Hybrid FDG-PET/MRI for Diagnosis and Clinical Management of Patients with Suspected Perihilar Cholangiocarcinoma: A Feasibility Pilot Study

Abstract

Recently introduced hybrid 2-[18 F]-fluoro-2-deoxy-D-glucose (18 F-FDG) Positron Emission Tomography (PET) combined with Magnetic Resonance Imaging (MRI) may aid in proper diagnosis and staging of perihilar cholangiocarcinoma (pCCA). The aim of this study is to assess the effect of 18 F-FDG PET/MRI on diagnosis and clinical decision making in the pre-operative work up of pCCA.
In this single-centre pilot study patients with presumed resectable pCCA underwent state-of-the-art 18 F-FDG hybrid PET/MRI using digital silicone photomultiplier detectors integrated within a 3-Tesla bore. Data were collected on several baseline and imaging characteristics. The primary outcome measure was the added diagnostic information and the effect on clinical decision making. Secondary aim was to correlate quantitative PET signal intensity to patient- and tumour characteristics. High and low SUVmax subgroups related to the mean value were made. Significance of lesion- and patient characteristics with the high and low SUVmax subgroups, as well as TLR and TBR, was evaluated with Fisher’s exact test or Mann-Whitney-U test.
In total 14 patients were included (mean age 62.4 years, 64% male). Final diagnosis was pCCA in 10 patients (71.4%), follicular lymphoma in one patient (7.1%) and benign disease in the remaining three patients. FDG-PET/MRI added valuable diagnostic information in six (43%) patients and affected clinical decision making in two of these patients (14%) by increasing confidence for malignancy which lead to the decision for surgery on short term. High SUVmax values were seen in half of cases with pCCA and half of cases with non-cancerous lesions. In addition, high SUVmax values were directly associated with primary sclerosing cholangitis when present (p = 0.03).
Simultaneous 18 F-FDG-PET/MRI added diagnostic information in six of fourteen patients and influenced clinical decision making in two patients (14%) with presumed resectable pCCA.

Full text

ORIGINAL ARTICLE
Nuclear Medicine and Molecular Imaging
https://doi.org/10.1007/s13139-024-00873-2
Abbreviations
FDG 18F-uro-deoxy-glucose
PET PositronEmissionTomography
MRI MagneticResonanceImaging
MRCP MagneticResonance
Cholangio-Pancreatography
CT ComputedTomography
pCCA PerihilarCholangiocarcinoma
SUV StandardizedUptakeValue
PSC PrimarySclerosingCholangitis
EANM EuropeanAssociationofNuclearMedicine
R.S.Dwarkasing
r.s.dwarkasing@erasmusmc.nl
D.M.deJong
d.m.dejong@erasmusmc.nl
1 DepartmentofGastroenterologyandHepatology,Erasmus
MCUniversityMedicalCenter,Rotterdam,theNetherlands
2 DepartmentofRadiologyandNuclearMedicine,Erasmus
MCUniversityMedicalCenter,Rotterdam,theNetherlands
3 DepartmentofSurgery,ErasmusMCUniversityMedical
Center,Rotterdam,theNetherlands
Abstract
Purpose Recentlyintroducedhybrid2-[18F]-uoro-2-deoxy-D-glucose(18F-FDG)PositronEmissionTomography(PET)
combinedwithMagneticResonanceImaging(MRI)mayaidinproperdiagnosisandstagingofperihilarcholangiocarci-
noma(pCCA).Theaimofthisstudyistoassesstheeectof18F-FDGPET/MRIondiagnosisandclinicaldecisionmaking
inthepre-operativeworkupofpCCA.
Methods Inthissingle-centrepilot studypatientswithpresumed resectablepCCAunderwentstate-of-the-art18 F-FDG
hybridPET/MRIusingdigitalsiliconephotomultiplierdetectorsintegratedwithina3-Teslabore.Datawerecollectedon
severalbaselineandimagingcharacteristics.Theprimaryoutcomemeasurewastheaddeddiagnosticinformationandthe
eectonclinicaldecisionmaking.SecondaryaimwastocorrelatequantitativePETsignalintensitytopatient-andtumour
characteristics.HighandlowSUVmaxsubgroupsrelatedtothemeanvalueweremade.Signicanceoflesion-andpatient
characteristicswiththehighandlowSUVmaxsubgroups,aswellasTLRandTBR,wasevaluatedwithFisher’sexacttest
orMann-Whitney-Utest.
Results Intotal14patientswereincluded(meanage62.4years,64% male). Final diagnosis was pCCAin10patients
(71.4%),follicularlymphomainone patient (7.1%) andbenigndiseaseintheremaining three patients. FDG-PET/MRI
addedvaluablediagnosticinformationinsix(43%)patientsandaectedclinicaldecisionmakingintwoofthesepatients
(14%)byincreasingcondenceformalignancywhichleadtothedecisionforsurgeryonshortterm.HighSUVmaxvalues
wereseeninhalfofcaseswithpCCAandhalfofcaseswithnon-cancerouslesions.Inaddition,highSUVmaxvalueswere
directlyassociatedwithprimarysclerosingcholangitiswhenpresent(p =0.03).
Conclusion Simultaneous18F-FDG-PET/MRIaddeddiagnosticinformationinsixoffourteenpatientsandinuencedclini-
caldecisionmakingintwopatients(14%)withpresumedresectablepCCA.
