Fluctuation analysis of postoperative secretory status in patients operated for acromegaly

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Fluctuation analysis of postoperative secretory status in

patients operated for acromegaly

Thomas Graillon, Frederic Castinetti, Mohamed Boucekine, Thomas Cuny,

Isabelle Morange, Stéphane Fuentes, Dominique Figarella-Branger, Frédérique

Albarel, Thierry Brue, Henry Dufour

To cite this version:

Thomas Graillon, Frederic Castinetti, Mohamed Boucekine, Thomas Cuny, Isabelle Morange, et

al.. Fluctuation analysis of postoperative secretory status in patients operated for acromegaly.

An-nales d’Endocrinologie, Elsevier Masson, 2020, 81 (1), pp.11-17. �10.1016/j.ando.2019.11.002�.

�hal-03223199�

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Original

article

Fluctuation

analysis

of

postoperative

secretory

status

in

patients

operated

for

acromegaly

Analyse

des

ﬂuctuations

sécrétoires

chez

les

patients

opérés

pour

acromégalie

Thomas

Graillon

a,b,∗

_,

_Frédéric

_Castinetti

b,c

_,

_Mohamed

_Boucekine

d

_,

_Thomas

_Cuny

b,c

_,

Isabelle

Morange

c

_,

_Stéphane

_Fuentes

a

_,

_Dominique

_{Figarella-Branger}

e

_,

Frédérique

Albarel

c

_,

_Thierry

_Brue

b,c

_,

_Henry

_Dufour

a,b

a_Neurosurgery_department,_CHU_Timone,_{Aix-Marseille}_university,_AP–HM,_Marseille,_France b_Inserm,_MMG,_{Aix-Marseille}_university,_Marseille,_France

c_{Endocrinology}_department,_CHU_Conception,_{Aix-Marseille}_university,_AP–HM,_Marseille,_France

d_EA₃₂₇₉_CEReSS,_Health_service_research_and_quality_of_life_center,_La_Timone_Medical_Campus,_School_of_medicine,_{Aix-Marseille}_university,_27,_boulevard,

Jean-Moulincedex05,13385Marseille,France

e_Service_d’anatomie_pathologique_et_de_{neuropathologie,}_CNRS,_INP,_Inst._{neurophysiopathol,}_CHU_Timone,_{Aix-Marseille}_university,_AP–HM,_Marseille,

France

a

r

t

i

c

l

e

i

n

f

o

Keywords: Acromegaly Classiﬁcation GH IGF-1 Recurrence Outcome

a

b

s

t

r

a

c

t

Objective.–Theaimofthisstudywastodescribeendocrinologicaloutcomeinpatientsoperatedonfor acromegaly.

Methods.–Aretrospectivestudyincluded167patients.Patientswereassessedintheearly postopera-tiveperiod(EPP),at3months(M3),at1year(Y1),andthenannually.TheywereclassiﬁedasgradeI (IGF-1levelnormal-for-ageandpositiveGHresponseonoralglucosetolerancetest[nadir<0.4ng/L]); gradeII(discordant);orgradeIIIorIV(acromegaly,controlledoruncontrolledundermedicaltherapy, respectively).

Results.–Takingallpatientswithallgrades,35%changedgradesbetweenEPPandM3,26%betweenM3 andY1and9%afterY1.IngradeI,respectively22%,15%and2%ofpatientschangedgradesbetweenEPP andM3,betweenM3andY1,andafterY1,comparedto31%,6%and6%ingradeIV.Respectively57%, 67%,and47%ofgradeIIpatientschangedgradesbetweenEPPandM3,betweenM3andY1,andafterY1; betweenEPPorM3andlastfollow-up(>1year),respectively74%and75%ofgradeIIpatientschanged grades.Knospcategory,resectionqualityandabnormalGHresponse(vs.abnormalIGF-1)signiﬁcantly impactedgradeIIpatients’outcome.

Conclusions.–WhereasoutcomeingradesIandIII–IVseemstobedeterminedby1year,gradeII discor-dantpatients’outcomeremainsuncertainevenafter1year.

