European Journal of Endocrinology 10.1530/EJE-17-0707 optic nerves and carotid arteries) characterize them optic nerves neurovascular structures (e.g. hypothalamus, pituitary, locally aggressivebehaviour andproximitytocritical contain calcificationsand fluid-filledcysts.Their located inthe(supra)sellar areaoftheskullthatoften are benign epithelial tumours Craniopharyngiomas Introduction hydrocephalus andtumourrecurrenceareimportantrisk factors. and mortalityduetocirculatoryrespiratorydiseases. Femalesex,childhood-onsetcraniopharyngioma, Conclusions infarction andtotalmortality. craniopharyngioma, hydrocephalusandtumourrecurrencewereidentifiedasriskfactorsforexcessT2DM,cerebral (SMR: 2.3,95%CI:1.1–4.5)andrespiratory6.0,2.5–14.5)diseases.Femalesex,childhood-onset craniopharyngioma alsohadexcessivetotalmortality(SMR:2.7,95%CI:2.0–3.8),andduetocirculatory population. Risksformalignantneoplasms,myocardialinfarctionsandfractureswerenotincreased.Patientswith 4.4, 95%confidenceinterval(CI):2.8–6.8)andcerebralinfarction(SIR:4.9,CI:3.1–8.0)comparedtothegeneral Results and SMRs).RiskfactorswereevaluatedunivariablybycomparingSIRsSMRsbetweennon-overlappingsubgroups. years offollow-up).Excessmorbidityandmortalitywereanalysedusingstandardizedincidenceratios (SIRs in themedicalrecords(105females(47%),112patientswithchildhood-onsetcraniopharyngioma(50%),3153person- Methods Design was toexamineexcessmorbidityandmortality, aswelltheirdeterminantsinpatientswithcraniopharyngioma. general populationnorevaluatedriskfactorsforexcessmorbidityandmortality. Therefore,theobjectiveofthisstudy Objective Abstract contributed equallytothiswork) *(M Wijnen,DSOlsson,MvandenHeuvel-Eibrink,CHammarstrand,GJohannssonandJNeggers Gothenburg, Sweden, 4 Rotterdam, TheNetherlands, The Netherlands, 1 Joseph A M J L Janssen Mark Wijnen retrospective cohortstudy with craniopharyngioma:ahospital-based Excess morbidityandmortalityinpatients Department ofInternalMedicineandClinicalNutrition,InstituteMedicine,SahlgrenskaAcademy, Universityof Department ofMedicine,SectionEndocrinology, PituitaryCentreRotterdam,ErasmusUniversityMedicalCentre, https://doi.org/10.1530/EJE-17-0707 www.eje-online.org Clinical Study : Hospital-basedretrospectivecohortstudyconductedbetween1987and2014. : Patientswithcraniopharyngiomaexperiencedexcessmorbidityduetotype2diabetesmellitus(T2DM)(SIR: : We included144Dutchand80Swedishpatientswithcraniopharyngioma identifiedbyacomputer-based search : Moststudiesinpatientswithcraniopharyngiomadidnotinvestigatemorbidityandmortalityrelativetothe : Patientswithcraniopharyngiomaareatanincreasedrisk forT2DM,cerebralinfarction,totalmortality 2 1 Department ofPaediatricOncology/Haematology, ErasmusMC–SophiaChildren’s Hospital, ,
2 , *, Daniel SOlsson 3 Department ofEndocrinology, SahlgrenskaUniversityHospital,Gothenburg,Sweden, 1 , Aart Jvan der Lely 5 Princess MaximaCentreforPaediatricOncology, Utrecht,TheNetherlands,and © 2017EuropeanSociety2018 ofEndocrinology M Wijnenandothers 3 , 4 , *, Marry Mvan den Heuvel-Eibrink Printed inGreatBritain 1 , GudmundurJohannsson with neurosurgery, whichissometimesfollowed by of age ( and havepeakincidencesbetween 5–9and40–44 years person-years ( rare withanestimatedincidence rateof1.7permillion as challengingtumours( craniopharyngioma Morbidity andmortalityin Published byBioscientifica Ltd. 3 ). Craniopharyngiomas are generally treated ). Craniopharyngiomas 3 2 2 , , 4 5 ). Theyaffectbothchildren andadults, , , * *, CasperHammarstrand and Sebastian J C M M Neggers Downloaded fromBioscientifica.com at09/25/202105:55:00PM 1 ). Craniopharyngiomas are ). Craniopharyngiomas (2018) Endocrinology European Journal of [email protected] Email to MWijnen should beaddressed Correspondence 178 178 : 1 178 :1 , 93–102 3 , 4
, *, 93 –102 1 , 2 , * via freeaccess European Journal of Endocrinology www.eje-online.org 1987 and 2014 because Swedish general population data (Gothenburg, Sweden).We conductedourstudybetween Netherlands) andtheSahlgrenska UniversityHospital the Erasmus University Medical Centre (Rotterdam, The at with datafrompatientstreated forcraniopharyngioma We performedahospital-basedretrospectivecohort study Study population Subjects andmethods and mortalityinpatientswithcraniopharyngioma. objective wastoidentifyriskfactorsforexcessmorbidity relation tothegeneralpopulation.Inaddition, in and mortality in patientswithcraniopharyngioma excess morbidityandmortality. and panhypopituitarismassignificantdeterminantsof factors butidentifiedfemalesex,childhood-onsetdisease ( and mortalityinpatientswithcraniopharyngioma previous studiesreportedriskfactorsforexcessmorbidity as theirassociatedhealthconditions.To