Welcome to the Clinical Center Grand Rounds, a weekly series of educational lectures for physicians and health care professionals broadcast from the Clinical Center at the National Institutes of Health in Bethesda, MD. The NIH Clinical Center is the world's largest hospital totally dedicated to investigational research and leads the global effort in training today's investigators and discovering tomorrow's cures. Learn more by visiting us online at http://clinicalcenter.nih.gov GOOD AFTERNOON, EVERYBODY. WELCOME TO CLINICAL CENTER GRAND ROUNDS. WE HAVE TWO COLLEAGUES FROM THE NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES WHO WILL PRESENT UPDATED ON DIAGNOSIS AND TREATMENT OF THYROID CANCER. OUR FIRST SPEAKER IS DR. MONICA SKARULIS, A GRADUATE OF THE DAVIS SCHOOL OF BIOMEDICAL EDUCATION AT THE CITY COLLEGE OF NEW YORK, AND WHO EARNED HER MEDICAL DEGREE FROM NEW YORK MEDICAL COLLEGE. AFTER COMPLETING AN INTERNSHIP AND RESIDENCY IN INTERNAL MEDICINE AT NORTH SHORE UNIVERSITY HOSPITAL CORNELL UNIVERSITY COLLEGE MEMORIAL SLOAN-KETTERING SHE JOINED THE NIH AS A CLINICAL ASSOCIATE TO PURSUIT ENDOCRINE TRAINING AND DEVELOPMENT ENDOCRINOLOGY BRANCH OF NICHD AND JOINED NIDDK. SHE WAS CHAIR OF THE TRANS-NIH GRADUATE MEDICAL EDUCATION COMMUNITY FROM 2007 TO 2012. SHE'S A CLINICAL CHIEF OF METABOLIC RESEARCH UNIT TO ENHANCE THE RESEARCH IN OBESITY AND METABOLISM CONDUCTED IN THE INTRAMURAL PROGRAM. CURRENTLY SHE AND HER COLLEAGUES ARE EXAMINING TRAITS TO LEAD TO OBESITY, WEIGHT LOSS OR RELAPSE AND PHARMACOLOGICAL AGENTS. ADDITIONAL SHE CONDUCTS RESEARCH ON THYROID HORMONE ACTION INCLUDING UNUSUAL CAUSES OF HYPER THYROIDISM AND HAS ACTIVE PROGRAM IN THE TREATMENT OF THYROID CANCER. THE NIH THYROID CANCER PROGRAM IS PART OF THE NATIONAL THYROID CANCER TREATMENT COOPERATIVE STUDY REGISTRY COORDINATED BY M.D. ANDERSON CANCER CENTER. SHE WILL PRESENT TODAY ON THYROID CANCER DIAGNOSTIC AND THERAPEUTIC PARADIGM SHIFT. DR. JOANNA KLUBO-GWIEZDZINSKA IS A CLINICAL FELLOW IN THE ENDOCRINOLOGY AND OBESITY BRANCH IN NIDDK, EARNED HER MEDICAL DEGREE AT COPERNICUS UNIVERSITY IN POLAND, DOCTORAL DEGREE IN ENDOCRINOLOGIES, RESIDENCY AT NICHOLAS COPERNICUS UNIVERSITY HOSPITAL IN 2008, COMPLETED A POSTDOCTORAL RESEARCH FELLOWSHIP IN THYROID CANCER AT GEORGETOWN UNIVERSITY IN 2012 AND COMPLETED AN INTERNAL MEDICINE RESIDENCY PROGRAM AT WASHINGTON HOSPITAL CENTER IN GEORGETOWN UNIVERSITY. SHE CAME TO NIDDK IN 2014 AS A CLINICAL FELLOW IN ENDOCRINOLOGY. HER RESEARCH FOCUSES ON OPTIMIZIZATION OF CANCER THERAPY TO IMPROVE MORBIDITY AND MORTALITY, STUDIES COMPARISONS OF DOSIMETRY BASED VERSUS FIXED DOSES OF IODINE IN HIGH RISK PATIENTS, OPTIMIZATION AND TRANSLATIONAL STUDIES ON GROWTH INHIBITORY EFFECTS IN VITRO AND IN VIVO, RECEIVED THE ENDOCRINE SOCIETY SCHOLARS AWARD FOR OUTSTANDING ACHIEVEMENT IN 2008, AND ENDOCRINE SOCIETY THYROID CLINICAL RESEARCH FELLOWSHIP AND MENTOR AWARD IN 2010. SHE WILL PRESENT ON FACTS AND MYTHS ON THE ROLE OF THYROID STIMULATING HORMONE IN THYROID CANCER. LET'S WELCOME OUR FIRST SPEAKER. [APPLAUSE] >> HOLD ON A SECOND. SO LET ME GET WIRED UP HERE. THANK YOU, FRED, FOR THAT NICE INTRODUCTION. SO MY TOPIC AS HE SAID IS LOOKING AT WHEN LESS IS MORE IN THYROID CANCER. I HAVE NO DISCLOSURES. LEARNING OBJECTIVES, AT THE END PERHAPS YOU'LL BE ABLE TO RECOGNIZE TYPES OF THYROID CANCER AND TRENDS AND INCIDENCE CURRENTLY, APPRAISE CURRENT STANDARDS OF CARE THAT WE HAVE FOR THYROID CANCER AND IDENTIFY FACTORS THAT ARE DRIVING OUR CURRENT RECONSIDERATION OF THESE STANDARDS. I'D LIKE TO ASSESS THE IMPACT OF MODIFYING THE TREATMENT APPROACH TO THYROID CANCER AND IDENTIFY AREAS FOR SCIENTIFIC ADVANCEMENT AND IMPROVED PATIENT CARE BY REVIEWING THE ANATOMY OF THE CURRENT SO-CALLED EPIDEMIC OF NON-MEDULLARY THYROID CANCER, LOOK AT THE CURRENT THERAPIES AND OUTCOMES BOTH GOOD AND BAD, LOOK TOWARDS IMPROVING THE STANDARD OF CARE, ASKING THE QUESTION, IS LESS THERAPY ACTUALLY MORE IN THIS CASE? AND THEN WE'LL DISCUSS SOME REASONS TO BE CAUTIOUS MOVING FORWARD. SO APPROXIMATELY 25 YEARS AGO, THERE WAS A COMBINED CLINICAL STAFF CONFERENCE HERE IN THE LIPSETT AUDITORIUM THAT WAS ENTITLED "THYROID CANCER, A LETHAL ENDOCRINE NEOPLASM." IT WAS MODERATED BY ONE OF MY MENTORS, THE LATE JACK ROBBINS, WHO DURING THIS CONFERENCE MENTIONED SORT OF THAT WHEN HE STARTED, HE SAID THE NAME OF THIS CONFERENCE IS ADMITTEDLY AMBITIOUS, PROVOCATIVE, THYROID CANCER MORTALITY EXCEEDS THAT OF ALL ENDOCRINE ORGANS COMBINED INCLUDING THE OVARY, AND TO THIS DAY THIS HOLDS TRUE. THIS IS A FACT. DURING THE CONFERENCE, THEY SHOWED THE AGE ADJUSTED RATE OF THYROID CANCER FROM THE YEARS 1935 TO 1985, DEMONSTRATING A RELATIVELY SHARP INCREASE, PARTICULARLY IN WOMEN, AND AT THE TIME IT WAS ATTRIBUTED TO A PRACTICE THAT HAD BEEN COMMON PREVIOUSLY OF TREATING CHILDREN WITH BENIGN DISORDERS WITH EXTERNAL RADIATION, INCLUDING TINEA CAPITUS, ACNE AND THYMIC ENLARGEMENT AND DEMONSTRATED THAT THE DEATH RATE ALTHOUGH SMALL AT THE TIME WAS SEEMING TO BE DECREASING, WHICH WE THOUGHT WAS A RESULT OF THE FACT THAT WE WERE NOW ADOPTING MORE MODERN APPROACHES TO THE TREATMENT OF THYROID CANCER, THESE TREATMENT APPROACHES WERE PIONEERED BY DR. ROBBINS AND HIS COLLEAGUES. SO HOW MUCH DOES THIS CONTRIBUTE TO CANCER DEATHS IN GENERAL? IF WE LOOK AT TRENDS AND INCIDENCE RATES FOR SELECTED CANCERS, YOU'LL SEE THYROID CANCER HERE WAY DOWN IN THIS ORANGE LINE, REPRESENTING ONLY APPROXIMATELY OR MAYBE A LITTLE LESS THAN 1% OF ALL CANCER DEATHS. HOWEVER, IT DOES APPEAR TO