:38then,
• 08:39genetics, cytology, and radiology. And,
• 08:42of course, this makes everything
• 08:44more complex,
• 08:45but it has
• 08:47made our role as pathologists
• 08:49to be increasingly
• 08:51relevant
• 08:52for clinical practice.
• 08:56So
• 08:57in order to design a
• 08:59classification,
• 08:59you have to,
• 09:01identify
• 09:01a need,
• 09:03for a classification or an
• 09:05update
• 09:06and,
• 09:07involve key stakeholders.
• 09:09And as we've learned in
• 09:11the last years, having a
• 09:12multidisciplinary,
• 09:15committee is very important.
• 09:18Then you have to obtain
• 09:19society sponsorship.
• 09:21Then you have to build
• 09:22an expert,
• 09:24multidisciplinary
• 09:25and collaborative team,
• 09:27provide strong leadership,
• 09:29run meetings
• 09:31in a way to achieve
• 09:32consensus,
• 09:33and then analyze
• 09:35evidence to support whatever changes
• 09:37you're planning to make.
• 09:40It should be, prompt comprehensive,
• 09:43leaving a minimal number of
• 09:45tumors unclassified. There always is
• 09:46gonna be unclassified tumors.
• 09:49It should be as simple
• 09:50as possible,
• 09:52precise with clear definitions.
• 09:55Morphology is the foundation,
• 09:58although we certainly are,
• 10:01cognizant of the need to,
• 10:03involve ancillary techniques, particular molecular
• 10:06techniques these days.
• 10:08And it should be
• 10:10sufficiently
• 10:11reproducible to allow pathologists to
• 10:13type
• 10:14a tumor, the same way.
• 10:17And we like to retain
• 10:18time honored terms and concepts
• 10:20until evidence,
• 10:22justifies
• 10:23a change.
• 10:25So when we started the
• 10:27two thousand eleven adenocarcinoma
• 10:29classification,
• 10:32multidisciplinary,
• 10:33classification of lung adenocarcinoma
• 10:35that could become an international
• 10:37standard.
• 10:39We sought sponsorship
• 10:40through the International Association of
• 10:42the Study of Lung Cancer,
• 10:43ISLC,
• 10:45American Thoracic Society, and European
• 10:47response Respiratory Society. It was
• 10:49not trivial to get
• 10:51any one of these, groups
• 10:53to support the project.
• 10:56So we designed a core
• 10:58multidisciplinary
• 10:59panel that,
• 11:00attended the meetings in person.
• 11:04They directed the system
• 11:06systematic review and,
• 11:09helped to write the document.
• 11:13So that was a finite
• 11:14relatively small group, although thirty
• 11:16to forty people.
• 11:19And then we had a
• 11:21reviewer group, and this is
• 11:23a great concept. These are
• 11:24people who reviewed the document.
• 11:26They were sent in advance.
• 11:28This was distributed to over
• 11:30a hundred people all over
• 11:31the world,
• 11:33soliciting
• 11:34their feedback. So they were
• 11:35then,
• 11:37the local champions
• 11:38of the classification, which is
• 11:40very important because we had
• 11:41a lot of major changes,
• 11:44to implement.
• 11:47So as this project was
• 11:49starting, I guess I had
• 11:50some sixth sense that this
• 11:52was really gonna be a
• 11:53big deal. I had no
• 11:54idea
• 11:55what a big deal it
• 11:56would turn out to be,
• 11:59But I felt very inadequate,
• 12:02in terms of my ability
• 12:04to run a meeting and
• 12:05to bring people together.
• 12:08And so I ran across
• 12:09this book in my research,
• 12:11facilitator's
• 12:12guide to
• 12:13Participatory
• 12:14Decision Making.
• 12:16And I just pulled out
• 12:17one of the,
• 12:19illustrations from this.
• 12:21And it's very helpful because
• 12:24it outlines the dynamics where
• 12:26in the beginning, you have
• 12:27divergent thinking. So you try
• 12:29to just get everyone to
• 12:31share their ideas.
• 12:33Then you go into this
• 12:35struggle
• 12:36in the service of integration.
• 12:38And then there's a sort
• 12:40of concluding phase, which you
• 12:42hope happens, doesn't
• 12:44necessarily have to happen, of
• 12:46convergent thinking.
• 12:48And that middle zone is
• 12:50also called the groan zone.
• 12:52And, I've always
• 12:55really felt
• 12:56in all classification
• 12:57efforts that I've led, it's
• 12:59so important
• 13:00to really get to the
• 13:02core issues and let people
• 13:03say whatever they want, feel
• 13:05free to say whatever they
• 13:06want, most importantly, that they
• 13:08all feel listened to
• 13:11so that if even if,
• 13:14the consensus goes in a
• 13:15different direction, they still are
• 13:17willing to take ownership
• 13:19that the conclusion is what
• 13:21is best for the field
• 13:22and,
• 13:24the,
• 13:25summary opinion of the group.
• 13:28So that but that groan
• 13:29zone can be very painful.
• 13:31And,
• 13:32you'd really if you don't
• 13:33ever go through that, then
• 13:34what you're doing probably isn't
• 13:35that important.
• 13:37So it's an important point
• 13:39for all you young folks
• 13:41to realize that disagreements
• 13:44are quite acceptable and actually
• 13:46will help make whatever you
• 13:48come up with
• 13:49to be a much stronger
• 13:50foundation. And if you never
• 13:52go into digging into those
• 13:54disagreements,
• 13:55before you come to,
• 13:57consensus,
• 13:58you you maybe you haven't
• 13:59really done your job in
• 14:00the best possible way.
• 14:04So my my wife is
• 14:05a, cancer epidemiologist,
• 14:07and she,
• 14:09was invited to attend
• 14:11a meeting
• 14:12at the Bellagio
• 14:14Center in Bellagio, Italy.
• 14:16And it gave me an
• 14:17idea, which is one of
• 14:18the most beautiful places in
• 14:19the world if you've never
• 14:20been there.
• 14:22So,
• 14:24the Rockefeller Foundation has
• 14:27the best property in Bellagio.
• 14:29It's on the tip
• 14:30facing Lake Como and the
• 14:32Swiss Alps.
• 14:34And from the vistas that
• 14:36you can, see from this,
• 14:38incredible place, there's a conference
• 14:40center. And you apply for
• 14:42a grant, and if you
• 14:43get approved, you can take
• 14:45a meeting there.
• 14:47So this is
• 14:49the very core writing group,
• 14:52from our,
• 14:54ISLC committee.
• 14:56And
• 15:00what I was able to
• 15:01do in a place like
• 15:01this was
• 15:03really push everybody's buttons
• 15:06to really bring out we
• 15:08had really difficult issues to
• 15:09sort through.
• 15:11And, so you would think
• 15:13people were almost at the
• 15:14point of blows with very
• 15:16strong disagreements, and then you
• 15:17go to a break and
• 15:19you, lower the shades and
• 15:20you look out of this
• 15:21view and you go, ah.
• 15:23You just
• 15:24you know, we're everything's fine,
• 15:26and, you know, we're we're
• 15:27we're in this together. And
• 15:29so it's the beauty of
• 15:30having a a resource like
• 15:32that. So that's the kind
• 15:33of thing as a leader
• 15:35of a project,
• 15:36when it's really difficult to
• 15:38come up with creative ideas
• 15:41to help your, committee
• 15:43work hard but enjoy the
• 15:45work that's being done.