date,onlythree related damagesofcriticalneurovascularstructures,aswell to bemultifactorial,andincludestumour-treatment- islikely and mortalityinpatientswithcraniopharyngioma cause-specific mortality. Theincreasedriskformorbidity studies werelimitedbyasamplesizetoosmalltoassess between 2.5and9.3( standardized mortalityratios(SMRs)fortotal excess mortalityreportedsignificantlyincreased and visualimpairment( mellitus (T2DM),fractures,infections,cerebralinfarction standardized incidenceratios(SIRs)fortype2diabetes significantlyincreased excess morbidityobserved population ( relativetoabackground patients withcraniopharyngioma six previousstudiesinvestigatedexcessmortalityin previous studyexaminedexcessmorbidity( to thegeneralpopulation.To ourknowledge,onlyone a fewinvestigatedmorbidityandmortalityinrelation only and mortalityinpatientswithcraniopharyngioma, ( craniopharyngioma long-termhealthconditionsinpatientswith observed visual impairmentandobesityarethemostfrequently ( term tumour-andtreatment-relatedmorbidityiscommon ratesbetween77and93%( survival radiotherapy ( 2 2 , , Clinical Study 15 5 The objective of our study was to examine morbidity Although previousstudieshaveexaminedmorbidity , , 17 6 , ). These studies evaluated only a few potential risk ). Thesestudiesevaluatedonlyafewpotentialrisk 7 , 2 8 , , 1 15 9 ). Despiteencouraging10-yearoverall , , 10 16 , 6 2 , , , 11 17 7 15 2 , , , ). The studies that investigated ). Thestudiesthatinvestigated 8 , 12 18 , 16 9 , , , , 10 19 13 17 M Wijnenandothers , ). The study examining ). Thestudyexamining , , 11 18 14 , , 2 ). Hypopituitarism, 14 19 , 4 ). ). Many of these ). Manyofthese , 5 , 2 6 ), and only ), andonly , 7 ), long- whereas data on morbidity and mortality from the Swedish whereas dataonmorbidityandmortalityfromtheSwedish population werederivedfromStatisticsNetherlands, records. DataonmortalityfromtheDutchgeneral werecollectedfromthemedical craniopharyngioma Data onmorbidityandmortalityinpatientswith Morbidity andmortality this study. Allpatientsgavetheirinformedconsent. ethical review board in Gothenburg, Sweden, approved Erasmus UniversityMedicalCentreandtheregional before 1987.Thelocalinstitutionalreviewboardofthe Swedish patients)ofwhom53patients(24%)weretreated and 80 (144 Dutch 224 patients with craniopharyngioma A computer-based search in themedical records identified 1987. Thesepatientsenteredthestudyon1st January 1987. treatedbefore included patientswithcraniopharyngioma period. To increasethestrengthofourstudy, wealso on morbidityandmortalitywereonlyavailableforthis < mass index patients. Weight status wasclassifiedasobese(i.e.body functiontestinginall diagnosed basedonformalpituitary the tumourafterpriortreatment. Panhypopituitarismwas recurrence was definedasreappearance or re-growth of reports.Craniopharyngioma and/or neurosurgery or thirdventricleasdocumentedinneuroimaging tothehypothalamus and/ treatment-related injury Hypothalamic damagewasdefinedastumour-and/or studied asriskfactorsforexcessmorbidityandmortality. and weightstatusatlastavailablefollow-upvisitwere recurrence,panhypopituitarism as craniopharyngioma Baseline, tumour and treatment characteristics, as well ischaemic heartdiseaseandcerebrovasculardisease). for a fewparticularconditions (i.e. malignant neoplasms, 10). Inaddition,cause-specificmortalitywasexamined diseases(ICD-10chapter (ICD-10 chapter9)andrespiratory Cause-specific mortality was studied for circulatory diseases cerebral infarction andfractures werestudiedasmorbidities. Malignant neoplasms,T2DM,myocardialinfarction, on Tenth Revision(ICD-10)( according totheInternationalClassificationofDiseases, Morbidity and cause-specificmortality werecategorized morbidity inDutchpatientswithcraniopharyngioma. we usedSwedish general population data toexamineexcess the Dutchgeneralpopulationwereunavailable.Therefore, National CauseofDeathRegistry. Dataonmorbidityfrom Registry, and the Swedish the Swedish Cancer Registry general populationfromtheSwedishNationalPatient craniopharyngioma Morbidity andmortalityin 30 kg/m supplementary data supplementary 2 ). ≥ 30 kg/m 2 ) and non-obese (i.e. body mass index ) andnon-obese(i.e.bodymass index given at the end of this article). givenattheendofthisarticle). Downloaded fromBioscientifica.com at09/25/202105:55:00PM Supplementary data Supplementary 178 :1 , see section , seesection 94 via freeaccess