BE RISING. IF YOU NOTE HERE, THE LEVEL OF -- THE RATE OF DEATH ACTUALLY APPROXIMATES THAT OF MELANOMA, IN WOMEN. SO I THINK WE SHOULD NOW REVIEW WHAT KIND OF CANCERS WE'RE ACTUALLY TALKING ABOUT BECAUSE THERE ARE SEVERAL THAT ARE DERIVED FROM THE THYROID GLAND. FOLLICULAR CELLS ARE RESPONSIBLE FOR THE MAJORITY OF THYROID CANCERS. FOLLICULAR CELLS CONCENTRATE IODINE, SYNTHESIZE THYROID HORMONE AND SECRETE THYROGLOBULIN. THE MOST COMMON CAUSE OF THYROID, FROM PAPILLARY, A HISTOLOGIC SECTION OF A CLASSICAL PAPILLARY CANCER SHOWING THE PAPILLARY PROJECTIONS, AND THE CLASSICAL CLEARING OF THE NUCLEI, SO-CALLED GIVING AN ORPHAN ANNIE APPEARANCE, THERE ARE CALL CELL AND SCLEROSING VARIANT THAT ARE ASSOCIATED WITH HIGHER RECURRENCE RATES AS WELL AS HIGHER DEATH RATES. AND RECENTLY MUTATIONS IN THE BRAF HAVE BEEN DEMONSTRATED IN UP TO 50% OF PAPILLARY THYROID CANCERS AND THEY ALSO ARE ASSOCIATED WITH MORE AGGRESSIVE PHENOTYPE. NOW, THERE IS ALSO THE SECOND DIFFERENTIATED THYROID CANCER, FOLLICULAR CANCER. HERE YOU SEE THE TYPICAL FOLLICULAR MICRO FOLLICLES OF FOLLICULAR CANCER, AND THE CHARACTERISTIC INVASION THROUGH THE CAPSULE. THERE'S ALSO FREQUENTLY VASCULAR INVASION. OF NOTE, THERE IS A FOLLICULAR VARIANT, HURTHLE CELLS, HURTHLE CELL TUMORS LOSE ABILITY TO CONCENTRATE IODINE EARLY IN THE COURSE AND CAN BE MORE AGGRESSIVE. NOW, SOMETIMES FOLLICULAR CELL TUMORS, PAPILLARY AND FOLLICULAR, WILL EXPERIENCE AND ACQUIRE NEW MUTATIONS, THAT CHANGES THE BIOLOGICAL ACTIVITY OF THE TUMOR. THIS DIFFERENTIATION TENDS TO RESULT IN INABILITY TO CONCENTRATE IODINE AND MAYBE DECREASED SECRETION OF THYROGLOBULIN. THE MOST AGGRESSIVE FORM ANAPLASTIC MAY BE ONE OF THE MOST AGGRESSIVE, PERIOD. THE MEDIAN SURVIVAL IS APPROXIMATELY FOUR MONTHS AND IT'S CHARACTERISTICALLY ASSOCIATED WITH P53 MUTATIONS. WE'RE NOT GOINGS TO TALK ABOUT THE D DIFFERENTIATED CANCERS DURING THIS TALK ANY LONGER. FINALLY TO ROUND OUT THYROID CANCER I JUST HAVE TO MENTION THAT THERE ARE TUMORS ARISING FROM THE PARA FOLLICULAR C CELLS, MEDULLARY, NEUROENDOCRINE TUMORS ASSOCIATED WITH RET PROTO-ONCOGENE MUTATIONS. THEY ARE DIFFERENTIATED AND SECRETE CALCITONIN. HOW COMMON ARE THESE IN I'M FREQUENTLY GOING TO BE REFERRING BACK TO THIS SEER DATA, THE NIH PROGRAM. WE NEED TO REALLY RELY ON THIS DATA BECAUSE WE HAVE REALLY NEW RANDOMIZED CONTROL TRIALS IN OUR THYROID CANCER AREA FOR REASONS THAT WE CAN PERHAPS DISCUSS DURING THE QUESTION AND ANSWER PERIOD. IF WE LOOK AT THIS PIECHART SHOWING THE DISTRIBUTION OF CANCERS BY HISTOLOGIC CELL TYPE, WE SEE THAT THE MAJORITY ARE PAPILLARY. 8% APPROXIMATELY ARE FOLLICULAR. AND MEDULLARY, ANAPLASTIC LYMPHOMA, SARCOMA AND OTHER TUMORS EACH REPRESENT LESS THAN 2% OF ALL THYROID CANCERS. NOW, I WILL SAY THAT IN MY CAREER, I HAVE NOTED A SHRINKING INCIDENCE OF FOLLICULAR CANCERS, I ALMOST THINK THEY ARE DISAPPEARING. IT'S INTERESTING AROUND THE WORLD THIS HAS BEEN OBSERVED, AND THAT THERE SEEMS TO BE A HISTOLOGIC -- A RELATIONSHIP BETWEEN THYROID HISTOLOGY AND ACTUALLY DIETARY INTAKE OF IODINE. WHEN COUNTRIES AROUND THE WORLD HAVE INSTITUTED IODINATION PROGRAMS THEY NODE A SHIFT FROM FOLLICULAR AND ANAPLASTIC TO PAPILLARY PHENOTYPES. HOW COMMON IS THYROID CANCER? WE HAVE A VIRTUAL EPIDEMIC, ACCORDING TO SOME. THESE DAT AT FROM SEER DATABASE PUBLISHED BY GILL WELCH FROM DARTMOUTH, WHERE HE LOOKED AT THE INCIDENCE OF DIFFERENTIATED THYROID CANCER PER 100,000 PEOPLE FROM 1975 TO 2010. AND HIS FIRST REPORT WHICH I HAVE NOT REFERENCED HERE OCCURRED IN 2002 WHEN HE SAID WE HAVE A PROBLEM, HOUSTON. THERE ARE MANY MORE DIFFERENTIATED THYROID CANCERS DIAGNOSED, WE NEED TO LOOK INTO THIS, SUSPICIOUS IT WAS DUE TO OVERDETECTION. WE SEE IN THE NEXT FEW YEARS AND EXTRAORDINARY RISE, NOW THREE-FOLD THE INCIDENCE WE WERE IN 1975. NOW, WHAT YOU MAY NOT HAVE NOTICED IS THE STONE COLD STABLE DEATH RATE THAT IS EXPERIENCED OVER THE SAME PERIOD. ONLY APPROXIMATELY .5 CASES PER 100,000 DEATHS OCCUR, DESPITE THE RISING INCIDENCE. AND THIS HAS CAUSED PEOPLE TO ASK THE QUESTION WHETHER THIS EPIDEMIC IS PRIMARILY A RESULT OF OVERDETECTION. WELL, THAT IS VERY POSSIBLE. WHEN WE CONSIDER PALPATION OF THE THYROID, PHYSICAL EXAMINATION, WE KNOW THIS IS ACTUALLY VERY TRICKY. YOU CAN ASK ANY OF THE ENDOCRINE FELLOWS SITTING IN THE AUDIENCE. IT'S VERY DIFFICULT TO FEEL TUMORS THAT ARE LESS THAN 2 CENTIMETERS, SOMETIMES WE HAVE A HARD TIME FEELING ONES LARGER. IF WE LOOK AT THE INCIDENCE OF THYROID TUMORS PER YEAR BASED ON THEIR SIZE WE CAN SEE THAT TUMORS THAT ARE OVER 2 CENTIMETERS BASICALLY HAVE REMAINED STABLE IN INCIDENCE OVER THESE YEARS. HOWEVER, WE ARE DETECTING MORE TUMORS THAT ARE LESS THAN 2 CENTIMETERS AND FAR MORE TUMORS THAT ARE 1 CENTIMETER OR LESS. THESE TUMORS ARE CONSIDERED MICRO PAPILLARY CARCINOMAS, SO IT WOULD BE FAIR TO CONCLUDE FROM THIS DATA THAT PERHAPS OUR DETECTION OF THESE TUMORS IS SIMPLY BY ACCIDENT, THAT THEY ARE FINDING THEM INCIDENTAL TO STUDIES THAT ARE BEING PERFORMED FOR OTHER INDICATIONS, OF COURSE CAROTID ARTERY, CERVICAL SPINE, ET CETERA, ET CETERA. SO WE CERTAINLY DO HAVE TO RECKON WITH THAT. WHAT HAPPENS TO A POPULATION WHO DECIDES TO LAUNCH A CAMPAIGN TO DETECT MORE CANCER? WELL, WE HAVE THAT INFORMATION. SOUTH KOREA 1999 DECIDED THAT THEY WERE GOING TO LAUNCH FREE CANCER SCREENING FOR MANY DIFFERENT MALIGNANCIES. THYROID CANCER ACTUALLY WAS NOT ONE OF THE CANCERS THAT THEY WERE LOOKING FOR. BUT MANY OF THE HOSPITALS AND CLINICS DECIDED TO THROW IN AN ULTRASOUND FOR A VERY CHEAP PRICE, AND WHAT THEY RESULT -- WHAT