• 15:48In that, book that I
• 15:49mentioned, the idea of chart
• 15:51writing came up, and this
• 15:53is
• 15:54incredibly valuable. Here you see,
• 15:57you get these large yellow,
• 16:01pads
• 16:02with sticky on the top.
• 16:04As the discussion goes on,
• 16:06you have a chart writer
• 16:08who summarizes the various points
• 16:10that are being made.
• 16:12And you need someone who
• 16:13can write legibly and also,
• 16:17well summarize what's being said.
• 16:20And then you post them
• 16:21all around the room.
• 16:23And then these create minutes
• 16:24of your meeting. So, you
• 16:26walk out, you take a
• 16:27picture of these,
• 16:28digital picture,
• 16:30and you have a a
• 16:31permanent record of those.
• 16:33And, this was incredibly valuable,
• 16:36and it was fun for
• 16:37me to go back and
• 16:38look at these.
• 16:41The other thing we did
• 16:42is we did this ATS
• 16:44required us to do a
• 16:45systematic review.
• 16:47Here you can see we
• 16:48had a Marco Gold, a
• 16:49methodologist,
• 16:51and, all the data was
• 16:53entered from the systematic review
• 16:55in an Excel file. And
• 16:56you could see we had,
• 16:58categories of oncology, pathology, radiology,
• 17:01molecular, and surgery.
• 17:03And, this was a huge
• 17:05work
• 17:06and,
• 17:06created a very strong foundation
• 17:08for the conclusions we made.
• 17:10This is the article,
• 17:11and you can see we
• 17:12had a very,
• 17:14multidisciplinary
• 17:15group, pathologists, cytopathologists,
• 17:17radiologists, pulmonologists,
• 17:20oncologists, molecular experts, and a
• 17:22methodologist.
• 17:24So out of this classification,
• 17:26there were multiple
• 17:28paradigm shifts
• 17:29in how we think about
• 17:31diagnosis and classification of lung
• 17:33cancer.
• 17:34We were focusing on lung
• 17:35adenocarcinoma,
• 17:37but in fact,
• 17:41a lot of the work
• 17:42we did spilled over into
• 17:43other tumors.
• 17:45Importantly,
• 17:46how we distinguish adenov from
• 17:48squamous carcinoma.
• 17:49So there were breakthrough discoveries
• 17:51happening at the same time
• 17:53in the medical oncology and
• 17:55molecular world
• 17:57with, breakthrough discoveries of, the
• 17:59eGFR
• 18:00ALT story,
• 18:02as
• 18:04a potential powerful molecular targets.
• 18:07And these led to a
• 18:08genetic revolution where, you know,
• 18:10every time you go to
• 18:10a lung cancer meeting, you
• 18:12sit on the edge of
• 18:12your seat. What's the next
• 18:14gene that's being discovered?
• 18:17We didn't have that before,
• 18:19but this was all going
• 18:20on at the time we
• 18:21were doing this classification project.
• 18:24The concept of personalized medicine
• 18:26and the role that pathologists,
• 18:29are playing in personalized medicine.
• 18:31So
• 18:32what we call adenor squamous
• 18:34drives how the patient gets
• 18:36how the tumor gets worked
• 18:37up and what tests you're
• 18:39going to do and then
• 18:40how the patient's going to
• 18:42get treated.
• 18:43So we developed a whole
• 18:44new approach to, small biopsies
• 18:46and cytology.
• 18:47It had never been done
• 18:49before in WHO classifications.
• 18:52There was a a legacy
• 18:54term called bronchiolo alveolar carcinoma
• 18:56or BAC.
• 18:59We chose to abandon that
• 19:01because we recognized,
• 19:03new entities,
• 19:04adenocarcinoma
• 19:05and site two, minimally invasive
• 19:07adenocarcinoma,
• 19:10lipidic predominant adenocarcinoma,
• 19:12invasive mucinous adenocarcinoma.
• 19:15We learned about multidisciplinary
• 19:17correlations,
• 19:18radiologic pathologic correlations, how lipidic
• 19:22patterns correlated with ground glass
• 19:24on CT
• 19:25or invasive patterns correlated with
• 19:27solder solid patterns on CT.
• 19:30This led to a whole
• 19:31new concept of TNM staging,
• 19:34which actually existed in other
• 19:36organ systems like breast cancer,
• 19:39for decades. We had never
• 19:40had
• 19:41the framework
• 19:42of, of pathology
• 19:44patterns
• 19:45to implement this. Now
• 19:47we regard
• 19:49invasive size
• 19:51by CT
• 19:52according to the solid size,
• 19:54not,
• 19:55the total size
• 19:57excluding the ground glass component.
• 19:58And similarly, by pathology, we
• 20:00only include
• 20:02the invasive size and not
• 20:04the lipidic component.
• 20:05This was a major change
• 20:07impacting staging.
• 20:09So as I mentioned, we
• 20:10developed a whole new classification
• 20:12for, small biopsies and cytology.
• 20:18It was really amazing.
• 20:20When we started this effort,
• 20:23within
• 20:24an hour
• 20:25so we created
• 20:27a list of key questions
• 20:29for each specialty and for
• 20:31the overall project. Within an
• 20:32hour of the first
• 20:34meeting we had,
• 20:36the medical oncologist
• 20:37told us
• 20:41that two thirds of lung
• 20:42cancer patients presented in advanced
• 20:44stages.
• 20:46So the WHO classification historically
• 20:49only addressed resected disease,
• 20:51resected tumors.
• 20:54So
• 20:55what we were doing in
• 20:56the WHO was really irrelevant
• 20:59to the majority of lung
• 21:00cancer patients. Boy, I tell
• 21:02you, when that
• 21:03message came out,
• 21:05I was just astonished.
• 21:07So we had a whole
• 21:08new work to do
• 21:10to address the small biopsies
• 21:12in cytology. And, you know,
• 21:14it's in the twenty twenty
• 21:16one book. It's the first
• 21:17chapter.
• 21:18I bet very few people
• 21:19read it, but it's actually
• 21:20the most important chapter in
• 21:22the whole book,
• 21:23because it addresses the majority
• 21:25of lung cancer patients.
• 21:27So now I hope you
• 21:27all go home and read
• 21:28it.
• 21:31So just to give you
• 21:32an idea of the percentage
• 21:34or the numbers of patients,
• 21:36in twenty twenty four,
• 21:38the American Cancer Society,
• 21:41predicts there are gonna be
• 21:42two hundred and over two
• 21:43hundred and thirty four thousand
• 21:45lung cancer patients.
• 21:47If you take out the
• 21:48estimated fifteen percent of small
• 21:50cell,
• 21:51you're left with about two
• 21:52hundred thousand cases.
• 21:54And then if you take
• 21:56the seventy percent of advanced
• 21:58stage,
• 21:59patients, it's, like, a hundred
• 22:00and forty thousand patients. It's
• 22:02a major public, health problem.
• 22:04So,
• 22:05we really had a major
• 22:07job to do to address
• 22:08that. And that was a
• 22:09huge work, which I think
• 22:10has,
• 22:11been a very valuable contribution.