Motsclés: Acromégalie Classiﬁcation Hormonedecroissance IGF-1 Récidive Pronostic

r

é

s

u

m

é

Objectif.–L’objectifdecetravailestdedécrirelepronosticendocriniendespatientsopérésd’une acromé-galie.

Méthodes.–Autotal,167patientsontétéinclusdanscetteétuderétrospective.Lespatientsontétéévalués enpostopératoireprécoce(POP),à3mois(M3),à1an(A1)etpuistouslesans.Lespatientsontétéclassés en4grades.GradeI:IGF-1normalecomptetenudel’âge,etprésenced’uneréponsedel’hormonede croissance(GH)autestoraldetoléranceauglucose(nadir<0,4ng/L);gradeII:patientsdiscordants; gradesIIIetIV:acromégaliecontrôléeounoncontrôléesoustraitementmédical,respectivement.

∗ Correspondingauthor.Servicedeneurochirurgie,hôpitalLaTimone,264,rueSaint-Pierre,13005Marseille,France. E-mailaddresses:Thomas.Graillon@ap-hm.fr,tom.graillon@free.fr(T.Graillon).

https://doi.org/10.1016/j.ando.2019.11.002

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12 T.Graillonetal./Annalesd’Endocrinologie81(2020)11–17

Résultats.–Enprenantencomptetouslespatientsavecdifférentsgrades,35%ontchangédegradeentre POPetM3,26%entreM3etA1,et9%aprèslapremièreannée.Respectivement,22,15et2%despatients gradeI,et31,6et6%despatientsgradeIVontchangédegradeaucoursdes3premiersmois,entreM3et A1etaprèslapremièreannée.Respectivement,57,67et47%despatientsgradeIIontchangédegrade aucoursdes3premiersmois,entreM3etA1etaprèslapremièreannée.EntrePOPouM3etledernier suivi(>1an),respectivement74et75%despatientsdegradeIIontchangédegrade.Laclassiﬁcation deKnosp,laqualitéd’exérèseetl’absencederéponsedutauxdeGH(vsIGF-1anormale)ontunimpact pronostiquesigniﬁcatifchezlespatientsdegradeII.

Conclusions.–AlorsquelepronosticendocriniendespatientsgradesIetIII–IVsembledéﬁnià1an,le pronosticdespatientsgradeIIdiscordantsdemeureincertain,mêmeaprèslapremièreannée.

1. Introduction

Acromegalyisararediseasetypicallycausedbyagrowth

hor-mone(GH)-secretingpituitaryadenomaforwhichtranssphenoidal

surgeryistheﬁrst-linetreatment.Accordingtorecentguidelines,

remissionisdeﬁnedasGHlevelsof<0.4ng/mLafteranoral

glu-cosetolerancetest(OGTT;exceptinpatientswithglucosedisorders

forwhom amean ofGH samplesshouldbe<1ng/mL)and

ref-erenceage-appropriateinsulin-like growthfactor (IGF-1)levels.

Thisdeﬁnitionofremissionraisesthepointoftheﬁnalstatusof

patientswithdiscordantGHandIGF-1levels(i.e.,suppressedGH

withincreasedIGF-1,ornormalIGF-1andunsuppressedGH).We

previouslyreportedthatuptoafourthofourpatientsoperatedfor

acromegalyhada3-monthevaluationwithdiscordantGHand

IGF-1levels[1].Althoughendocrinologistsareusedtodealingwiththis

discrepancyinclinicalpracticeformanyyears,discordantpatients’

outcomeremainsuncertainandundeﬁned[2,3].Most

neurosur-gicalstudies focusingonacromegalyoutcomesclassifypatients

withoperatedacromegalyascuredoruncured,without

consider-ingdiscordanthormonelevelsobviouslyalsorelatedtobiological

thresholdofGHandIGF-1level[1].

Nevertheless, it is now commonly accepted that, after the

surgeryandthen thedeterminationoftheendorinologicalﬁnal

status,theoutcomeofacromegalycomorbiditiesisobviously

cor-relatedtotheresidualGHhypersecretion.Holdawayetal.reported

thatpatientswithGHhypersecretionhadanincreasedmorbidity

andmortalityrate,becauseofcardiovasculardiseaseandstroke[4].