HAPPENED AS A RESULT OF THIS IS THAT THERE WAS AN EXTRAORDINARY INCREASE IN THE NUMBER OF THYROID CANCERS DETECTED FROM 1993 TO THE CURRENT TIME. IN FACT, IT ROSE APPROXIMATELY 15-FOLD. IN THIS LITTLE FIGURE FROM THE "NEW YORK TIMES," YOU CAN SEE THAT NOW THE INCIDENCE IS SOMEWHERE AROUND 70 OR SO CASES PER 100,000 PATIENTS. AGAIN, LIKE I SHOWED YOU EARLIER, AND CONSISTENT WITH THE UNITED STATES, THE DEATH RATE OF THESE TUMORS REMAINS STONE COLD STABLE, WHICH IS THANKFUL. IF WE LOOK AT THE REGIONAL INCIDENCE, SO IF YOU BREAK THE COUNTRY UP INTO STATES AND LOOK AT THEM BY STATES AND THE PERCENTAGE OF PATIENTS WITHIN EACH OF THOSE REGIONS BEING SCREENED, YOU CAN SEE A NICE LINEAR RELATIONSHIP BETWEEN THESE, SUGGESTING THAT FRANKLY THE MORE YOU LOOK, THE MORE YOU'LL FIND. THESE AUTHORS ACTUALLY SUGGESTED A METHOD TO CURTAIL FUTURE EPIDEMICS. THEY BASICALLY SAID DON'T LOOK. I WOULD AGREE. WHAT IF YOU HAVE A SITUATION IN WHICH THERE IS AN EXPOSURE OR A POTENTIAL EXPOSURE LIKE WHAT HAPPENED IN THE TSUNAMI AND THE FUKUSHIMA REACTOR ACCIDENT IN MARCH OF 2011? WELL, THAT COMPELLED THE JAPANESE GOVERNMENT TO GO AHEAD AND START SCREENING WITH ULTRASOUND, WITHIN THE YEAR THAT THE ACTUAL ACCIDENT OCCURRED. AND THEY LAUNCHED SCREENING OF RESIDENTS LESS THAN OR EQUAL TO 18 YEARS. THEY ACCOMPLISHED THIS AND SCREENED A LITTLE BIT OVER 300,000 CHILDREN. AND WHAT THEY FOUND WAS COMPARED TO PREVALENCE RATES THAT WERE DETERMINED AND THEN MODELED FORWARD, EXPECTING SOME INCREASE IN CANCER AS SEEN AROUND THE WORLD, COMPARED TO WHAT THEY OBSERVED, THEY SAW MANY MORE CASES. THESE WERE ALL SMALL CASES IN BOTH MALES AND FEMALES. AS A RESULT OF THIS, THERE WERE MAYBE OVER 2500 OR MORE ULTRASOUNDS, REPEATED ULTRASOUND PERFORMED ON THESE CHILDREN, AND MORE THAN 500 FINE NEEDLE ASPIRATION BIOPSIES TO FIND APPROXIMATELY 100 CASES OF THYROID CANCER. MANY PEOPLE CRY THAT THIS IS OVERMEDICINE AND WE SHOULD BE THINKING MORE JUDICIOUSLY ABOUT THE USE OF THIS. SINCE THERE IS SORT OF A DEBATE, SOME PEOPLE ARE CLAIMING THIS IS RADIATION INDUCED, BUT THIS IS NOT A CHERNOBYL ACCIDENT. THE RADIATION EXPOSURE WAS MUCH LOWER. CHILDREN AND ADULTS WERE GIVEN IODINE PROPHYLAXIS AND HAD DONE THYROID DOSIMETRY TO SEE IF ANY CHILDREN HAD BEEN EXPOSED EXCESSIVELY AND REALLY APPEARS THE RADIATION EXPOSURE WAS NOT VERY HIGH. THE QUESTION HERE IS, WE'RE ABLE TO DIAGNOSE AND FIND MANY THYROID CANCERS, HOW DO WE TREAT THEM? SO LET'S REVIEW BRIEFLY THE STANDARD THERAPY OF THYROID CANCER. IT CONSISTS OF SURGERY, RADIOACTIVE IODINE, AND THYROID HORMONE. MOST TUMORS 1.5 CENTIMETERS OR GREATER WE RECOMMEND THEM TO HAVE A TOTAL OR NEAR TOTAL THYROIDECTOMY WHICH IS FOLLOWED BY REMNANT ABLATION, SO A DOSE -- AN ACTIVITY OF RADIOACTIVE IODINE GIVEN TO ABLATE RESIDUAL NORMAL THYROID AS WELL AS POTENTIAL NODAL METASTASES AND START THE TREATMENT OF DISTANT METASTASES. AND OF NOTE, RADIO IODINE STUDIES ARE GOOD IN STAGING THE DISEASE. AND THEN THE THIRD PILLAR IS THYROID HORMONE, GIVEN IN SUPER PHYSIOLOGIC LEVELS TO DECREASE T ASSAY STIMULATION, AND THE NOTION IS WE WOULD LIKE TO DISCOURAGE TSH FROM PROMOTING CANCER CELL GROWTH AND PROLIFERATION. THAT IS THE TOPIC OF DR. KLUBO'S DISCUSSION AFTER MINE. THIS IS A VERY COMPLICATED THERAPY THAT REQUIRES A HUGE GROUP OF PEOPLE. BETWEEN THE PATIENTS, THE MEDICAL ENDOCRINOLOGIES, NUCLEAR MEDICINE PHYSICIANS, MOST NOTABLY JAMES REYNOLDS HERE, THE RADIATION PHARMACIST, THE RADIATION SAFETY OFFICERS, THE NURSING STAFF, THE FELLOWS AND DIETITIANS, ALL HAVE TO COME TOGETHER JUST TO GIVE A SINGLE LITTLE BIT OF ACTIVITY. WE USUALLY DO IT APPROXIMATELY SIX WEEKS AFTER SURGERY SO WE DECREASE NON-SPECIFIC UPTAKE IN A HEALING SITE, AND HAVE TO CHOOSE A METHOD TO INCREASE TSH TO A CERTAIN LEVEL TO PROMOTE SODIUM IODINE AND UPTAKE INTO THE THYROSITE. WE HAVE TWO CHOICES, HYPOTHYROID PREP OR RECOMBINANT HUMAN TSH DEVELOPED HERE AT THE NIH. ALL OF OUR PATIENTS ARE PUT ON A LOW IODINE DIET WHICH THEY DON'T LIKE. AND IT IS -- ACTUALLY THEY TEND TO LOSE WEIGHT SO I THINK IT'S A GOOD THING. THEY NEED TO AVOID I.V. CONTRAST. THE CHOICE OF ACTIVITY THAT WE GIVE THESE PATIENTS IS ANYWHERE FROM 30 TO 150 MILICURIE, IT DEPENDS ON TUMOR CHARACTERISTICS AND HISTOLOGIC SUBTYPE. HOW DO WE DO? IF WE LOOK AT -- THESE ARE DATA FROM THE NATIONAL THYROID CANCER COOPERATIVE TREATMENT GROUP THAT WE'RE A PART OF. IF WE LOOK AT OVERALL SURVIVAL OF PATIENTS WITH WELL DIFFERENTIATED THYROID CANCER, WE'VE GOT STAGE 1 AND 2, LOW RISK, STAGE 3 AND 4, HIGH RISK, THAT'S HIGH RISK FOR DEATH, THESE ARE -- THEY ARE STAGED ACCORDING TO A UNIQUE SYSTEM THAT WE USE IN THE THYROID CANCER REGISTRY THAT'S LIKE THE TNM SYSTEM. WE DO MULTI-VARIABLE ANALYSIS TO LOOK AT WHAT THE IMPACT OF TOTAL OR NEAR TOTAL THYROIDECTOMY VERSUS A LESSER OPERATION, OR RADIOACTIVE IODINE VERSUS KNOW RADIOACTIVE IODINE, WE CAN SEE THAT THERE IS ONLY AN IMPROVEMENT IN OVERALL SURVIVAL IN OUR HIGH RISK PATIENTS. SO MORE AGGRESSIVE THERAPY IS BENEFICIAL TO OUR PATIENTS WITH STAGE 3 AND STAGE 4 DISEASE. THIS HAS NEVER BEEN DOCUMENTED IN THE MAJORITY OF THYROID CANCER PATIENTS WHO FALL INTO STAGE 1 AND 2. IN FACT, AND SORT OF TO OUR DISMAY, WE ALWAYS SEE A DECREASE IN DISEASE-FREE SURVIVAL WHEN WE TREAT PATIENTS AGGRESSIVELY WITH NEAR TOTAL OR TOTAL THYROIDECTOMY AND IODINE. THIS MAY BE A REFLECTION OF BIAS OF TREATING HABITS THAT IN THIS CATEGORY OF STAGE 1 THERE ARE GOING TO BE THE FOLKS THAT ARE ACTUALLY BEING TREATED, MAY HAVE TENDENCIES OR SOME CLINICAL SUSPICIONS THAT WOULD PREDICT THAT THEY WOULD