Keywords HilarCholangiocarcinoma·PET/MRI·ClinicalDecisionMaking· BiliaryTractcancer
Received: 15 February 2024 / Revised: 14 June 2024 / Accepted: 8 July 2024
© The Author(s) 2024
Hybrid FDG-PET/MRI for Diagnosis and Clinical Management of
Patients with Suspected Perihilar Cholangiocarcinoma: A Feasibility
Pilot Study
D. M.deJong1· K.Chehin2· T. L.N.Meijering1· M.Segbers2· L. M.J.W.vanDriel1· M. J.Bruno1·
B.Groot Koerkamp3· J. N.M.IJzermans3· F. A.Verburg2· Q. G.de Lussanet de la Sabloniere2·
R. S.Dwarkasing2
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Nuclear Medicine and Molecular Imaging
EARL EANMResearchLtd
TNM Tumour,Node,Metastasis
STROBE StrengtheningtheReportingofObservational
StudiesinEpidemiology
MDTB MultidisciplinaryTumourboard
BC Bismuth-Corlette
VOI Volumeofinterest
TLR Tumourtoliverratio
TBR Tumourtobackgroundratio
SD StandardDeviation
Introduction
Perihilar cholangiocarcinoma (pCCA) is an uncommon
malignancyandoftenpatients present atalatestage with
advanced disease [1]. Radical surgical resection or liver
transplantation are the only potential means of achiev-
ing long term survival [2, 3]. Many patients have locally
advanced disease with vascular encasement, positive
regionalorextraregionallymphnodes,ordistantmetastasis
uponrstpresentation [4].Additionally,upto 47%ofthe
eligiblepatientsarefoundtohaveunresectablediseasedur-
ingexplorativelaparotomy[3,5,6].
Incurrent clinicalpractice,computedtomography(CT)
andmagneticresonanceimaging (MRI)areusedtoevalu-
atelocaltumourextentandresectabilityofpCCA.CTwith
intravenous contrast is especially useful for determining
tumourextentandinparticularvascularinvolvementofthe
hepaticarteryandportalvein,includingdistantmetastases
[7]. MRI in combination with cholangiography (MRCP)
providesdetailedanatomicalinformationofthebiliarytree,
whichisimportantforsurgicalplanningduetoawidevari-
etyofanatomicalvariations[8,9].BothCTandMRI/MRCP
understageresectablepCCAoften,asunderlinedbythehigh
numberofpatientswithunresectablediseaseatexplorative
laparotomy[3,5,6].Pangetal.demonstratedthevalueof
dual-time point 18 F-uorodeoxyglucose (FDG) positron
emission tomography (PET) CT (PET/CT) for primary
tumour location(s), including lymph node metastases in
pCCA.Inaddition,theauthorsdescribedthatthemaximum
standardizeduptakevalue(SUVmax)maybeindicativefor
tumouraggressiveness[10].Thelastyears,moreevidence
hasbeenpublishedontheincorporationof2-[18F]-uoro-
2-deoxy-D-glucose(18F-FDG)PETimagingintothecur-
rentstandardofcareforbiliarytractcancerstaging,butthe
exactroleremainscontroversial[11].PrimarilyPET/CThas
notbeenthemajorbreakthroughashoped.
Recently, 18 F-FDG PET with MRI (PET/MRI) has
become available. FDG-PET/MRI has shown additional
value for pre-treatment work up in several malignan-
cies, such as breast- and pancreatic cancer [12, 13]. The
combinationoftheinformationonsoft-tissuesobtainedby
theMRIandmetabolicinformationofthePETcouldprove
a favourable utility. So far, small studies have been per-
formedinpatientswithhepatobiliaryneoplasms,including
pCCA.ItwasreportedthatsimultaneoushybridFDG-PET/
MRI has promising benets over conventional preopera-
tiveimaging with CT and MRI/MRCPorcombinedwith
PET/CT[14–17].InthestudyofObmannetal.onsixteen
patientswithhepatobiliaryneoplasms,FDG-PET/MRIcor-
rectly changed the cTNM stage in 22% of patients with
consequentchangeinmanagementin11%ofpatientswith
extrahepaticcholangiocarcinoma[14].
WhenmeasuringSUVin additiontovisualassessment
ofPETimagesone should consider possible confounding
eectsowingtodierencesamongPETsystemsanddif-
ferencesinacquisitionandimagereconstructiontechniques
thatmaysubstantiallyaectthemeasuredSUVvalues[18].
Forthesereasons eortsaremade toharmonizeand stan-
dardizeSUVmeasurementsforPET/CTsuchastheEuro-
peanAssociation of Nuclear Medicine (EANM)Research
Ltd. (EARL) guidelines. These recommendations, named
theEARL2,recentlybecame availableforPET/MRI,that
also include the higher spatial resolution based EARL2
standard.AspCCAisoftentimesanon-bulkytumour with
linear tumour spread along the biliary tree, and conse-
quentlylikelysubject to partial-volumeeectsSUVmea-
surementsonEARL2 PETimagingreconstructions seems
mostappropriate.
Theaimof thisstudywasto assesstheaddedvalue of
FDG-PET/MRIfordiagnosisandclinicaldecisionmaking
inpatientswithsuspectpCCAoptingforsurgicalresection.
ThesecondaryaimwastomeasurequantitativePETsignal
intensityfeatureswiththeuseofEARL2onthelesion,liver
parenchyma,bloodpooland correlatethesemeasurements
topatient-andtumourcharacteristics.
