>> WELL, WELCOME.
I'M PLEASED TO INTRODUCE YOU TO
ELAINE JAFFE AN INVESTIGATOR AT
THE NATIONAL CANCER INSTITUTE
AND COMPLETED HER TRAINING AT
U-PENN AND WAS AN EDITOR FOR
W.H.O. CLASSIFICATION OF TUMORS
OF LYMPHOID MALIGNANCIES AND WAS
NAMED ONE OF THE MOST HIGHLY
CITED RESEARCHERS IN CLINICAL
ONCOLOGY AND AMONG THE TOP 400
CITED RESEARCHERS.
SHE'S HAD ACHIEVEMENTS IN THE
AMERICAN SOCIETY OF HEMATOLOGY
AND PRESIDENT FOR THE UNITED
STATES AND CANADA ACADEMY OF
PATHOLOGY AND THE SOCIETY FOR
HEMATOPATHOLOGY.
IN 2008 SHE WAS ELECTED TO WHAT
IS NOW KNOWN AS THE NATIONAL
ACADEMY OF MEDICINE.
SHE'S HAD MANY OTHER PRESTIGIOUS
AWARDS INCLUDING THE
DISTINGUISHED PATHOLOGY AWARD IN
2009 AND IN THE INAUGURAL AWARD
FOR OUTSTANDING ACHIEVEMENT IN
PATHOLOGY IN CANCER RESEARCH
FROM AACR AND IN 2023 FROM FASB
RECOGNIZED WITH A LIFE TIME
ACHIEVEMENT AWARD.
I HAVE TO SAY I DID MY CLINICAL
TRAINING HERE AS A MEDICAL
ONCOLOGY FELLOW AND MANY TIMES I
WOULD SIT DOWN WITH THE LYMPHOMA
TEAM AND DR. JAFFE AND SHOW US
UNDER THE MICROSCOPE ON WHY THIS
WAS A GIVEN LYMPHOMA.
SHE'LL TALK ABOUT THE MICROSCOPE
AS A TOOL FOR DISEASE DISCOVERY.
ELAINE, THANK YOU.
>> THE CODE IS 57678 FOR THOSE
LISTENING.
57678.
YOU'RE ON.
>> TODAY I'LL TRY TO CONVINCE
YOU THE MICROSCOPE IS NOT AN
OBSOLETE PIECE OF EQUIPMENT IN
THE LABORATORY BUT STILL HAS A
ROLE IN DISEASE DISCOVERY.
SO WHY DO WE CLASSIFY TUMORS?
WELL, WE CLASSIFY TO DELINEATE
DISEASE ENTITIES.
I'M GOING DISEASE DEFINITION IS
ESSENTIAL FOR ONGOING STUDIES OF
PATHOGENESIS.
COMPARISON OF CLINICAL TRIALS,
EPIDEMIOLOGICAL STUDIES AND THE
CORRECT THERAPY OF THE
INDIVIDUAL PATIENT.
WILL THE FATHER OF SURGICAL
PSYCHOLOGY COINED TERMS MORE
THAN 100 YEARS AGO.
WE HAVE OTHER TOOLS TO DIAGNOSE
DISEASE BUT THE MICROSCOPE STILL
HAS AN IMPORTANT PLACE IN THE
MEDICAL ARMAMENTARIUM.
WHEN I STARTED IN PATHOLOGY WE
USED THE RAPPAPORT SYSTEM OF
LYMPHOMA CLASSIFICATION.
IT WAS A PRETTY PRIMITIVE
APPROACH.
THEY WERE BASED ON CELL SIZE
WITH HISTOCYTES BEING LARGE.
THIS WAS NOT BIO LOGICALLY
CORRECT AND ALSO CLAIMED MOST
LYMPHOMAS COULD NODULEAR AND
CAREFUL STUDIES WERE STARTED OF
THE LYMPHOID SYSTEM UNDER THE
MICROSCOPE.
IN THE EXEMPTION OF GERMINAL
CENTERS HE CHARACTERIZED THE
CELL TYPES AND DESCRIBED
CENTROBLASTS AND CENTROCYTES AND
THOSE WITH A PATTERN WERE
DERIVED FROM THE GERMINAL
CENTER.
THIS HAD BEEN REFUTED BY
RAPPAPORT'S EARLIER WORK.
WHEN I STARTED AS A RESIDENT
BACK IN 1970, THE STARS WERE
REALLY ALIGNED FOR THE
REVOLUTION OF LYMPHOMA
DIAGNOSIS.
THERE WERE NEW ADVANCES IN THE
TREATMENT AND ADVANCES IN
IMMUNOLOGY AND NEW INSIGHTS INTO
THE NATURE OF IMMUNE CELLS AND
EMERGING TECHNIQUES TO
CHARACTERIZE LYMPHOCYTES AND
HISTIOCYTES.
I WAS LUCKY TO BECOME A FELLOW
WITH MOST THE LYMPHOMA DIAGNOSIS
AT THAT POINT AND HAD THE GOOD
FORTUNE TO WORK WITH THREE
IMMUNOLOGISTS IN NIAID, IRA
GREEN, DR. FRANK AND ETHAN
SHEVACH THEY WERE DEVELOPING
TOOLS TO IDENTIFY B CELLS AND T
CELLS AND IT WAS KNOWN T CELLS
HAD RECEPTORS FOR COMPLEMENT.
NOW WE KNOW THAT ANTIGEN IS CD
21 AND DETECTED BY WHAT WAS
CALLED EAC CELLS CODED WITH
ANTIBODY IN COMPLEMENT AND BIND
TO CELLS WITH THE CD 21
RECEPTOR.
SO I UNDERTOOK AN ATTEMPT TO TRY
AND USE THIS TECHNIQUE TO LOOK
AT TISSUE SECTIONS.
DEVELOPED WHAT WE CALL THE
HANGING DROP TECHNIQUE IN WHICH
WE CUT FROZEN SECTIONS ON
MICROSCOPIC SLIDES.
WE LOADED THE EAC RED CELLS IN A
MICROCULTURE CHAMBER AND
INCUBATED THE SECTION WITH THE
EAC RED CELLS.
AFTER GENTLE TAPPING THE SLIDE
WAS DETACHED AND WE LOOKED UNDER
THE MICROSCOPE TO SEE WHERE THE
EAC CELLS HAD BOUND.
LO AND BEHOLD WE SAW BINDING TO
THE REACTIVE FOLLICLES IN LYMPH
NODE SECTION.
I USED THE TECHNIQUE TO LOOK AT
NODULAR LYMPHOMA AND FOUND THE
NODULES BOUND THE RED CELLS
PROVIDING ORIGIN FOR FOLLICULAR
B LYMPHOCYTES.
THIS WAS PUBLISHED IN THE NEW
ENGLAND JOURNAL AND ULTIMATELY
NAMED A CITATION CLASSIC.
WHEN THERE WAS THE INTRODUCTION
OF ADDITIONAL TECHNIQUES THAT
COULD IDENTIFY T CELLS AND B
CELLS, WE HAD SHEEP ERYTHROCYTE
ROSETTES AND I MENTIONED THIS
THE OTHER DAY AND THEY HAD NO
IDEA WHAT THIS WAS AND I WAS
SURPRISED.