Therefore,themanagementof patientswithacromegalyshould

alsobeaimedatexplainingtheprobabilityofobtainingnormal

GHhypersecretionwithappropriatemeans[5].Comparisonofthe

efﬁcacyoftechniquesishoweverdifﬁcultbecauseofthelackofa

universaldeﬁnitionofcured/uncured/uncertainremissionor

con-trolofGHhypersecretion.

Inthisstudy,weaimedtodescribetheendocrinological

out-come of patients operated for acromegaly in a single tertiary

referralcenter,withthedescriptionofanewclassiﬁcation.This

classiﬁcationaimstofacilitatethestudyanalysisandcouldalso

helpthephysicianinclinicalpracticetodeterminetheprobability

ofrecurrenceatagiventimeframeoffollow-up.

2. Materialandmethods

2.1. Patientcharacteristics

Patients operated for newly-diagnosed acromegaly in our

departmentbetween1997and2014wereincludedinthestudy.

Patientswhowerenotfollowed-upinourendocrinology

depart-mentwereexcluded.EndocrineassessmentincludingOGTTwas

performedin theearly postoperative period (EPP)

correspond-ingapproximatelyto7postoperativedays,at3months(M3),at

oneyear(Y1)theneveryyear.Twenty-treepatients(14%)didnot

Table1

GH-secretingpatientstatusclassiﬁcation.

GH-secretingpatientstatus

GradeI NormalIGF-1(age-gender)andHPOGH<1,2mU/L(0,4ng/mL) Notherapy

GradeII IGF-1non-normalizedorGHslowdown IGF-1normalizedorGHnon-slowdown Notherapy

GradeIII Controlledundertherapywhateverthetherapycombination GradeIV IVA:non-controlledandnon-treated

IVB:non-controlledundertherapy R Treatedbyradiotherapyorradiosurgery

achieveOGTTrelatedmainlytodiabetesmellitus.Pituitary mag-neticresonanceimaging(MRI)wasperformedat3months,1year, theneveryyearafterthesurgery.TheMRIresultswereinterpreted byanindependentneuroradiologist.Neuropathologicalstatusof eachtumorwasbasedonitsatypicalfeatures,mitosisnumber,and immunohistochemicalcharacters.Patientsstilltreatedby somato-statintherapy in the month beforesurgery were not included. Patientstreatedbypegvisomantandsomatostatinanalogsduring thefollow-upwereassessedbyIGF-1andclassifiedasgradeIIIor gradeIVBdependingonIGF-1level.ProliferationindexKi-67and p53expressionwerecollectedfor2008–2014series.Cavernous sinusinvasionwasdefinedasagrade3or4Knosp.Peroperative neurosurgeonfindingswerecollectedandresumedaslikely com-plete,uncertaincomplete,orincomplete.Outcomeanalysesonly includedpatientswith follow-up of>1year. Thepresent study receivedapprovalfromtheethicscommitteeoftheAix-Marseille University.

2.2. Classiﬁcationdeﬁnition

Patients were classiﬁed into fourgrades according to IGF-1 andGHsecretiontosimplifystudyanalysis(Table1).Thosewith

acromegalyremissiondeﬁnedasnormalized-ageIGF-1leveland

normalOGTTGHresponse(nadir<0.4ng/L),orameanGHlevelof

<1.0ng/Linpatientswithglucosedisorderswereincludedingrade

I.Discordantnon-treatedpatientswithnormalIGF-1andabnormal

GHresponsetoOGTT(ormeanGH>1ng/L)orabnormalIGF-1and

normalGHresponsetoOGTT(ornormalbasalGH)wereincluded

ingradeII.GradeIIIpatientsrepresentedthosewithacromegaly

controlledundermedicaltherapy.GradeIVpatientsrepresented

thosewithuncontrolledacromegalywithouttreatment(gradeIVA)

orundertreatment(gradeIVB).Letter“R”wasaddedforpatients

whohadreceivedradiotherapyorradiosurgicaltreatment.

