Presentation and Outcome of Subsequent Thyroid Cancer Among Childhood Cancer Survivors Compared to Sporadic Thyroid Cancer: a Matched National Study

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S C Clement and others Subsequent vs sporadic thyroid 183:2 169–180 Clinical Study cancer

Presentation and outcome of subsequent thyroid cancer among childhood cancer survivors compared to sporadic thyroid cancer: a matched national study

Sarah C Clement1,2, Chantal A Lebbink 1,4, Mariëlle S Klein Hesselink3, Jop C Teepen4, Thera P Links3, Cecile M Ronckers4,5 and Hanneke M van Santen1,4 on behalf of the DCOG-LATER Study Group, The Netherlands and the Dutch (Pediatric) Thyroid Cancer Consortium

1Department of Pediatric Endocrinology, Wilhelmina Children’s Hospital/University Medical Center Utrecht, Utrecht, The Netherlands, 2Department of Pediatrics, Amsterdam University Medical Center location VU Medical Center, Amsterdam, The Netherlands, 3Department of Endocrinology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands, 4Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands, and Correspondence 5Medical University Brandenburg - Theodor Fontane, Institute of Biostatistics and Registry Research, should be addressed Neuruppin, Germany to H M van Santen Email *(S C Clement and C A Lebbink contributed equally to this work) h.m.vansanten@ umcutrecht.nl

Abstract

Objective: Childhood cancer survivors (CCS) are at increased risk to develop differentiated thyroid cancer predominantly after radiotherapy (subsequent DTC). It is insufficiently known whether subsequent DTC in CCS has a different presentation or outcome than sporadic DTC. Methods: Patients with subsequent DTC (n = 31) were matched to patients with sporadic DTC (n = 93) on gender, age and year of diagnosis to compare presentation and DTC outcomes. Clinical data were collected retrospectively.

European Journal of Endocrinology Results: Among the CCS with subsequent DTC, all but one had received chemotherapy for their childhood cancer, 19 (61.3%) had received radiotherapy including the thyroid region, 3 (9.7%) 131I-MIBG and 8 (25.8%) had received treatment with chemotherapy only. Subsequent DTC was detected by surveillance through neck palpation (46.2%), as a self-identified mass (34.6%), or by chance. Among sporadic DTC patients, self detection predominated (68.8%). CCS with subsequent DTC tended to have on average smaller tumors (1.9 vs 2.4 cm, respectively, (P = 0.051), and more often bilateral (5/25 (60.0%) vs 28/92 (30.4%), P = 0.024). There were no significant differences in the occurrence of surgical complications, recurrence rate or disease-related death. Conclusion: When compared to patients with sporadic DTC, CCS with subsequent DTC seem to present with smaller tumors and more frequent bilateral tumors. Treatment outcome seems to be similar. The finding that one-third of subsequent DTC cases had been treated with chemotherapy only needs further investigation. These results are important for the development of surveillance programs for CCS at risk for DTC and for treatment guidelines of subsequent DTC. European Journal of Endocrinology (2020) 183, 169–180

Introduction

Treatment of pediatric malignancies has improved cancer survivors (CCS) (1). CCS are at a risk to develop substantially over the past several decades, resulting in subsequent malignancies, of which approximately 10% a rapidly growing population of long-term childhood involve the thyroid gland (2, 3, 4, 5).