• 22:15So,
• 22:17I know many of you,
• 22:18certainly those involved in thoracic,
• 22:20are very well aware of
• 22:21this, discovery.
• 22:23This is
• 22:25a patient with
• 22:28advanced lung adenocarcinoma
• 22:30with bilateral
• 22:31extensive infiltrates.
• 22:35And for whatever reason, this
• 22:37patient was given,
• 22:39gefitinib,
• 22:40which is a tyrosine kinase
• 22:41inhibitor that
• 22:43targets the EGFR,
• 22:45mutation,
• 22:46the EGFR gene.
• 22:49In five days, look at
• 22:51what happened.
• 22:54And
• 22:54they had no idea what
• 22:56had happened.
• 22:57This was an empirical observation,
• 22:59and only later was it
• 23:00figured out that it was
• 23:02because,
• 23:03it tar this,
• 23:05drug targets
• 23:06the EGFR gene. But
• 23:10I know and I expect
• 23:12that many of you were
• 23:13at this meeting,
• 23:15here at Yale
• 23:17that was sponsored to celebrate
• 23:19the twentieth anniversary
• 23:20of the discovery of EGFR
• 23:22mutations
• 23:23and development
• 23:24of tyrosine kinase inhibitors.
• 23:27So
• 23:28congratulations to all of you
• 23:29for organizing that and hosting
• 23:31it here
• 23:32at Yale. And you have
• 23:34all the major players,
• 23:37at that meeting.
• 23:40So
• 23:42there were two papers published,
• 23:44one in science and one
• 23:45in New England Journal.
• 23:49Two weeks before, I was
• 23:52going to Zurich, Switzerland to
• 23:54finish the final edits on
• 23:56the two thousand four WHO
• 23:57book.
• 23:59And when I when I
• 24:00got there,
• 24:03Paul Klyhuis,
• 24:04he could word,
• 24:07he could edit
• 24:08live the document. I told
• 24:10him we gotta put these
• 24:11references in the book.
• 24:13So
• 24:15here, there's one sentence. We
• 24:17had no idea how incredibly
• 24:19important this was going to
• 24:20be. There's one sentence at
• 24:22the bottom of a paragraph
• 24:23in these two references. We
• 24:24just slipped them in at
• 24:25the last minute.
• 24:27And I have to say,
• 24:28in retrospect, I'm I'm very
• 24:31proud and happy that we
• 24:32did that, but we really
• 24:33had no clue that this
• 24:35was going to be the
• 24:36beginning of the most one
• 24:37of the most incredible
• 24:39stories in all of oncology,
• 24:41not just lung cancer.
• 24:44So as we were starting
• 24:45this adenocarcinoma
• 24:46classification, we were
• 24:49happy
• 24:50that data like this was
• 24:51emerging. This is a study
• 24:53published in the New England
• 24:54Journal by Tony Mok,
• 24:56looking at,
• 24:58Asian patients,
• 24:59mostly never smokers,
• 25:01who had eGFR mutations,
• 25:05or some had them and
• 25:06some did not.
• 25:07And what they were able
• 25:08to show is over here
• 25:09on the left, if there
• 25:11was an eGFR mutation,
• 25:14comparing in green,
• 25:17tyrosine kinase inhibitor
• 25:19versus,
• 25:20conventional chemotherapy
• 25:21in yellow,
• 25:23that if there was an
• 25:24EGFR mutation,
• 25:26there was a significant
• 25:28improvement in progression free survival.
• 25:32But
• 25:34if
• 25:35there was no mutation,
• 25:37these patients actually did worse.
• 25:40And we were really struggling.
• 25:42Should we write in our
• 25:43classification document that patients should,
• 25:47should receive,
• 25:49eGFR mutation testing because that
• 25:51was that was debatable at
• 25:53the time. There was argument
• 25:54about whether we should do
• 25:55that. But it was based
• 25:57on literature like this that
• 25:58we
• 25:59felt it should be recommended
• 26:01that all patients with advanced
• 26:02lung adenocarcinomas
• 26:04should routinely be tested for
• 26:06eGFR mutation. And, of course,
• 26:08now we have all sorts
• 26:09of other,
• 26:11driver mutations that we look
• 26:13for.
• 26:14But, that that was a
• 26:15big deal. And,
• 26:18but that was all happening
• 26:19at the time we were
• 26:20working on this. It was
• 26:21very, very exciting time.
• 26:24So we were
• 26:26then looking at
• 26:28different,
• 26:30reasons to separate adenocarcinoma
• 26:33from squamous carcinoma.
• 26:35And,
• 26:36and one of the
• 26:38reasons were for adenocarcinomas,
• 26:41the eGFR story I've mentioned,
• 26:43but also ALK was being
• 26:45discovered at that time,
• 26:46and patients would respond to
• 26:48crizotinib.
• 26:50And then patients who had
• 26:52adenocarcinoma
• 26:53also were who did not
• 26:55have one of these driver
• 26:56mutations
• 26:58were thought to be more
• 26:59responsive to Pemetrexate.
• 27:01And then there was some
• 27:02evidence that patients with squamous
• 27:04cell carcinomas,
• 27:06were susceptible to pulmonary,
• 27:09hemorrhage
• 27:09if they,
• 27:11got bevacizumab.
• 27:13So there were all these
• 27:14reasons why before we just
• 27:16said, Oh, it's a non
• 27:18small cell carcinoma, not all
• 27:19the way to specify it.
• 27:20Who cares?
• 27:21Now it was important that
• 27:23we
• 27:24go to the extra effort
• 27:25to distinguish adenine from squamous
• 27:27carcinoma as pathologists.
• 27:30And, I'll never forget,
• 27:33you know
• 27:34you know, when you work
• 27:36on a WHO, you kinda
• 27:37like to think you know
• 27:38what's going on. And,
• 27:40I'll never forget, I signed
• 27:41this case out because we
• 27:42didn't think we needed immunohistochemistry
• 27:44to diagnose squamous cell carcinoma.
• 27:47I mean, look at that
• 27:47tumor on the left. It's
• 27:49got all this abundant eosinophilic
• 27:51cytoplasm,
• 27:52sharp
• 27:53cytoplasmic borders. I even think
• 27:54I can see some intracellular
• 27:56bridges.
• 27:57So that's a tumor I
• 27:58signed out without doing any
• 28:00immunostains
• 28:01as squamous carcinoma. And I
• 28:03get a call from the
• 28:03oncologist.
• 28:06By the way, we found
• 28:07out this patient
• 28:08has an EGFR mutation, can
• 28:10you go back and look?
• 28:12And so we did a
• 28:13TTF1,
• 28:14you can see it's positive
• 28:15and there's even some mucin
• 28:17in the tumor.
• 28:18So,
• 28:19we then came up
• 28:21these are
• 28:24tumors
• 28:25where
• 28:26if we do a TTF
• 28:27and a p forty, the
• 28:28recognition of
• 28:30P forty as an immune
• 28:31stain marker for squamous carcinoma,
• 28:34was just coming out as
• 28:36we were working on this
• 28:37classification.
• 28:39So we look for TTF
• 28:43positivity,
• 28:45and p forty negativity.
• 28:47And as you see on
• 28:48the left,
• 28:49if there's no morphologic evidence
• 28:51of gladiator morphology, we call
• 28:53it non small cell favor.