2.3. Recurrencedeﬁnition

RecurrencewasbiologicallydeﬁnedbygradeIIIandIV(elevated

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Fig.1.Gradedistributionduringthefollow-up(EPP:earlypostoperativeperiod;M3:3months;Y1:1year;EndofF/U:endoffollow-up).

previouslygradeIandIIpatientsattheEPPand3months.Tumor

residuevisualizedonMRIwasnotrequiredtodeﬁnerecurrence.

GradeIRpatientscorrespondedtothosewithrecurrencecuredby

radiotherapyorradiosurgery,andthesepatientswereconsidered

asrecurredinstatisticalanalyses.GradeIII–IVpatientsattheEPP

remaininggradeIII–IVatM3,Y1andattheendoffollow-upwere

consideredasuncured.

2.4. Statisticalanalysis

Quantitativevariablesarepresentedasmeanandstandard

devi-ationormedianandinterquartilerange,andwerecomparedusing

the Mann-Whitney test. Qualitative variables are presented as

numbersandrate,andwerecomparedusingChi2_or_Fischer_exact

test.Foreachgrade(I,II,IV)andtime(EPP,M3,Y1),the

associa-tionsbetweenrecurrenceandlikelycompleteresection,uncertain

complete resection,and incompleteresection;CS invasion;and

abnormalIGF-1/abnormalGHresponsetoOGTTfactorswere

ana-lyzedusingunivariateFirth’sbias-reducedlogisticregression[6].

Oddsratiosaredisplayedwith95%conﬁdenceinterval(CI).A

two-sidedP-valueof<0.05wasconsideredasstatisticallysigniﬁcant.

StatisticalanalysiswasperformedusingRsoftware“logistf”

pack-age.StatisticalassociationbetweenpretreatmentandgradeIor

gradeIIstatusattheEPPwasanalyzedbycontingencytableand

Chi2_test._Statistical_association_between_pretreatment_and_grade_II

orIII–IVpatientsatthelastfollow-up(1year)wasalsoanalyzed

bycontingencytableandChi2_test.

3. Results

Atotalof167patientswereincludedinthisretrospectivestudy.

Thefemale-to-maleratiointhestudywas1.4,themeanageof

theincludedpatientswas58years,themedianfollow-upperiod

was35 (3–135) months,and themedian follow-up of patients

withfollow-updurationof>1yearwas60(18–135)months.Inall,

104/167patients(62%)werepretreatedbysomatostatinagonists

ordopamineagonists.Nearly16% patientshadmicroadenomas,

whereas84% hadmacroadenomas. Knospgrades3,and 4were

observedin36%patients. Surgicalremovalwasassessedbythe

neurosurgeontobelikelycompletein45%,uncertainin30%,and

incompletein 25%patients. Oftheincluded patients,112were

operated between 1997 and 2008, and 55 between 2008 and

2014.In all, 18/167 patientsunderwent radiation therapy

dur-ingthefollow-up.Amongpatientsoperatedfrom2008to2014,8

(14%)wereconsideredtopresentpathologicalaggressivefeatures

(Ki≥3).

3.1. Distributionofthedifferentgradesduringthefollow-up

Ofthe167includedpatients,167presentedanalyzabledatain

theearlypostoperativeperiod(EPP)andat3months,whereas142

wereanalyzableat1year.And139werefollowed-upformorethan

1year.Somepatientspresentedincompletedatainthefollow-up.

ThedistributionofpatientsineachgradeisdetailedinFig.1.

3.2. Gradevariationduringthefollow-up

Includingallthepatientswithallgrades,58/167(35%)moved

toanothergradefromEPPto3postoperativemonths,37/142(26%)

movedtoanothergradefrom3postoperativemonthsto1

postop-erativeyearand12/130(9%)fromonepostoperativeyeartolast

follow-up.FromEPPorM3tolastfollow-up(>1year)respectively

54/139(39%)and33/138(24%)movedtoanothergrade(Fig.2).