HAVE A RECURRENCE, OR IT MAY SIMPLY BE A FACT THAT ONCE WE HAVE WIPED OUT ALL OF THE NORMAL THYROID IT'S JUST EASIER FOR US TO FIND RECURRENCES. THIS IS STILL A POINT OF QUESTION, BUT IT'S CERTAINLY A REPRODUCIBLE RESULT. SO WE RECOGNIZE THAT WE DON'T APPEAR TO BE HAVING MUCH EFFECT IN STAGE 1 OR STAGE 2 PATIENTS. SO WHAT EXACTLY ARE WE DOING? AND THAT IS AN EXCELLENT QUESTION. DR. GILL WELCH AT DARTMOUTH WANTED TO EXPLORE THIS INITIALLY AND I THINK HE WAS VERY CLEVER IN DOING THIS, ALTHOUGH THE STUDY HAS SOME FLAWS. HE LOOKED AT THE SEER DATABASE TO IDENTIFY PATIENTS BETWEEN 197 AND 2005 WHO HAD TUMORS THAT WERE RESTRICTED TO THE THYROID. SOME 35,000+ CASES. OF THOSE PATIENTS, 440 OF THEM DID NOT UNDERGO IMMEDIATE THERAPY EITHER BECAUSE THE TREATMENT WAS NOT RECOMMENDED, PERHAPS BECAUSE OF PREEXISTING COMORBIDITIES OR SOME OTHER ISSUES OR THE TREATMENT WAS RECOMMENDED BUT NOT ADMINISTERED. HERE WE CAN SEE THE DISTRIBUTION OF TUMOR SIZES. I SAID THEY TOOK TUMORS OF ANY SIZE, SOME ARE ACTUALLY QUITE LARGE. YOU CAN SEE A FEW 6 TO 7 CENTIMETERS, BUT THE MAJORITY OF THEM FALL INTO THE 1-2-CENTIMETER RANGE IN BOTH THE TREATED AND IN THE UNTREATED CATEGORIES. HERE WE CAN SEE THE 5 AND 10 YEAR SURVIVALS. CLEARLY THERE'S NOT A HUGE IMPACT OF OUR TREATMENT IN THIS PARTICULAR STUDY, THAT THE SURVIVAL OF PATIENTS THAT WERE GIVEN DEFINITIVE TREATMENT INITIALLY IS CLOSE TO 100%, AND NOT TREATING THEM DOESN'T CHANGE THAT VERY MUCH. THE QUESTION IS, AGAIN, WHAT ARE WE TRYING TO IMPROVE UPON? IF WE LOOK TO OUR COLLEAGUES IN JAPAN, DR. ITO AND HIS GROUP HAVE BEEN STUDYING MICROCARCINOMAS AND ASKING PRETTY MUCH THE SAME QUESTION. WHEN A PATIENT IS IDENTIFIED WITH MICRO CARCINOMA, HE ASKS THEM, DO YOU WANT TO HAVE SURGERY OR NOT? DO YOU WANT TO GO INTO AN ACTIVE SURVEILLANCE PROGRAM OR HAVE IMMEDIATE SURGERY? AND THROUGH THIS STUDY, ACTUALLY WE'VE LEARNED QUITE A BIT ABOUT THE BIOLOGICAL BEHAVIOR OF THESE TINY TUMORS. FIRST OFF, LYMPH NODE METS ARE COMMON IN THEM. AND YOU'LL SEE THEM FREQUENTLY IN THE CENTRAL AND LATERAL COMPARTMENT AND MULTI-FOCALITY IS COMMON AS WELL. WHEN YOU LOOK AT ACTIVE SURVEILLANCE VERSUS IMMEDIATE SURGERY AND LOOK FOR TENDENCIES FOR GROWTH IT HAPPENS IN THE MINORITY OF PATIENTS, OVER 10-YEAR PERIOD. SO ONLY 16% OF PATIENTS HAD AN INCREASE IN TUMOR SIZE GREATER THAN 3 MILLIMETERS. AND THOSE INCREASES OCCURRED MOSTLY IN PATIENTS THAT WERE RELATIVELY YOUNG. IN REGARDS TO LYMPH NODE METS, EITHER DETECTED BY ULTRASOUND OR CLINICAL EXAMINATION, THIS TOO WAS EXTREMELY RARE, ONLY 3.4% MUCH PATIENTS. THERE WERE MORE ADVERSE EFFECTS IN THE SURGICAL TREATMENT GROUP THAT WENT TO IMMEDIATE SURGERY AS OPPOSED TO AFTER A PERIOD OF TIME OF OBSERVATION. THERE WAS MORE TRANSIENT VOCAL CORD PARALYSIS, PERMANENT VOCAL CORD PARALYSIS, TRANSIENT AND PERMANENT VOCAL CORD PARALYSIS. WHAT ABOUT THE HARMS OF TREATMENT? RADIOACTIVE IODINE? IN RADIOACTIVE IODINE WE'VE LEARN FROM COLLEAGUES THERE IS A SMALL BUT STATISTICALLY SIGNIFICANT INCREASE IN SECONDARY MALIGNANCY, PARTICULARLY THE SALIVARY GRAND AND A COUPLE EXCESS CASES OF LEUKEMIA WITH A RATIO, 1.8. FORTUNATELY WHEN PEOPLE HAVE TRIED TO LOOK FOR IMPACT ON REPRODUCTIVE ABILITY, THERE DOESN'T SEEM TO BE ANY IMPACT ON BIRTH RATES OR TROUBLE GETTING -- BEARING CHILDREN. BUT RECENT STUDY DEMONSTRATED THAT PATIENTS WITH THYROID CANCER HAVE DIMINISHED QUALITY OF LIFE SIMILAR TO COLON, GLIOMA, BREAST AND GYNECOLOGIC CANCERS. WHEN THEY STUDIED 1100 PATIENTS FROM THE U.S. AND CANADA, MOST OF THEM ARE IN THE LOW RISK CATEGORY AND ARE GOING TO BE CURED OF THEIR DISEASE. AND YET THERE IS THIS IMPACT ON THEIR PERCEPTION OF HOW GOOD THEIR LIFE IS AFTER THE DIAGNOSIS. ONE GLIMMER OF GOOD HOPE IS THAT WHEN THEY LOOKED AT IT, LOOKED AT THE QUALITY OF LIFE SCORES AS THEY RELATE TO YEARS FROM DIAGNOSIS, THERE APPEAR TO BE IMPROVEMENTS AS YOU GOT FARTHER AWAY FROM YOUR DIAGNOSIS. SO THIS REALLY ALL CALLS FOR US TO CONSIDER A NEW APPROACH TO SMALL TUMORS, PARTICULARLY MICROPAPILLARIES. WE NUDE TO CONSIDER TUMOR CHARACTERISTICS, WE CAN SEE THAT THIS IS A VERY WONDERFUL HYPOTHESIS TO TEST AND COULD AND SHOULD BE DONE ACTUALLY IN A GOOD CENTER WITH -- IN THE CONTEXT OF A RESEARCH STUDY. BUT THE CAVEATS INCLUDE SOME OF THE DATA THAT WE'VE GENERATED ABOUT MICROPAPILLARY RECURRENCE, JUST A CAUTIONARY TALE, THAT OF MICROPAPILLARIES THAT ARE TREATED WITH SURGERY, 6.7% TEND -- RECURRED, NOT JUST IN THE THYROID BED BUT THEY CAN RECUR AT DISTANT SITES AND THERE'S ALWAYS THE LOOMING POSSIBILITY OF ANAPLASTIC TRANSFORMATION, AN UNLUCKY PERSON HAD THAT AFTER 11 MONTHS AND DIED. THE DOCTORS PUSHED BACK FARTHER BECAUSE THERE'S A TREND TO SAY WHY DON'T WE JUST OBSERVE EVEN LARGER TUMORS?%-œANDTHEY, GAIN, MININGTHE SEER DATABASE IDENTIFIED 1753 DEATHS, 12% FROM TUMORS LESS THAN 2 CENTIMETERS AND 5% CAME FROM MICROCARCINOMAS. VERY IMPORTANTLY IN MY MIND ARE THE CHARACTERISTICS OF THE PATIENTS THAT DIED OF THESE TUMORS. THEY INCLUDED MALES GREATER THAN 45 YEARS AND ESPECIALLY IMPORTANT BLACK AND OTHER RACIAL CATEGORIES AND MINORITIES. SO I THINK THAT WHILE WE'RE TRYING TO SCALE BACK TREATMENT AT THIS POINT WE HAVE TO ALWAYS BE CONSIDERING THE IMPACT OF SOCIOECONOMIC STATUS ON OUR PATIENTS. IT IS WELL RECOGNIZED BY MANY STUDIES THAT LOWER SOCIOECONOMIC STATUS, PATIENTS USUALLY HAVE A HIGHER STAGE OF PAPILLARY THYROID CANCER AT PRESENTATION AND WE TEND TO USE LESS RADIOACTIVE IODINE IN THOSE PATIENTS AND SAW IN THE PREVIOUS SLIDE THAT MORE PATIENTS DIE. IF YOU HAPPEN TO BE IN THE PRIVILEGED 1%, YOU'RE GOING TO