THIS ANTIGEN IS NOW KNOWN AS CD
2.
THERE WAS THE EXPRESSION IMM
IMMUNOGLOBULIN LEADING TO AN
INTERESTING DEVELOP IING.
AND THERE WERE MEETINGS IN ITALY
AND VIRGINIA.
THIS PRESENTED PROBLEMS FOR THE
HEMATOLOGY, IMMUNOLOGY
COMMUNITY, WHICH CLASSIFICATION
SHOULD BE USED.
THE NCI SPONSORED A STUDY OF THE
VARIOUS SIX CLASSIFICATIONS.
THEY HAD NEARLY 1200 CASES OF
NON HODGKIN'S LYMPHOMA AND HAD A
PATHOLOGIST FROM EACH OF THE
CLASSIFICATIONS AND SIX CONTROL
PATHOLOGISTS.
AND THEY REVIEWED THE NEARLY
1200 CASES.
THEY WERE MADE FIRST WITHOUT
CLINICAL DATA AND GOT TO REVIEW
THE SLIDE KNOWING ONLY AGE, SEX
AND ANATOMIC SITE.
KAP
KAPLAN
KAPLAN-MEIER CURVES WERE
GENERATE AND NO CLASSIFICATION
EMERGED AS SUPERIOR.
THIS LED TO THE WORKING
FORMULATION FOR CLINICAL USAGE.
IT WAS SUPPOSED SORT OF AN
ESPERANTO OF LYMPHOMA
CLASSIFICATIONS YOU CAN USE AND
IT WAS ESSENTIALLY THE RAPPAPORT
SYSTEM WITH MINOR CHANGES IN
TERMINOLOGY.
IT WAS NEVER INTEND BE TO BE A
FREE-STANDING CLASSIFICATION.
THE DIFFUSE MIX WAS HANDY AND IT
WAS ACCEPTED IN THE U.S. BUT
RESISTED IN EUROPE AND ASIA
WHERE THE KEEL SYSTEM PROPOSED
BY CARL LEONARD AND COLLEAGUES
WAS POPULAR.
MEANWHILE RAPID PROGRESS WAS
BEING MADE IN NEOPLASMS.
THERE WAS DEVELOPED
IMMUNOHISTOCHEMISTRY FOR USE ON
ROUTINE PARAFFIN SECTIONS AND
HAD THE EXPLOSION OF MONOCLONAL
ANTIBODIES AND IN 1982 DAVID
MASON USED MONOCLONAL ANTIBODIES
FOR HUMO HISTOCHEMISTRY IN
PARAFFIN SECTIONS.
AND IMMUNOGLOBULIN GENE
ARRANGEMENTS WERE IDENTIFIED AND
THEN BCL2 GENE ARRANGEMENTS WERE
IDENTIFIED.
IMMUNOPATHOLOGISTS WERE STARTING
TO SEE A WAY FORWARD.
.
A GROUP WILL LOOKED TO SEE IF
THEY CAN ARRIVE AT A BETTER
UNDERSTANDING OF THE
CLASSIFICATION OF LYMPHOMAS.
19 INDIVIDUALS WERE INVITED TO
ATTEND THE MEETING IN LONDON AND
THE AGENDA INCLUDED THREE
TOPICS.
ONE DISCUSSION OF LYMPHOMA THAT
WAS CALLED INTERMEDIATE
LYMPHOCIDIC AND THE TOPIC OF
GASTROINTESTINAL LYMPHOMAS AS A
UNIQUE BIOLOGICAL ENTITY AND
FINALLY A DISCUSSION OF THE
INTERRELATIONSHIP OF HODGKIN'S
AND NON-HODGKINS LYMPHOMA.
CONSENSUS WAS EMERGING AND THE
PATHOLOGISTS REALIZED WE WERE
ALL TALKING THE SAME LANGUAGE.
HERE'S SOME OF THE FOLKS AT THAT
MEETING.
NANCY HARRIS, HERALD STEIN, S
STEFANO PALARI AND OTHERS AND
ME.
THERE WAS THE DISCUSSION OF
INTERMED
INTERMEDIATE CENTROCYTIC
LYMPHOMA AND PROPOSED THE THIS
MIGHT BE DERIVED FROM THE LY
LYMPHOSITE OBSERVED IN
HISTOLOGIC SECTIONS.
AN IMPORTANT PIECE OF
INFORMATION WAS THE
IDENTIFICATION OF REARRANGEMENTS
INVOLVING THE BREAK POINT REGION
BCL1 BY SOUTHERN BLOT AND
SEVERAL GROUPS DEMONSTRATED THIS
REARRANGEMENT INVOLVING THE 1114
TRANS LOCATION WAS SEEN IN
CENTROCYTIC LYMPHOMA AND
INTERMEDIATE LYMPHOMA SUGGESTING
THE SAME DISEASE ENTITY.
AT THIS TIME WE AUTHORED AN
EDITORIAL IN BLOOD PROPOSING
THIS DISEASE SHOULD BE
DESIGNATED AS MANTLE CELL
LYMPHOMA AND THIS WAS A CONCEPT
EMBRACED BY THE INTERNATIONAL
LYMPHOMA STUDY GROUP IN A SECOND
ARTICLE.
SUBSEQUENTLY, CYCLIN D1 WAS
IDENTIFIED IMPORTANT IN THE
LOCUS AND THE ANTIBODIES SHOWED
OVER EXPRESSION BY
IMMUNOHISTOCHEMISTRY.
HERE SHOWING THE CHARACTERISTIC
MANTLE ZONE PATTERN.
I WE DESCRIBED A BLASTOID
VARIANT FROM THE DISEASE AND
THIS BLASTOID VARIANT HAD A MORE
AGGRESSIVE CLINICAL COURSE.
IN SUBSEQUENT STUDIES USING GENE
EXPRESSION PROFILING TO SHOW
THAT THE PROLIFERATION SIGNATURE
WAS KEY IN THE PROGNOSIS OF
MANTLE CELL LYMPHOMA AND NOT
SURPRISINGLY THE BLASTOID
VARIANT HAD THE HIGHEST
PROLIFERATION SIGNATURE.
THE MOLECULAR PATHOGENESIS OF
MANTLE CELL LYMPHOMA WAS
INTERESTING IN DEMONSTRATING THE
DISEASE AND MANY STUDIES
DEMONSTRATED MANTLE CELL
VARIANTS INCLUDING THE BLASTOID
MANTLE CELL NON-NODAL CELL AND
EVEN SOME CASES WITH
PLASMACYTOID DIFFERENTIATION.
AND A SECOND RECOMMENDED A
FORMAL WILL DESCRIPTION OF THE
LYMPHOMA FROM CLASSIC HODGKIN'S
LYMPHOMA SAYING IT WAS BIO
LOGICALLY AND CLINICALLY A
TOTALLY SEPARATE DISEASE.
SOMETHING BORN TRUE IN
SUBSEQUENT YEARS.