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-20-0153 European Journal of Endocrinology https://eje.bioscientifica.com found, itcouldbeusedto inform currentcarepractices patients withsporadicDTC. Ifsuchdifferencesweretobe Netherlands incomparison withamatchedsampleof and outcomeofsubsequent DTCamongCCSinThe evaluate the modeofdetection,presentation, treatment presentation ofdiseaseaswelltheoutcome. matched cohortstocomparethemodeofdetectionand for these individuals, more information is needed in andtreatment strategies of appropriatesurveillance reactors. To strengthentheevidence for development exposed toradioiodineisotopesreleasedbynuclear radiotherapy forbenignlesionsorpatientswhowere unmatched studiesfocusingonpatientswhoreceived 24 with sporadic DTC ( radiation-exposed patients in comparison to individuals clinical presentationandoutcomeofDTCamongionizing cancer ( established treatmentalgorithmsforsporadicthyroid for DTCiscurrentlyperformedinaccordancewith foreachspecificindividual( surveillance shared-decision-making, determinetheoptimalmodeof and,using it wasrecommendedtocounselthesurvivor strategiesweresummarized,and cons ofbothsurveillance Guideline Harmanization Group (IGHG) the prosand thyroid ultrasound.InarecentreportoftheInternational ( risk forDTCbasedonpreviouslygiventreatments (palpation) ofthethyroidglandforCCSatincreased LATER) recommendsyearlyphysicalexamination stage ( rates, evenifthediseasepresentsatamoreadvanced for othersubsequentmalignancies( the etiologyofDTCisemerging,consistentwithevidence recent years,apossibleroleofchemotherapeuticagentsin 131 of neuroblastoma treated with reported among survivors radiotherapy ( < ( a plateauaround10–30Gyanddeclineathigherdose with increasingestimateddosetothethyroidgland, gland ( therapy thatdirectlyorincidentallyinvolvesthethyroid (DTC) inCCSispredominantlyattributabletoradiation 10 2 5 years)confersanadditionalriskfactorforDTCafter , Clinical Study I-Metaiodobenzylguanidine (MIBG) ( ). Thesereports,however, concernedpredominantly ). ScreeningforDTCinCCScanalsobedoneusing 6 For thesereasons,theaimofpresentstudywasto There areseveralstudiesthatreportgenerallyasimilar Children with DTC generally have excellent survival The occurrenceofdifferentiatedthyroidcarcinoma ). Ionizingradiationexposureatayoungage(e.g. 9 6 ). TheDutchChildhoodOncologyGroup(DCOG- 12 ). TheriskforsubsequentDTCincreaseslinearly , 13 ). 6 ). TheoccurrenceofDTChasalsobeen 14 , 15 , 16 , 17 S CClementandothers , 18 5 , , 6 19 , 7 8 ). Moreover, in , ). 11 20 ). Treatment , 21 , 22 , 23 , cyto-pathology inTheNetherlands(PALGA) revealedtwo ofhisto-and with thenationwidenetworkandregistry patients (period2013–2015),additionalrecordlinkage DTC ( 1,2013,revealed28patientswithsubsequent January and pathologyregistries),withfollow-upcoverageuntil follow-up andrecordlinkagestudies(includingcancer between 1963and2001inTheNetherlands( tumor than 60005-yearCCSdiagnosedwithaprimary subsequent DTC:(1.)TheDCOG-LATER cohortofmore We included two source populations to identify CCS with Study populations Subjects andmethods studies basedonseveralnationwidepatientcohorts. objectives, weconductedretrospectivechartreview (screening andmanagement)inCCS.To addressour the UniversityMedicalCenter ofGroningen( subjects of the adult study cohort with sporadic DTC from DTC aftertheageof18( DTC study ( DTC wereidentifiedfromanongoingNationalPediatric years) ( diagnosed with subsequent DTC during childhood ( for non-thyroidneoplasiaorbenignlesions.ForCCS chemotherapy orhematopoieticstemcelltransplantation another malignancy;(3.)noexposuretoradiotherapy, ( thyroidcarcinoma, microcarcinomais, papillary papillary DTC,that inclusion criteria:(1.)diagnosedwithaprimary were sampled from two patient series using the following sporadic DTCpatient.Eligiblepatients patients were matched with the best possible matching were notabletomatchforgender. ThesesubsequentDTC possible tomatchforcalendaryears,andinthreecaseswe for 24/31subsequentDTCpatients.Infourcasesitwasnot of DTCdiagnosis( based on gender, age at DTC diagnosis ( sporadic DTCpatients(totalcomparisongroup histologically confirmed. The firstandsubsequentmalignanciesamongCCSwere DTC patients,onepatienthadasthirdmalignancy. and identifiedoneadditionaleligiblecase.Ofthese31 (IKNL) 2001, wequeriedTheNetherlandsCancerRegistry subsequent DTCcasesamongCCSinitiallydiagnosedafter additional caseswithsubsequentDTC( cancer Subsequent vssporadicthyroid < 1 cm),orfollicularcarcinoma; of (2.)nohistory Every subsequentDTCpatientwasmatchedtothree Every 5 ). To completetheinclusionofsubsequentDTC n

= 9), matchingsubjects( 26 ). For CCS who developed subsequent ± 5years).Thesestrictcriteriaweremet Downloaded fromBioscientifica.com at09/30/202103:25:13PM n

= 22), matchingwasdonewith n 7 wt sporadic with =27) 183 ± 25 2 years), and year :2 ); (2.)To obtain n 5 6 ( =66) ). Clinical n =93), 170 ≤ 27 18 via freeaccess ). European Journal of Endocrinology injury after surgery weredefined,respectively, aftersurgery injury asinjury (RLN) nerve documented permanentrecurrent laryngeal last moment of follow-up. Documented transient and of medication (Calcitriol, Alfacalcidol, or calcium) at the was definedaspostoperative hypocalcaemiawiththeuse after surgery. Documentedpermanent hypoparathyroidism medication (Calcitriol,Alfacalcidolorcalcium)at6months andnouseof value belowthereferencerange)withrecovery defined aspostoperativehypocalcaemia(serumcalcium taken intoaccount. only ablativeandtherapeuticI-131administrationswere To calculatethecumulativeadministered I-131activity, those performedatmost1yearafterinitialthyroidsurgery. with localprotocols.Initialneckdissectionwasdefined as edition ( of diagnosis,tumorstagewasreclassifiedintothe7th I-131 treatment. If previous editions were used at time Control (UICC).TNMstagewasclassifiedafterthefirst system forDTCoftheUnionInternationalCancer edition TNM(Tumor, Node,Metastasis) classification and reviewedbytworeviewers(CL/HvS). data wereobtainedfromtheoriginalpathologyreports findings, andbenignfindings.HistopathologicalDTC subdivided into:malignantfindings,indeterminate little cellstoallowadiagnosis.Diagnosticfindingswere were, ingeneral,cytologicalsmearsampleswithtoo used todefineaconfirmedDTC.Non-diagnosticfindings within 6monthsofahistologicalDTCdiagnosiswere Fine needleaspiration cytology (FNAC) results recorded were scored to determine the characteristics of DTC. were summed. the smallestfieldofneck;full-fieldandboostdose dose wasbasedontheprescribedradiotherapyto body irradiation(TBI).Cumulativethyroid-directed (cervical the thyroidglandincludedfollowingfields:neck the DCOG-LATER registry. Radiotherapyexposing histories forsubsequentDTCpatientsweretakenfrom patients’ medicalrecords.Pediatriccancertreatment existing databases( Data werecollected retrospectively and extractedfrom Data collectionandstudydefinitions analysis wasneeded,inaccordancewithDutchlaw. No furtherapprovalforretrospectivedatacollectionand Clinical Study Documented transient hypoparathyroidism was Documented transienthypoparathyroidismwas All patientshadbeentreatedforDTCinaccordance Tumor stagingwasrecordedaccordingtothe7th For allpatients,cytologyandhistopathologyfindings 28 + mantle), head/brain,mediastinum,ortotal ). 5 , 26 , 27 ) orcollected from individual S CClementandothers