GET THE OVERMEDICINE AND DO JUST FINE WITH YOUR MEDICATION AT YOUR OVERTREATMENT, BUT WE HAVE TO BE CAREFUL ABOUT THE WAY WE ADOPT NEW STRATEGIES IN OUR LOWER SES PATIENTS. WE'RE PROPOSING A PARADIGM SHIFT FOR THYROID CANCER. WE NEED TO MINIMIZE ADVERSE OUTCOMES WITHOUT SACRIFICING SURVIVAL RATES, CURTAILING THE WORKUP AND PREVENTING AN EPIDEMIC. WE'RE GOING TO AVOID ROUTINE THYROID SCREENING. JUDICIOUSLY USE RADIOACTIVE IODINE IN LOW RISK PATIENTS, WE'VE NOT YET LEARNED HOW TO TRULY INCORPORATE INFORMATION FROM MOLECULAR AND GENETIC STUDIES SO THERE'S WORK TO BE DONE. WE HAVE A LOT OF JOB SECURITY. WE NEED TO WORK TO IMPROVE QUALITY OF LIFE AND ESTABLISH APPROACHES TO MANAGE INCIDENTALLY FOUND PATHOLOGIES WITHOUT DRAINING RESOURCES AND QUOTE/UNQUOTE MAKING PEOPLE SICK IN THE PURSUIT OF HEALTH. WE CERTAINLY HAVE TO WORK TO UNDERSTAND AND ELIMINATE THE IMPACT OF HEALTH DISPARITIES ON THYROID CANCER OUTCOMES, AND HOPEFULLY INSTITUTE RANDOMIZED CONTROL STUDIES INCORPORATING NEW END POINTS LIKE PATIENT REPORTED OUTCOMES. THIS WOULD BE A GOOD PLACE TO THINK ABOUT THIS. OBVIOUSLY WE NEED TO ADVANCE MOLECULAR AND GENETIC PROFILING TO GUIDE TREATMENT OF FOLLOW-UP AND IT'S IMPORTANT WE QUESTION THE DOGMA THAT THE RISE IS DUE TO OVERDETECTION BECAUSE THERE MAY BE SIGNAL IN HERE THAT WE'RE MISSING. SO I'M GOING TO END THERE AND I THANK YOU FOR YOUR ATTENTION. I'LL TURN THE PODIUM OVER TO DR. KLUBO. THANK YOU. [APPLAUSE] >> I'M TRULY HONORED, VERY GRATEFUL FOR THE OPPORTUNITY TO PRESENT ON TSH AND THYROID CANCER. I'M GOING TO REVIEW GUIDELINES ON THE ROLE OF TSH IN LONG-TERM MANAGEMENT OF THYROID CANCER. WE'RE GOING TO ASSESS THE PATHOLOGIC ROLE OF SIGNALING IN VITRO AND IN VIVO. WE'RE GOING TO EVALUATE LARGE COHORT STUDIES FOCUSED ON ASSOCIATION BETWEEN TSH LEVEL AND RESPONSE AND WE'RE GOING TO ACKNOWLEDGE THE RISKS AN BENEFITS OF TREATMENT WITH THE SUPPRESSIVE DOSES. I WOULD LIKE TO FOCUS ON LONG-TERM MANAGEMENT INVOLVING TREATMENT WITH THYROID HORMONES WITH THE DOSE NOT ONLY REPLACING THYROID OR MONIES BUT ALSO I JUSTED TO SPECIFIC TSH LEVEL GOALS. FOR LOW RISK PATIENTS WE TEND TO AIM FOR LOW NORMAL TSH GOAL. SO WHY IS THAT? WHAT IS THE EVIDENCE FOR TSH SUPPRESSION? IS THIS THE THYROID STIMULATING HORMONE ABLE TO STIMULATE REGROWTH OF THYROID CANCER AFTER THE SURGERY? GUIDELINES ARE BASED ON SEVERAL STUDIES. I FOCUSED ON THE STUDIES WHICH THE POPULATION FROM THE STUDIES WHICH INVOLVED INTERMEDIATE AND HIGH RISK PATIENTS. AS WE CAN SEE HERE, THE NUMBER OF PATIENTS ARE DECENT, HOWEVER THEY ARE FOLLOWED FOR RELATIVELY SHORT PERIODS OF TIME, MOREOVER THE NUMBER OF TSH MEASUREMENTS WAS ALSO RELATIVELY LOW. WHAT WE CAN SAY IS THAT THOSE STUDIES ARE PRETTY CONSISTENT IN TERMS OF PREDICTORS OF PROGRESSION, THEY ARE NOT THAT CONSISTENT IN TERMS OF ROLE THE TSH SUPPRESSION AS INDEPENDENT FACTORS ASSOCIATED WITH BETTER OUTCOMES. STUDIES DOCUMENT TSH SUPPRESSION IS ASSOCIATED WITH LONGER DISEASE-FREE SURVIVAL. HOWEVER, WHEN THEY ADJUSTED FOR RADIOACTIVE IODINE TREATMENT TSH SUPPRESSION WAS NO LONGER A SIGNIFICANT FACTOR. A LITTLE BIT DIFFERENT RESULTS COME FROM DR. PUJO'S STUDIES, EVIDENCE TSH SUPPRESSION IS ASSOCIATED WITH LARGER OUTCOMES. IN OTHER STUDIES WHAT'S BENEFICIAL IN TERMS OF OVERALL SURVIVAL, HOWEVER IN TERMS OF DISEASE SPECIFIC SURVIVAL NOT ANY MORE. I WOULD LIKE TO FOCUS ALSO ON TWO OTHER STUDIES WHICH ARE CHARACTERIZED BY SIGNIFICANTLY LONGER SITUATION OF FOLLOW-UP AND SIGNIFICANTLY LARGER DATA POINTS OF TSH MEASUREMENTS. AGAIN, EVEN THOSE TWO STUDIES ARE NOT CONSISTENT. ONE OF THE STUDIES REVEALED TSH SUPPRESSION IS INDEPENDENT FACTORS ASSOCIATED WITH OUTCOME, THE OTHER NOT. ON HIGHER END OF NORMAL RANGE, IT WAS ASSOCIATED WITH WORSE OUTCOME BUT TSH SUPPRESSION WAS NOT THE INDEPENDENT FACTORS. BELIEVE IT OR NOT THERE'S ONLY ONE PROSPECTIVE STUDY ADDRESSING THIS QUESTION PERFORMED IN JAPAN, AND THIS STUDY MAJORITY OF THE PATIENTS, 80%, WERE LOW RISK PATIENTS. HOWEVER, THERE WAS A SEPARATE RELATION OF ALMOST 300 HIGH RISK PATIENTS. AND THIS STUDY WHICH AGAIN HAD DECENT DURATION OF FOLLOW-UP AND VERY NICE NUMBER OF DATA POINTS IN TERMS OF TSH MEASUREMENT, NO DIFFERENCE FOUND IN TERMS OF DISEASE-FREE SURVIVAL BETWEEN THE PATIENTS WHO UNDERWENT TSH SUPPRESSION AND THOSE WHO DID NOT UNDERGO TSH SUPPRESSION, TRUE NOT ONLY FOR LOW RISK PATIENTS BUT ALSO FOR HIGH RISK PATIENTS. SO TO SUMMARIZE CURRENT GUIDELINES, IT IS BASED ON LOW TO MODERATE QUALITY EVIDENCE, MOREOVER CHARACTERIZED BY INCONSISTENCY AND RISK OF BIAS. SO MAYBE WE SHOULD STEP BACK AND REVIEW PHYSIOLOGY BEHIND TSH, RECEPTOR SIGNALING, SIMPLISTICALLY AND BASICALLY IT BINDS TO TSH RECEPTORS LEADING TO ACTIVATION OF CAMP AND THEN SUBSEQUENTLY ACTIVATION OF PKA SIGNALING. PKA TOGETHER WITH OTHER SIGNALING PATHWAYS LEADS TO UP OR DOWNREGULATION OF TRANSCRIPTION FACTORS AND CELL RENEWAL AND DIFFERENTIATION. IF THAT'S THE CASE LET'S THINK ABOUT ACTIVATION OF SIGNALING PATHWAY, THE ROLE IN THYROID CANCER. WE KNOW FROM CLINICAL EXPERIENCE GERM LINES ACTIVATING TSH RECEPTOR MUTATION IN HUMANS ARE NOT ASSOCIATED WITH INCREASED RISK OF THYROID CANCER, THEY ARE ASSOCIATED WITH HYPER THYROIDISM. SOMATIC MUTATIONS ARE ASSOCIATED WITH OVERACTIVE/HOT NODULES, LOW RISK OF MALIGNANCY. A LARGE DATABASE, TCGA DATABASE, CONTAINS TUMOR SAMPLES FROM THYROID CANCER PATIENTS, 5% PRESENT WITH SOMATIC MUTATION IN TSH RECEPTOR. TSH RECEPTOR MUTATIONS DRIVER MUTATION IS UNLIKELY. WHAT'S GOING ON IN VITRO? WE HAVE OTHER LEVEL OF EVIDENCE. FOLLICULAR CELLS WHICH EXPRESSED CONSTITUTIVELILY