SO, AS THE DISCUSSIONS AMONG THE
PATHOLOGISTS WENT ON, WE
REALIZED THAT THE MOST PRACTICAL
APPROACH TO LYMPHOMA
CLASSIFICATION AT THIS TIME IS
TO SIMPLY DEFINE DISEASES THAT
WE THINK WE CAN RECOGNIZE WITH
CURRENTLY AVAILABLE MORPHOLOGIC
PHENOTYPIC AND GENETIC
TECHNIQUES.
THUS WAS BORN THE REVISED
EUROPEAN LYMPHOMA CLASSIFICATION
ALSO CALLED IT THE REAL
CLASSIFICATION SOMEWHAT TONGUE
AND CHEEK.
AS THESE WERE THE REAL ENTITIES.
IT REPRESENTED A NEW
CLASSIFICATION.
INDIVIDUALS DISEASES WERE
DEFINED BASED ON A CONSTELLATION
OF CLINICAL AND LABORATORY
FEATURES.
IMPORTANTLY THE CLINICAL
PRESENTATION AND COURSE WAS A
MAJOR FACTOR.
THE SITE OF INVOLVEMENT WAS
OBSERVED AS OFTEN A SIGN POST
FOR UNDERLYING BIOLOGICAL
DISTINCTIONS AS IN MALT LYMPHOMA
AND IMPORTANTLY BASED ON THE
BUILDING OF CONSENSUS THROUGH
INPUT FROM 19 EXPERT HEM
HEMATOPATHOLOGISTS AND AN ENTITY
COULD NOT BE INCLUDED IN THE
CLASSIFICATION UNLESS THERE WERE
AT LEAST TWO PUBLICATIONS ON IT
IN THE PEER REVIEWED LITERATURE.
SO IN ADVANCE OF THE PUBLICATION
WHICH WAS COMING OUT SHORTLY IN
BLOOD, VINCE LAVIDA CONVENED
REPRESENTATIVES FROM 42
INTERNATIONAL LYMPHOMA STUDY
GROUP TO MEET WITH THE CLINICAL
ONCOLOGY COMMUNITY TO PRESENT
THE CLASSIFICATION AND OUR
PROPOSED IDEAS.
MOST QUESTIONING THE VALUE OF
THE APPROACH.
WHEN THE REAL CLASSIFICATION WAS
SUBSEQUENTLY PUBLISHED IN BLOOD
IN SEPTEMBER OF 1994 SAUL
ROSENBERG LEADING ONCOLOGIST AT
STANFORD UNIVERSITY PUBLISHED
THE FOLLOWING EDITORIAL AND
STATED DESPITE THE HOPE OF MANY,
SEPARATION OF LYMPHOID TUMORS
INTO B OR T-CELL ORIGIN AS MAJOR
SUB TYPES, IS NOT HELPFUL TO THE
CLINICIAN.
I SO I WANT TO SEE A SHOW OF
HAND FROM THE CLINICIANS IN THE
AUDIENCE, HOW MANY AGREE WITH
THAT?
OKAY.
HE ALSO OBJECTED TO THE FACT THE
CLASSIFICATION DID NOT CLEARLY
IDENTIFY PROGNOSTIC GROUPS.
CLINICIANS LIKED THE WORKING
FORMULATION BECAUSE THEY HAD
LOW, INTERMEDIATE AND HIGH AND
ONLY HAD THREE BOXES TO PUT THE
TUMORS.
WE FELT YOU COULDN'T RANK
LYMPHOMAS BASED ON PROGNOSIS.
AND FOR MANY DISEASE ENTITIES
THERE WAS A SPECTRUM OF CLINICAL
BEHAVIOR AS WE SEE IN FOLLICULAR
LYMPHOMA OR ADULT T CELL
LEUKEMIA LYMPHOMA.
AND WENT ON WITH TOOLS AND
METHODS TO DISSECT THE CELL OF
ORIGIN AND LEVEL OF
DIFFERENTIATION, EVERY PATIENT'S
LYMPHOMA MIGHT BE DIFFERENT AND
IT'S DOUBTFUL SUCH COMPLETE
KNOWLEDGE WOULD BE HELPFUL.
WELL, I THINK THAT'S ALSO SOME
OF US WOULD DISPUTE TODAY.
HE WENT ON TO SAY IT HAD TO BE
CAPABLE OF USED BY THE WELL
TRAINED PATHOLOGIST USING EASILY
USABLE TECHNIQUES.
THUS WAS BORN ANOTHER STUDY TO
EVALUATE THE CLASSIFICATION.
THE MAIN CLINICIAN AT THE
MEETING THAT EMBRACED OUR
APPROACH AND THE STUDY HE
CONDUCTED VALIDATED THE CLINICAL
CLASSIFICATION FOR CLINICAL
USAGE AND TRIALS.
IT WAS INDEED USEFUL AND
REPRODUCIBLE.
SO WHAT ARE THE ADVANTAGES OF A
DISEASE ORIENTED APPROACH TO
CLASSIFICATION?
IT HAS TO BE REQUIRED FOR THE
DEVELOPMENT OF NEW THERAPIES.
SHOWN HERE ARE THREE LYMPHOID
MALIGNANCIES DERIVED FROM SMALL
B CELLS.
CLEARLY THEY'RE DIFFERENT BIO
LOGICALLY AND TREATED IN
DIFFERENT WAYS.
IT'S ALSO REQUIRED FOR THE
INVESTIGATION INTO THE
PATHOGENESIS OF SPECIFIC
ENTITIES SUCH AS ADULT T CELL
LEUKEMIA, BURKITT LYMPHOMA OR
ANAPLASTIC LARGE CELL LYMPHOMA.
AND THE W.H.O. INVITE THE MAJOR
SOCIETIES TO DEVELOP A
CLASSIFICATION FOR THE UPCOMING
THIRD EDITION OF THE W.H.O. BLUE
BOOK.
THE FIRST EDITION WAS IN 1976.
THERE WAS NEVER A THIRD
ADDITION.
IN 1994 ABOUT THIS TIME THE
DIRECTOR TRANSFORMED THE BLUE
BOOK SERIES TO ITS CURRENT
FORMAT.
THE PRIOR BLUE BOOKS WERE SIMPLE
HANDBOOKS WITH A SERIES OF PHOTO
MICROGRAPHS AND FIGURE LEGENDS
WITHOUT DISCUSSION OF THE
DISEASE ENTITIES.
IN THE NEW BLUE BOOK FORMAT HE
SAWS THE IMPORTANCE OF
INTEGRATING PATHOLOGY, GENETICS
AND CLINICAL FINDINGS AS
PROPOSED IN THE REAL
CLASSIFICATION AND THUS THE
W.H.O. 2001 CLASSIFICATION WAS
BORN.
HOWEVER PRIOR TO PUBLICATION OF
THE CLASSIFICATION, WE REALIZED
THAT AT THIS POINT IT WAS
IMPORTANT TO INVOLVE CLINICIANS.
SO IN PREPARATION FOR THIS WE
ORGANIZED A CLINICAL ADVISORY
COMMITTEE MEETING.
THE MEETING WAS ORGANIZED AROUND
A SERIES OF QUESTIONS.
THE PATHOLOGISTS PRESENTED THEIR
PROPOSED CLASSIFICATIONS.