3.3. GradeIpatientoutcomeduringthefollow-up

Twenty-twopercentofEPPgradeIpatientsmovedtoanother

gradeduringtheﬁrst3postoperativemonths,whereas15%moved

toanothergradebetween3monthsand1yearafterthesurgery.

Aftertheﬁrstpostoperativeyear,only2%ofgradeIpatientsmoved

toanothergrade(Fig.2).

AmongthegradeIpatientsatEPP,3%escalatedtogradeIIand

9%togradeIII–IVattheendoffollow-up(Fig.3).At3months,5%

escalatedtogradeIIand7%togradeIII–IV(Fig.4).At1yearonly

2%escalatedtogradeIII–IV(Fig.5).

3.4. GradeIIpatientoutcomeduringthefollow-up

Fifty-sevenpercentofEPPgradeIIpatientsmovedtoanother

gradeintheﬁrst3postoperativemonths,andthen67%movedto

anothergradebetween3postoperativemonthsand1

postopera-tiveyear.Forty-sevenpercentofgradeIIpatientsat1yearmovedto

anothergradeaftertheﬁrstpostoperativeyear.BetweenEPPorM3

andlastfollow-up(>1year)respectively74%and75%ofpatients

movedtoanothergrade(Fig.2).

IntheEPP,amongthe49gradeIIpatientswithafollow-up>1

year:58%movedtogradeI,20%remainedatgradeII,and22%

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Fig.2.PercentageofgradeI,IIandIII–IVpatientsmovingtoanothergradeduringthefollow-up(EPP:earlypostoperativeperiod;M3:3months;Y1:oneyear;EoF:endof follow-up).

Fig.3. A–C:follow-upofpatientsclassiﬁedgradeI(A),II(B),III–IV(C)intheearlypostoperativeperiod(EPP)displayinggradechangeat3months(M3),atoneyear(Y1) andattheendoffollow-up(EofF/U).

patientswithfollowed-upfor>1year:47%movedtogradeI,25%

remainedatgradeII,and28%escalatedtogradeIII,IV,orIR(Fig.4).

At1year,amongthe19gradeIIpatientswithafollow-up>1year:

32%movedtogradeI,58%remainedatgradeII,10%escalatedto

gradeIII,IVAR,orIVB(Fig.5).

3.5. GradeIII–IVpatientoutcomeduringthefollow-up

Thirty-onepercentofgradeIVApatientsmovedtogradeIorII

duringtheﬁrst3postoperativemonths,and6%ofgradeIII-IVA-B

movedtogradeI–IIbetween3postoperativemonthsand1

post-operativeyear,asbetween1postoperativeyearandlastfollow-up

(Fig.2).

Amongthe55gradeIVpatientsatEPPwithafollow-up>1year:

20%movedtogradeIorIIwithoutprovenrecurrenceattheendof

follow-up(Fig.3).Amongthe50gradeIVpatientsat3monthswith

afollow-up>1year:14%movedtogradeI–IIand86%remained

atgradeIII,IV,orIR(Fig.4).Amongthe54gradeIII–IVpatients

withafollow-upfor>1year:only6%movedtogradeI–IIand94%

remainedatgradeIII,IV,orIR(Fig.5).

3.6. Factorsinﬂuencingthegradechangeduringthefollow-up

3.6.1. GradeIpatients

Irrespectiveoftheperiod(EPP,3months,and 1year),grade

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Fig.4. A–C:follow-upofpatientsclassiﬁedgradeI(A),II(B),andIII–IV(C)at3monthsdisplayinggradechangeatoneyear(Y1)andattheendoffollow-up(EofF/U).

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Table2

AssociationanalysesforgradeIIandIII–IVatEPP,3months(M3),and1year(Y1)betweenrecurrenceandlikelycompleteresection,uncertaincompleteresection,complete resection(includinglikelyanduncertaincompleteresection)andincompleteresection,CSinvasion,andabnormalIGF-1/abnormalGHresponsetoOGTT.Oddsratiosare displayedwith95%conﬁdenceinterval(CI).Atwo-sidedP-valueof<0.05wasconsideredtoindicatestatisticalsigniﬁcance.