European Journal of Endocrinology (29% vs16%; hypertension (51%vs33%; were similarinfemalescompared tomales,exceptfor (interquartile range20–22.5). Patientcharacteristics median dailyhydrocortisoneequivalentdosewas20 adrenalinsufficiency,patients withsecondary the females withhypogonadotropichypogonadism.In therapy wasusedby92%ofmalesandpremenopausal with growthhormonedeficiency. Sexsteroid replacement replacement therapy was used by 78% of the patients years(interquartilerange:27–59).Growthhormone 42 3153 person-years. Median age at the end of study was years(interquartilerange:6–21),representing of 13 (50%). Patientswerefollowed-upforamedianperiod < females (47%))( We (105 included224patientswithcraniopharyngioma Patient characteristics Results conducted usingSPSS(version24)andStata14). considered statisticallysignificant.Statisticalanalyseswere bias.A to accountforsurvivorship treatment months aftertheirinitialcraniopharyngioma with theexclusionofpatientswhodiedwithinfirstsix subgroups ( by comparingSIRsandSMRsbetweennon-overlapping excess morbidity and mortality were evaluated univariably Riskfactorsfor case lessthanthreeeventswereobserved. the firsteventonly. SIRsandSMRswerenotcalculatedin except forthediagnosisofT2DM,whichwasassessedat diagnosed withaspecificmorbidityonanyearlybasis, were calculateddependingonwhetherthepatientwas used tocalculatetheexpectednumberofevents.SIRs five-year agegroupandone-yearcalendarperiodwere 2014). Generalpopulationdatastratifiedaccordingtosex, to thedateofaneventorendstudy(i.e.31stDecember Person-years werecalculatedfromthedateofstudyentry numberofevents. a Poissondistributionoftheobserved (CIs)werecalculatedassuming 95% confidenceintervals study period,asmeasuredinperson-years.Corresponding the expectednumberofeventsencounteredduring to and SMRswerecalculatedastheratioofobserved and thegeneralpopulationusingSIRsSMRs. compared betweenpatientswithcraniopharyngioma Morbidity andmortalitywerestudiedasevents Statistical analysis 8 yearsofage(i.e.childhood-onset)in112patients 18 Clinical Study 20 ). Relevant comparisons were also conducted ). Relevantcomparisonswerealsoconducted P
< Table 1 0.05). ). Craniopharyngiomas presented ). Craniopharyngiomas P
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0.05) anddyslipidaemia M Wijnenandothers P -value < 0.05 was 0.05 was mg malignant neoplasms,myocardialinfarction orfractures. hadnoincreasedriskfor Patients withcraniopharyngioma hydrocephalusandtumourrecurrence. craniopharyngioma, higher inpatientswithfemalesex,childhood-onset 8.0). The excess risk for cerebral infarction was significantly (SIR:4.9,95%CI:3.1– in patientswithcraniopharyngioma asignificantlyincreasedriskforcerebralinfarction observed recurrence, panhypopituitarismandobesity. We also incomplete tumourresection,radiotherapy, tumour hydrocephalus,hypothalamicdamage, craniopharyngioma, higher inpatientswithfemalesex,childhood-onset CI: 2.8–6.8).TheexcessriskforT2DMwassignificantly of 4.6,resultinginasignificantlyincreasedSIR4.4(95% diagnosed withT2DMcomparedtotheexpectednumber respectively. Twenty were patientswithcraniopharyngioma areshownin craniopharyngioma Excess morbidityandtheirriskfactorsinpatientswith Excess morbidity was similarinDutchandSwedish patients( before andafter1987.Inaddition, excesstotalmortality difference in excess total mortality between patients treated panhypopituitarism (SMR4.3 vs2.0; 1.6; compared towithouttumourrecurrence(SMR:5.1 vs hydrocephalus (SMR:10.5vs1.8; vs 1.9; (SMR: 9.0 compared to adult-onset craniopharyngioma males (SMR:5.3vs1.8; mortality wassignificantlyhigherinfemalescompared to mortality of2.7(95%CI:2.0–3.8).Theriskforexcesstotal expected, resulting in asignificantlyincreasedSMRfortotal compared to 12.4 in patients with craniopharyngioma and areshownin in patientswithcraniopharyngioma Excess mortalityandriskfactorsforexcesstotal Excess mortality affect theresults( treatment (i.e.threepatients).Thisdidnotsignificantly the first sixmonthsafter their initial craniopharyngioma morbidity aftertheexclusionofpatientswhodiedwithin panhypopituitarism andobesityasriskfactorsforexcess bias, wealsoevaluatedradiotherapy, tumourrecurrence, ( in excess morbidity between Dutch and Swedish patients fractures (SIR:2.2vs0.7; and after1987,exceptforT2DM(SIR:1.8vs5.9; craniopharyngioma Morbidity andmortalityin upeetr al 1 Table Supplementary Excess morbidity was similar in patients treated before Excess morbidity was similar in patients treated before al 3 Table P