ACTIVE TSH RECEPTOR CHARACTERIZED BY INCREASE THE I125 UPTAKE, USING THE CELLS UNDER INFLUENCE OF TSH TAKE UP MORE ACTIVE IODINE. YOU CAN SEE HERE IN THE COLUMNS THE CELLS TRANSSECTED TO CONSTITUTIVELY ACTIVE TSH RECEPTOR HAVE BASELINE HIGHER OF R 125 COMPARED WITH THOSE WHITE COLUMNS. DECREASE THE FURTHER AFTER TSH STIMULATION. AT THE SAME TIME WE CAN SEE HERE THAT GROWTH PROLIFERATION RATES WAS NOT AFFECTED COMPARED WITH CONTROL. IN FACT, WE CAN SEE EVEN SLOWER PROLIFERATION. SO THESE WERE CELLS, MOLECULARLY ENGINEERED. WHAT ABOUT PLAIN HUMAN FOLLICULAR CELLS? THE GROUP HERE AT THE NIH PRESENTED A NICE STUDY AT THE ATA MEETING SHOWING CELLS GROWING IN GROWTH FACTOR DEPLETE CONDITIONS, .1% BSA OR 1% SERUM, WERE ABLE TO PROLIFERATE. WHEN WE ADDED SOME FOOD TO THE CELLS, WHAT WE OBSERVED WAS LACK OF INCLEMENT PROLIFERATION IN THESE CELLS. THOSE WERE NORMAL FOLLICULAR THYROID CELLS. WHAT ABOUT THYROID CANCER CELLS? A NICE STUDY WAS PRESENTED WHEN THEY CULTURED CELLS DERIVED FROM 13 THYROID CANCER PATIENTS, INCUBATED FOR 48 HOURS WITH DIFFERENT TSH CONCENTRATION AND THIS STUDY PROLIFERATION WERE NOT INFLUENCED BY TSH LEVELS. SUMMARIZING, ADDITIONAL BODY OF EVIDENCE ON IN VITRO STUDIES WE COULD STATE THAT IN A NORMAL HUMAN THYROID FOLLICULAR CELL MODEL THE STIMULATION OF THE SYNTHESIS AND PROLIFERATION IS WEAK OR ABSENT IN TISSUE DERIVED FROM ELDERLY, PREVIOUSLY REASON OR SUBCULTIVATED MARKED STIMULATION WAS DEMONSTRATED ONLY USING HUMAN FETAL THYROCYTES, DEPENDING ON THE PRESENCE OF IGF 1 OR INSURE LINE. -- INSULIN. IT IS ALONE DOES NOT STIMULATE. WE USE TSH STIMULATION TO INCREASE SODIUM IODINE AND INCREASE RADIOACTIVE IODINE UPTAKE. THE SAME STUDY REVEALED THAT CULTURING CELLS INCREASED EXPRESSION OF THYROID SPECIFIC GENE SUCH AS THYROGLOBULIN, TPR AND SODIUM IODINE. TREATMENT WITH TSH IS ASSOCIATED WITH SIGNIFICANT MORPHOLOGY CHANGES OF THE CELLS. THEY BECAME -- THEY CHANGE FROM SPINDLE LIKE MESENCHYMAL CELLS TO EPITHELIAL-LIKE CELLS. IS THERE ANY EVIDENCE OF TSH DIFFERENTIAL FACTOR IN VIVO? WE USE IT ALL THE TIME FOR IODINE TREATMENT BUT WHAT ABOUT THE OPPOSITE, WHAT ABOUT TSH SUPPRESSION LEADING TO DECREASE IN THYROID SPECIFIC GENE EXPRESSION? BRUNO, ET AL., DIVIDED PATIENTS INTO TWO GROUPS. ONE GROUP RECEIVED SUPPRESSIVE NOTICE OF LIVER THYROXINE, THE OTHER TSH LEVEL WAS NORMAL. IN THIS STUDY RNA TAKEN FROM TISSUE AFTER THYROIDECTOMY, PCR MEASUREMENTS REVEALED WHAT WAS SIGNIFICANTLY LOWER. ANOTHER QUESTION, WHAT ABOUT TSH RECEPTOR ITSELF? MY STUDY BY DURANT REVEALED TSH RECEPTOR EXPRESSION IN THYROID CANCER IS DECREASED, SPECIFICALLY IN PATIENTS WHO HAVE B-RAS MUTATION. WE ALSO DO SEE IT IN VITRO STUDIES, MAJORITY OF THYROID CANCER CELL LINES DO NOT EXPRESS TSH RECEPTOR. IT'S ALSO DOCUMENTED IN TRANSGENIC MICE MODEL DR. FAGAN'S MOUSE MODEL WITH BRAF MUTATION DEVELOP AGGRESSIVE PAPILLARY THYROID CANCER BY 3 TO 5 WEEKS OF AGE, HIGH HIGH LEVEL OF TSH LEVEL. IT DID NOT PREVENT DEVELOPMENT OF PTC. MAYBE THE TSH SIGNALING LEADS TO DIFFERENTIATION RATHER THAN PROLIFERATION, ALMOST UNHEARD OF IN FACT ONE STIMULUS COULD INCREASE BOTH, WHEN CELLS WANT TO PROLIFERATE THEY WANT TO BE AS SIMPLE AS POSSIBLE. THEY DON'T NEED DIFFERENTIATION. WHEN WE SHIFT OUR ENERGY FOR DIFFERENTIATION WE'RE NOT ABLE TO PROLIFERATE AS MUCH. SO THESE OBSERVATIONS LET US TO HYPOTHESIZE THAT PROLONGED TSH SUPPRESSION IN INTERMEDIATE AND HIGH RISK THYROID CANCER PATIENTS IS NOT SUPERIOR TO TARGETING SLOW NORMAL. WE ANALYZED DATABASES COMING FROM FOUR INSTITUTIONS, NIH, THYROID CANCER COLLABORATIVE, MED STAR AND MAYO CLINIC. WE INCLUDESSED HIGH RISK PATIENTS, PRESENCE OF DISTANT METASTASES, TREATED UNIFORMLY WITH TOTAL THYROIDECTOMY, LYMPH NODE DISSECTION IF INDICATED, AND UNIFORMLY WITH IODINE, INCLUDING PATIENTS FOR WHOM FOLLOW-UP DATA ENABLES ASSESSMENT OF RESPONSE TO TREATMENT. WE EXCLUDED LOW RISK PATIENTS AND PATIENTS FOR WHOM FOLLOW-UP DATA WERE NOT AVAILABLE. AT EACH FOLLOW-UP VISIT TSH LEVEL WAS SCORED AS 1 FROM DETECTABLE, 2 FOR TSH MODERATELY SUPPRESSED, 3 FOR TSH IN THE LOW NORMAL RANGE, AND 4 FOR TSH MORE THAN 2. THE PATIENTS SUBSEQUENTLY WERE DIVIDED INTO THREE GROUPS, GROUP 1 CHARACTERIZED BY SUPPRESSED TSH, THROUGHOUT FOLLOW-UP PERIODS. GROUP B CHARACTERIZED BY MODERATELY SUPPRESSED TO LOW NORMAL TSH. GROUP C CHARACTERIZED BY LEVELS NORMAL OR EVEN ELEVATED. WE USED LOGISTIC REGRESSION MODELS TO ASSESS ASSOCIATION BETWEEN TSH LEVELS AND BEST RESPONSE TO TREATMENT. THERE WAS ASSOCIATION BETWEEN TSH AND PROGRESSION FREE SURVIVAL AND OVERALL SURVIVAL. WE FOUND 913 PATIENTS ELIGIBLE. UNFORTUNATELY 597 HAD ALREADY NECESSARY DATA COLLECTED DURING THE FOLLOW-UP PERIODS, AS LONG AS 7 YEARS. AVERAGE AGE AT DIAGNOSIS WAS 49 YEARS, WE HAD PREDOMINANCE OF FEMALES, WHICH IS TYPICAL. TUMOR SIZE LARGE 3.3 CENTIMETERS, 36% PRESENTED WITH EXTRATHYROID EXTENSION, 16% PRESENTED WITH DISTANT METASTASES. 