Materials and methods
Patient Population
BetweenNovember2021andApril2022,a single-centre,
prospective, observational cohort study was conducted
(POELHtrial;NL9599).Eligiblepatientswerediscussedin
themultidisciplinarytumourboard (MDTB) andincluded
afterPET/MRIforworkupofsuspectedresectablepCCA,
regardlessof eventual histopathology results.The MDTB
approved the indication for PET/MRI when diagnosis
and staging was uncertain and deemed possible bene-
cial for clinical management. This study was conducted
in accordance with the Helsinki declaration and followed
theSTROBEguidelinesafterbeingapproved bythelocal
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Nuclear Medicine and Molecular Imaging
ethicalreviewcommittee(MEC-2021-0524).Fivepatients
underwentPET/MRIshortlybeforethetrialformallystarted
andwereincludedretrospectivelyafterprovidinginformed
consent.TheindicationsandPET/MRIitselfwereidentical
to(therestof)thestudycohort.
Surgery Work-Up
AttheMDTB,comprisedofspecializedgastroenterologists,
oncologists,surgeons,radiologists,andnuclearphysicians,
allpatientswithsuspectedpCCAarediscussedtodetermine
thebestcourseofaction.All patients underwent a multi-
phase CT scan of the liver, including imaging of the full
abdomenandthorax,aswellasMRIoftheliver,including
MRCP,forinitialassessment.FindingsfromCTandMRI/
MRCParepresentedanddiscussedduringthemeeting,with
particularattentionpaidtolongitudinaltumourextent,vas-
cular invasion and suspect distant metastases. Suspected
pCCAisclassiedaccordingtotheBismuth-Corlette(BC)
classicationsystem.Positiveregionallymphnodeswere
notconsideredacontra-indicationforresection,exceptfor
livertransplantation.Inaddition,inthesurgeryworkupan
endoscopicbiliarydrainagewithplastic stentsisroutinely
performedinpatients.Giventhatjaundiceorcholestasisis
acommonpresentingsymptomofpCCA,preoperativebili-
arydrainageistypicallyperformedatourcentrewhenbili-
rubinlevelsriseabove70mmol/L.
Imaging Protocol for FDG-PET/MRI
Simultaneous PET/MR imaging was performed using a
General Electric Healthcare (GE) Signa PET/MR (GE
Healthcare, Waukesha, MI, USA). Median time intervals
between CT and PET/MRI were 1 week [IQR: 1–2] and
between MRI and PET/MRI were 2 weeks [IQR: 0.5–3].
Patient preparation and PET image acquisition was per-
formed in accordance with the European Association of
NuclearMedicine(EANM)ResearchLtd.(EARL2)guide-
lines[19].Preparationconsistsoffastingatleast6hbefore
thePET/MRI.Priortothescan,serumglucoselevelswere
measuredinmmol/L.Eachpatientunderwentwhole-body
hybrid PET/MRI at 60 (+/-5) minutes after injection of
18 F-FDG (weight 55–100 kg: 0.033 MBq * (kg)2, 101–
140kg:0.025MBq*(kg)2;maximumactivity:500MBq).
Three(55–100kg)tofourminutes(>100kg)perbedposi-
tion;vertex–mid-thigh.Directlyfollowing(approximately
120minafterinjection),hybridPET/MRIwasacquiredfor
onetableposition oftheupperabdomen, withafullMRI
of the liver including contrast- enhanced (Gadolinium-
chelates) series, and continuous PET acquisition for the
fulldurationoftheMRIliverprotocol.AllPETdatawere
reconstructedaccordingto therecentEARL2 standardfor
PET/MR [18]. Standard DIXON based attenuation cor-
rectionwasappliedusingafour tissueclasssegmentation
(water,fat,lung,air).
SUVmeanoftheliverwasmeasuredbya100mlspheri-
calvolumeofinterest(VOI)intherightupperrightlobeof
theliver(excludingmainvascularstructures)andSUVmean
ofthebackgroundwasmeasuredbya10mlsphericalVOI
intherightheartchamber.SUVpeak, dened by the hot-
test1mlspherical region intheVOI,and SUVmax were
measuredinsphericalVOI’saroundthepCCAlesions.The
highestSUVpeakandSUVmeanwerereportedforpatients
with multiple or extended pCCA lesions requiring mul-
tipleVOImeasurements. The tumourtoliverratio(TLR)
andtumourtobackground ratio(TBR)werecalculatedby
dividing the lesion SUVmax and SUVpeak with respec-
tivelytheliver SUVmean and background SUVmean. Of
note,aspCCAisoftentimesanon-bulkytumourwithlinear
tumourspreadalongthebiliarytree,it islikelythatSUV-
peakmeasurements willnotbepossibleand/orunreliable
insomepatients.AllSUVmeasurementswereperformedin
thePhilipsVUEPACSviewer(version12.2).
Outcome Measures
Theprimaryoutcomewasthe(1)addedvaluefordiagnosis
and(2) inuence on clinical decision making. The added
valuefornaldiagnosiswastwofold.Firstly,itwasbased
onchangesintheTNM stagingofPET/MRIcomparedto
CTandMRI/MRCP.Secondly,it wasbasedoncombined
expert opinion by the reporting radiologist (Dwarkasing)
andnuclearphysician(LussanetdelaSabloniere).Inuence
onclinicaldecisionmakingwasdenedasanadjustmentin
managementplanafterPET/MRI.Thiswasassessedretro-
spectivelybytheresearchteam(Meijering,deJong,Dwar-
kasing,LussanetdelaSabloniere)basedonthestructured
reports of MDTB before and after PET/MRI available in
patientsdigitalrecords.FindingsonPET/MRIthatshowed
additionalvalue,butdidnotaectclinicaldecisionmak-
ing,suchas increasingthesuspicion ofmetastaticdisease
orbenigndiseasewerereportedassuch,conformtworecent
studies[20,21].