Baseline factors, cancer-related characteristics, treatment Statistical analysis > assessed ifthelasttreatmentforDTChadbeengiven follow-up wasnotedasunknown.Outcomeonly data wereknown,thediseasestatusatlastmomentof recurrence atlastmomentoffollow-up.Ifnofollow-up Persistent diseasewasdefinedaspersistentor ( undetectable serumthyroglobulin(Tg)concentration and scintigraphic absence of disease activity with an Remission ofDTCwasdefinedasclinical, radiological radiological evidenceofdiseaseactivityafterremission. within6monthsaftersurgery.recovery was available,inothermedicalrecords,withorwithout mentioned in ear, noseandthroatreport,or if no report GBq for neuroblastoma, including thyroid prophylaxis 131 (range 7.0–55.8)Gy. Threepatients(9.7%)hadreceived patients (58.1%), with a mean cumulative dose of 32.0 to afieldlincludingthethyroid glandwasgivento18 of theCCSandanthracyclinesin55.2%.Radiotherapy and alkylating agents had been administered in 75.9% Almost all patients (93.5%) had received chemotherapy, (35.5%) andlymphomas(19.4%)weremostfrequent. cancer was6.1(range:0.3–16.4)years,ofwhichleukemias childhood included. Medianageatdiagnosisoftheprimary Thirty-one eligibleCCSwithsubsequentDTCwere CCS withsubsequentDTC Patient characteristics Results (25.0) statisticalpackagewasusedforanalysis. < P interest wasobtained,definedas complete information on theclinical characteristics of were used.Tests wereonlyperformedifreasonably exact tests(iftheassumptionsforchi-squarewereviolated) distributed. Forcategoricaldatachi-squaretestsorFisher’s were performedifthecontinuousdatanon-normally for continuousmeasurements.Mann–Whitney and sporadicDTCwerecomparedusingStudent’s modalities andoutcomeinpatientswithsubsequentDTC cancer Subsequent vssporadicthyroid < -values werebasedontwo-sidedtestingand 1 yearago. 0.05 were considered as statistically significant. The SPSS 1.0 ng/mL)atleast1yearafterthelastI-131therapy. I-MIBG treatment,withamean totalactivityof12.93 Recurrence of DTC was defined as laboratory or Recurrence ofDTCwasdefinedaslaboratory Downloaded fromBioscientifica.com at09/30/202103:25:13PM https://eje.bioscientifica.com > 50% ofeachgroup.All 183 :2 P -values of U 171 -tests t -test via freeaccess

European Journal of Endocrinology https://eje.bioscientifica.com in tumorsize(median1.25 cmvs2.40cm,respectively treatment ( ofneckradiation,TBIorMIBG the CCSwithahistory presentation ofDTC,asubgroup analysiswasdonefor carcinomas, inbothgroups. ( 21.1% (15/71)ofthesporadicDTCpatients( subsequent DTCpatientsthetumorsizewas 7%) ( (6/23, 26%)comparedtosporadicDTCpatients(5/71, < 2.40 (0.60–6.50) cm ( DTC patients(sizeatdiagnosis1.90(0.10–5.00)cm vs tumors tendedtobemoreoftensmallerinsubsequent 60%) thansporadicDTCs(28/92,30%)( two timesmorelikelytobebilateralatdiagnosis(15/25, showed aPTC( features; however, afterhemithyroidectomy, histology ( months ofahistologicalDTCdiagnosis)werecomparable 2.3 ( fer betweensubsequentandsporadicDTCpatients(mean patients. Maximum nodule size on ultrasound did not dif retrieved in58.1%ofCCSand15.1%thematched ative ultrasoundreportswerecollectedandcouldbe Ultrasound, cytology and histology findings between subsequentandsporadicDTC( lymphnodes were allcomparable pathological cervical examination, median tumor size and presence of palpable themselves whichwassignificantlydifferent. to sporadicDTCpatients,33/48detectedathyroidmass for non-Hodgkinlymphomafollow-up.Whencompared hypothyroidism, hyperparathyroidismorPETscanning found aschancefindingduringdiagnosticwork-upfor neck themselves.Fiveoutof26subsequentDTCwere LATER outpatientclinicand9/26detectedamassinthe (12/26) weredetectedbyneckpalpationattheDCOG- of DTC Diagnosis Comparison withsporadicDTCpatients 5.7–33.8) years. cancer andsubsequentDTCwas17.2years(range ( 8 Table 2 Table 2 1 cmweremoreoftenseeninsubsequentDTCpatients , Clinical Study 29 For evaluation of radiation effects specifically on the Based onhistologicresults,subsequentDTCswere Overall distribution of FNAC results (within 6 At DTCdiagnosis,palpabilityofthenodule at physical ± P ) Median latency time between primary childhood ) Medianlatencytimebetweenprimary s .

= d ). FNACresultsoffourpatientsshowedbenign ). Approximately15%ofDTCswerefollicular . 0.023). Conversely, inonly8.6%(2/23)of the 1.2)and2.6( n