• 28:56Adenocarcinoma
• 28:57and on the right, if
• 28:59it's p forty positive, TTF
• 29:01negative, we say non small
• 29:02cell favor
• 29:03squamous.
• 29:04And there are tables, I
• 29:05won't go through all of
• 29:06this, but, we created a
• 29:08whole set of terminology for
• 29:11classification in small biopsies.
• 29:14So
• 29:15previously,
• 29:17in literature and in clinical
• 29:19trials, anywhere from twenty to
• 29:21forty percent of tumors,
• 29:24in advanced patients were classified
• 29:26as non small cell carcinoma
• 29:27NOS.
• 29:28By introducing these immunostains
• 29:30in our recommendations,
• 29:32our goal was to reduce
• 29:33that to less than five
• 29:34percent. And I think we've
• 29:35done that in clinical practice.
• 29:39Here's a table. Again,
• 29:41I'm not sure anybody reads
• 29:43this, but it's probably one
• 29:44of the most important
• 29:45things to look at, because
• 29:47it impacts on the small
• 29:48biopsy
• 29:49diagnosis.
• 29:52There are good, guidelines for
• 29:53good, clinical practice
• 29:56in, in approaching this whole
• 29:57problem. This
• 29:59is tabled from the chapter
• 30:00one in the twenty twenty
• 30:01one WHO.
• 30:04And
• 30:04simple basic things,
• 30:08such as are shown in
• 30:09this particular slide,
• 30:11given to me by Natasha
• 30:13Rekman, my colleague at Memorial.
• 30:15So if you ever get
• 30:16a block
• 30:17that has
• 30:19so they do a biopsy.
• 30:21They take two cores. And
• 30:23in the PathLab,
• 30:24they put both cores in
• 30:25one block.
• 30:27And I go through this
• 30:29with it happens at Memorial
• 30:30even though
• 30:32the PAs have been instructed
• 30:34not to do this.
• 30:36I I put the slide
• 30:37under the microscope, and I
• 30:38asked the fellows, what's the
• 30:39first thing that we should
• 30:40do? And they start talking
• 30:41about stains and everything.
• 30:43And I say, we go
• 30:44to the lab and ask
• 30:45them to divide the tissue
• 30:47and make two blocks out
• 30:48of this. So we can
• 30:49use one for immunohistochemistry
• 30:51and the other for molecular
• 30:53testing.
• 30:54And that's one of the
• 30:55major goals of this whole
• 30:57small biopsy story is to
• 30:59minimize stains to maximize tissue
• 31:01for molecular testing.
• 31:04And this is a history
• 31:05of molecular testing,
• 31:07at Memorial, and I'm not
• 31:09gonna go through this in
• 31:10detail.
• 31:10But but you can see
• 31:11we basically started only doing
• 31:13eGFR mutation analysis,
• 31:16by a PCR,
• 31:18technique. And now,
• 31:20we just added on Tuesday,
• 31:21I found out we're doing
• 31:23a new MSK REACT.
• 31:25Our impact takes two to
• 31:26three weeks.
• 31:27That used to be three
• 31:28to four weeks. They've gotten
• 31:30that to be shorter.
• 31:31But with MSK React,
• 31:33and,
• 31:35an Adela fusion,
• 31:36panel,
• 31:38we can get virtually all
• 31:39the major genes that we
• 31:41would expect to see abnormal
• 31:43abnormal
• 31:44in lung cancer in,
• 31:46four to five days.
• 31:48And we're just getting started
• 31:49on this. And I predict
• 31:51for young people,
• 31:53these
• 31:54these molecular tests will be,
• 31:55like,
• 31:56one or two day immunosy
• 31:57chemistry test,
• 31:59before your
• 32:00careers are over. Who knows
• 32:02what you'll be doing in
• 32:03thirty years? I get excited
• 32:04to think about that.
• 32:06And we're fortunate that,
• 32:08for ALK rearrangements, immunohistochemistry,
• 32:11there are several antibodies. We
• 32:12use the D5F3,
• 32:14highly specific.
• 32:16You can do FISH if
• 32:17you have doubts.
• 32:19Now Archer also is another
• 32:21way. There are all kinds
• 32:22of molecular ways to
• 32:24investigate this.
• 32:28And
• 32:29this is from Lynette Scholl
• 32:30up at the Brigham
• 32:32where in their,
• 32:34data,
• 32:35only about seventeen percent of
• 32:37lung cancers have no driver.
• 32:39When you think about the
• 32:40molecular revolution that we've been
• 32:42in over the last twenty
• 32:43years, it's mind boggling
• 32:45and very exciting.
• 32:47And what I like, because
• 32:48my career is devoted to
• 32:50training
• 32:52of,
• 32:53thoracic pathology fellows,
• 32:56is we're attracting some of
• 32:57the best residents
• 32:59to our fellowship training program
• 33:01because what we do is
• 33:03so unbelievably excite unbelievably exciting.
• 33:06And here you can see,
• 33:09this is just an article
• 33:10from new at New England
• 33:12Journal,
• 33:13from the MGH group where
• 33:17over seventy percent,
• 33:20overall survival
• 33:22for advanced lung cancer patients.
• 33:24These are patients that would
• 33:26die in weeks to months.
• 33:29There's over seventy percent,
• 33:32survival here. It's just
• 33:35mind boggling the impact that's
• 33:38going on with,
• 33:40all of these targeted,
• 33:42molecular targeted therapies.
• 33:45So that's in summary for
• 33:47the advanced lung cancer patients.
• 33:50We define criteria and terminology
• 33:52for small biopsies and cytology.
• 33:55We develop more accurate histologic
• 33:58subtyping.
• 33:59We developed a whole strategic
• 34:01management
• 34:03approach to small biopsies
• 34:05and streamlining
• 34:07the workflow for molecular testing
• 34:09and the need for a
• 34:10local multidisciplinary
• 34:11team.
• 34:14And you can see, I
• 34:15mean,
• 34:16there are all kinds of
• 34:17things that have contributed to
• 34:18the rapid drop in lung
• 34:19cancer mortality,
• 34:23including,
• 34:24cessation of smoking,
• 34:26introduction of c CT screening
• 34:27or throughout the world,
• 34:29and more in the US.
• 34:36But, we as pathologists
• 34:38are right smack in the
• 34:39middle of contributing
• 34:41to this, reduction in mortality
• 34:43because of the what we've
• 34:44been able to bring to
• 34:45the table
• 34:47in helping to make earlier
• 34:49diagnoses,
• 34:52more accurate,
• 34:54pathologic classification in our role
• 34:57in,
• 34:58contributing to the whole process
• 35:00of molecular testing.
• 35:01So I always make this
• 35:02point when I give this
• 35:03talk to our, pathology fellows
• 35:06is what you are doing.
• 35:08It seems like a lot
• 35:10of mundane pushing around of
• 35:11blocks and slides and ordering
• 35:13things,
• 35:14but it's making a huge
• 35:15difference in, patients' lives.
• 35:19Okay. Surgically resected lung adenocarcinomas.
• 35:23So we
• 35:25also made significant advances here
• 35:27in predicting survival and recurrence.
• 35:30We define, as I mentioned
• 35:31earlier, AIS and MIA to
• 35:33have one hundred percent or
• 35:35near one hundred percent
• 35:37disease free survival if completely
• 35:39resected.