CLINICIANS PRESENTED DATA
RELEVANT TO THE FACT.
A DISCUSSION WAS HELD AND VOTING
WAS HELD IF NECESSARY.
MEETING REPORTS WERE PUBLISHED
IN BOTH CLINICAL AND PATHOLOGY
JOURNALS IN ADVANCE OF THE BLUE
BOOK AND THE MEETING WAS A GREAT
SUCCESS WITH PARTICIPATION OF
MORE THAN 200 INDIVIDUALS FROM
24 DIFFERENT COUNTRIES.
THIS IS THE GROUP THAT GATHERED
IN VIRGINIA AND AS YOU CAN SEE
PEACE AND TRANQUILITY PREVAILED
IN THE VIRGINIA COUNTRY SIDE.
AT A CONFERENCE IN 1975 WHICH
FAILED, WHILE THIS THIS WAS ONE
HIGHLY SUCCESSFUL.
SO WHAT WERE THE DIFFERENCES?
WELL, IN 1975 THE CLASS
CLASSIFICATIONS WERE THE WORK OF
INDIVIDUAL EXPERTS BROUGHT TO
ARLIE UNDER DURESS.
AT THIS TIME THE KNOWLEDGE OF
THE IMMUNE SYSTEM WAS AT INFANCY
AND PHENOTYPING WAS NOT
AVAILABLE.
MOLECULAR ONCOLOGY WAS STILL
UNDISCOVERED AND THERE WAS NO
WAY TO TEST THE PROPOSALS
EMPIRICALLY.
IN 1997 THE WORK WAS THE RESULT
OF MULTIPLE EXPERTS AND THE
PATHOLOGISTS AND CLINICIANS
WORKED SIDE BY SIDE TO FORMULATE
THE CLASSIFICATION.
AT THIS POINT WE HAD A BETTER
UNDERSTANDING OF THE IMMUNE
SYSTEM.
PRAYER FIN HISTOCHEMISTRY COULD
DETECT MOST ANTIGENS IN ROUTINE
BIOPSIES AND MOLECULAR STUDIES
WERE BEING AVAILABLE TO
DELINEATE DISEASE.
THIS WAS NOT ONLY USED IN 1997
BUT IN SUBSEQUENT EDITIONS IN
2008 AND 2017.
SO AT THIS TIME WE FULFILLED THE
HOLY GRAIL OF LYMPHOMA
CLASSIFICATION AND DEVELOPED A
MODERN TAXONOMY AND DISEASE AS
RECOMMENDED IN THE REPORT
BUILDING A NETWORK TO PROMOTE
DISEASE DISCOVERY AND
PATHOGENETIC INSIGHTS PROVIDING
A FRAMEWORK FOR MEDICINE AND
FACILITATING CLINICAL TRIALS AND
HOPEFULLY IMPROVING THE STANDARD
OF DIAGNOSIS AND TREATMENT IN
THE COMMUNITY.
SO I THINK THE MICROSCOPE TODAY
IS STILL A TOOL FOR DISEASE
DISCOVERY.
FOR MOST OF THE DISEASE ENTITIES
THAT HAVE BEEN INCLUDED, THE
DISEASE WAS FIRST DESIGN BY
CLINICAL CRITERIA LEADING TO
IDENTIFICATION OF THE
PATHOGENESIS.
THAT'S TRUE FOR ANPLASTIC LARGE
CELL AND T CELL LEUKEMIA
LYMPHOMA AND ALL THE DISEASES
LISTED HERE.
ONCE YOU UNDERSTAND THE GENESIS
YOU HAVE THE DIAGNOSTIC TOOLS
YOU CAN USE TO STUDY THE DISEASE
AND THIS HELPS DEFINE THE
DISEASE AND IDENTIFY IT'S BORDER
LANDS.
SO IN MY REMAINING TIME TODAY,
I'D LIKE TO ILLUSTRATE THREE
VIGNETTES THAT ILLUSTRATE THE
IMPORTANCE OF THIS APPROACH.
WE'LL REVIEW INCIPIENT NEOPLASIA
AND CLONAL EVOLUTION, LINEAGE
PLASTICITY OF LYMPHOID NEOPLASMS
AND THE INTERFACE OF HODGKIN'S
AND NON-HODGE KINGS LYMPHOMA.
SOME ARE LINKED TO THE BCL II
REARRANGEMENT AND IN ADDITION
THERE'S CHARACTERISTIC AND
RECURRENT MUTATIONS LISTED HERE.
THIS IS A DISEASE ESSENTIALLY
CONFINED TO ADULTS AND MOSTLY
INCURABLE AND MOST PATIENTS
PRESENTING WITH ADVANCED STAGE
DISEASE.
AN IMPORTANT STEP AFTER THE
IDENTIFICATION OF THE TRANS
LOCATION WAS OF WAS THE
DEVELOPMENT OF MONOCLONAL
ANTIBODIES TO BCL2 BY DAVID
MASON SHOWING THE CELLS OF
FOLLICULAR LYMPHOMA SHOWED OVER
EXPRESSION OF BCL2 AND NORMAL
GERMINAL CENTERS WERE NEGATIVE.
WE RECEIVED A CASE AND
PRESENTATION FROM A 23-YEAR-OLD
FEMALE WHO PRESENTED WITH AN
ISOLATED AND LARGE FEMORAL LYMPH
NODE AND THE CLINICIAN SENT IT
FOR CYTOGENETICS.
WHILE THE LYMPH NODE SHOWED
REACTIVE IT SHOWED A LOW NUMBER
OF CELLS WITH THE 1418 TRANS
LOCATION BY ROUTINE TYPE AND
SEPT THE CASE WITH US IN
CONSULTATION.
FORTUNATELY, I JUST HAD GOTTEN A
BCL2 BEYOND AND WERE STARTING TO
USE IT IN THE LAB TO SEE ITS
UTILITY AND WHEN I STAINED THIS
LYMPH NODE I SAW SELECTIVE
GERMINAL CENTERS POSITIVE OF
CELLS EXPRESSING THE PROTEIN.
INTERESTINGLY, WE CONTINUED AT
FOLLOW-UP OF THE INDIVIDUAL
PATIENT FOR MORE THAN 15 YEARS
SHOWED SHE NEVER DEVELOPED
FOLLICULAR LYMPHOMA.
WE WENT ON TO STUDY ADDITIONAL
CASES AND IDENTIFIED WHAT WE
TERMED FOLLICULAR LYMPHOMA IN
SI
SITU.
THE LYMPH NODE LOOKS REACTIVE
AND SEE WELL FORMED GERMINAL
CENTERS BUT WHEN YOU STAIN FOR
THE BCL2 YOU SEE SEVERAL OF THE
CENTERS HAVE CELLS THAT STRONGLY
EXPRESS THE BCL2 PROTEIN.
IN FURTHER STUDIES WE SHOWED THE
BCL2 POSITIVE CELLS WERE CLONAL
BY GENE REARRANGEMENT AND
CONTAINED THE REARRANGEMENT AS
WELL.