= 22). Asignificantdifference wasfound n

3) andFTC( Nearly halfofthesubsequentDTCs P

= ± 0.051)). Of all, DTC tumorssized s . d . 0.9)cm,respectively). n ) ( =1) S CClementandothers 30 ). Table 1 P .2) and =0.024) ≥ Pre-oper ). 4.0 cmvs P =0.226) - -

the sporadicpatients.OfsixsubsequentDTCpatients patients hadlymph-nodemetastasisvs41/77(53.2%)in DTC patients( not differ between subsequent DTC patients and sporadic sporadic DTCpatients( patients showedmorefrequentT1astagingcomparedto or lymph-nodemetastases( thyroid extension ( invasion ( encapsulation ofthetumor( differences were found in spread of DTC with regards to had amultifocalcharacter( and sporadicDTCpatients,respectively, thetumor respectively, matched controls(mediantumorsize2.80cmvs2.40 between CCSwithoutradiationexposureandtheir ( may havebeengivenRAIat later timeduringfollow-up. gone totalthyroidectomyat timeofdatacollectionand with nolymphnodemetastases, onepatienthadunder microcarcinoma ment hadbeendiagnosedwith apapillary subsequent DTCpatientswho didnotreceiveI-131treat (23/27, 85.2%vs92/93,98.9%, the numberofDTCpatientsthatweretreatedwithI-131 DTC patients.Asignificantdifferencewasfoundbetween and 98.9%of,respectively, subsequent DTCvssporadic eral levels,andI-131treatmentwasadministeredin85.2% lymph-nodedissection(s)of central and/orlat underwent of thesubsequentandsporadicDTCpatients,respectively, patients ( and in55.9%,1.1%43.0%ofthesporadicDTC 66.7%, 7.4%,and25.9%ofthesubsequentDTCpatients hemithyroidectomy wereperformedin,respectively, tomy, unilateralhemithyroidectomy, andbilateral cedures aspartoftheirDTCtreatment.Total thyroidec All patients ( teristics differedbetweensubsequentvssporadicpatients. DTC treatment 7.7% vs7.1%insubsequentsporadicDTCpatients. groups, theprevalenceoflungmetastasesweresimilar, these patientsrangedbetween1.0and6.2cm.Inboth which sixwere In total,sevenpatientshaddistant(lung)metastases,of tumor sizeandoccurrenceoflymph-nodemetastases. node metastases.Noassociationwasfoundbetween microcarcinomawith papillary ( cancer Subsequent vssporadicthyroid P

= 0.010)). Nodifferencewasfoundintumorsize Thirteen outof21(61.9%)thesubsequentDTC In 15/23(65.2%)and37/80(46.3%)ofsubsequent P P .6) ( =0.060)

= n 0.186), extracapsulargrowth( P

=0.847). = P 124) underwent oneor more surgicalpro 124) underwent =0.701). ≤

18 yearsatdiagnosis.Thetumorsizeof None ofthesurgicaltreatmentcharac Table 3 P

= 0.386), vessel invasion ( P Downloaded fromBioscientifica.com at09/30/202103:25:13PM

= 0.046). Overall,TNMstagedid ). Fifty-twopercent and52.7% P .7) Sbeun DTC Subsequent =0.277). P P P

.7) tmr capsular tumor =0.177), = .0) N significant No =0.109). < 0.009). Three out of four 0.009). Threeoutoffour 1 cm),twohadlymph- 183 :2 P 0.743), extra =0.743), P =0.467) 172 via freeaccess ------European Journal of Endocrinology radic DTCpatients( of thesubsequentDTCand in10/88(11.4%)ofthespo rate between the two groups was comparable;4/20 (20.0%) (0.7–41.5) forsporadicDTC patients ( was 5.2years(0.1–22.5)forsubsequentDTCvs7.5 of follow-up Disease recurrence and disease status at last moment DTC, differentiatedthyroidcarcinoma. calculated (denotedasNA,NotApplicable); of diagnosis; Percentages ofknownvariablesareshown, Unknown Central hypothyroidism Subclinical hypothyroidism Hypothyroidism No Thyroid dysfunctionattimeofdiagnosisDTC Unknown No Yes Lymphadenopathy Maximum size(cm)nodule,mean( Ultrasound findingatdiagnosis Unknown No Yes Palpable cervicallymph-nodes Size (cm)ofthenodule,median(range) Unknown No Yes Palpable nodule Unknown Other Thyroid nodulefoundonultrasound Symptoms/signs duetothyroidnodules Symptoms/signs ofthyroiddysfunction Palpable massdetectedbypatient Palpable massfoundbyscreening(neck Reason forevaluation Deceased atendoffollow-up 2010–2015 2000–2009 1990–1999 1970–1989 Calendar yearofdiagnosis(range) Gender: numberoffemales(%) % DTCchild( Adults ( Children ( All patients Age atdiagnosisDTC,median(range),years Characteristics Table 1 Clinical Study n n palpation) availabledata availabledata ≥ Comparison ofpresentationbetweensubsequentDTCpatientsandsporadicinTheNetherlands(1968–2015). 18 years) b < Missing orunknownvaluesareexcludedfromstatisticaltesting.Forcharacteristics with < 18 years)

18 years) Median follow-up time after DTC diagnosis Median follow-up timeafterDTC diagnosis P

= 0.288) (have)hadrecurrentdisease. c S CClementandothers c ± P Causes ofdeath:duetoothermalignancies( -value* significant s . d . Table 3 ) ). Recurrence ). Recurrence < Subsequent DTC 0.05; 29.8 (18.03–38.0) 13.3 (6.1–17.7) 25.6 (6.1–38.0) 2.3 (1.2) 3.5 (0.5–5.0) 12 (46.2%) 14 (45.2%) 11 (35.5%) 21 (67.7%) 12 (70.6%) 12 (66.7%) 21 (87.5%) 1986–2015 a 3 (11.5%) 0 (0%) 0 (0%) 2 (7.7%) 9 (34.6%) 4 (13%) 5 (16.1%) 1 (3.2%) 7 (23%) 1 (5.9%) 3 (17.6%) 1 (5.9%) 8 (61.5%) 5 (38.5%) 6 (33.3%) 3 (12.5%) All controlpatientswerematchedbyageatdiagnosis,gender,andcalendar year - 18/31 12/31 14 18 13 5 7 recurrence of disease at last moment of follow-up. Outcome recurrence ofdiseaseatlastmoment offollow-up.Outcome respectively). Inbothgroups, twopatientsexperienced respectively. Persistent disease was similar (4.3% and 4.8%, (92.9%) ofsubsequentand sporadicDTCpatients, with remissionofdiseasein18/23(78.3%)and78/84 found tobedifferent( cancer Subsequent vssporadicthyroid ( n = 31) At last moment of follow-up, the disease status was At lastmomentoffollow-up,thediseasestatuswas n = 3) ornon-cancerrelateddeath( > Sporadic DTC 50% missingvaluespergroup, 13.5 (5.8–17.7) 26.3 (5.8–38.7) 29.3(18.2–38.7) 1973–2015 2.6 (0.9) 3.0 (1.0–6.0) 33 (68.8%) 23 (24.7%) 44 (47.3%) 14 (15.1%) 12 (13.0%) 67 (72.0%) 20 (22%) 15 (88.2%) 20 (62.5%) 12 (37.5%) 38 (92.7%) P 4 (8.3%) 1 (2.1%) 4 (8.3%) 2 (4.2%) 4 (8.3%) 0 (0%) 0 (0%) 0 (0%) 2 (11.8%) 5 (50.0%) 5 (50.0%) 3 (7.3%) Downloaded fromBioscientifica.com at09/30/202103:25:13PM 14/93 24/93