Grade AnalyzedFactor Delay OR Lower95% Upper95% pval

GradeII Completeresection EPP 0.154 0.032 0.681 0.014

M3 0.133 0.022 0.68 0.015

Y1 0.161 0.009 2.57 0.181

SCinvasion EPP 4.241 1.091 17.464 0.037

M3 3.479 0.761 17.188 0.108

Y1 9.667 0.915 149.543 0.059

AbnormalIGF-1 EPP 0.448 0.116 1.669 0.229

M3 0.421 0.089 1.874 0.255

Y1 0.058 0.003 0.701 0.025

AbnormalGH EPP 2.232 0.599 8.642 0.229

M3 2.373 0.534 11.191 0.255

Y1 17.22 1.427 350.28 0.025

GradeIII–IV Likelycompleteresection EPP 0.151 0.037 0.568 0.005

M3 0.452 0.087 2.894 0.373

Y1 1.565 0.134 217.111 0.762

SCinvasion EPP 7.671 2.034 35.441 0.002

M3 4.067 0.796 25.818 0.092

Y1 3.286 0.406 37.976 0.258

ThecharacterareinboldwhenP-value<0.05.

respectively).CombininggradeIpatientsand(likelyoruncertain) completeresectionledtoaverylowrateoflong-termrecurrence (9.5%,3%,and0%,respectively).CSinvasiondidnotsigniﬁcantly impactthe rateof recurrence in grade Ipatients in this series (Table2;Suppl.Table1and2).

3.6.2. GradeIIpatients

Irrespectiveoftheperiod,likelycompleteresectionwas

corre-latedtoalowrateofrecurrenceingradeIIpatients(0%,6.5%,and

0%atEPP,3months,and1year,respectively).Therateof

recur-rencewashigherinpatientswithuncertaincompleteorincomplete

resection(28.5%and50%,respectively,vs.0%inpatientswithlikely

completeresectionat1year(Table1andSuppl.Table.1and2).CS

invasionalsoincreasedtherateofrecurrenceingradeIIpatients

irrespectiveoftheperiod(50%vs.6.5%at1year).Interestingly,

patientsclassiﬁedingradeIIbecauseofanelevatedGH

concen-trationafterOGTTpresentedahigherrateofrecurrencecompared

topatientsclassiﬁedingradeIIbecauseofanelevatedIGF-1

con-centration(at1year,40%ofrecurrenceifabnormalGHvs.7%if

abnormalIGF-1(Table2andSuppl.Table1).Elevenoutof15grade

IIpatientsattheendoffollow-upwerepretreatedbysomatostatin

ordopamineagonists.Onlyoneofthese15patientswasgradeIat

theEPPandthispatientdidnotreceiveanypretreatment.

There-fore,pretreatmentdoesnotseem toimpactonEPP assessment

ingradeIIpatients.Nosigniﬁcantdifferencewasfound

compar-ingperoperativeIGF-1levelinnon-pretreatedpatientscomparing

gradeIwithgradeIIpatientsattheEPP(datanotshown).

3.6.3. GradeIII–IVpatients

ThepercentageofgradeIII–IVpatientsremaininguncuredatthe

endoffollow-upwashighirrespectiveoftheperiod.IntheEPP,in

patientswithlikelycompletesurgicalresection,only46%gradeIV

patientsremainedatgradeIII–IVagainst78%and100%at3months

and1year,respectively(Table2andSuppl.Table3).Conversely,

gradeIVpatientsat3monthsand1yearpresentedhighrateof

persistentdiseaseevenincaseoflikelycompletetumorresection

(respectively74%and100%ofuncuredpatientsatthelast

follow-up).IngradeIVpatients,exceptintheEPP,cavernoussinusinvasion

didnotimpactsigniﬁcantlytherateofpersistentdisease(Table2

andSuppl.Table3).Amongthe56gradeIII–IVpatientsattheend

offollow-up,33(59%)werepretreated;3/56weregradeIatthe

EPPand3/3ofthesegradeIpatientswerepretreated.Moreover,

11/56patientsweregradeIIattheEPPand6/11ofthesegradeII

patientswerepretreated.Correlationanalysiswithpretreatment

andgradeIandIIatEPPdisplayedaP-valueatrespectively0.0001

and1.25.Theseresultssuggestthatpretreatmentcouldimpacton

GHandIGF-1intheEPPinnon-curedpatients.