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European Journal of Endocrinology www.eje-online.org HC, hydrocortisone; mg,milligrams; ACTH, adrenocorticotropichormone;ADH,antidiureticFSH/LH,folliclestimulatinghormone/luteinizingGH,growth hypogonadotropic hypogonadism(92%ofmalesandpremenopausalfemales); replacement therapywasusedby141patientswithgrowthhormonedeficiency(78%); correction forrefractiondisorderand/orasthepresenceofavisualfielddefect; a in areshown of deathinpatientswithcraniopharyngioma determinants of cause-specific mortality. Individual causes deaths precludedthereliableassessmentof of observed neoplasms andischaemicheart disease.Thelownumber disease. We no excess mortality due to malignant observed to circulatory diseases was mainly due to cerebrovascular 6.0, 95%CI:2.5–14.5).Theexcessriskformortalitydue diseases (ICD-10 chapter 10) (SMR: 1.1–4.5) and respiratory circulatory diseases(ICD-10chapter9)(SMR:2.3,95%CI: asignificantlyincreasedriskfor mortalitydueto observed factors forexcesstotalmortality( treatment didnotsignificantlyaffecttheresultsonrisk the first sixmonths after their initialcraniopharyngioma 1 Table Panhypopituitarism ADH ACTH TSH FSH/LH GH dose GH (mg/day) Long-term healthconditions Incomplete resection Complete resection Craniopharyngioma treatment Intra-/suprasellar Suprasellar Intrasellar Tumour characteristics Adult-onset ( Childhood-onset ( Baseline characteristics Table 1 Evaluations werebasedonthenumberofpatientswithavailabledata; Dyslipidaemia ( Hypertension ( Obesity ( Visual impairment( Pituitary hormonedeficiencies( Recurrence ( Radiotherapy ( Neurosurgery ( Hypothalamic damage( Hydrocephalus ( Location ( Age atendofstudy(years) Follow-up (years) Age atpresentation(years) Clinical Study Supplementary Table 3Supplementary In theanalysesoncause-specificmortality, we HC equivalentdose(mg/day) ). The exclusion of the patients who died within ). Theexclusionofthepatientswhodiedwithin Patient characteristics. n n (%)) (%)) n (%)) n n n n n (%)) n (%)) (%)) (%)) (%)) b (%)) n n (%)) (%)) d b n (%)) . c b b n , number;TSH,thyroidstimulatinghormone. a n b (%)) Supplementary Table 2Supplementary M Wijnenandothers
All patients 215 (96) 101 (45) 106 (61) 210 (94) 120 (57) 112 (50) 112 (50) 101 (50) 156 (77) 114 (51) 141 (63) 183 (82) 202 (91) 183 (85) 180 (83) 0.4 (0.3–0.8) 89 (40) 69 (39) 90 (43) 62 (28) 87 (41) 42 (27–59) 13 (6–21) 47 (22) 76 (41) 20 (20–22.5) 20 (9–42) 5 (2)
). b median (interquartilerange); e g g g f ( n =224) mortality inaseriesofunivariable analyses. obesity assignificantriskfactors forexcessmorbidityand radiotherapy, tumour recurrence,panhypopituitarismand hypothalamic damage,incomplete tumourresection, hydrocephalus, sex, childhood-onsetcraniopharyngioma, due toahighcerebrovascularmortality. We identifiedfemale excess risk for mortality due to circulatory diseases was mainly diseasesrelative to thegeneral population. The and respiratory infarction, totalmortalityandduetocirculatory to beatasignificantlyincreasedriskforT2DM,cerebral follow-up. We patients with craniopharyngioma observed after3153 person-yearsof patients withcraniopharyngioma we investigatedexcessmorbidityandmortalityin224 In this large hospital-based retrospective cohort study, Discussion craniopharyngioma Morbidity andmortalityin g d all patientsusedhormonereplacementtherapy. defined astheuseoflipid-loweringdrugs; f sex steroidreplacementtherapywasusedby143patientswith
c defined asadecreasedvisualacuityafter Females 100 (95) 0.5 (0.3–0.8) 45 (43) 48 (46) 53 (64) 30 (36) 99 (94) 43 (43) 32 (31) 58 (59) 40 (40) 42 (27–57) 14 (7–22) 42 (40) 53 (50) 28 (29) 44 (51) 52 (54) 72 (76) 58 (55) 69 (66) 20 (16–20) 83 (79) 92 (89) 86 (86) 85 (82) 20 (10–41) 1 (1)
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115 (97) 111 (93) 100 (84) 110 (92) Males 0.4 (0.3–0.7) 44 (38) 53 (45) 53 (58) 39 (42) 47 (43) 30 (26) 62 (55) 47 (42) 41 (26–60) 12 (6–21) 60 (50) 59 (50) 19 (16) 32 (33) 49 (47) 84 (79) 56 (48) 72 (61) 20 (20–25) 97 (84) 95 (83) 20 (8–42) 4 (4)
( n =119) 96 via freeaccess European Journal of Endocrinology pituitary physiology ( pituitary regimens thatdonotappropriately simulatehypothalamic– as well as tocurrentlyavailable hormone replacement hormonedeficiencies, due toinadequatelytreatedpituitary metabolic profileassociated withhypopituitarismmaybe its associatedmetabolicderangements( may altogetherpromotethedevelopmentofobesityand systemdysfunction, which well asautonomicnervous may resultinacquiredleptinandinsulinresistance, as and hypopituitarism( metabolic profileassociatedwithhypothalamicdamage seems to be mainly due to an adverse craniopharyngioma The increasedriskforcirculatory diseasesinpatientswith diseasesinpatientswithcraniopharyngioma. respiratory total mortalityandduetocirculatory and significantly increasedriskforT2DM,cerebralinfarction, are in concordance with our findings regarding the ( relativetothegeneralpopulation craniopharyngioma investigated morbidityandmortalityinpatientswith ratio; T2DM,type2diabetesmellitus. standardized incidenceratio;SMR,mortality CI, confidenceinterval;E,expected;O,observed;SIR, cancer ( neuro-endocrine tumouroftheappendix( brain tumour( malignant neoplasmsincludedbreastcancer( craniopharyngioma. (A)Morbidity. (B)Mortality. Excess morbidityandmortalityinpatientswith Figure 1 Respiratory diseases(chapter10 Table 4 Circulatory diseases(chapter9) Clinical Study Similar to our study, some previous studies Malignant neoplasm Myocardial infarctio Cerebral infarction Cause-specific mortality n ) (