Secondary outcomes were associations of SUVmax,
TLRandTBR,withpatientage,sex,histology,historyof
PrimarySclerosingCholangitis(PSC), CA19.9 levelsand
BCclassication.Finaldiagnosiswasbasedonhistopathol-
ogyprovendiseaseorclinicalmanagementwithlongterm
followup,includingconrmationbytheMDTB.
Statistical Analysis
Fornalanalysispatientswerecategorizedintotwosub-
groups based on the mean SUVmax of the (suspected)
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Nuclear Medicine and Molecular Imaging
TNM Staging, Additional Value and Accuracy
Inhalfofthepatients(n =7,50%),PET/MRIdidnotpres-
entchangestotheTNMstagingcomparedtoCTandMRI/
MRCP.Intwocases(14%)theTstagewaschangedtoT2b
byPET/MRIinstead ofT3on CT(patient#4 &#9).In 7
cases(50%), regional lymph nodes were down staged by
PET/MRIduetothefollowingreasons:nonFDG-avidLN
with a FDG-avid tumour (from N1 to N0, (n =2) and in
another5patientsregionalLNidentiedonCTandMRI/
MRCPwerenotseenonPET/MRI:N2toN1(n =1);N2to
N0(n =1);andN1toN0(n =3)(Fig.1).PET/MRIdidnot
changeM-stage,asinallpatientsnoextrahepaticdisease
wasidentiedbyCT,MRI/MRCPandPET/MRIandclini-
calfollowup.Inonecase(14%)ofpCCABCclassication
waschangedfromtype2totype3A(patient#9)byPET/
MRI.
In most cases (n =11, 79%) PET/MRI did not present
additionaldiagnosticinformationtopreviousCTandMRI/
MRCP.Thesuspicionforprimarymalignancychangedafter
PET/MRIinthreecases(21%). In one case(7%),benign
diseasewasmoreprobablebasedonPET/MRIastherewas
noFDG-avidityofthelesion, noclearmassandno archi-
tecturedistortionofperihilaranatomy(patient#8).Intwo
cases,highFDG-avidityincreasedthecondenceformalig-
nancywithnotableFDG-avidityofa smalllesion(patient
#5&#11).
In11cases,asurgicalstagingprocedurewithorwithout
resection was performed. In two patients, no malignancy
wasidentiedandinone patient no pCCA,butafollicu-
larlymphomawasidentied.SurgicalassessedTstagewas
availablein5caseswithNstageavailablein8cases.Tstage
was correctly identied on CT (n =2, 40%); MRI/MRCP
(n =3, 60%); and PET/MRI (n =2, 40%) respectively. N
pCCAlesionswithhighandlowSUVmaxsubgroupswith
cut-ovalueequaltothemeanvalue.Signicanceofpatient
characteristicswiththehighandlowSUVmax subgroups,
aswellasTLRandTBR,wasevaluatedwithFisher’sexact
testor Mann-Whitney-U test. Other features were patient
age (older or younger than 65 years) and CA19.9-levels
(patientswithmoreoflessthan37kU/L).Inaddition,SUV-
maxwasrelatedtothepresenceofPSC,naldiagnosisand
totheBCclassicationincaseofpCCA.Alltestsweretwo-
sided,andaP-valueoflessthan0.05was consideredsta-
tisticallysignicant.IBMSPSSStatistics(Version27)was
usedtoperformallstatisticalanalyses.
Results
Baseline Characteristics
We included 14 patients (64% male, mean age 62.4
(Standard Deviation (SD) 13.5)). Median BMI was 25.3
[IQR: 23.3–26.7]. Elevated levels of CA19.9 were seen
in9patients(64%).Ahistory of PSCwaspresentinve
patients(36%) (Table1).FinaldiagnosiswaspCCAin10
patients (71%), intra-ductal papillary mucinous neoplasm
ofthebileductinonepatient(7.1%),follicularlymphoma
inonepatient (7%),IgG4-mediateddisease inonepatient
(7%),andunspeciedbenigndiseaseinonepatient(7%)
(Table2). In 12 patients (86%) nal diagnosis wasbased
onpatho-histologicalproof,intwopatients(14%)onlong
termclinicalfollow-up.InpCCApatients,BCclassication
basedonCTand MRI/MRCPweretype1(n =3); type 2
(n =3),type3A(n =3),type 3B(n =2),and type4(n =1)
respectively. Median serum glucose levels prior to PET
MRIwere6.1mmol/L[IQR:5.4–6.2].