30% OF PATIENTS HAD SUPPRESSED TSH DURING THE FOLLOW-UP HEARDS AND ANOTHER 40% MODERATELY SUPPRESSED TO LOW NORMAL TSH DURING THE FOLLOW-UP PERIOD. AND THE SMALLER POPULATION OF PATIENTS AS EXPECTED HAD NORMAL TO ELEVATED TSH. OF NOTE, VERY IMPORTANTLY, THE GROUPS WERE COMPARABLE IN TERMS OF BASIC PREDICTORS, FOR RESPONSE TO TREATMENT, SUCH AS AGE, SEX, TUMOR SIZE, MULTI-FOCALITY, SURGICAL MODELS, LYMPH NODE METASTASIS AND DISTANT METASTASIS. IN TERMS OF THE NUMBER OF TSH MEASUREMENTS GROUP A AND B WERE SIMILAR. AS WELL THERE THEY WERE SIMILAR IN TERMS OF DURATION OF FOLLOW-UP. IMPORTANTLY GROUP C SAW THIS GROUP WITH THE SMALLEST AMOUNT OF -- SMALLEST NUMBER OF PATIENTS WITH NORMAL TO ELEVATED TSH FOLLOWED FOR SHORTER PERIODS OF TIME AND WE HAD TO TAKE INTO CONSIDERATION WHEN WE'RE GOING TO INTERPRET OUR RESULTS. WHAT ARE THE RESULTS? THERE WAS NO ASSOCIATION BETWEEN TSH LEVEL AND EXCELLENT RESPONSE RATES IN THIS COHORT. WE OBSERVED DECREASED RISK OF STRUCTURAL INCOMPLETE RESPONSE, AND AS EXPECTED SHOWN IN MULTIPLE STUDIES INCREASED RISK OF STRUCTURAL INCOMPLETE RESPONSE, AND WITH MALE GENDER. PROGRESSION-FREE SURVIVAL? WE OBSERVED LONGER PROGRESSION-FREE SURVIVAL IN PATIENTS WITHOUT SUPPRESSED TSH, GROUP C AND B, COMPARED WITH GROUP A. IT WAS ADJUSTED BY AGE, SEX, TUMOR SIZE, PRESENCE OF LATERAL LYMPH NODE METASTASIS AND DISTANT METASTASIS, AND POORLY DIFFERENTIATED HISTOLOGY. THERE WAS NO DIFFERENCE IN TERMS OF OVERALL SURVIVAL BETWEEN SUPPRESSED AND MODERATELY SUPPRESSED GROUP SO TSH RANGE BETWEEN 0 TO 2 HAD SIMILAR OVERALL SURVIVAL. THE FACTORS INDEPENDENTLY ASSOCIATED WITH DECREASED OVERALL SURVIVAL WERE TSH MORE THAN 2, AGE, MALE GENDER, AND PRESENCE OF DISTANT METASTASIS AND WE CAN SEE HERE IN THIS SURVIVAL PATIENTS WITH SUPPRESSED TSH LOW NORMAL TSH HAD BETTER OVERALL SURVIVAL THAN PATIENTS WITH NORMAL TO ELEVATED TSH. TO SUMMARIZE THE RESULT ALSO OF OUR STUDY, WE COULD SAY THAT AGGRESSIVE TSH SUPPRESSION TO UNDETECTABLE LEVEL IS NOT ASSOCIATED WITH BETTER OUTCOMES. AND THEREFORE MAY NOT BE REQUIRED FOR INTERMEDIATE AND HIGH RISK THYROID CANCER PATIENTS. OTHER DATA CONSISTENT WITH OUR FINDINGS, DR. SHERMAN'S GROUP VERY RECENTLY PUBLISHED THE STUDY WHICH SHOWS VERY SIMILAR RESULTS, OVERALL SURVIVAL WAS SIMILAR FOR THE PATIENTS WITH UNDETECTABLE SUBNORMAL TSH AND SUBNORMAL TO NORMAL TSH AND AFFECTED ONLY IN PATIENTS WITH ELEVATED TSH LEVELS, HOLDING TRUE FOR HIGH RISK PATIENTS WITH STAGE 4 DISEASE AND FOR THE SUBGROUP OF PATIENTS WITH DISTANT METASTASIS. SO WHAT SHOULD WE TELL OUR PATIENTS? SHALL WE GIVE SUPPRESSIVE DOSES OF LEVETHYROXINE OR NOT? WE KNOW TSH IS LEADING TO DECREASE BONE DENSITY, SEVERAL PAPERS DOCUMENTING THAT. MOREOVER, TSH SUPPRESSION LEADS TO CARDIOVASCULAR COMPLICATIONS, PREDOMINANTLY AFIB, PREDOMINANTLY IN OLDER PATIENTS. TO CONCLUDE, WHAT ARE FACTS, TSH SUPPRESSION IS NOT CONSISTENTLY ASSOCIATED WITH BETTER OUTCOMES AND INTERMEDIATE AND HIGH RISK THYROID CANCER PATIENTS. BUT TSH SUPPRESSION IS ASSOCIATED WITH INCREASED LIKELIHOOD OF OSTEOPOROSIS, AND ATRIAL FIBRILLATION. MAYBE THE COMMON BELIEF TSH SUPPRESSION IS REQUIRED IS A MYTH, MAYBE WE NEED TO DESIGN A PROSPECTIVE RANDOMIZED CONTROL STUDY VERSUS NO SUPPRESSION TO FINALLY ADDRESS THIS PROBLEM. I WOULD LIKE TO THANK MY WONDERFUL MENTORS, THE DOCTOR WHO PERFORMED STATISTICAL ANALYSIS AND THE ONE WHO ENCOURAGED PURSUIT AND MY PAST MENTORS, FROM MOUNT SINAI, SLOAN-KETTERING AND MAYO CLINIC. I WOULD LIKE TO MANAGE MY WONDERFUL CO-FELLOWS AND MY COLLEAGUES FROM THE LAB FROM THE DREAM TEAM. THANK YOU. [APPLAUSE] >> WE HAVE TIME FOR QUESTIONS FOR BOTH SPEAKERS. IF YOU HAVE ONE PLEASE GO TO A MICROPHONE. >> JUST FOR THE FIRST SPEAKER, YOU WENT TO THE THROUGH THE DIAGNOSIS AND TALKED ABOUT PERHAPS OVERDIAGNOSIS, EXPERIENCE HAS SHOWN ME THE FINE NEEDLE ASPIRATION IS WHAT'S THE NEXT STAGE, WE USED TO HAVE A THYROID CLINIC BUT WE DID NOT BUT FNAs AND WHAT THE ENDOCRINOLOGIES DICTATED. SOME PROBLEMS WITH SAMPLING, ADEQUACY, YOU CAN'T DETERMINE INVASION, SOME LABS AREN'T GOING TO EMBODY THE ENTIRE THYROID, THAT ADDS INTO YOUR OVERDIAGNOSIS THING AND FNA AND THE PATHOLOGY MIGHT IN TERMS OF SUBJECTIVENESS AND HOW THEY ARE SAMPLED MIGHT CAUSE AN OVERDIAGNOSIS. SECOND, MY QUESTION IS YOU SAID THERE WAS SOME TYPE OF INCIDENTAL FINDINGS, IN TERMS OF PATHOLOGY OF THE THYROID. WHAT WERE YOU REFERRING TO. >> INCIDENTAL FINDINGS? WELL, SO I THINK I WAS -- I THINK I WAS REFERRING TO WHEN ONE DOES A STUDY FOR ANOTHER INDICATION, FOR EXAMPLE A CT OF THE NECK FOR, YOU KNOW, ASSESSING A CAR ACCIDENT, AND ONE FINDS THYROID PATHOLOGY ON THAT AND THEN KICKS OFF THE ENTIRE CYCLE OF A WORKUP OF THAT TUMOR WHICH WOULD NOT HAVE COME TO CLINICAL DETECTION IF THAT STUDY HAD NOT BEEN DONE. >> YOU'RE TALKING ABOUT IMAGING THEN? >> I'M SORRY? >> YOU'RE TALKING ABOUT IMAGING STUDIES? CORRECT. >> OKAY. THANK YOU. >> AND WE HAVE THIS, YOU KNOW, IN OTHER ENDOCRINE ORGANS AS WELL, INCIDENTALOMAS OF THE ADRENAL, OF THE PITUITARY. WE ARE AS A SUBSPECIALLY ENDOCRINOLOGIESES USED TO DEALING WITH THIS ALL THE TIME. YOUR POINT ABOUT THYROID ASPIRATION BIOPSY IS WELL TAKEN, IT'S BEEN THOUGHT OF COURSE THAT PERHAPS MOLECULAR DIAGNOSIS WOULD TAKE SOME OF THIS UNCERTAINTY OUT OF IT AND WHILE THIS COULD BE THE SUBJECT OF AN ENTIRE, YOU KNOW, DISCUSSION, I THINK IT HAS ACTUALLY ADDED ADDITIONAL CONFUSION TO THE MIX. SO I THINK, YOU KNOW, WE HAVE A LONG WAYS TO GO IN TERMS OF REALLY COMING UP WITH BEST MOLECULAR MARKERS TO INDICATE BENIGNITY. >> OKAY, THANK YOU. >> A QUESTION FOR DR. KLUBO. EXCELLENT TALK. BASED ON YOUR SLIDES INULINS IS MORE CONCERTING FOR STIMULATING HYPERPLASIA THAN TSH. IS THERE EVIDENCE TO SUPPORT THAT AND SHOULD WE BE CONCERNED ABOUT PEOPLE WITH HYPER INSULINEMIA? >> FOR THIS COHORT WE DID NOT HAVE BMI DATA OR IGF OR INSULIN LEVELS IN THE BLOOD. I THINK THEY MIGHT BE AVAILABLE FOR NIH COHORTS BECAUSE WE DO HAVE BLOOD AND WE COULD DO THOSE ASSOCIATIONS. NIH COHORTS CONSISTED OF ROUGHLY 150 PATIENTS SO THE NUMBER IS RELATIVELY DECENT SO WE COULD PURSUE THAT AND THIS IS VERY IMPORTANT. THANK YOU FOR THE SUGGESTION. >> THANK YOU FOR YOUR EXCELLENT TALKS. FOR JOANNA, GIVEN YOUR BACKGROUND