• 35:41It led to allowing better
• 35:44radiologic pathologic correlations,
• 35:47impacted T and M staging.
• 35:48I've mentioned the invasive size,
• 35:50also comparing multiple tumors.
• 35:53And then predicting survival benefit
• 35:55in patients with,
• 35:56adjuvant cisplatinum
• 35:58based therapy.
• 36:01So this is
• 36:02the pattern of a non
• 36:04mucinous,
• 36:05what we used to call
• 36:06bronchioloalveolar
• 36:07carcinoma.
• 36:08And
• 36:09this was a huge work
• 36:10to come up with a
• 36:12term that was better, and
• 36:13we came up with this
• 36:15lipidic,
• 36:16pattern,
• 36:17which I think has served
• 36:18to be quite useful.
• 36:21And, the old concept of
• 36:22bronchiolalveolar
• 36:23carcinoma, I've already alluded to
• 36:25this, we split it into
• 36:26five different
• 36:28categories that we currently recognize,
• 36:30and I've already,
• 36:32mentioned each one of those.
• 36:35And
• 36:38it's very important
• 36:42to remember where you're coming
• 36:43from and remember it in
• 36:45a respectful way.
• 36:47So maybe you have an
• 36:48idea
• 36:49of how to improve something,
• 36:51but the way you go
• 36:51about
• 36:53implementing that idea is not
• 36:55to bash the people that
• 36:56came before you
• 36:58and say that it was
• 36:59wrong or it's not good
• 37:01and what I'm doing is
• 37:02better,
• 37:04but to recognize and give
• 37:06respect to the
• 37:08predecessors. And
• 37:10so you're seeing here on
• 37:11the left survival curves from,
• 37:14what I call an earthquake
• 37:15paper paper,
• 37:18where,
• 37:19Masayuki Noguchi, who you see
• 37:21on the top, and it
• 37:22was really Yukio Shimasada's
• 37:25brainchild
• 37:26idea
• 37:28to identify a pattern of
• 37:30lung adenocarcinoma,
• 37:31and they called it a
• 37:32Noguchi classification
• 37:34and type a and b
• 37:35were what we would call
• 37:37AIS and MIA.
• 37:39And then a type c,
• 37:40which we would think of
• 37:42as a lipidic predominant adenoid
• 37:44in our current thinking,
• 37:45and then overtly invasive adenocarcinomas.
• 37:49But it was a big
• 37:50deal because we were coming
• 37:52up with something that was
• 37:53going to change everybody from
• 37:55quoting the Gucci classification,
• 37:57which I think he liked.
• 38:00So
• 38:02I always
• 38:03and it's I don't know
• 38:04how it happened. It just
• 38:05is something that I innately
• 38:08had an instinct to do,
• 38:10because of the work that
• 38:12I have done in my
• 38:15academic work and the places
• 38:17I was able to work,
• 38:18like AFIP,
• 38:19I got invited all over
• 38:21the world, and I made
• 38:22a point to go to
• 38:23these places and make friends
• 38:26with these,
• 38:27international colleagues. So when it
• 38:29came down
• 38:31to disagreeing with a colleague
• 38:32where the consensus is not
• 38:34going maybe in the direction
• 38:35that they would prefer,
• 38:37they knew we were friends,
• 38:39And I cared about them
• 38:41as people,
• 38:42and you can see up
• 38:43there, I play golf with
• 38:44an Noguchi,
• 38:45and he's much better golfer
• 38:46than I am.
• 38:48But, you know,
• 38:50really treat your colleagues as,
• 38:53friends and spend time with
• 38:55them.
• 38:56Now with the by Zoom
• 38:57and all of this remote,
• 38:59working and interacting,
• 39:01it really,
• 39:03is not the same.
• 39:04So put in the extra
• 39:05effort. And Yuki Yoshimasada
• 39:08regard as a mentor, that's
• 39:09a whole another whole story.
• 39:12So at the time,
• 39:14he was defining BAC as
• 39:16having a hundred percent disease
• 39:18free survival.
• 39:20Our clinical colleagues were calling
• 39:22BAC
• 39:23advanced BAC with poor survival.
• 39:25And you can see here,
• 39:26three year survival, twenty to
• 39:28thirty percent.
• 39:29I was saying, how in
• 39:30the world can we be
• 39:31using the same term for
• 39:32such different tumors?
• 39:34And that was part of
• 39:35the justification
• 39:36for coming up with a
• 39:38new classification.
• 39:39So here's the classification. We
• 39:41had,
• 39:42preinvasive,
• 39:43on the lipidic side. We
• 39:44had the preinvasive
• 39:46lesions of atypical adenomatous hyperplasia,
• 39:49adenocarcinoma
• 39:50in situ. Defined very carefully
• 39:52is three sonometers or less
• 39:53in size,
• 39:54no invasive component.
• 39:56Most of these are non
• 39:57mucinous rare mucinous variants.
• 40:00And minimally invasive also, three
• 40:02sonometers or less,
• 40:04lipidic predominant with a size
• 40:06of invasive component, five millimeters
• 40:08or less.
• 40:10And
• 40:11in order to make those
• 40:12diagnoses, the entire tumor must
• 40:14must be sampled.
• 40:15And if you don't have
• 40:16that, you just call it
• 40:17lipidic predominant and mention that,
• 40:20you know, we could not
• 40:21exclude an invasive component.
• 40:23So here is a,
• 40:26AIS,
• 40:27a pure
• 40:28lipidic lesion.
• 40:30As you look,
• 40:31closely, you can see there's
• 40:32no invasive component.
• 40:35By CT, here you see
• 40:36it's a pure ground glass
• 40:37lesion.
• 40:39And one of the things
• 40:41about classification is have a
• 40:42little fun along the way.
• 40:44Enjoy your life.
• 40:46And it became apparent that
• 40:48there was this in situ
• 40:49wine.
• 40:50And so,
• 40:52I got a case of
• 40:53in situ wine, and we
• 40:54had our consensus.
• 40:56You see me in the
• 40:57back holding the bottle up.
• 40:59And,
• 41:00once again, you know, you
• 41:01have all these people arguing
• 41:02and, you know,
• 41:04going after subjects from different
• 41:06perspectives,
• 41:08and all you need is
• 41:09a little wine to bring
• 41:10the consensus.
• 41:12So but have have fun
• 41:14as you do this. And,
• 41:18during a meeting, having an
• 41:19icebreaker thing like that is
• 41:21very handy. So this is
• 41:22the ninety nine and two
• 41:24thousand four, classification where we
• 41:26had mixed subtype
• 41:28as number one
• 41:29along with these other patterns.
• 41:31And the problem was, in
• 41:33retrospect, of course, we didn't
• 41:34think about it as we
• 41:35were using that term,
• 41:38is is that, you know,
• 41:40this is from a study
• 41:41of cases we had at
• 41:42at Memorial,
• 41:44less than one percent of
• 41:45the cases were BAC.
• 41:47Everything else was mixed up
• 41:49type.
• 41:50It was ridiculous.
• 41:52So so when you're trying
• 41:53to do survival, there's there's
• 41:55no chance to do any
• 41:56survival.
• 41:57So I was privileged to
• 41:58have two wonderful,
• 42:00fellows from Japan come work
• 42:02with us,
• 42:03Aki Yoshizawa
• 42:04on the left and,
• 42:06Noriko Motoyi on the right.