= Cerebrovascular diseas Ischemic heartdiseas 2 1), pancreaticcancer( Malignant neoplasms Particular conditions Fractures , ICD-10 chapters To 15 To T2DM tal mortality n tal mortalit Morbidity inpatientswithcraniopharyngioma ) mlnm ( melanoma =1), , n s 16 a
1 , Standardized incidenceratio±95%CI e e ) Mortality inpatientswithcraniopharyngioma 17 y 1 , 23 Standardized mortality 18 14 ,
, 5 24 , 19 5 21 , ). The results of these studies ). Theresultsofthesestudies n n 25 ). Hypothalamic damage ). Hypothalamicdamage
) msteim ( mesothelioma =1),
= 1 0 ). The increased risk for ). Theincreasedriskfor M Wijnenandothers 1), prostatecancer( ratio±95%CI 15
10 n ) ovarian =1), 22 n 17 14 20 10 OE 74 ). The adverse ). Theadverse ) malignant =1), 20 34 OE 50 83 40 44 43 a 11 11 Observed 3. 4. .8 12.4 44 64 .5 .3 .8 .5 .7 .6 .5 1.2 (0.7-2.1 1.5 (0.7-3.1 0.9 (0.5-1.6 S S .9 (3.1-8.0 .4 (2.8-6.8 IR (95%CI) 5.8 (2.2-15.5) 6.0 (2.5-14.5) 2.3 (1.1-4.5 0.9 (0.3-2.3 1.1 (0.4-3.0 2.7 (2.0-3.8 n MR (95%CI) n =1), =3). ) ) ) ) ) ) ) ) ) specific factors,likealocallyaggressivetumourbehaviour, to othercauses( mortality comparedtopatientswithhypopituitarismdue seemtobeatanincreasedriskfor with craniopharyngioma death of adult patients with hypopituitarism ( to acutestressandintercurrent illnesscontributetothe by Burman adrenalinsufficiency.related tosecondary Thisissupported events wereprobablyatleastpartlyduetoadrenalcrises adrenal insufficiency.secondary In these patients, fatal diseasessufferedfrom patients whodiedfromrespiratory risk inpatientswithhypopituitarism( deficiencies seemtoberesponsibleforanincreasedinfection hormone dysfunction associated with other pituitary glucocorticoid replacementtherapy, aswellimmune adrenal insufficiency and tract infections.Secondary to be due toan increased incidence of severe respiratory with hypopituitarismduetoothercauses( inpatients mortalityhasalsobeenobserved respiratory ( whodiedofcerebrovasculardisease craniopharyngioma) (but not tumours(including inmale)patientswithpituitary longer durationofuntreated hypopituitarisminfemale adenoma. In addition, Erfurth fornonfunctioning pituitary male patientsaftersurgery hormone deficienciesinfemalepatientscompared to asubstantiallylowerprevalence ofpituitary they observed absence ofsex-specificdiagnostictests( underdiagnosed infemalescomparedtomalesduethe et al excess mortalityassociatedwithfemalesex( asignificantly increasedriskfor causes thatalsoobserved by studiesinpatientswithhypopituitarismduetovarious management arelikelytobeinvolved( sex-specific factorsassociatedwithhypopituitarism andits isunknown,but male patientswithcraniopharyngioma morbidity andmortalityinfemalepatientscomparedto panhypopituitarism ( and female sex,childhood-onsetcraniopharyngioma risk forexcessmorbidityandmortalityassociatedwith asignificantlyincreased some ofthemalsoobserved and mortalityinpatientswithcraniopharyngioma, only afewpotentialdeterminantsofexcessmorbidity univariable analyses.Althoughpreviousstudiesevaluated inaseriesof mortality inpatientswithcraniopharyngioma as themostimportantriskfactorsforexcessmorbidityand hydrocephalus, tumourrecurrenceandpanhypopituitarism frequency ofhypothalamicdamage. a high recurrence rate, severe hypopituitarism and a high craniopharyngioma Morbidity andmortalityin 30 ). Moreover, somestudiessuggestedthat sex-specific . suggested that pituitary hormone deficiencies may be hormonedeficiencies maybe . suggestedthatpituitary We identifiedfemalesex,childhood-onsetdisease, et al . who found that adrenal crises in response . whofoundthatadrenalcrisesinresponse 4 ). Thismaybeduetocraniopharyngioma- 2 , 15 Downloaded fromBioscientifica.com at09/25/202105:55:00PM , 17 ). The reason for the increased ). Thereasonfortheincreased et al . reported a significantly . reported a significantly 178 26 4 29 ). This is illustrated ). Thisisillustrated www.eje-online.org ). Inourstudy, all :1 ). Intheirstudy, 4 ), and is likely ), andislikely 27 28 ). Patients ). Patients ). Nielsen ). Nielsen 97 via freeaccess European Journal of Endocrinology www.eje-online.org Clinical Study
Table 2 Risk factors for excess morbidity in patients with craniopharyngioma.