SLIDES HAD I NOT UNDERGONE ENDOCRINOLOGY TRAINING AND KNOWN ABOUT THIS DOGMA OF TSH SUPPRESSION YOUR BACKGROUND SLIDES WOULD HAVE MADE ME THINK TO EXPECT TSH RECEPTOR STIMULATION CAUSES DIFFERENTIATION AND THE PEOPLE WITH THE HIGHEST TSH LEVELS SHOULD HAVE THE BEST OUTCOMES AND NOT THE WORST OUTCOMES. IF ANYTHING, THAT YOUR RESULTS GIVEN YOUR BACKGROUND SLIDES ARE SURPRISING. DO YOU HAVE ANY EXPLANATIONS FOR WHY THAT STILL SHOULD BE? >> SO IN TERMS OF PROGRESSION FREE SURVIVAL IT WAS ACTUALLY THE CASE. A GROUP WITH MODERATELY SUPPRESSED TSH AND NORMAL TSH DID BETTER. GROUPS WITH NORMAL AND ELEVATED DID BETTER THAN SUPPRESSED. FOR PROGRESSION FREE SURVIVAL, WHAT IS A LITTLE BIT CONFLICTING AND DIFFICULT TO INTERPRET IS OVERALL SURVIVAL WHERE WE, YES, DID SEE THAT PATIENTS WITH TSH HAD SHORTER OVERALL SURVIVAL. HOW TO INTERPRET THAT? WE DON'T HAVE DATA ON OTHER MORBIDITIES. THIS IS OVERALL SURVIVAL NOT DISEASE-SPECIFIC SURVIVAL UNFORTUNATELY, WE DO NOT HAVE PATHOLOGY -- DEATH REPORTS TO HAVE DIRECT CAUSE OF DEATH. IT WOULD BE DIFFICULT TO ASSESSMENT WE CAN ONLY SAY ABOUT OVERALL SURVIVAL. I THINK FOR OVERALL SURVIVAL WE HAD 33 DEATHS IN OUR COHORT, SO, YES, THIS QUESTION REMAINS AND I THINK THIS IS A RETROSPECTIVE STUDY ASSOCIATED, AND WHAT MAY ANSWER THE QUESTION IS A NICE LARGE PRODUCTIVE COHORT STUDY. >> TWO QUICK POINTS. FIRST, BEAUTIFUL TALK FROM BOTH OF YOU. FIRST, IS IT -- I GOT THE COMPRESSION FROM THE FIRST QUESTION THAT THERE WAS A CONCERN ABOUT FINE NEEDLE ASPIRATION. FROM MY PERSPECTIVE IT'S BEEN ONE OF THE MAJOR ADVANCES IN MEDICINE. I'D LIKE FOR DR. SKRULIS TO COMMENT ON FINE NEEDLE ASPIRATION TO THEY FIELD. >> CERTAINLY. I THINK DR. GESSENGORN IS ONE OF THE FIRST THAT PERFORMED THESE TYPE OF STUDIES. IT HAS CHANGED, REVOLUTIONIZED THE WAY WE APPROACH CANCERS OR TUMORS OF THE THYROID. PREVIOUSLY ALL TUMORS WENT TO THE OPERATING ROOM BALLS OF THE FEAR THERE MIGHT BE MALIGNANCY. THAT HAS CERTAINLY CHANGED TREMENDOUSLY THE NUMBER OF UNNECESSARY SURGERIES. THE NEXT PROBLEM OF COURSE IS TRYING TO DETERMINE NOW WHO TO ACTUALLY ASPIRATE BECAUSE OUR PROBLEM THAT EXISTS AT THIS TIME IS THAT NOW THAT WE'RE DETECTING SO MANY THYROID PATHOLOGIES, WHAT ARE THE TUMORS THAT ACTUALLY REALLY SHOULD BE ASPIRATED BEFORE WE START GETTING OURSELVES INTO A TAILSPIN OF DOING A LOT OF OPERATIONS ON WHAT IS ESSENTIALLY INNOCUOUS POTENTIALLY NON-LIFE-THREATENING TUMORS OF THE THYROID. AND THE REASON FOR THIS, I MEAN, IF YOU LOOK AT AUTOPSY STUDIES, THERE WAS A VERY INTERESTING STUDY THAT CAME OUT OF FINLAND, A NUMBER OF YEARS AGO, WHERE THEY JUST LOOKED AT 100 CONSECUTIVE AUTOPSIES AND THEY LOOKED AT THE THYROID EXTREMELY CAREFULLY, MUCH MORE CAREFULLY THAN ANYBODY WOULD DO, 2 TO 3-MILLIMETER SLICES AND FOUND IN PATIENTS FROM AGE SEVERAL MONTHS TO 100 YEARS THAT 36% OF THESE PATIENTS HAD MICROPAPILLARY CANCERS. OKAY? THESE PATIENTS HAD DIED FOR DISEASES OTHER THAN THYROID CANCER. THESE WOULD NEVER HAVE COME TO CLINICAL DETECTION. SO OUR CHALLENGE RIGHT NOW IS WHEN TO ACTUALLY DO THE ASPIRATION, AND WE'RE TRYING TO LEARN THAT TOGETHER. WE'VE GOT TO USE OTHER CHARACTERISTICS LIKE ULTRASOUND CHARACTERISTICS BEFORE WE START ENTERING INTO THE INVASIVE PROCEEDER, IT WILL BE THE SECOND GAME CHANGER IN THE COURSE OF THYROID PATHOLOGY AND DIAGNOSIS AND TREATMENT. >> ONE OTHER QUICK QUESTION. IT'S MY UNDERSTANDING THAT THE TSH STORY IN GENERAL GREW OUT OF RODENT STUDIES AND THE TSH STIMULATES PERHAPS THYROID NODULARITY IN A RODENT AND SUPPRESSION, THE THYROID HORMONE SUPPRESSES THIS. SO MUCH OF THIS SORT OF WHAT YOU REFER TO AS MYTHOLOGY CLINICALLY HAS GROWN OUT OF RODENT STUDIES. IS A MOUSE DIFFERENT FROM A HUMAN WITH RESPECT TO TSH RESPONSE TO THE THYROID GLAND WITH RESPECT TO GROWTH OR SUPPRESSION OF GROWTH? >> SO, I'M NOT AWARE OF ANY STUDIES ON HUMANS TO COMPARE THE EFFECT OF TSH STIMULATION ON THE VOLUME OF THE REMAINING TISSUE. WHAT I DO SUSPECT IS MAYBE WITH TSH STIMULATION WE MAY EXPECT HYPERTROPHY AND SWELLING SURROUNDING THE TISSUE BECAUSE IN FACT I REMEMBER LIKE INCIDENTAL CASES WHERE UNDER TSH SUPPRESSION, THERE WAS SOME SWELLING OF THE NECK AND WE THOUGHT MAYBE WE STIMULATED THE GROWTH OF THE TUMOR. YOU KNOW, DATA FROM THE '70s WHERE THE TITLE TSH IS NOT PROLIFERATION STIMULUS IN HUMAN THYROID CANCER, THIS IS ALL BASED ON IN VITRO STUDIES, WITH A SIMILAR MODEL I PRESENTED WITH DR. GERSHON'S GROUP, DIRECTLY TRANSLATED TO HUMAN MODELS, YOU KNOW, THIS IS A GOOD QUESTION, EVEN MORE DIFFICULT TO ANSWER. >> YES? >> MAYBE I CAN ANSWER THE FIRST PART OF PHIL'S QUESTION. IS THERE A DIFFERENCE BETWEEN RODENTS AND HUMANS, AND I'LL GIVE YOU A VERY LONG ANSWER TO THAT. YES. [LAUGHTER] >> SO, LADIES, BOTH OF YOU, LOVELY TALKS. I HAVE A QUESTION RELATED TO THE PROGRESSION-FREE SURVIVAL WHEN YOU GIVE T 4 AND YOU'RE IMPROVING PROGRESSION-FREE SURVIVAL IF YOU'RE NOT HAVING A EXPRESSED TSH. WE TEND TO FOCUS ON TSH BUT I'M WONDERING IN THE GROUP THAT WAS GIVEN T 4 CHANGING THE RATIO OF AMOUNT OF T 4 AND RATIO TO T3, IS THERE AN EFFECT OF T 4 TO PROMOTE GROWTH? >> PRECISELY THE EVIDENCE AND PRECISELY TO (INDISCERNIBLE) SIGNALING, SO THIS IS OBSERVED IN DIFFERENT CANCER MODELS SUCH AS BREAST CANCER APPLICATION OF T3 NEEDS TO INCREASE PROLIFERATION OF CANCER CELLS. WE ARE PLANNING TO ANALYZE (INDISCERNIBLE) LEVELS IN OUR COHORT AND TO ASSOCIATE WITH THE OUTCOME BUT THIS BODY OF EVIDENCE DO EXIST THAT MORE T3 AND THAN T4. >> THANK YOU, AUDIENCE AND SPEAKERS. THEY WILL TAKE QUESTIONS UP FRONT IF YOU HAVE ANY. >> THANK YOU. [APPLAUSE]