• 42:08Noriko and I spent
• 42:09many, many hours over the
• 42:11microscope looking at
• 42:13a hundred cases from the
• 42:14director's challenge. They're subject of
• 42:16this publication.
• 42:17And somehow or another, we
• 42:19came up with this idea
• 42:20of comprehensive histologic subtyping,
• 42:23estimating percentages of the different
• 42:25patterns.
• 42:26And, then Aki Yoshizawa came
• 42:29along behind, and I'll show
• 42:30you his paper in a
• 42:31moment, and actually did a
• 42:33survival analysis based on that
• 42:34concept. So this was the
• 42:37proposed classification
• 42:38by the ISLC.
• 42:40And, without going through it
• 42:42on all detail,
• 42:43this
• 42:44concept of comprehensive
• 42:46histologic subtyping
• 42:48in five percent increments
• 42:53was like
• 42:54a key opening a magic
• 42:55box.
• 42:58Because once we had this
• 42:59tool,
• 43:01all of a sudden,
• 43:03papers that we were writing
• 43:04about lung adenocarcinoma,
• 43:06trying to predict prognosis,
• 43:07and really beating our head
• 43:09against the wall.
• 43:12These are the various patterns,
• 43:14which I won't go into.
• 43:16All of a sudden, we
• 43:16were able to stratify
• 43:18these subtypes in a more
• 43:20meaningful,
• 43:22percentages.
• 43:24And then
• 43:26I literally almost fell out
• 43:27of my chair when we
• 43:29did the first survival analysis.
• 43:31This is the first paper
• 43:33to show the prognostic significance
• 43:35of the various patterns. And
• 43:37we had the low grade
• 43:38AIS,
• 43:39MIA, lipidic predominant,
• 43:41intermediate grade, papillary and acinar,
• 43:43and then the higher grade,
• 43:46patterns.
• 43:47And,
• 43:48and the rest is history.
• 43:49I mean, this has now
• 43:51been shown in study after
• 43:52study.
• 43:53Yes, what I call,
• 43:56you know, fifty five percent
• 43:59lipidic,
• 44:00Sonya may call fifty five
• 44:02percent acid or it. There's
• 44:04gotta be some degree of
• 44:05disagreement. It's okay.
• 44:07I mean, once you get
• 44:08into that middle range, it
• 44:10you know,
• 44:13you just have to think
• 44:14back, and a lot of
• 44:14people today don't think back.
• 44:17Before we had this tool,
• 44:18we had nothing.
• 44:20I mean, all we had
• 44:21was BAC, which in Japan
• 44:23may be more common, but
• 44:24here in North America, very
• 44:27uncommon.
• 44:28So,
• 44:30you know, can we do
• 44:31better? And there are attempts
• 44:33to make things better.
• 44:35But this was a big,
• 44:36big progress. And here you
• 44:38can see now I'm going
• 44:40to show radiologic pathologic correlation.
• 44:45This is a tumor that
• 44:46shows lipidic on the bottom,
• 44:48an invasive component on the
• 44:49right. This is high power
• 44:50of the lipidic
• 44:52and high power of the
• 44:53acinar pattern.
• 44:55And from this tumor, you
• 44:56can see it's a part
• 44:57solid lesion you have on
• 44:59CT,
• 45:00mostly ground glass,
• 45:02which measures about four point
• 45:04two centimeters,
• 45:05and then a solid component
• 45:07measuring about fifteen
• 45:09one point five centimeters.
• 45:11And
• 45:12basically,
• 45:13in our reports, we document
• 45:15the percentage of the
• 45:17lipidic versus the other patterns,
• 45:19which would be invasive patterns.
• 45:21Here is sixty five percent
• 45:23lipidic,
• 45:24thirty five percent invasive.
• 45:27And sometimes the invasive components
• 45:30are on different slides, multiple
• 45:31slides, you can't stick a
• 45:33ruler on it.
• 45:34And so what we do
• 45:35is we take the total
• 45:36size and multiply it times
• 45:38the percentage of the invasive
• 45:40components.
• 45:41And you can see this
• 45:44downstage this particular tumor
• 45:46from T2B to T1B.
• 45:50And Frank, I hope you're
• 45:51on watching. I wanted to
• 45:53give a shout out to
• 45:54you.
• 45:55I'm trying to identify all
• 45:56the Yale
• 45:58input on these efforts.
• 46:01We published this article about
• 46:03how to use,
• 46:05this apply the new classification
• 46:07to TNM staging in the
• 46:09part solid, part lipidic tumors.
• 46:11And
• 46:13so this was the proposal
• 46:15that we made.
• 46:17So for
• 46:19AIS, we have
• 46:21TIS
• 46:22for parentheses AIS for adenocarcinoma
• 46:25in situ, SCIS for squamous
• 46:27carcinoma in situ,
• 46:29and T1AMI
• 46:30for minimally invasive adenocarcinoma.
• 46:32And then we use invasive
• 46:34size
• 46:35rather than total size for
• 46:36these partlipidic,
• 46:37non mucinous adenocarcinoma.
• 46:40And here, this is a
• 46:41study from Memorial where we
• 46:42looked at
• 46:46over seventeen hundred patients and
• 46:48using invasive size
• 46:51in this
• 46:52survival curve on the left,
• 46:53we have a much better
• 46:54separation than if we use
• 46:56total size.
• 46:58So here's a,
• 47:00study where we identified that
• 47:02small percentages of micropapillary,
• 47:05had a significant
• 47:07impact on outcomes.
• 47:11And this
• 47:13was one of the observations
• 47:14that led me to thinking
• 47:15about
• 47:18the concept of STAS.
• 47:21And there are two articles
• 47:22published in this past year,
• 47:25one from the ISLC
• 47:27database, another is a review
• 47:29article, and there's this is
• 47:31the pro article, there was
• 47:32a con article as well.
• 47:34But I encourage you to
• 47:35consider reading this. Don't have
• 47:37time to go into that
• 47:38concept,
• 47:40but it's something that really
• 47:41came out of this classification
• 47:42effort.
• 47:43The ISLC came up with
• 47:45a grading system, which was
• 47:46possible because of this concept
• 47:48of comprehensive histologic subtyping.
• 47:51So well differentiated, this is
• 47:52for non mucinous adenocarcinomas, well
• 47:53differentiated tumors, lipitic
• 47:53predominant
• 47:55differentiated tumors,
• 47:56lipitic
• 47:58predominant with no or less
• 47:58than twenty percent of high
• 47:59grade patterns, moderately differentiated, acinar
• 48:02or papillary predominant with no
• 48:03or less than
• 48:04high grade patterns, and the
• 48:06poorly differentiated is any tumor
• 48:08with twenty percent or more
• 48:09of the high grade patterns.
• 48:11You can see the survival
• 48:12curve on the left. High
• 48:14grade patterns are solid micropapillary
• 48:16and cribriform are complex plans.
• 48:18And this has been validated
• 48:19in multiple studies.
• 48:21And I know some of
• 48:22you are the young folks
• 48:25artificial intelligence.
• 48:27So we've applied AI to
• 48:29this, model, and
• 48:31it beautifully
• 48:32separates out the ISLC
• 48:34grades.