= 45 76 83 61 52 0.024) in the four categories, 0.024) inthefourcategories, a

( n https://eje.bioscientifica.com = 93) n = 1). 183 :2 P -values werenot P 0.001* 0.003* 0.236 0.982 0.797 0.875 -value NA NA NA NA NA NA 173 b via freeaccess European Journal of Endocrinology Unknown No Yes Extracapsular growth Unknown No Yes Tumor capsularinvasion Unknown No Yes Encapsulated Histology –SpreadofDTC 4.0–4.9 cm 3.0–3.9 cm 2.0–2.9 cm 1.0–1.9 cm 0.1–0.9 cm Tumor sizecategories Tumor size(cm;largesttumornodule)median Unknown No Yes Multifocality Unknown Isthmus Bilateral Unilateral DTC Laterality Unknown Widely invasive Minimal invasive https://eje.bioscientifica.com Follicular carcinoma Unknown Other Diffuse sclerosing Follicular Classic variant Papillary (micro)carcinoma Unknown Follicular thyroidcarcinoma Papillary microcarcinoma( Papillary thyroidcarcinoma Histology DTC Unknown Benign Indeterminate Malignant Non diagnostic FNAC findings n Mean numberofFNACs Cytology (1968–2015). Table 2 availabledata > n Clinical Study (range) availabledata 5.0 cm Comparison ofcytologyandhistologybetweensubsequentDTCpatientssporadicinTheNetherlands c d b < 1 cm) S CClementandothers Subsequent 1.90 (0.10–5.00) 10 (71.4%) 14 (73.7%) 15 (65.2%) 15 (60.0%) 10 (40.0%) 10 (45.5%) 10 (45.5%) 16 (61.5%) 5 (41.7%) 7 (58.3%) 4 (28.6%) 5 (26.3%) 1 (4.3%) 1 (4.3%) 4 (17.4%) 5 (21.7%) 6 (26.1%) 6 (26.1%) 8 (34.8%) 0 (0%) 0 (0%) 3 (100%) 1 (4.5%) 1 (4.5%) 4 (15.4%) 6 (23.1%) 2 (13.3%) 5 (33.3%) 6 (40.0%) 2 (13.3%) 23/31 22/31 1.55 cancer Subsequent vssporadicthyroid 12 16 2 0 8 6 1 0 5 ( n = 31) Sporadic 2.40 (0.60–6.50) Downloaded fromBioscientifica.com at09/30/202103:25:13PM 36 (65.5%) 19 (34.5%) 27 (48.2%) 29 (51.8%) 59 (86.8%) 11 (15.5%) 23 (32.4%) 17 (23.9%) 43 (53.8%) 37 (46.3%) 28 (30.4%) 60 (65.2%) 20 (35.7%) 28 (50.0%) 14 (15.4%) 72 (79.1%) 15 (51.7%) 9 (13.2%) 7 (9.9%) 8 (11.3%) 5 (7.0) 4 (4.3%) 1 (12.5%) 7 (87.5%) 6 (10.7%) 2 (3.6%) 7 (7.5%) 2 (6.9%) 8 (27.6%) 4 (13.8%) 71/93 39/93 1.44 25 13 23 64 4 3 1 6 0 ( n = 93) 183 :2 (Continued) P 0.024* 0.743 0.186 0.177 0.239 0.051 0.109 1.000 0.233 0.095 0.585 -value NA 174 a via freeaccess European Journal of Endocrinology FNAC, fineneedleaspirationcytology. f classification wasusedforallpatients,ifpreviouseditionswereinthepatientrecord,recodedinto7 two sporadicDTCpatients,thepathologyreportshowedmicrocarcinoma;however,noexacttumorsizewasmentioned; of allperformedFNACsbeforediagnosisDTC; Percentages ofknownvariablesareshown, Mx M1 M0 M Nx N1a-N1 N0 N Tx T4 T3 T2 T1 T TNM classification7thedition Unknown No Yes Lymph-node metastases Unknown No Yes Vessel invasion Unknown No Yes Extrathyroid extension(tissueinvasion) Cytology parathyroidism anddocumented permanenthypopara Surgical complications as expectedfromtheper-protocol matching. age, gender, anddiagnosisperiodwerefairlycomparable all aliveatlastmomentoffollow-up.Thedistributions of related death( follow-up due toother malignancies ( four subsequentDTCpatientsweredeceasedatend of status atendoffollow-updifferedbetweenthegroups: ofpositiveserumTgantibodies( a history subsequent andsporadicDTCpatients,respectively, had materials supplementary Tableof follow-up(Supplementary A,seesectionon microcarcinomas, except fordiseasestatusatlastmoment not changewhenexcludingpediatricDTCpatientsand because diagnosisofDTCwas could notbeassessedfortwosubsequentDTCpatients, Table 2 M1 Clinical Study = Three outof14(21.4%)and10/88(11.4%) only lungmetastaseswerefound. f Continued. n

= 1), whereassporadicDTCpatientswere givenattheendofthisarticle).