4. Discussion

The status of GH hypersecretion (remission or persistence)

variesduringtheﬁrstyearaftersurgery.Thisisexempliﬁedbythe

factthatathirdofpatientschangedtheirstatusbetween

immedi-atepost-surgicalperiodand3months,afourthbetween3months

and1year,andalmost10%after1year.Forinstance,despite

strin-gentcriteriaofremission,22%ofsupposedlycuredgradeIpatients

immediatelyaftersurgery,and15%ofgradeIpatientsconsidered

cured3monthsaftersurgeryﬁnallybecameGH/IGF-1discordant

orrecurredduringthefollow-up.Previousliteraturedatamainly

focusontheremission/failuretodescribesurgicalresult,aviewthat

ishighlysimple,butthepresentstudyhighlightthatpostoperative

outcomeconsideringGHandIGF-1biologicalstatusremainmore

complexandcouldleadtoundeﬁnedanduncertainsituations.The

presentclassiﬁcationishelpfulinassessingtheprobabilityofgrade

changeduringthefollow-upandthereforetopredict

endocrino-logicalpatientoutcomeorincontrasttohighlighttheﬁnalpatient

outcomeuncertainty,whichcouldhelpcliniciansintheircurrent

practice.Inthisstudy,wehighlighttheﬂuctuatingpostoperative

endocrinologicalstatusof patientsoperatedforacromegaly. For

instance,12%ofgradeI,80%ofgradeII,and20%ofgradeIVatthe

EPPmovedtoanothergradeattheendoffollow-up,whereas12%

ofgradeI,75%ofgradeII,and14%ofgradeIVat3monthsmoved

toanothergradeattheendoffollow-up.

TheoutcomeingradeIpatientswasexcellent.Thesecretory

status ofthemajority of gradeI patientsseemtobe deﬁnitely

determined1yearaftersurgery.Combinationwithneurosurgeon

peroperativeimpressionof(likelyoruncertain)completeremoval

ledtoaremissionrateof>90%attheendoffollow-up.Inthese

patients,adding theﬁve-tieredclassiﬁcationusinginvasion and

proliferation would probablyhelp determinethe optimal

long-termmonitoringmodalities,especiallyforthe10%patientswho

willchangestatusduringthefollow-up[7].Thiswasnotpossible

inourstudy,asthepathologysamplesfrom1997to2008didnot

includeadequateproliferationdata.

Grade II patients, i.e., those with discordant GH and IGF-1

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numberofpatientswithbiologicalstatuschangeduringfollow-up,

evenaftertheﬁrstpostoperativeyear.Inliterature,these

discor-dantpatientswithuncertainremission remainrarelydescribed

[2,3,8].However,theyrepresentanon-negligiblepartofpatients

(35.5%immediatelyaftersurgery,24.5%at3months,and11–13.5%

duringtheremainingfollow-up),andtheconsequencesof such

discordanceremainunclear in terms ofpersistence or

worsen-ingofcomorbidities.Nevertheless,theoutcomeofthesepatients

seemsfavorable:approximately50%of gradeIIpatientsatEPP,

M3,andY1movedtogradeI.Afteroneyear,only10%ofgradeII

recurred.Intheﬁrstpostoperativeweeks,IGF-1couldremainhigh

givenitsslowerbloodleveldecreasecomparedtoGH.This

prob-ablyexplainsthefavorableoutcomeofapproximatelyonehalfof

gradeIIpatients,particularlyincaseofabnormalIGF-1compared

topatientswithabnormalGHinthe3ﬁrstpostoperativemonths.