Table 1 Baselinecharacteristicsofthestudypopulation
Patient# Sex Age(inyears) HistoryofPSC BMI CA19.9(inkU/L) Glucoselevels(mmol/L)*
1 F 81 - 27.9 183 6.1
2 M 69 -25.7 348 4.5
3 F 61 +25.1 111 6.2
4M74 -24.4 1096 5.3
5 M 79 +20.9 1987 6.2
6M69 - 25.3 99 7.2
7F68 -22.6 284 6.9
8 F 64 -26.9 < 2 5.7
9 M 52 - 26.2 6802 5.8
10 M61 +22.4 -6.3
11 M56 -23.4 11 5.1
12 M 50 +23.2 14 6.1
13 F 28 +28.4 159 5.3
14 M61 -28.6 < 2 6.0
BMI=BodyMassIndex,PSC=PrimarySclerosingCholangitis
* = Prior to PET/MRI
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Nuclear Medicine and Molecular Imaging
Patient
#
CT MRI/MRCP PET/MRI Stentinsitu SUVmax TLR TBR Diagnosticvalue Eect
on
CDM
FinalDiagnosis Surgery
TNMaBC TNMaBC TNM BC TNM
1T2aN2M0 3a T2aN2M0 3a T2aN1M0 3A -3.7 1.09 2.18 PETMRImadelymphnodes
suspiciousformetastases
- apCCA,clinicalfollow-up X
2T2bN1M0 3b T2bN1M0 3b T2bN0M0 3B - 1.8 0.9 1.06 Noadditionalinformation -pCCA,resection
(path-proven)
T3N0Mx
3T2bN2M0 2T2bN2M0 2T2bN0M0 2 - 5.6 2.15 2.95 Noadditionalinformation -pCCA,biopsy
(path-proven)
X
4 T3N1M0 3a T3N1M0 3a T2bN1M0 3A PS + PTCD 4.2 1.75 2.21 Noadditionalinformation -UnresectablepCCA,DLS
(path-proven)
T4N1Mx
5T2aN1M0 1T2aN1M0 1T2aN1M0 1 - 6.2 2.58 4.77 Increasesuspicionofmalig-
nancycomparedtoprevious
imaging
+UnresectablepCCA,DLS
(path-proven)
TxN2Mx
6 T2aN1M0 3b T2aN1M0 3b T2aN1M0 3B -6.3 1.91 2.74 Noadditionalinformation -Intraductalhighgradedysplasia,
resection
(path-proven)
Tx/1N0Mxb
7 T2aN1M0 3a T2aN1M0 3a T2aN0M0 3A PS + 2
ucSEMS
2.9 1.26 1.71 Noadditionalinformation -pCCA,resection
(path-proven)
T2aN0Mx
8T2bN1M0 1T2bN1M0 1X X PS +fcSEMS 5.5 2.2 3.06 PETavidityaroundthe
plasticstentmostlikelydue
toreactiveorinammatory
changes
-Benignpathology,resection
(path-proven)
X
9T3N1Mx 2T3N1Mx 2T2bN0Mx 3A 2xPS 5.3 2.3 4.08 EnlargedregionalLNpos-
siblemalignantonCTand
MRI,notPETavidandnot
suspiciouswithPET
- cpCCA,resectionwithLNnegative
(path-proven)
T2aN0Mx
10 T2aN1M0 2T2aN1M0 2T2aN0M0 2 PS 6.9 3.45 3.14 Noadditionalinformation -pCCA,biopsy
(path-proven)
TxN1Mx
11 T1N0M0 1T1N0M0 1T1N0M0 1 - 3.1 1.41 2.07 Increasesuspicionofmalig-
nancycomparedtoprevious
imaging
+pCCA,resection
(path-proven)
T1N1Mx
12 X X X X X X - 5 2.5 3.33 Noadditionalinformation -Follicularlymphoma,resection
(path-proven)
X
Table 2 Cross-sectionalimaging,PET/MRIcharacteristicsandfollow-up
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Nuclear Medicine and Molecular Imaging
stagewascorrectlyidentiedonCT,MRI/MRCP,andPET/
MRIin4cases(50%),respectively.
Inuence on Clinical Decision Making
PET/MRIaectedclinicaldecisionmakingintwopatients
(14%).Inthesetwopatients(patient#5&#11),PET/MRI
increasedthesuspicionofprimarymalignancysolelybased
onhightumourFDGaviditycomparedto theliver,which
resultedinadecisiontoperformsurgery,insteadofpossible
furtherinvasivediagnosticproceduresorconservativeman-
agement.BothpatientshadsurgicallyconrmedpCCA.In
theremaining12patients(85.7%),PET/MRIdidnotaect
clinicaldecisionmaking(Table2).
Measurement of SUVmax, Correlated with Patient
Characteristics
The mean SUVmax value for the PET/MRI of the liver
was4.59[95%CI:3.81–5.37].HighandlowSUVmaxsub-
groupswerecreatedrelativetothemeanSUVmaxvalueof
theliver(4.59);bothconsistedof7patientseach.Correla-
tionsofSUVmaxwithbaselineclinicalcharacteristicswas
evaluated(Table3).Inmostpatients(n =13)onespherical
VOI’saroundtheperihilarlesionwasappliedforSUVmax
measurement.Onepatienthadmeasurementswithmultiple
sphericalVOIsof thelesiondue totheextendedshape of
thetumour.
A signicant correlation was found for high SUVmax
andhistoryofPSC(p =0.03).Nosignicantcorrelationwas
foundbetweenSUVmaxandage(p =0.28),sex(p =0.99),
CA19.9 levels (p =0.99), histopathology proven cholan-
giocarcinoma (p =0.99), and BC type pCCA (p =0.99)
(Table 3). SUVmax threshold that could dierentiate
betweenbenignand malignantlesionswasnot achievable
mainlybecauseofthelimited number of non-CCAcases.
Cases with pCCA (n =10) showed either relatively high
SUVmax values (n =5) (Fig. 2) or low SUVmax values
(n =5)(Fig. 3).Furthermore,benignlesions demonstrated
bothlow(n =1)andhigh(n =1)SUVmaxvalues(Fig.4).
Measurements of TLR and TBR, Correlated with
Patient Characteristics
The mean TLR was 1.87 [95%CI: 1.51–2.23]; the mean
TBR was 2.63 [95%CI: 2.13–3.14]. There were no sig-
nicant associations between TLR and nal diagnosis
(p =0.67),norbetweenTBRandnaldiagnosis(p =0.89).
NosignicantcorrelationwasfoundwhenanalysingTLR
asdichotomousoutcomeswithcut-ovalueof1.3.