Documented transienthypo e < S CClementandothers 1 year ago. Results did 1 yearago.Resultsdid P -value* significant c Last FNACbeforehistologicaldiagnosis n

= 3) or non cancer P .8) Vital =0.381). < 13 0.05; a Subsequent Missing orunknownvalueswereexcludedfromstatisticaltesting; - - 24 (92.3%) 13 (61.9%) 10 (40.0%) 13 (68.4%) 14 (73.7%) 12 (66.7%) 26 (33.3%) 8 (38.1%) 6 (24.0%) 8 (32.0%) 6 (31.6%) 5 (26.3%) 2 (7.7%) 1 (4.0%) is knowntobeexcellent, even whenfoundinadvanced thyroid cancer. Theprognosis ofsporadicthyroidcancer is requireduponitsbehavior incomparisontosporadic most appropriatewaytoscreen forDTC,moreknowledge chemotherapy ( that subsequentDTCinCCSmayalsoberelated to childhood cancermayresultinDTC.Ithasbeensuggested Radiation therapyincludingtheneckregionfor Discussion radic DTCpatientens( patients andin7/93(7.5%)17/93(18.3%)ofthespo 1/31 (3.2%)and3/31(9.7%)ofthesubsequentDTC wasfoundin,respectively,and permanentRLNinjury patients ( 21/93 (22.6%)and33/93(35.5%)ofthesporadicDTC and 11/31(35.5%)ofthesubsequentDTCpatientsin in,respectively,thyroidism wereobserved 4/31(12.9%) cancer Subsequent vssporadicthyroid 10 12 12 5 6 ( n < = 31) 6 months; P

= 0.456). Documentedpostoperativetransient d Tumor categoriesarebasedoncontinuousdata.In 2 17 , 3 , 4 , Sporadic P 6 =0.327). 78 (94.9%) 36 (46.8%) 41 (53.2%) 22 (25.9%) 33 (38.8%) 24 (28.2%) 38 (45.2%) 46 (54.8%) 48 (64.9%) 26 (35.1%) 58 (76.3%) 18 (23.7%) Downloaded fromBioscientifica.com at09/30/202103:25:13PM ). Inordertocounsel CCS onthe 6 (7.1%) 6 (7.1%) 16 19 9 8 9 th ( n editionofTNMclassification; = 93) https://eje.bioscientifica.com e The 7 183 th editionofTNM :2 b Mean number P 1.000 0.480 0.701 0.277 0.467 0.386 -value 175 a via freeaccess - European Journal of Endocrinology https://eje.bioscientifica.com Permanent RLNinjury Transient RLNinjury Documented recurrentlaryngealnerve(RLN)injury Permanent hypoparathyroidism Transient hypoparathyroidism Documented hypoparathyroidism Surgical Complications Unknown No Yes Serum Tgantibodies Unknown No Yes T4 supplementation Unknown Last treatment Active disease:recurrence Active disease:persistentdisease Remission Disease statusatlastmomentoffollow-up Time (years)betweenDxandlastmomentof Disease statusatlastmomentoffollow-up Unknown No Yes Most recentTgdeterminationelevated Cumulative administereddoseofI-131 I-131 treatments Lymph-node dissection Treatment recurrence Unknown No Yes Recurrence Recurrence Cumulative administereddoseofI-131 Number ofI-131treatments,median(range) Number ofpatientstreatedwithI-131treatment I-131 treatment Unknown LND, locationunknown LND incl.laterallevels Central LND None Lymph-node dissection(LND) Unknown Bilateral hemithyroidectomy Unilateral hemithyroidectomy Total thyroidectomy Surgical treatment Initial treatmentofthyroidcancer patients inTheNetherlands(1968–2015). Table 3 follow-up unknownin17patients total(subsequent hemithyroidectomy; Percentages ofknownvariablesare shown, Clinical Study follow-up, median(range) n treatment, median(range)GBq treatment, median(range)GBq availabledata Comparison oftreatment,outcome,andcomplicationratesbetweensubsequentDTCpatientssporadic c c Five patientsdidnotreceiveI-131treatment (subsequent:

< 1 yearago b S CClementandothers P -value* significant d n = 8, sporadic < 0.05; n a = 9). 23/27 (85.2%) Missing orunknownvaluesexcluded fromstatisticaltesting; Subsequent 5.399 (1.850–17.910) 5.550 (5.550–6.008) 5.2 (0.1–22.5) 12 (48.0%) 18 (66.7%) 11 (35.5%) 11 (78.6%) 24 (96.0%) 18 (78.3%) 18 (85.7%) 16 (80.0%) 4 (20.0%) 1 (1–3) 2 (8.0%) 9 (36.0%) 2 (8.0%) 7 (25.9%) 2 (7.4%) 3 (9.7%) 1 (3.2%) 4 (12.9%) 3 (21.4%) 1 (4.0%) 2 (8.7%) 2 (8.7%) 1 (4.3%) 3 (14.3%) 3 (60.0%) 2 (40.0%) 23/31 cancer Subsequent vssporadicthyroid n 17 10 11 6 4 6 8 = 4, sporadic: ( n = 31) n = 1); d Loss offollow-up,diseasestatusatlast momentof 92/93 (98.9%) 7.400 (1.480–35.150) 5.550 (5.550–5.550) 7.5 (0.7–41.5) Sporadic 10 (11.4%) 34 (37.4%) 11 (12.1%) 43 (47.3%) 40 (43.0%) 52 (55.9%) 17 (18.3%) 33 (35.5%) 21 (22.6%) 78 (88.6%) 10 (11.4%) 91 (100%) 78 (92.9%) 87 (94.6%) 78 (88.6%) 2 (1–6) 3 (3.3%) 1 (1.1%) 7 (7.5%) 0 (0%) 0 (0%) 2 (2.4%) 4 (4.8%) 5 (5.4%) 6 (66.7%) 3 (33.3%) Downloaded fromBioscientifica.com at09/30/202103:25:13PM 92/93 2 0 5 2 9 1 5 ( n = 93) 183 :2 b Consecutive P 0.327 0.456 0.381 0.216 0.024* 0.240 0.166 0.288 0.242 0.268 0.009 0.732 0.060 -value 176 a via freeaccess European Journal of Endocrinology 1% ofpatientswithsubsequent DTCweretreated that,inthiscohort,indeedonly it wasobserved radiation exposure( suggesting thatmultifocality isadirectconsequenceof those whoreceivedhigherradiationdoseatyoungerage by Rubino compared tosporadicDTCpatients( tumors aremorefrequentinsubsequentDTCpatients DTC etiology. diffuse toxicity and is the major contributing factor in with thehypothesisthatradiationexposureresults in diagnosed insubsequentDTCpatients.Thisisconsistent toI-131. cancer survivors may reflectmorehesitanceinproviderstofurtherexpose micorcarcinoma ( with I-131,whileallpatientssporadicand patients with microcarcinoma had notbeentreated However, itwasremarkablethatthreesubsequentDTC surgical complications when compared to sporadicDTC. outcome results,suchasdecreasedrecurrenceratesor subsequent DTCpatientsdidnotresultinimproved the occurrenceoflymph-nodemetastases( previous findingsthattumorsizeisnotassociatedwith factor influencingDTCprognosisandweconfirmedfrom earlier T stage. Tumor size has shown to be animportant follow-up clinics,leadingtothedetectionofDTCinan explained bythefactthatCCSarecarefullyfollowedat several previous studies ( sporadic patients.Theseresultsareinagreementwith ofneckradiation,TBIorMIBG,comparedto history the subsequent DTC group, especially in CCS witha number ofsmalltumorswassignificantlyincreasedin head/neck/upper chest. ofradiotherapydirectedtothe DTC didnothaveahistory similar. Ofnote,one-thirdofthepatientswithsubsequent with sporadic DTC. Other characteristics were statistically with smallertumorsandbilateraldiseasethanpatients that CCS with subsequent DTC more likely tend to present presentation ofsubsequentDTC.Ourresultsdemonstrate enabled ustoaddressthemodeofdetectionand national initiatives spanning four decades of inclusion, cohort analysiswasperformed. has beenstudiedinsufficiently, forwhichthismatched stage. However, thebehaviorofradiation-inducedDTC Clinical Study Our dataconfirmspreviousthatmultifocal Bilateral tumorsweresignificantlymoreoften The highprevalenceofmicrocarcinoma among A noteworthy finding of this study is that the The uniquedatainthisstudy, integratedfromthree Bilaterality requirestotal thyroidectomy, and t al. et n , multifocality was more frequent in

= 19 7) hadbeentreatedwithI-131.This ). 14 , 15 , 18 S CClementandothers , 20 19 , , 31 23 ) and might be 32 ). Inthestudy , 33 ). groups ( were found,norwastheremortalityduetoDTCinboth and neitherdifferencesinrecurrenceratesbetweengroups and onlybedoneinanexperiencedDTCcenter. rareness ofthedisease,careforDTCshouldbecentralized To reduce complications of treatment and considering the strict definitionofhypoparathyroidismusedinourstudy. be furtherexploredandmaypossiblyexplainedbythe and adults( patients, whencomparedtopreviousstudiesinchildren documented permanenthypoparathyroidisminallDTC histological findings. between subsequentandsporadicDTCpatientsregarding no othersignificantdifferenceswerefoundinthisstudy sporadic DTC. with hemithyroidecomy, incomparison to 7%of values owingtothecharacter oftheretrospectivechart comparisons possible. the DTCcases,in-depthdata wereavailable,makingthese outcome characteristics.Lastly, forafairproportionof could be made unbiased by factors affecting tumor and the CCStopatientswithsporadicDTC,comparisons in TheNetherlandsthestudyperiod.Bymatching study captures prospective case-findingforDTC. We estimate thatour including validmethodswithretrospectiveand retrieved fromwell-characterizedstudypopulations be exploredinsubsequentwork( for someindividuals)isnotanegligible factor andshould DTC amongCCS( 3 demonstrated inalargepoolingeffortbyVeiga agents andanthracyclinesonthethyroidglandwere been treatedwith chemotherapy. Effects of alkylating be consideredwhichjustifiesfutureresearch. Allhad that other causes for subsequent tumor formation must study hadnotbeenexposedtoradiotherapy. Thisimplies patients. Thismustbefurtherstudiedinfuturecohorts. patients ofwhomlasttreatmentwas ago intwopatients,comparisontothesporadicDTC subsequent DTCpatients,thelasttreatmentwas A possibleexplanationmaybethefactthat,in DTC hadsignificantlymorefrequentpersistentdisease. cancer Subsequent vssporadicthyroid ). Also,geneticpredisposingfactorsmayincreaseriskof A weaknessofthisstudyis thenumberofmissing The strengthofthisstudyisthefactthatdatawere One-third ofthesubsequentDTCpatientsinthis At lastmomentoffollow-up,patientswithsubsequent Recurrence rates were in line with previous literature, In thiscohort,wefoundastrikinghighincidenceof Next tobilaterality, multifocalityandtumorsize, 38 , 34 39 , ). > 35 90% ofallpatientswithsubsequentDTC , 40 36 ). ThelargenumberofCTscans( , 37 Downloaded fromBioscientifica.com at09/30/202103:25:13PM ). Thesehighpercentages should https://eje.bioscientifica.com 41 , 42 183 > ). :2 1 yearagoinall < et al 1 year 177 > .( 50 via freeaccess 2 ,