Malignant neoplasms T2DM Myocardial infarction Cerebral infarction Fractures Risk factors SIR (95% CI) P SIR (95% CI) P SIR (95% CI) P SIR (95% CI) P SIR (95% CI) P Sex 0.62 <0.05 0.11 <0.05 0.31 Female 1.1 (0.4–2.5) 7.3 (3.9–13.5) 3.4 (1.1–10.5) 8.1 (4.1–16.2) 1.7 (0.8–3.5) M Wijnenandothers Male 0.8 (0.3–1.8) 3.1 (1.7–5.8) 1.0 (0.4–2.7) 3.7 (1.9–7.1) 1.0 (0.5–2.0) Onset NC <0.05 NC <0.05 0.76 Childhood NC 10.7 (5.4–21.4) NC 16.0 (6.7–38.4) 1.3 (0.6–2.8) Adult 0.8 (0.4–1.7) 3.1 (1.8–5.5) 1.4 (0.6–3.1) 3.8 (2.2–6.8) 1.1 (0.5–2.4) Hydrocephalus NC <0.05 NC <0.05 1.00 Yes NC 10.1 (4.5–22.4) NC 14.6 (6.6–32.5) 1.2 (0.4–3.8) No 0.9 (0.4–1.7) 3.7 (2.2–6.3) 1.2 (0.5–3.0) 3.9 (2.1–7.0) 1.2 (0.7–2.3) Hypothalamic damage 1.00 <0.05 0.32 0.83 NC Yes 0.9 (0.3–2.9)a 8.4 (4.3–16.1)b 2.3 (0.7–7.0)d 5.5 (2.5–12.3)f NC No 0.9 (0.4–1.9) 3.3 (1.8–6.2) 1.0 (0.3–3.2) 4.9 (2.6–9.0) 1.8 (1.0–3.2) Resection 0.18 <0.05 NC 0.97 0.54 Complete 1.7 (0.7–4.0)a 2.6 (1.0–6.9)c NCe 4.7 (2.0–11.4)g 0.8 (0.3–2.4)h Incomplete 0.7 (0.3–2.0) 7.1 (4.2–11.9) 2.1 (0.8–5.7) 4.8 (2.3–10.0) 1.2 (0.6–2.7) Radiotherapy 0.32 <0.05 0.47 0.97 0.34 Yes 1.2 (0.5–2.7) 6.8 (4.0–11.5) 1.9 (0.7–5.0) 4.9 (2.3–10.2) 0.9 (0.4–2.2) craniopharyngioma Morbidity andmortalityin No 0.6 (0.2–1.7) 2.4 (1.1–5.3) 1.1 (0.4–3.5) 5.0 (2.7–9.3) 1.5 (0.8–2.8) Recurrence 0.61 <0.05 0.33 <0.05 NC Yes 1.1 (0.4–2.8) 6.5 (3.5–12.2) 2.0 (0.6–6.1)d 8.0 (4.2–15.3)f NCi No 0.8 (0.4–1.8) 3.3 (1.8–6.2) 0.9 (0.3–2.8) 3.0 (1.5–6.4) 1.5 (0.8–2.7) Panhypopituitarism 0.62 <0.05 0.45 0.29 0.75 Yes 0.7 (0.2–2.2) 7.3 (4.1–12.8) 2.1 (0.7–6.4) 6.9 (3.3–14.4) 1.1 (0.5–2.4) No 1.0 (0.5–2.1) 2.7 (1.4–5.5) 1.2 (0.5–3.2) 4.1 (2.2–7.7) 1.3 (0.7–2.7) Obesity 0.46 <0.05 NC 0.70 0.48 Yes 0.6 (0.2–1.9)a 8.8 (5.3–14.7) 2.4 (0.9–6.3)d 5.6 (2.7–11.8)f 1.0 (0.4–2.3)i No 1.0 (0.5–2.3) 1.9 (0.8–4.7) NC 4.6 (2.4–8.8) 1.5 (0.7–2.9) Treated 0.76 <0.05 0.47 0.94 <0.05
Downloaded fromBioscientifica.com at09/25/202105:55:00PM <1987 0.8 (0.2–2.4) 1.8 (0.6–5.5) 2.1 (0.7–6.7) 4.8 (1.8–12.7) 2.2 (1.1–4.2) ≥1987 1.0 (0.5–2.0) 5.9 (3.7–9.5) 1.2 (0.4–3.1) 5.0 (2.9–8.6) 0.7 (0.3–1.6)
aData missing in one patient with a malignant neoplasm; bdata missing in one patient with T2DM; cdata missing in two patients with T2DM; ddata missing in one patient with a myocardial infarction; edata missing in two patients with a myocardial infarction; fdata missing in one patient with a cerebral infarction; gdata missing in five patients with a cerebral infarction;h data missing in five patients with a fracture;i data missing in one patient with a fracture.