Patient
#
CT MRI/MRCP PET/MRI Stentinsitu SUVmax TLR TBR Diagnosticvalue Eect
on
CDM
FinalDiagnosis Surgery
TNMaBC TNMaBC TNM BC TNM
13 T4N1M0 4 T4N1M0 4 T4N0M0 4 - 5.1 1.59 2.68 EnlargedregionalLNpos-
siblemalignantonCTand
MRI,notPETavidandnot
suspiciouswithPET
-pCCA,brush
(path-proven)
TxN1Mx
14 X X X X X X -2.7 1.08 1.59 Noadditionalinformation -IgG4mediateddisease,prednisone
treatmentwithgoodeect.FUfor
9months
X
IgG4=ImmunoglobulinG4,SUV=StandardizedUptakeValue,TLR=TumourtoLiverRatio,TBR=TumourtoBloodpoolRatio,DLS=diagnosticlaparoscopy,LN=lymphnodes,path-
proven=histopathologyprovendisease,PS=plasticstent,PTCD=percutaneoustrans-hepaticcatheterdrainage,ucSEMS=uncoveredself-expandingmetalstent,fcSEMS=fullycovered
self-expandingmetalstent,BC=Bismuth-Corlette,CDM=ClinicalDecisionMaking,TNM=Tumour,Node,Metastasis
aPalliativetreatmentperrequestofthepatient
bIPNBwithoutinltrativegrowth
cRegardlessofsuspiciouslymphnodessurgery,thereforenoimpactonclinicaldecisionmaking
Table 2 (continued)
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estimatedtheTstageintwopatientsandincorrectlychanged
theNstagefromN1toN0intwopatients.Thesendings
alignwitha recentstudyofObman et al.,whichreported
thatFDG-PET/MRIcorrectly adjustedthecTNMstage in
22% of patients with various hepatobiliary malignancies
[14].RegardingchangesintheNstage,apotentialexplana-
tionmaybethatprominentlymphnodesaremoredistinctly
visualizedusingdedicatedCTandMRI/MRCPscans with
contrast.InPET/MRI,theselymphnodesareonlyidentied
whentheydemonstrateavidactivityonthePETimage,and
correlatedwiththeMRIimage.Normallymphnodeslack-
ingPETavidityarethereforenot visible on regular PET/
MRI,whiletheseareclearlydiscernibleondedicatedCT
andMRI/MRCP.ApotentialadvantageofPET/MRIcom-
pared to PET/CT has been described by Catalano et al.,
which found PET/MRI to characterize lymphadenopathy
Discussion
Our study found a notable disparity in TNM staging,
observedin50%ofpatients,betweenhybrid18-FDG-PET/
MRI and conventional cross-sectional imaging using CT
andMRI/MRCP.Theadditionaldiagnosticbenetprovided
byPET/MRIamountedto 21%, andPET/MRIinuenced
clinicalmanagementinmerely14%ofpatientswithsus-
pectedpCCAeligible for surgery.Furthermore, with PET
signalintensitymeasurementswefound a signicant cor-
relationbetweenahighlesionSUVmaxandhistoryofPSC
(p =0.03).
Among the eleven patients that underwent surgical
exploration or resection, PET/MRI accurately altered the
Nstageinthreepatients.Conversely,PET/MRIincorrectly
Fig. 1 PET/MRIofpatientwith pathologicallyconrmed pCCAand
negativeregionallymphnode(#9).Anillustrativecase ofa52-year-
oldmalewithpCCA (histopathologyproven).A,B) Small enhanc-
ingtumourmass(B,longarrow)islocatedatthehilumofthebiliary
treewithdilatation ofintrahepaticducts. Bismuth-CorletteII lesion.
Inaddition, enlargedloco regionallymph nodes(A, B,small arrow)
wereseeninthehepatoduodenalligament.TNMstagingbasedonCT
(A,axialcontras-enhancedCTimage)andMRI/MRCP(B,axialcon-
trast-enhancedT1-weightedMRimage)wasT3N1MxandT2aN1M0
respectively.C,D)AxialPET/MRIimage.Theprimarytumourdem-
onstratesFDG-avidity(C)withnoFDG-avidityoftheregionallymph
nodes(D).TNMstageafterPET/MRIwasT2bN0Mx(N-stagedown-
gradedfromN1toN0afterPET/MRI)
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mucinous neoplasms [29]. We were unable to reproduce
these ndings with pCCA both as a continuous variable
andasadichotomousvariableusingthesamecut-ovalue.
Twopatientswithnon-malignantdiseaseinourstudy,spe-
cically with high-grade dysplasia and unspecic benign
disease who underwent resection, had high TLR values.
Inclinicalpractice, itisgenerally assumedthatmalignant
lesions will display notable FDG-avidity with high TLR
value.Ourobservationdoesnotsupporttheseassumptions,
althoughourndingsarelimitedby the small number of
includedpatientswithbenigndisease.Inaddition,allcases
of pCCA in underlying PSC livers (n =5) demonstrated
high SUVmax values. This was a signicant nding and
may be an important imaging marker for pCCA in PSC
patients. Validation of this nding is warranted in larger
studypopulations.
Tomimaru et al. investigated the use of SUVmax val-
ues in dierentiating malignant from benign intraductal
papillary mucinous neoplasms (IPMNs) in 29 patients
[31]. The results showed that SUVmax values were sig-
nicantlyhigherinmalignantIPMNscompared tobenign
IPMNsandwerepositivelycorrelatedwiththehistopatho-
logicaltypesofIPMN.Thebestdiagnosticaccuracywas
achievedbyusingaSUVmaxcutovalueof2.5.Combin-
ingthiswiththedetectionofamuralnoduleonCToered
the most eective diagnosis of malignant IPMN. In our
studywecouldnotndatrendtodierentiatemalignancy
from benign disease based on SUVmax, TLR, and TBR.