IN SUBSEQUENT STUDIES WE STUDY
THE CLINICAL OUTCOME OF THESE
CASES WITH FOLLICULAR LYMPHOMA
IN SITU AND OBSERVED THE
PATIENTS AT LOW RISK TO DEVELOP
SUBSEQUENT FOLLICULAR LYMPHOMA
FIT WASN'T DETECTED AT INITIAL
STAINING AND WERE INCIDENTAL
FINDINGS SEEN IN OTHER B CELL
LYMPHOMAS SEEN ABOUT 15% OF THE
IN SITU CASES.
BUT MOST THE PATIENTS HAD NO
EVIDENCE OF DISEASE ON LONG-TERM
FOLLOW-UP.
IT'S SUBSEQUENTLY BEEN
RECOGNIZED BCL2 TRANS LOCATION
IS NOT RARE IN HEALTHY
INDIVIDUALS.
IT'S FOUND IN THE PERIPHERAL
BLOOD UP TO 70% OF NORMAL ADULTS
OVER THE AGE OF 50.
THE NUMBERS INCREASE WITH AGE
AND INCREASE WITH PESTICIDE USE
IN FARMERS AS SHOWN WE THE WORK
DONE.
THE BCL2 ARE MEMORY B CELLS THAT
HAVE UNDER GONE CLASS SWITCHING.
THEY AND PRONE TO INTENSE
TRAFFICKING AMONG GERMINAL
CENTERS LEADING TO THEIR READY
IDENTIFICATION BY IMMUNOHISTORIC
CHEMISTRY.
AND FOLLICULAR LYMPHOMA IN SITU
AND B CELLS CO-EXIST IN THE SAME
PATIENT.
IT'S USUALLY A LARGE LYMPH NODE
FOR DIAGNOSIS AND THEY FOUND IN
IT BIOPSIES REMOVED FOR A
VARIETY OF CAUSES.
IT'S LIKELY AN IMMUNE STIMULUS
LEADS TO THE INCREASED
TRAFFICKING OF THE B CELLS IN
GERMINAL CENTERS.
THESE LYMPH NODES ALWAYS SHOW
FOLLICULAR HYPERPLASIA THE B
CELLS ARE ALWAYS FOUND WITHIN
THE GERMINAL CENTER AND NOT
RANDOMLY IN THE LYMPH NODE.
THIS IS THE MODEL OF GENESIS
THAT EMERGED.
IT OCCURS BY A MISTAKE IN VDJ
REARRANGE
REARRANGEMENT.
THE CELLS LEAVE THE BONE MARROW
TO ENCOUNTER ANTIGEN IN THE
GERMINAL CENTER AND EXPAND OVER
TIME AND SECONDARY GENOMIC
CHANGES ULTIMATELY LEAD TO
FOLLICULAR LYMPHOMA.
SOMEWHAT RELATED DISEASE IS A
SIMILAR IT FOLLICULAR LYMPHOMA
BUT POSITIVE FOR IGA AND
COMMONLY PRESENTS IN THE
DUODENUM AND OTHER SITES IN THE
BOWEL AND INTERESTINGLY THE
CELLS HAVE A HOMING CENTER AND
HAVE LOCAL REOCCURRENCES BUT
GENERALLY DO NOT DEVELOP
DISSEMINATED DISEASE AND USUALLY
HAVE A BENIGN CLINICAL COURSE.
HERE'S AN EXAMPLE OF DUO DENIAL
TYPE FOLLICULAR LYMPHOMA
PRESENTING AS A SMALL POLYP AS A
PATIENT UNDERGOING ENDOSCOPY FOR
AN UNRELATED CAUSE.
WE WANTED TO FURTHER INVESTIGATE
THE GENOMIC PROFILE OF THE
LESIONS.
A FELLOW IN THE HEMOPATH SECTION
PERFORMED LASER CAPTURE
DISSECTION OF THE BCL2 POSITIVE
CELLS.
WE STUDIED A SERIES OF CASES
INCLUDING FOLLICULAR LYMPHOMA IN
SITU AND WERE SOMEWHAT BEYOND
WHAT WE CALLED IN SITU DUO
DENIAL TYPE FOLLICULAR LYMPHOMA.
WE PERFORMED A RAY CGH IN THE
CASES AND WHAT WE SAW WAS DUE
AND FOUND A LOW NUMBER OF
ALTERATIONS OR GENOMIC CHANGES
IN DUODENAL TYPE LYMPHOMA AND
THOSE WE CALLED PARTIALLY
INVOLVED.
THEY SEEM RELATIVELY CLOSE TO IN
SITU BUT CLEARLY AND OTHERS IN
FULL BLOWN FOLLICULAR LYMPHOMA
AND BEING GREATER THAN GRADE 2.
NOTABLY WE DID NOT DETECT
ABERRATIONS IN CASES OF
FOLLICULAR HYPERPLASIA NOR IN
THE BACKGROUND TISSUE AWAY FROM
THE INVOLVED FOLLICLES.
SO, THIS SUMMARIZES THE
EVOLUTION OF FOLLICULAR LYMPHOMA
AS THE EPIGENOMIC LEVEL.
IT BEGINS IN THE BONE MARROW
WITH THE 418 TRANS LOCATION.
FL LIKE B CELLS IN HEALTHY
INDIVIDUALS HAVE AN ALMOST
INFINITE RISK WHERE THE RISK IN
IN SITU FOLLICULAR IS 2-3%.
IN ADDITION TO THE BCL2 REA
MAN
RANGEMENT WE SEE SOME INCLUDING
KREB EP AND TNFRSF14 AND
MUTATIONS APPEAR TO BE A LATE
EVENT AND GENERALLY ABSENT.
SO THIS SUMMARIZES THE
CONCEPTUAL MODEL OF FOLLICULAR
LYMPHOMA FROM PRECURSOR B CELLS
AND ACQUIRE THE 14-18.
MOST PATIENT WITH THESE CELLS IN
THE BLOOD WILL NEVER PROGRESS.
FOLLOWING ANTIGEN STIMULATION
THE CLONAL PROGENITORS UNDER GO
CYCLES OF GERMINAL CENTER
RE-ENTRY WITH CLONAL EXPANSION
AND GENOMIC INSTABILITY AND
ULTIMATELY DISSEMINATION.
AND KMT2D IS RELATED TO RISK BE
WITH DEVELOPMENT OF CLINICALLY
SIGNIFICANT DISEASE.
THE RELAPSES DEVELOP BY LINEAR
EVOLUTION AND DIVERGENT
EVOLUTION AND THAT MAY LEAD TO
TRANSFORMATION WHICH CAN ACQUIRE
DIVERSION PHENOTYPES AND EVEN
LINEAR SWITCH AS WE'LL SEE
LATER.
SO, A COMMON ASSOCIATION WITH
PROGRESSION OF FOLLICULAR
LYMPHOMA IS THE DEVELOPMENT OF
LARGE B CELL LYMPHOMA AND OFTEN
ASSOCIATED WITH B53 MUTATION.
IN A SERIES OF STUDIES LED BY A
GROUP THEY STUDIED SECONDARY
GENETIC EVENTS ASSOCIATED WITH
FOLLICULAR LYMPHOMA PROGRESSION.