ProgressivenormalizationofIGF-1alsoprobablyatleastexplains

thedecreaseinthepercentageofgradeIIpatientsduringtheﬁrst

postoperativeyear.Butthisremainsuncleargiventhelackof

dif-ferenceinpreoperativeIGF-1levelcomparinggradeIandgrade

IIpatientsattheEPP.Nevertheless,itisinterestingtonotethat

gradeIIpatients’outcomeremainsuncertainevenafterone

post-operativeyear.TheremaininggradeIIpatients’outcomewasquite

sharedbetweenpersistentgradeIIpatientswithoutdemonstrated

recurrence,andgradeIII–IVpatientswithprovenrecurrence.CS

invasionasuncertaincompleteorincompleteremovalsigniﬁcantly

increasedrecurrencerateand shouldbeconsideredasrelevant

prognosis factors, in accordance with the ﬁve-tiered

classiﬁca-tion[7].Interestingly,expertneurosurgeonperoperativeﬁnding

of complete or incomplete resection, which includes a part of

subjectivity,appearsrelevantinassessingtheriskofrecurrence.

AbnormalOGTT or highGH level seemed more predictive and

speciﬁcofrecurrencethanhighIGF-1levelinthethirdﬁrst

post-operative monthsbut alsoatone year.Previous literaturedata

reporteddiscordantresultsonthispoint[8–14].Verruaetal.

sug-gestedthattheGHnadir<0.4ng/LonOGTTmaybetoolowand

thatIGF-1level3monthsaftersurgerywouldbemorerobustto

assessremission[15].GradeIIdeﬁnitionremainsdirectlyrelatedto

selectedbiologicalthresholdsandtheimpactoftheIGF-1andGH

dosagetechnicsshouldbeconsidered.Thresholdsdetermination

remainschallengingandcurrentlystilldebated[2].Establishment

ofmorestringentbiologicalthresholdswillleadtoahigher

speci-ﬁcitybutincontrastwillincreasethenumberofdiscordantgrade

IIpatientsand conversely[3,15].Inthis study,pretreatmentby

somatostatinanddopamineagonistsdoesnotseemtoimpactthe

EPPassessmentinthegradeIIpatients.GradeIIpatientsshouldin

anycasebeneﬁtfromalong-termfollow-up,whichisalsoalimit

ofthepresentstudyandwhichshouldbeofhighinterest.

GradeIII,IV,andIRpatientsrepresented37%,32%,39.5%,and

40% at EPP,M3, Y1,and theend of follow-up, respectively. At

EPP and 3 months, 20% and 12% of grade IV patients moved

to grade I–II at the end of follow-up, respectively. Moreover,

31%grade IVpatientsmove toanothergrade betweenEPPand

3 months, which could be at least partially explained by

pre-treatmentwithsomatostatinordopamineanalogues.Thisisalso

probably related to the variable postoperative decrease in GH

andIGF-1 blood level.In theEPP,likely completetumor

resec-tionaslackofcavernoussinusinvasionsigniﬁcantlydecreasedthe

riskofrecurrence.Conversely,after1postoperativeyear,only6%

patientsmovedtoanothergrade.Thesecretorystatusofmostgrade

III–IVpatientsseemstobedeﬁnitelydeterminedat1yearafter

surgery.At3monthsand1year,gradeIVpatientsmostlyremained

uncuredirrespectiveofcavernoussinusinvasionorneurosurgeon

observations.

Toconclude,weanalyzedthetimeframepostoperative

GH/IGF-1secretorystatuswiththehelpofaclassiﬁcationthatshouldalso

help clinicianstobetterdeﬁnethecertainty and uncertaintyof

theirpatients’outcome.GradeIandIII–IVpatients’outcomeseems

deﬁnedaftertheﬁrstpostoperativeyear.Incontrast,for

discor-dantgradeIIpatients,theoutcomedespitequitefavorableremains

undefinedanddifficulttopredictevenafterthefirstpostoperative

year.

Funding

NoFunding.

EthicalApproval

Allproceduresperformedinstudiesinvolvinghuman

partici-pantswereinaccordancewiththe1964Helsinkideclarationand

itslateramendments.

Disclosureofinterest

Theauthorsdeclarethattheyhavenocompetinginterest.

AppendixA. Supplementarydata

Supplementarydataassociatedwiththisarticlecanbefound,in

theonlineversion,at:https://doi.org/10.1016/j.ando.2019.11.002.

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