• 48:37Okay. I'm gonna briefly touch
• 48:39on interstitial lung disease. This
• 48:40has got to go very
• 48:41quickly.
• 48:42I've been privileged to,
• 48:44be involved with,
• 48:46classifications
• 48:47of idiopathic interstitial amoneus in
• 48:49two thousand and two, twenty
• 48:50thirteen,
• 48:52and currently is one ongoing.
• 48:54This,
• 48:56the principles learned there were
• 48:57applied for pediatric
• 48:59interstitial lung disease classification.
• 49:02We, did a workshop on
• 49:04nonspecific interstitial pneumonia when I
• 49:06was still at the AFIP.
• 49:09And I was involved with
• 49:10the IPF guidelines for both
• 49:12the ATS and ERS and
• 49:13the Fleischner Society in twenty
• 49:15eighteen.
• 49:16And then recently
• 49:18hypersensitivity
• 49:19pneumonitis guidelines.
• 49:21So these are historical classifications
• 49:23by Doctor. Liebau from
• 49:26Yale, one of your
• 49:27former faculty,
• 49:29and
• 49:30Anna Katzenstein.
• 49:32This is a group of
• 49:34from the two thousand two,
• 49:37classification.
• 49:38And I wanted to give
• 49:39a shout out. I went
• 49:40back and I saw
• 49:42that, doctor Mathay,
• 49:44who some of the older
• 49:45people probably know,
• 49:47very illustrious,
• 49:49pulmonologist.
• 49:50He was one of our
• 49:51reviewers.
• 49:52He's a part of the
• 49:53reviewer panel.
• 49:56So,
• 49:58in two thousand two, we
• 49:59were able to crystallize narrowing
• 50:01the definition of the UIP
• 50:03pattern, introduce the concept of
• 50:05NSIP,
• 50:06recognize these other patterns, and,
• 50:09the importance of radiology,
• 50:11to,
• 50:12recognize the UIP pattern,
• 50:15minimally invasive
• 50:16thoracoscopic
• 50:17surgery,
• 50:18and
• 50:19publication of large series. This
• 50:21is the classification.
• 50:23By the way, NSIP was
• 50:24regarded as a provisional category.
• 50:27So we had morphologic patterns,
• 50:29histologic
• 50:30and by CT, and then
• 50:31clinical diagnoses.
• 50:33This is the NSIP project.
• 50:37In our two thousand two
• 50:38classification,
• 50:40under each entity, we had
• 50:41a list of areas of
• 50:42uncertainty.
• 50:44And one of the nice
• 50:45things was when we went
• 50:46back in two thousand thirteen,
• 50:47we found we had actually
• 50:49addressed,
• 50:50many of these, concerns.
• 50:52And that's part of the
• 50:53idea of doing classifications
• 50:55and updating them.
• 50:57The the idea is that
• 50:59you
• 50:59have learned something in the
• 51:01meantime,
• 51:02but it really helps to
• 51:03outline what are the,
• 51:04what is the remaining work
• 51:06to be done.
• 51:08Then this is the two
• 51:09thousand thirteen,
• 51:10classification.
• 51:12We have fun.
• 51:13This is one of my
• 51:14Japanese colleagues put this in
• 51:15Japanese. I've had this translated
• 51:17into all kinds of different
• 51:18languages.
• 51:19It's fun in the middle
• 51:20of a talk to just
• 51:21to flop up a slide
• 51:22and
• 51:23see what all the local
• 51:24people have to
• 51:26say. So this is the
• 51:27two thousand thirteen IAP classification.
• 51:29I don't have time to
• 51:30go through that.
• 51:32One thing I would say
• 51:33is
• 51:34there was an emerging entity
• 51:36of idiopathic pleuroperenchymal
• 51:37fibroelastosis,
• 51:39And we really debated, should
• 51:41it be in, should it
• 51:41be out? And,
• 51:43you know, it was one
• 51:44of these,
• 51:46not so clear issues.
• 51:48And in the end, we
• 51:48decided to put it in.
• 51:50And as I look back,
• 51:51it's one of the best
• 51:52things that we did. It's
• 51:53a small uncommon entity, but
• 51:55there's been a real explosion
• 51:57of literature about this and
• 51:59much better understanding.
• 52:01So when you do a
• 52:02classification,
• 52:04adding certain things really can
• 52:06draw attention to it and
• 52:08help people
• 52:09recognize it more frequently.
• 52:12And I'm not an alcoholic,
• 52:15but honeycombing
• 52:16is an important
• 52:18feature seen by CT and
• 52:19pathology for interstitial disease. And
• 52:22I was asked to lead
• 52:24a session at the Fleischner
• 52:25back
• 52:27in many years ago.
• 52:30And I was I looked,
• 52:31is there a honeycomb wine?
• 52:33And sure enough, there's a
• 52:34honeycomb wine.
• 52:36Now, the In situ wine
• 52:37is really good. This is
• 52:38horrible.
• 52:39So
• 52:40don't go out and buy
• 52:41any honeycomb wine.
• 52:43And here you can see
• 52:44once again, you know, and
• 52:46there were some serious arguments
• 52:48this morning,
• 52:49but everyone's smiling,
• 52:52and holding up their,
• 52:54honeycomb wine. By the way,
• 52:55I've switched it out for
• 52:57a I emptied the honeycomb
• 52:59wine and put it in
• 53:00a real good wine.
• 53:02And this has happened this
• 53:03is what happens when people
• 53:05have drunk the honeycomb wine,
• 53:06get a little drunk.
• 53:08So in two thousand thirteen,
• 53:09you know, we had made
• 53:10progress. So NSIP was accepted,
• 53:13and defined.
• 53:14We had better understanding of
• 53:16smoking related interstitial disease.
• 53:18One of the really important
• 53:20things here was a disease
• 53:22behavior classification.
• 53:24Tumor classification, especially with genetics,
• 53:28can be
• 53:29much more precise. In ILD,
• 53:31things are more
• 53:35complicated. And this is one
• 53:36of the white papers on
• 53:38classification of idiopathic and diagnosis
• 53:41of idiopathic pulmonary fibrosis.
• 53:43These are two documents on
• 53:46hypersensitivity
• 53:47pneumonitis.
• 53:49And we're working on the
• 53:50twenty twenty five ATS ERS
• 53:53IAP classification, so stay tuned
• 53:55for that.
• 53:57So one of the important
• 53:59things in completing a classification
• 54:01is disseminate the draft in
• 54:03advance.
• 54:04Don't keep it secret.
• 54:06The the broader
• 54:07the distribution
• 54:09and and feedback, the better
• 54:10it will be.
• 54:13Enjoy the journey.
• 54:15Make friends out of the
• 54:16colleagues even if you have
• 54:17strong disagreements.
• 54:19Let make sure everybody knows
• 54:20you're good friends.
• 54:23Having a final editing session
• 54:25is really important. We learned
• 54:26this with the WHO.
• 54:28Paul Klyhus
• 54:29had us go to Zurich
• 54:33and to Lyon to do
• 54:34final editings.
• 54:35It's astonishing with a book
• 54:37like the WHO, all the
• 54:38things you find at the
• 54:39last minute.
• 54:41And remember, no no classification
• 54:43is perfect.