Ontopofthat, we would liketoemphasizethata cut-o
valueforhighorlowSUVmaxthatcouldbeindicativefor
moreaccuratelythensame-dayPET/CT[20].Correctiden-
ticationoflymphnodesoncross-sectionalimagingmay
guidepreoperativeendoscopicultrasoundtotargetspecic
suspicious lymph nodes, which can preclude unnecessary
surgicalexploration[22–25].
Correlation of our ndings to recent literature is chal-
lenging, as other studies primarily focused on dierent
types of hepatobiliary cancer [14, 20, 21, 26, 27]. For
instance,Obmanetal.reportedachangeinmanagementin
11%ofpatients[14].Inastudyinvolvingpatientswithcan-
cer (excluding pCCA) who underwent same-day PET/CT
and PET/MRI, PET/MRI inuenced clinical management
in18%ofpatientscomparedtoPET/CT[20].Thecriteria
forinuenceonclinicalmanagementin these papers was
similarasappliedinour study.Inanotherstudyinvolving
263patients,including threepatientswithcholangiocarci-
noma,PET/MRIinuencedmanagementin8%,although
notinthecholangiocarcinomapatients[21].Arecentstudy
offteenpatientswithhepatocellularcarcinomashowedno
impactof PET/MRIonclinicaldecisionmaking[28].Our
studyisthe rstexclusivelyfocused onpCCA,wherethe
roleofPET/MRIwasevaluated.Clinicaldecisionmaking
wasaectedintwopatients(14%),bothhadanincreased
suspicionofmalignancyduetohighSUVmaxofthepCCA
lesions.
PreviousstudiesonPET/MRIusing18-FDGhavesug-
gestedthathighvaluesofSUVmax,TLR,andTBRwould
favourmalignanttumours[29,30].Utsonomiyaetal.found
aTLR>1.3measuredonPET/CTtobeanindependentpre-
dictor of malignancy for pancreatic intra-ductal papillary
Table 3 CorrelationofbaselinecharacteristicsandSUVmax(Fisher’sexacttest)
Characteristic HighSUVmax(>4.59) LowSUVmax(<4.59) Total P-value
Ageinyears
- ≥65 24 6 0.28
- <65 62 8
Sex
-Male 5490.99
-Female 3 2 5
Histologya
-Malignant 5 5 6 1.00
-Benign 1 1 6
PSCdiagnosis
-Yes 5050.03
-No 369
CA19.9
- ≥37kU/L 63 9 0.99
- <37kU/L 2 2 4
BC-type
-I-IIIA 5490.99
-IIIB-IV 2 1 3
PSC =PrimarySclerosingCholangitis,SUV=StandardizedUptakeValue,BC=Bismuth-Corlette
aExcludingthepatientwithlymphomaandIPNB
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measurementaswasimplementedinourstudy.Ourresults
showthatPET/MRImayincreasethecondencelevelfor
malignancywhichmayspeeduptheclinicaldecisiontoper-
formsurgery.TheindicationforPET/MRIshouldtherefore
be considered on a case-by-case basis. PET/MRI may be
valuabletodemonstrate thefullextentof lesions(Fig.2),
assist in characterization of enlarged lymph nodes and
detectdistantmetastasesthatwerenotapparentonprevious
CTandMRI/MRCP.AnotheradvantageofPET/MRIcom-
paredtoPET/CTishighersensitivityforbonyandhepatic
metastases[20].Inourstudyhowever,wehadnocaseswith
distantmetastases.
Cholangiocarcinomaishistologicallyanadenocarcinoma
andtypically shows elevated FDG uptake. There are two
importantlimitationswithFDGuptakeincaseofpCCA:(1)
FDG-aviditymaybedecreased,duetoabundanceofbrotic
dierentiating malignancy from benign disease was not
achievedinourstudy.Webelieve,basedonourresults,that
SUVmaxshouldbeinterpretedasacontinuousvariableand
future(large)studiesshouldrevealthe truevalueofSUV-
max measurements for diagnosis and treatment outcome.
Consequently, one cannot rely solely on these quantita-
tiveparametersfordiagnosisandclinicalmanagementof
obstructiveperihilarbiliarylesions.Clinicalworkup,expert
readingofbaselineimaging(CTscanandMRI/MRCP)and
multidisciplinaryevaluationin expertisecentresisrecom-
mendedforthesepatients.FDG-PETimagingofpCCAis
challengingbecauseofthenon-bulky,lineartumourspread
alongthebiliarytreethatmaynegativelyaectvisiblePET
avidityowingtopartialvolumeeectsandmotionartefacts.
Forthisreason,wewelcomeeortstostandardizerepro-
ducibilityofPETimagingfeaturessuchasEARL2inSUV
Fig. 2 PET/MRIofpatientwithpathologicallyconrmedpCCA(#10).