P53 MUTATION IS A COMMON EVENT
AND ASSOCIATED WITH
TRANSFORMATION DIFFUSE LARGE B
CELL LYMPHOMA AND SUPPRESSER
GENES ARE ASSOCIATED WITH
PROGRESSION AND SIGNIFICANTLY
MICK REARRANGEMENT HIT NO DOUBLE
HIT LYMPHOMAS HAVING AN
AGGRESSIVE CLINICAL COURSE.
SO, THESE ARE THE VARIOUS FORMS
DIFFUSED B CELL AND DOUBLE HIT
AND INTERESTINGLY SOME OF THESE
DOUBLE HIT LYMPHOMAS EXPRESS TDT
AND CAN MIMIC LYMPHOBLASTIC
LYMPHOMA AND ONE CAN SEE
DEVELOPMENT OF HODGKIN'S
LYMPHOMA AND WERE SURPRISED TO
ENCOUNTER CASES THAT RESEMBLE
SARCOMA OR DENDRITIC CELLS.
THIS IS CASE 2.
A 60-YEAR-OLD MAN WITH A
DIAGNOSIS OF FOLLICULAR
LYMPHOMA.
THREE YEARS AFTER DIAGNOSIS HE
HAD A SECOND LYMPH NODE BIOPSY
SHOWING A PLEOMORPHIC AND
PLASTIC LOOKING TUMOR THAT
EXPRESSED MARKERS OF HISTIOCYTES
AND NEGATIVE FOR CU20 AND FOR
PAX 5 BUT POSITIVE FOR CD 68 AND
S100 AMONG OTHERS.
IN A SUBSEQUENT STUDY CONDUCTED
BY ANDY FELDMAN A FELLOW IN THE
LABORATORY, WE STUDIED THE
FOLLICULAR LYMPHOMAS WITH
SARCOMA AND PROVIDED EVIDENCE
FOR TRANS DIFFERENTIATION FROM
THE FOLLICULAR LYMPHOMA CLONE.
ALL EIGHT CASES SHARED CLONAL
IDENTITY WITH THE PRIOR
FOLLICULAR LYMPHOMA BASED ON
IMMUNOGLOBULIN SEQUENCING AND
IDENTICAL BCL2 REARRANGEMENT.
THERE WAS A CHANGE IN THE
TRANSCRIPTION FACTORS WITH LOSS
OF PAX 5, LOSS OF OTHER MARKERS
OF B CELL LINEAGE BUT EXPRESSION
OF WILL PU 1 AND THE BETA
ASSOCIATE WILL WITH THE
DIFFERENT IS SAYING THATS.
THIS WAS A SURPRISE TO US AND
THIS PROVIDED THE DIFFERENCE AND
IN EARLIER WORK DONE BY GRAPH
AND COLLEAGUES, THEY SHOWED
MATURE B CELLS COULD BE
REPROGRAMMED FUNCTIONALLY INTO
MACROPHAGES WITH BLOCKAGE OF PAX
5 AND OVER EXPRESSION OF PU 1 AS
WE SAW IN OUR CLINICAL CASES.
IN SUBSEQUENT WORK DONE AND WE
HAVE A HISTORY OF SARCOMA
ASSOCIATED WITH LYMPHOID
MALIGNANCY.
IN THIS SETTING THE HISTIOCYTIC
TUMORS ARE SEEN IN MALIGNANCIES
SEEN WITH FOLLICULAR LYMPHOMA.
HERE'S ONE OF THE CASES STUDIED.
HERE'S A NUMBER OF MUTATIONS
THAT WERE SHARED BY BOTH THE
FOLLICULAR LYMPHOMA AND
HISTORYIOCYTIC LYMPHOMA AND SOME
MUTATIONS UNIQUE TO THE
FOLLICULAR LYMPHOMA AND OTHERS
TO THE KEV DEF
HISTIOCYTIC LYMPHOMA AND SOME
ARE ASSOCIATED WITH THE GENE
ARRANGEMENT AND CONVENTIONAL
FOLLICULAR LYMPHOMA AND THAT'S
NOT THE CASE FOR ALL.
CASE 3 WAS A LYMPH NODE THAT
SHOWED SCLERROSING HODGKIN'S AND
ONE MONTH FOLLOWING COMPLETION
OF THERAPY HE PRESENTED WITH A
NEW MEDIASTINAL MASK.
WE DIDN'T SEE EVIDENCE OF
HODGKIN'S BUT SAW A TUMOR THAT
RESEMBLED LARGE B CELL LYMPHOMA.
THE QUESTION WAS IS THIS ONE OR
TWO TUMOR.
ON THE RIGHT YOU SEE THE PRIMARY
MEDIASTINNAL LARGE B CELL
LYMPHOMA AND THE AND ON THE LEFT
HODGKINS EXPRESSING CD 30 AND 15
AND ON THE RIGHT A B CELL
EXPRESSING OCT 2 AND SINGLE CELL
MICROEXPRESSION OF BOTH DON'TS
SHOWED THEY WERE CLONALLY
RELATED.
SO IT HAD BEEN RECOGNIZED FOR
SOME TIME THERE WERE COMMON
FEATURES OF PRIMARY MEDIA STINAL
OR THYMIC LARGE B CELL LYMPHOMA
AND HODGKIN'S.
BOTH ARE MORE COMMON IN FEMALES
AND PRESENT IN ADOLESCENCE AND
YOUNG ADULTS AN SHARE
ALTERATIONS AND HAVE A SIMILAR
GENE EXPRESSION PROFILE WITH
ACTIVATION OF THE NF CAPA B
PATHWAY SHOWN IN LABS.
AND BOTH ARE THOUGHT ARISE FROM
A THYMIC B CELL.
WE PROPOSED A B CELL SARCOMA
PRESENTING A MISSING LINK FROM A
TYPE OF HODGKIN'S AND PMBL.
THEY CAN'T BE READILY CLASSIFIED
AS PMBL OR CLASSIC HODGKIN'S AND
THERE'S ASYNCHRONY IN THE
PHENOTYPE.
THEY'RE SIMILAR TO THE ENTITIES
EXCEPT FOR UNKNOWN REASONS
THEY'RE MORE COMMON IN MALES
THAN FEMALES AND COMPOSITE AND
SEQUENTIAL LYMPHOMAS ARE A
RELATED PHENOMENON.
HERE'S ONE EXAMPLE OF MEDIA
STINAL GRAY ZONE LYMPHOMA WITH
AN ARRANGEMENT OF CELLS THAT
SHOW STRONG EXPRESSION OF THE B
CELL LOCATION PROGRAM AND
ANOTHER TYPE OF GRAY ZONE
LYMPHOMA IN WHICH HISTOLOGICALLY
IT LOOKS LIKE B CELL LYMPHOMA
BUT EXPRESS THE IMMUNOTYPIC
MARKERS OF CLASSIC HODGKIN'S
LYMPHOMA.
MEDIASTINAL GRADE CELL LYMPHOMA
IS THIS INTERMEDIATE FORM AND
INTERESTINGLY THIS IS A
TWO-DIRECTIONAL HIGHWAY.