• 54:44So people who get out
• 54:46and try to bash your
• 54:47classification and say,
• 54:48they got all that wrong.
• 54:52Don't
• 54:55be respectful of who went
• 54:57before and just realize that
• 54:59we're all in a journey
• 55:00to improve what we're doing.
• 55:03So I've gone through,
• 55:05the history and approach to
• 55:07WHO classification,
• 55:09talked about the two thousand
• 55:10eleven adenocarcinoma
• 55:11classification
• 55:13and ILD classification.
• 55:15And I
• 55:16sorry. I can't
• 55:17finish without
• 55:19giving a shout out to
• 55:20my colleagues. This is our
• 55:21our faculty,
• 55:23absolutely amazing team,
• 55:25faculty at Memorial, and these
• 55:27are our fellows.
• 55:29We have an ACGME accredited
• 55:31training program. We have three
• 55:32fellows per year. The three
• 55:33on the top
• 55:34are our fellows, and we
• 55:36have openings starting
• 55:38in July of twenty twenty
• 55:39seven. We're filled all the
• 55:41way through there. So if
• 55:42any of you interested in
• 55:43thoracic pathology, it's an amazing
• 55:45field.
• 55:46You can call up and
• 55:47talk to any one of
• 55:48these colleagues.
• 55:49Oh, oh, oh, okay. I'm
• 55:51sorry.
• 55:53I don't want you to
• 55:54defect from doctor Dasik. Sorry.
• 55:56But if she fails, then
• 55:57there's an extra
• 55:59person. Anyway,
• 56:00we
• 56:01really wanna support your team
• 56:03here, and, I'm sorry. I
• 56:05didn't mean to recruit away.
• 56:08Okay. Thank
• 56:11you
• 56:13very
• 56:15much.
• 56:17Any questions, comments?
• 56:21Yes. It's amazing to see
• 56:23how much of the black
• 56:24box of genetic drivers has
• 56:26shrunk, due to our knowledge,
• 56:28but still seventeen percent is
• 56:30a decent chunk without any
• 56:32known drivers.
• 56:34What's kinda on the horizon
• 56:35of what people think might
• 56:37be driving
• 56:38those non genetic identifiable causes?
• 56:41Well, there's some a lot
• 56:43of,
• 56:45molecular,
• 56:46clinical
• 56:47power going into just that.
• 56:49And there's a there's a
• 56:51whole study trying to identify
• 56:53the so called driverless,
• 56:56adenocarcinomas.
• 56:58And I don't know what's
• 56:59gonna be found. I mean,
• 56:59there have been attempts at
• 57:00this before without,
• 57:03so some of it is
• 57:04the sensitivity
• 57:05of the testing methods that
• 57:07we have.
• 57:09And
• 57:11remember, when I started pathology
• 57:13training,
• 57:14some few years ago, forty
• 57:16years ago,
• 57:17We didn't have immunosic chemistry.
• 57:20Now look at what we
• 57:21have. So I look at
• 57:22you and you've got probably
• 57:24thirty years, forty years in
• 57:25front of you.
• 57:27Can you imagine
• 57:28what you're gonna be doing
• 57:29in thirty, forty? You probably
• 57:31can't. I mean, there's probably
• 57:33gonna be discover all kinds
• 57:34of discoveries made.
• 57:38So just a matter of
• 57:39time. There are a lot
• 57:40of really smart people,
• 57:42working
• 57:43on exactly the question you
• 57:44asked. That's a great question.
• 57:45I don't know the answer.
• 57:47A lot of really smart
• 57:49people working on it.
• 57:52Yeah. Yes.
• 57:53With Staph, there is any
• 57:54value in chasing Staph on
• 57:57frozen section?
• 57:58Oh, I'm glad you asked
• 57:59that question. So
• 58:02can stats be detected on
• 58:04frozen? And I would say
• 58:05yes,
• 58:07but it's very difficult. And
• 58:09should it
• 58:11be recommended to be done
• 58:14by pathologists of the day?
• 58:15And I would say absolutely
• 58:17not.
• 58:21And if there's any doubt
• 58:23or uncertainty whether it really
• 58:25it's real status or not,
• 58:26it should not be called.
• 58:29And,
• 58:30and, you know, at Memorial,
• 58:32art even at a place
• 58:33like Memorial,
• 58:35the the the frozen are
• 58:35done by the pathologist of
• 58:36the day,
• 58:38and they don't always,
• 58:39you know,
• 58:41call us to go down
• 58:42and look.
• 58:44I have to say, I
• 58:45think every time I've been
• 58:46asked, which hasn't maybe
• 58:48half a dozen times in
• 58:50the last ten years,
• 58:52a surgeon will ask that
• 58:53question.
• 58:56You know, I've been right,
• 58:58but if I'm not sure,
• 58:59I just I don't call.
• 59:01So I I don't think
• 59:02it's something for prime time.
• 59:05Yeah.
• 59:10Yes.
• 59:12Yeah. Question. We have a
• 59:13left field.
• 59:14It's interesting. The lipidic pattern
• 59:16that we defined now is
• 59:18I know there's some insight
• 59:19you were with.
• 59:22And the
• 59:23some of them, as you
• 59:24point out, when they're diagnosed
• 59:26clinically,
• 59:27which you're based in your
• 59:28studies, I do very well.
• 59:30I I'm trying to oh,
• 59:32yes.
• 59:34And do you know I
• 59:35this is anecdotal.
• 59:37So my experience
• 59:38of autopsies,
• 59:39if you look at very
• 59:40much, the lab you find
• 59:42histologic,
• 59:43lipids,
• 59:44atypical
• 59:45adenos and psyche very common,
• 59:48and they're never present.
• 59:51But those are different in
• 59:52any of these just such
• 59:53slow growing or new vision
• 59:55bursts, like, sometimes we think
• 59:56too. Has anybody actually looked
• 59:58at autopsy incidents?
• 01:00:02So Arbanda Frere, did a
• 01:00:04autopsy study, I think, looking
• 01:00:05at atypical adenomas hypoplasia. I'll
• 01:00:07I'll try to find that
• 01:00:08and send that to you.
• 01:00:10This should be easy to
• 01:00:11find.
• 01:00:12And, I forget what the
• 01:00:14percentage was of cases where
• 01:00:15he found it.
• 01:00:16It's very high, I suspect.
• 01:00:18Yeah. It was it was
• 01:00:20it was a reasonable,
• 01:00:21percentage of of of,
• 01:00:24of cases.
• 01:00:25So,
• 01:00:26incident a different hit.
• 01:00:29No.
• 01:00:30But clearly, in an autopsy
• 01:00:31setting, it's an incidental finding
• 01:00:33of no clinical significance.
• 01:00:36But, there are definitely cases
• 01:00:38where
• 01:00:40the lungs are just riddled
• 01:00:42with
• 01:00:44various lipidic adenos and,
• 01:00:47often multicentric
• 01:00:49Ah.
• 01:00:50And we we see those,
• 01:00:52on a regular basis in
• 01:00:53our clinical practice.
• 01:00:57I mean, Ah is a
• 01:00:58precursor for an admin person.
• 01:01:01Yes.
• 01:01:01I saw a hand go
• 01:01:02up.
• 01:01:07Anybody else?
• 01:01:11Well, it's been a pleasure
• 01:01:13to speak with all of
• 01:01:14you and,