European Journal of Endocrinology https://eje.bioscientifica.com account whendecidingonthe surgicalprocedure. treatment forchildhood cancer mustbetakeninto be used. different ormoreaggressivetreatmentregimensshould of thisstudydonotprovideevidenceorargumentsthat seems to be similar to thatofsporadic DTC. The results In termsofmorbidityandmortality, subsequent DTC tumor localizationsthanpatientswithsporadicDTC. present withsmallertumorsandmorefrequentbilateral for adultsmaybeused. underway. Forpatients The NetherlandsandinlargerEuropeanconsortiaare for standardization of care for children with DTC in to allow for future evaluation of care ( should berecorded according tostandardized definitions on diagnostics, treatment, adverse effects and outcome expertise ( DTC are prospectively recorded and treated in centers of For the future, we recommend that all patients with strategies, suchasneckpalpationorthyroidultrasound. this studycannotbeused,however, toinformscreening ( be aconsequenceofsurveillance staging) insubsequentDTCpatientsThismaypossibly overall TNMstage,moretumors taken intoaccount.Althoughnodifferencewasfoundin conclusions. Thereareseveralaspectsthatshouldbe cohort isamodestsizesamplewhichprecludesstrong create largercohortsenablingmoresolidanalyses. future, internationalcollaborationshouldbeaimedto tumor characteristicsandtreatment methods. Inthe not possible.Outcomesarethereforecontrolledfor were quitelow, analysis makingmultivariateorsurvival subsequent DTCthiswasanationalcohort,thenumbers a limitation. dependent treatmentprotocols,mayalsobeconsidered in asystematicway, becauseofpluralisminhospital- had not been treated with the same treatment protocol denominator. Thefactthatsubjectsincludedinthisstudy based onthenumberofCCSswithavailabledatain insight inthemagnitudeofmissingdata,percentages are academic hospitalsandthereforedataaremissing.To give were onlyabletoretrievedatafrompatientchartsinthe hospitals andwerethenreferredtoacademichospitals.We by thefactthatthesepatientspresentedinnon-academic review. Themissingdatainmostcasescouldbeexplained Clinical Study In conclusion, patients withsubsequent DTC seem to Despite thefactthatwehadnationwidecoverage,our Also, despitethefactthatforpatientswith The multifocalityandbilaterality ofDTCafter 12 ). Inthemedicalfilesofthesepatients,data > 18 yearsofage,standardscare S CClementandothers < 1 cmwerefound(T1a 10 12 ). Theresultsof ). Development The authorshavenothingtodisclose. Declaration ofinterest EJE-20-0153 at paper the of version online the to linked is This Supplementary materials cancer.radiation treatmentfortheirprimary the potentialcauseofsubsequentDTCinpatientswithout with DTC( and treatmentguidelinesforCCSatriskorpresenting programs further developmentofexistingsurveillance not beexcluded. programcould without followinganactivesurveillance References Plukker, andAHBrouwers. Dam, van B Havekes, EPM Corssmit, RT Netea-Maier, RP EWCM Peeters, JWA Smit, JTM Burgerhof, JGM Bocca, G following: the includes Consortium Cancer Thyroid (Pediatric) Dutch The Maduro. J FE Janssens, G Leeuwen, Neggers, van S Bresters, D Pal, der van HJH Versluys, AB Heiden, der van M Heuvel-Eibrink, den van MM Tissing, WJE Broeder, Dulmen-den van E The DCOG LATER Study Group includes the following: LCM Kremer, J Loonen, Acknowledgements equally tothiswork. contributed Santen van M H and Ronckers M C Lebbink, A C Clement, C S Author contributionstatement be could that interest of conflict perceived asprejudicingtheimpartialityofthisstudy. no is there that declare authors The Funding cancer Subsequent vssporadicthyroid 4 3 2 1 Bhatti P, Veiga LHS, Ronckers CM,Sigurdson AJ,Stovall M,Smith SA, Veiga LHS, Bhatti P, Ronckers CM,Sigurdson AJ,Stovall M, Veiga LHS, Lubin JH,Anderson H, deVathaire F, Tucker M, Bhatti P, Mariotto AB, Rowland JH,Yabroff KR, Scoppa S, Hachey M,Ries L Weathers R, Leisenring W, Mertens AC,Hammond S 2012 study.cancer survivor Chemotherapy andthyroidcancerrisk: areportfromthechildhood Smith SA, Weathers R, Leisenring W, Mertens AC,Hammond S org/10.1667/rr2889.1) childhood cancer. analysis ofthyroidcancerincidencefollowingradiotherapyfor Schneider A, Johansson R,Inskip P, Kleinerman R 1033–1040. States. ofchildhoodcancersintheUnited & Feuer EJ.Long-termsurvivors These resultsareanimportantcornerstoneforthe Differences inoutcomeandprognosisofDTCCCS 21 Cancer Epidemiology, Biomarkers andPrevention . 92–101. 11 (https://doi.org/10.1158/1055-9965.EPI-08-0988) ). Follow-upstudiesareneededtoexplore (https://doi.org/10.1158/1055-9965.EPI-11-0576) Radiation Research Cancer Epidemiology, BiomarkersandPrevention Downloaded fromBioscientifica.com at09/30/202103:25:13PM 2012 178 183 https://doi.org/10.1530/ 365–376. :2 et al. 2009 et al. Apooled (https://doi. Riskof 18

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