CI, confidence interval; NC, not calculated;P , P-value; SIR, standardized incidence ratio; T2DM, type 2 diabetes mellitus. 178 :1 98 via freeaccess European Journal of Endocrinology and mortality. damage, therebyincreasing theriskforexcessmorbidity may inducemoretumour- andtreatment-relatedbrain cause hydrocephalus and tend to recur after treatment that recurrence. Largeandaggressive craniopharyngiomas mortality associatedwithhydrocephalusandtumour the significantlyincreasedriskforexcessmorbidityand onset disease( hypothalamic damage compared to patients with adult- as welltumoursassociatedwithhydrocephalusand disease presentsignificantlymoremulticystictumours, al et may beexplainedbytumourcharacteristics.Wijnen childhood- comparedtoadult-onsetcraniopharyngioma disease( compared tomalepatientswithpituitary the increasedmorbidityandmortalityinfemalepatients available hormone replacement regimens contribute to hormonedeficienciesandeffectsofcurrently pituitary differences in the pathophysiological states associated with CI, confidenceinterval;SMR,standardizedmortalityratio. who died. a Treatment Obesity Panhypopituitarism Recurrence Radiotherapy Resection Hypothalamic damage Hydrocephalus Onset Sex Risk factors Table 3 Data missinginthreepatientswhodied; ≥ < No Yes No Yes No Yes No Yes Incomplete Complete No Yes No Yes Adult Childhood Male Female Clinical Study 1987 1987 The increasedmorbidityandmortalityinpatientswith d c c . reportedthatpatientswithchildhood-onset Risk factorsforexcesstotalmortalityinpatientswithcraniopharyngioma. b 7 ). Tumour characteristics may alsoexplain a b M Wijnenandothers data missingin12patientswhodied; Observed 26 13 14 18 15 14 19 19 15 16 15 16 19 15 21 13 16 18 8 6 4 , 21 , 28 Expected 10.5 11.0 ). 8.7 3.7 7.6 4.8 5.0 3.5 6.9 4.3 1.4 1.4 9.0 3.4 9.1 3.4 7.5 4.2 8.9 3.5 morbidity andmortality inpatientswith in ourstudy. malignant neoplasmsinpatients withcraniopharyngioma absence ofanincreasedrisk for myocardialinfarction and The latterexplanationmaypotentiallyalsoapplytothe factors forradiation-inducedcerebrovasculardisease( follow-up durationafterradiotherapyasimportantrisk Previous studiesidentifiedanadvancedageandaprolonged risk forcerebralinfarction associated with radiotherapy. an increased our follow-updurationtooshorttoobserve Additionally, ourstudypopulationmaybetooyoung and cerebral infarction inpatientswithcraniopharyngioma. and hypopituitarism,alsocontributetotheexcessriskfor metabolic profileassociatedwithhypothalamicdamage andanadverse that otherfactors,likeneurosurgery treated withandwithoutradiotherapy. Thisindicates an equalexcessriskforcerebralinfarction inpatients cerebrovascular disease ( craniopharyngioma Morbidity andmortalityin c data missinginonepatientwhodied; Our studyhasseveralstrengths. We investigated Radiotherapy isanimportantriskfactorfor 10.5 SMR 1.6 5.1 2.5 3.1 3.2 1.7 2.2 3.7 1.8 1.9 9.0 1.8 5.3 2.9 2.4 1.7 3.3 2.0 4.3 Downloaded fromBioscientifica.com at09/25/202105:55:00PM 31 ). Interestingly, we observed 1.0–2.7 3.3–8.0 1.6–3.9 1.9–5.2 2.0–5.2 0.8–3.9 1.3–3.6 2.3–6.0 1.2–2.8 6.3–17.4 1.2–2.9 5.3–15.6 1.1–2.9 3.3–8.4 2.0–4.2 1.2–4.8 1.0–3.0 2.0–5.6 1.3–3.2 2.6–7.1 95% CI d data missinginsevenpatients 178 www.eje-online.org :1 P < < < < < value 0.64 0.08 0.05 0.05 0.53 0.15 0.12 0.05 0.05 0.05
99 31 via freeaccess ). European Journal of Endocrinology www.eje-online.org Clinical Study
Table 4 Other studies that investigated excess mortality in patients with craniopharyngioma.
Median age at Median craniopharyngioma dx. follow-up SMR for total References Country Setting Period n (%) (range) (years) (range) (years) Person-years mortality (95% CI) (15) Sweden Hospital-based 1951–1988 ♀ 24 (40) 28 (3–71) 13 (0–40) NA 5.6 (3.7–8.2) ♂ 36 (60) (16) United Kingdom Hospital-based 1992–2000 ♀/♂ 118 NA NA NA 9.3 (5.8–14.8) (17) The Netherlands Hospital-based 1965–2002 ♀ 30 (55) 29 (4–74) 10 (1–37) 828 2.9 (1.4–5.0) ♂ 25 (45) (18) Ireland Hospital-based 1980–2008 ♀ 31 (44) 28 (0–80) 8 (1–50) NA 8.8 (5.4–13.3)
♂ 39 (56) M Wijnenandothers (19) KIMS-databasea Hospital-based 1994–2011 ♀/♂ 1562 NA NA 8392 2.5 (1.9–3.1) (2) Sweden Population-based 1987–2011 ♀ 156 (51) 35 (0–81)b 9 (0–25)c 2882 3.8 (2.9–5.0) ♂ 151 (49) This study The Netherlands and Sweden Hospital-based 1987–2014 ♀ 105 (47) 20 (9–42)c 13 (6–21)d 3153 2.7 (2.0–3.8) ♂ 119 (43)