YOU CAN SEE NS HODGKIN'S RELAPSE
AS PMBL OR PMBL RELAPSING AS NS
HODGE KINDS AND IT'S THE MISSING
LINK WE DESCRIBED.
THERE WERE A NUMBER OF
CONTINUING QUESTIONS.
CAN BIOLOGICAL STUDIES PROVIDE
INSIGHTS INTO THE BIOLOGY OF
MEDIASTINAL GRAY CELL IS IT
CLOSER TO HODGKIN'S OR PMBL.
IN INITIAL WORK DONE IN THE LAB
THEY PERFORMED A METHYLATION
PROFILING.
SHE DID MICRODISSECTION OF TUMOR
CELLS FROM GRAY CELL,ING
HODGKIN'S AND PMBL AND SHOWED
THE EPIGENETIC PROFILE OF THE
GRAY ZONE PHOMAS HAD A SHOWING
AND GRAY ZONE LYMPHOMA AND PMB
4L
AND THE GRAY CELL SHOWED CLOSER
TO CLASSIC HODGKIN'S THAN PMBL.
IN WORK THEY LOOKED AT A VARIETY
OF KEY SIGNATURES AGAIN SHOWING
MEDIASTINAL GRAY ZONE LYMPHOMA
IN GENERAL ABUTTED THE GENE
EXPRESSION PROFILE OF HODGKIN'S
MORE THAN THAT OF PMBL.
NEVERTHELESS THE DIFFERENTIAL
DIAGNOSIS OF CLASSIC HODGKIN'S
IS STILL IMPORTANT AS THERE'S
MAJOR TREATMENT DIFFERENCES.
TO ANSWER HOW THESE PATIENTS
SHOULD BE TREATED, LINDA WILSON
LED A STUDY OF MEDIASTINAL GRAY
CELL LYMPHOMA WITH EPOCR AND
SUCCESSFUL IN CURING PMBL AND
WAS EFFICACIOUS IN THE GRAY ZONE
LYMPHOMAS BUT STILL WITH
INFERIOR OUTCOME THOSE PATIENTS
WITH THE RELAPSE DISEASE COULD
BE RESCUED WITH RADIATION
THERAPY OR OTHER THERAPEUTIC
APPROACHES.
IN ADDITION THE BLOCKADE HAS
EMERGED AS A TOOL IN THE
TREATMENT OF NON HODGKIN'S
LYMPHOMA HAS EXPRESSION OF PHO
XSTAT 3 AND SHOWN TO BE
EFFECTIVE IN CLASSIC HODGKIN'S
LYMPHOMA AND ANOW USED IN
UNTREATED PATIENTS.
IN A PILOT CLINICAL STUDY, CHRIS
MELANI SHOWED THE APPROACH IS
ALSO EFFECTIVE IN MEDIA STINAL
GRAY CELL LYMPHOMA WITH PATIENTS
ACHIEVING COMPLETE REMISSION
AFTER RELAPSE WITH JAK POINT
INHIBITOR THERAPY.
IN CONCLUSION THE TIME LINE
ILLUSTRATES THE CHANGES IN
LYMPHOMA CLASSIFICATION AND THE
IMPACT IN CLINICAL AND TECHNICAL
ADVANCES.
AND WE HAVE SEEN THE IMPACT OF
IMMUNOLOGIC CHARACTERIZATION,
MOLECULAR CHARACTERIZATION WITH
NGS EMERGING AS AN IMPORTANT NEW
TOOL FOR DIAGNOSIS AND
CLASSIFICATION.
SO SOME CLOSING THOUGHTS, THESE
ARE CARICATURES OF THE SYSTEM
AND INFORM OUR THINK OF CLASSIC
AND NEOPLASTIC CELLS AND SPREAD
AS PART OF THEIR FUNCTION.
BENIGN CLONAL EXPANSIONS OF
LYMPHOCYTES DO NOT REMAIN
LOCALIZED BY DISSEMINATE ON
HOMING AND THUS WITH LYMPHOID
NEOPLASMS THE DISTINCTION
BETWEEN BENIGN AND MALIGNANT AND
MIGHT BE LOOKED AT AND ONE OF
THE LYMPHOMA OF THE LYMPHOID
SYSTEM AND OBSERVATIONS THAT WE
MAKE AT THE MICROSCOPE AND IN
THE CLINIC ARE STILL A STARTING
POINT FOR DISEASE DISCOVERY.
SO I'D LIKE TO ACKNOWLEDGE
MEMBERS OF THE TEAM AT THE NCI
AND OF COURSE FROM THE LYMPHOMA
BRANCH, .
I'VE HAD WONDERFUL LONG-TERM
INTERNATIONAL COLLABORATORS.
INTERESTINGLY, BOTH DID
FELLOWSHIPS HERE AT THE NCI AND
WENT ON TO HAVE STELLAR CAREERS
IN LYMPHOMA RESEARCH.
OTHER COLLABORATORS IN
MARSEILLE, FRANCE AND THE ANSWER
AGENCY AND MEMBERS OF THIS LLMPP
AND OTHER MEMBERS OF THE NCI,
CCR TEAM SHOWN HERE.
I THINK NONE OF THIS WOULD HAVE
HAPPENED WITHOUT THE WORK OF SO
MANY -- I'M GOING TO TEAR UP.
SO MANY FELLOWS OVER THE YEAR.
IT'S BEEN AN HONOR AND PRIVILEGE
TO TRAIN THESE WONDERFUL PEOPLE.
SINCE 1974 WE'VE TRAINED MORE
THAN 80 CLINICAL FELLOWS, MORE
THAN 25 VISITING FELLOWS.
THESE ARE LEADERS IN THEHEMATO
PATHOLOGY COMMUNITY IN THE
U.S. AND AROUND THE WORLD A --
AND AN IMPORTANT MISSION I HOPE
WILL BE FULFILLED IN THE FUTURE
AT THE NCI.
THANK YOU.
>> YOU CAN STAY THERE.
SO PLEASE USE THE MICS FOR
QUESTIONS.
NO QUESTIONS ONLINE YET.
DR. STOUT, YOU WANT TO LEAD OFF?
>> WONDERFUL, ELAINE.
I HAVE ENJOYED YOU ON PART OF
THAT RIDE.
I WANTED YOU TO WAX A LITTLE
PHILOSOPHICAL.
I THINK YOU NICELY CATEGORIZED
THE MISSION OF THE PATHOLOGISTS
AS ONE THAT DEFINES BIOLOGICAL
DISEASE ENTITIES.
AND IT STARTS WITH THE
MICROSCOPE BUT THE SCOPE OF IT
ENCOMPASSES THE MOLECULAR
ABNORMALITIES AS WELL.
THE QUESTION IS HOW DOES ONE
DIAGNOSE DISEASE?
THAT'S ONE POINT OF VIEW BUT THE
OTHER POINT OF VIEW SO
ELOQUENTLY PUT BY HENRY KAPLAN
IS I DON'T CARE ABOUT IT UNTIL
IT'S GOING TO CHANGE HOW I TREAT
THE PATIENT.
THOSE CAN BE SEEN AS IN CONFLICT
BUT I DON'T SEE THEM AS IN
CONFLICT.
I WANTED TO SEE HOW WE SHOULD
ARRIVE AT A REAL CLASSIFICATION
OF CANCERS AND WHEN TO
INCORPORATE MOLECULAR
UNDERSTANDING IN THAT.
>> I MEAN, I THINK THE MOLECULAR
TECHNIQUES ARE BECOMING PART OF
OUR DAILY ARMAMENTARIUM AND I
TALKED ABOUT THE CLASSIC FORM OF
FOLLICULAR LYMPHOMA BUT WE HAVE
OTHER TUMORS WE CALL, QUOTE,
FOLLICULAR LYMPHOMA DIFFERENT AT
THE MOLECULAR LEVEL AND
UNDERSTAND THOSE HAVE TO BE
TREATED IN DIFFERENT WAYS.
AS AN EXAMPLE, WE HAVE QUOTE,
PEDIATRIC TYPE FOLLICULAR
LYMPHOMA WHICH IS A BENIGN
DISEASE.
YOU TAKE OUT THE LYMPH NODE AND
THE CANCER IS CURED AND YOU HAVE
OTHER LYMPHOMA THAT MAY HAVE
MORE EXTENSIVE DISEASE BUT ARE
STILL BIO LOGICALLY AND
CLINICALLY DIFFERENT AND THEY
EXPRESS CD 23 AND MUTATIONS.
WE DON'T KNOW HOW MUCH THERAPY
THOSE PATIENTS NEED.
THAT'S SOMETHING WE NEED TO WORK
WITH CLINICIANS TO ANSWER.
WHAT NEEDS SYSTEMIC THERAPY?
WHAT CAN WE WAIT AND WATCH?
WE HAVE TO WORK HAND IN HAND TO
ANSWER THESE QUESTIONS.
I DIDN'T TOUCH ON B CELL
LYMPHOMA BECAUSE THAT'S YOU'RE
DISEASE AND NEED YOU THERE.
WHEN IT COMES TO THE
MICROSCOPE -- WHEN IT COMES TO
DIFFUSE B CELL LYMPHOMA WE'RE
NOT AS HELPFUL AS WE NEED TO BE
BUT YOU'RE SHOWING UP THE WAY IN
TERMS OF UNDERSTANDING DIFFUSE B
CELL LYMPHOMA AND HOPEFULLY IT
WILL HAVE RELATIVENESS FOR THE
TREATMENT.
WE STILL DON'T KNOW HOW THE
INFORMATION SHOULD BE USED IN
THE CLINICAL SETTING AND THAT'S
WE NEED TO WORK TOGETHER TO
ANSWER.
>> THANK YOU.
WHAT A WONDERFUL TALK.
I ALWAYS LOVE THINKING ABOUT THE
HISTORY.
MY MIND WENT IN A SIMILAR
DIRECTION AS LOU'S.
AS A CLINICIAN WE'RE REALLY
FORTUNATE TO HAVE YOU AND STEFAN
AND RELY ON THAT AND SOME OF THE
PROBLEMS WE SEE ACROSS THE FULL
FIELD OF LYMPHOMA IS WE CHANGE
DIAGNOSIS AND THEN ALSO SEE THAT
MEANING NOT EVERYONE IS AS
ACCURATE IN MAKING THESE
DECISION -- DIAGNOSES AND MY
QUESTION IS DO YOU THINK THERE
ARE OPPORTUNITIES PERHAPS WITH
ARTIFICIAL INTELLIGENCE OR OTHER
THINGS TO CLOSE THESE GAPS TO
MAYBE SYNCHRONIZE THE INPUTS
WHERE THERE'S UNMET NEEDS OR
LACK OF EXPERTISE OR SYNTHESIS
OF ACCURATE SYNTHESIS OF
INFORMATION.
>> ARTIFICIAL INTELLIGENCE MAY
PLAY A ROLE IN THE FUTURE.
WE'RE NOT THERE YET.
IN FRANCE THEY'RE ACTIVELY
WORKING ON THIS AND TRYING TO
DEVELOP MODELS.
WE'VE DABBLED IN IT A LITTLE BIT
HERE AT NIH.
I THINK IT HAS POTENTIAL.
SOMETHING THEY DO IN FRANCE
SUCCESSFULLY IS DEVELOPED
CENTERS OF DIAGNOSTIC EXCELLENCE
ACROSS THE COUNTRY AND ALMOST
EVERY NEWLY DIAGNOSED PATIENT
HAS A BIOPSY THAT GETS SENT TO A
PATHOLOGIST.
THAT DOESN'T EXIST IN THE
U.S. AND THERE'S A HUGE
VARIATION INABILITY AMONG
DIFFERENT PATHOLOGISTS AND
EXPERIENCE 37
ANOTHER UNFORTUNATE SITUATION IS
MORE AND MORE WE SEE THESE TINY
NEEDLE CORE BIOPSIES THAT ARE
INADEQUATE.
IT HURTS THE FIELD CLINICALLY
BECAUSE IT'S HARD TO MAKE A
DIAGNOSIS AND IT HURTS IN TERMS
OF RESEARCH BECAUSE YOU DON'T
HAVE THE MATERIALS YOU NEED TO
REALLY STUDY THE DISEASES.
>> ELAINE, THANK YOU SO MUCH.
YOU'VE CLEARLY HAD A FANTASTIC
CAREER.
I WAS JUST WONDERING IF YOU
WOULD JUST IN THE LAST QUESTION
HERE, JUST WHAT ADVICE WOULD YOU
HAVE FOR THE TRAINEES NOW HERE?
YOU'VE DONE PHENOMENALLY WELL.
IS THERE ANYTHING YOU CAN TELL
THEM TO TAKE A GRAIN OF WHAT
YOU'VE ACCOMPLISHED AND WHY
YOU'VE ACCOMPLISHED THAT AND USE
THAT IN THEIR CAREER?
>> MY APPROACH TO MY RESEARCH IS
OFTEN TO FOCUS ON THE CASES THAT
I DON'T UNDERSTAND RATHER THAN
THE ONES I DO UNDERSTAND.
I USED TO HAVE A GOODY FILE.
A LITTLE BLACK BOX OF 3X5 CARDS
AND SAW A CASE AND DIDN'T KNOW
WHAT IT WAS OR PRESENTED A
QUESTION I'D MAKE A NOTE ON THIS
CARD AND PUT IT IN THE BOX AND
IF I SAW ANOTHER ONE I'D GO TO
THE BOX AND GO I REMEMBER THAT
CASE.
ACTUALLY THAT'S HOW I CAME UP
WITH THE EIGHT CASES OF
HISTIOCYTIC SARCOMA.
THEY WERE ALL IN MY LITTLE BLACK
BOX.
WE HAVE TO MAINTAIN A
QUESTIONING MIND SET AND
CONTINUE TO ASK THE NEXT
QUESTION AND NOT SIT BACK ON OUR
LAURELS.
THANK YOU.
>> JOIN ME IN SAYING THANK YOU
TO ELAINE AND I WANT TO ALSO
INVITE ALL OF YOU TO THE
RECEPTION OUT FRONT IMMEDIATELY
FOLLOWING THIS.
THANK YOU SO MUCH.