aPfizer International Metabolic Database;b mean (range); cmedian (interquartile range). ♀, female; ♂, male; CI, confidence interval; dx., diagnosis;n , number; NA, not available; SMR, standardized mortality ratio. (95% CI:2.8–6.8).Anotherlimitationofourstudyisthe excess riskforT2DMmightbeevenhigherthanSIR:4.4 bias, except for T2DM. This indicates thatthetrue analysed this issue, we did not findanysurvivorship bias.However,also inducedasurvivorship whenwe and therebythestrengthofouranalyses,butmayhave 1987, which increased the size of our study population treatedbeforeincluded patientswithcraniopharyngioma of patientswithmoreadvanceddisease.Additionally, we hospital-basedsettingmayinduceselectionbias(tertiary) some limitationsofourstudyshouldbediscussed.The in twostudypopulations.Despitethesestrengths, collaboration alsoenabledustoreplicateourfindings Theinternationaladult-onset craniopharyngioma. a largecohortofbothpatientswithchildhood-and through internationalcollaboration,wecouldestablish factors for excess morbidity and mortality. Furthermore, Additionally, westudiedalargenumberofpotentialrisk relativetothegeneralpopulation.craniopharyngioma addition, apreviousstudy by Burman diseases may have been underestimated inourstudy. In that mortalityduetocirculatory, aswellrespiratory mortalities ( respiratory are knowntobeassociated withexcesscirculatory and adrenal insufficiency( from growthhormonedeficiencyandsecondary sufferSince manypatientswithcraniopharyngioma the cause-specificSMRscouldhavebeenunderestimated. Although thisdidnotaffecttheSMRfortotalmortality, unknown insevenpatientswithcraniopharyngioma. limitation ofourstudyisthatthecausedeathwas wereunavailable. Anotherof craniopharyngioma data onlifestylefactorsandthehistologicalsubtype hypothalamic damage.Furthermore,inourstudy, investigate theircorrelationwithothersymptomsof are neededtovalidatethesegradingsystemsand unable tousetheseclassificationsystems.Futurestudies due to the retrospective design of our study, we were their correlationwithobesity( validated someoftheseclassificationsystemsregarding have beendeveloped( hypothalamicdamagefor craniopharyngioma-related Recently, severalneuroradiologicalgradingsystems based ondatareportedinthemedicalrecords. of ourstudyisthatwedefinedhypothalamicdamage the differenceisminimal( slightly healthierthantheDutchgeneralpopulation, the Swedishgeneralpopulationhasbeenreportedtobe Althoughin Dutchpatientswithcraniopharyngioma. use of Swedish general population data to calculate SIRs craniopharyngioma Morbidity andmortalityin 7 Downloaded fromBioscientifica.com at09/25/202105:55:00PM 33 4 ), andsincetheseconditions ), itistemptingtospeculate , 32 34 ). Anadditionallimitation , 35 , 37 178 36 ). Unfortunately, :1 ). Mortini et al . hasshown 100 t al et via freeaccess . European Journal of Endocrinology perceived asprejudicingtheimpartiality ofthisstudy. The authorsdeclarethatthereis no conflictofinterestthatcouldbe Declaration ofinterest EJE-17-0707. This is linked to the online version of the paper at Supplementary data provide optimalendocrinecare. functionand hypothalamic–pituitary that aimtopreserve damage, weadvocateindividualizedtreatmentstrategies on tumour-andtreatment-relatedhypothalamic–pituitary in patients with craniophayrngioma are highly dependent univariable analyses.Sinceexcessmorbidityandmortality in a series of mortality in patients with craniopharyngioma as themostimportantriskfactorsforexcessmorbidityand hydrocephalus, tumourrecurrenceandpanhypopituitarism We identified femalesex, childhood-onset disease, diseases wasmainlyduetoahighcerebrovascularmortality. population. Theexcessriskformortalityduetocirculatory diseasesrelativetothegeneral to circulatory andrespiratory T2DM, cerebralinfarction, totalmortalityanddue tobeatsignificantlyincreasedriskfor craniopharyngioma panhypopituitarism andobesity). interrelated (e.g.radiotherapy, hypothalamicdamage, aremortality inpatientswithcraniopharyngioma because manydeterminantsofexcessmorbidityand and mortalityshouldbeinterpretedcautiously Finally, ourresultsonriskfactorsforexcessmorbidity study byOlsson study isconsiderablylongercomparedtotheprevious In addition,thefollow-updurationincurrent of newriskfactorsforexcessmorbidityandmortality. et al and extensive compared to the previous study by Olsson results providedinthe present studyaremoreaccurate records toexamineexcessmorbidityandmortality, the the currentstudyuseddataderivedfrommedical dataonly.were investigatedusingregistry-provided Since Sweden. Inthisstudy, excessmorbidityandmortality fromincluded 307patientswithcraniopharyngioma study byOlsson ( craniopharyngioma on excessmorbidityandmortalityinpatientswith enrolled inourstudyalsotookpartaprevious 67 ofthe80Swedishpatientswithcraniopharyngioma patients withhypopituitarismaswell( adrenal insufficiencyareprobablyunderestimatedin that deathsduetoadrenalcrisesrelatedsecondary Clinical Study In conclusion, we observed patients with patientswith In conclusion, we observed . ( 2 ). We wereabletostudyarelativelylargenumber t al et t al et 2 ie ein1 s8 years)( . (i.e.median13vs8 ). Thispreviouspopulation-based . wasanationwidestudythat M Wijnenandothers https://doi.org/10.1530/ 27 ). Moreover, 2 ). ). References and follow-upcareofourpatients. The authorswouldliketothankthephysiciansinvolvedintreatment Acknowledgements the public,commercialornot-for-profit sector. This researchdidnotreceiveanyspecificgrantfromfundingagencyin Funding
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