ThePET/MRIshowsapCCA, BCtype IIIB.Measurementsshow a
SUVmaxof6.9,TLRof3.45andTBRof3.14.Anillustrativecaseof
a61-year-old malewith pCCA(histopathologyproven).Thetumour
is located in the perihilar region (A, arrow) and extending past the
rstbranchingofthelefthepaticmainduct(B,arrows),classiedas
a Bismuth-Corlette III-B tumour.A) With CT no obvious lesion is
discernibleintheperihilarregion.B)On contrast-enhancedMRIthe
tumourcanbeseenassubtleirregularthickenedbileductwallwithno
cleartumourmass(arrows).C,D)ClearFDG-avidlesionwithlimited
tumourvolume (segmented),includingROIplacement(C,arrow)to
measureliverbackgroundactivityandtumouractivity
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Tothebestofourknowledge,thisistherstprospective
studyontheaddedvalueofPET/MRIinpresumedresect-
able pCCA patients exclusively. Limitations include the
smallnumberofpatientsinthisstudy.Althoughourcentre
isoneofthelargestreferralcentresforcholangiocarcinoma
management in the Netherlands, the number of patients
presenting annually with potentially resectable pCCA is
low.Unfortunatelyduetothesmallnumberofpatientswe
wereunabletoperformadditionalanalyses,suchascorrela-
tionbetweenPET/MRIfeaturesandclinicaldata.Another
limitationmightbeselectionbias,whichmayhaveinu-
encedourresults.PatientswereincludedwhenpCCAwas
suggested on clinical grounds. Still three patients were
includedwithnomalignancy. Weconsider this nding in
linewithrealworlddata.Itisawell-knownfactthatbenign
biliaryobstructivelesions,especiallyinammatorydisease,
stromainpCCAand(2)FDGtracerenablesdetectionof
glycolysis,presentinthewholebody,andincreasedinareas
ofinfection andinammationwhichiscommonalongthe
biliarytreeafterstentplacementforpCCA.Itistherefore
recommended to perform PET/MRI before biliary stent
placement.Since2019,broblastactivationproteininhibi-
tor (FAPI) is being investigated in the setting of cholan-
giocarcinomaasanewPET-tracer[32].Cancer-associated
broblastsshowahigh expressionofbroblastactivation
protein,whichcanbebetterdemonstratedbyusingFAPI-
tracer,whileexpressionlevelsinnormalhuman tissueare
generallyverylow[33].Arecentsystematicreviewshows
thepotentialthatFAPIPET/MRIholdsforpCCApatients
[34].FuturestudieswithFAPIPET/MRImayshowhigher
specicityfordiagnosisandstagingofpCCA.
Fig. 3 PET/MRIofpatientwithpathologicallyconrmedpCCA(#2).
An illustrative case of a 69-year-old male with pCCA(histopathol-
ogyproven).Smalltumourmassislocatedatthehilumofthebiliary
treewithmarkeddilatationofthelefthepaticducts,includingatrophy
oftheleftliverlobe,Bismuth-CorletteIIlesion. A)CoronalCTiage
witha smallobstructive tumourin thebiliary hilum(arrow), includ-
ing proximal intrahepatic bile duct dilatation. B) On axial contrast-
enhanced MRI the lesion can be appreciated as a small localized
enhancingtumour(arrow).C,D)AxialandcoronoalPET/MRIimages
showasmallpCCA,BCtypeIwithlowPETavidity(arrows),includ-
ingrelativelylowSUVmax(1.8),TLR(0.9),andTBR(1.06)
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Nuclear Medicine and Molecular Imaging
selectivelyonacase-by-casebasis.Prospectivemulticentre
trialsonhybridPET/MRIwithmoresensitivetracers(e.g.
FAPI) and standardized evaluation methods (e.g. EARL2
basedSUV)inthesettingofpCCAarewarranted.
Acknowledgements Notapplicable.
Author Contributions Allauthorscontributedtothestudyconception
and design. Material preparation, data collection and analysis were
performedbyD.M.deJong,K. Chehin, T.L.N.Meijering, Q.G. de
LussanetdelaSabloniere,andR.S.Dwarkasing.Therstdraftofthe
manuscriptwaswritten byD.M.de JongandR.S. Dwarkasing,and
allauthorscommentedonpreviousversionsofthemanuscript.Allau-
thorsreadandapprovedthenalmanuscript.
Funding Thereisnosourceoffunding.
Data Availability Thedatasets analysedduringthe currentstudy are
availablefromthecorrespondingauthoruponreasonablerequest.
may mimic pCCA [35].Another limitation might be that
the inuence on clinical decision making was not clearly
denedinadvancebutwasinterpretedretrospectively.Our
patientshavestructureddocumentationontheMDTBdeci-
sionandrecommendationforclinicalmanagementintheir
electronicmedicalles.Inaddition,theinuenceonclini-
caldecisionmaking was basedongroupdiscussions with
fourmembersofourresearchteamonMDTBreportsbefore
andafterPET/MRI.
Conclusions
In summary, 18 F-FDG-PET/MRI has limited value for
diagnosisofpCCAandinuencedclinicaldecisionmaking
in14%ofpCCApatientsoptingforsurgery.Theindication
for 18 F-FDG-PET/MRI should therefore be considered
Fig. 4 PET/MRIofpatientwithpathologicallyconrmedintra-ductal
tubulopapillary neoplasm with dysplastic cells (#6). An illustrative
caseofa69-year-oldmalewithintra-ductaltubulopapillaryneoplasm
withdysplasticcells (histopathologyproven),noinltrative growth.
A,B)CTimages demonstrate awell-denedintra-ductal obstructive
mass lesion with contrast enhancement (arrows) similar to the sur-
roundingliverparenchyma.C)AxialContrast-enhancedT1-weighted
MRIimagewithno additional ndingscomparedtoCT (A,B),D)
AxialPET/MRIshowsanobviousFDG-avidlesion(arrow)
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Nuclear Medicine and Molecular Imaging
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Declarations
Ethics Approval This study was conducted in accordance with the
HelsinkideclarationandfollowedtheSTROBEguidelinesafterbeing
approvedbythelocalethicalreviewcommittee(ErasmusMC,MEC-
2021-0524).Fivepatientsunderwenta PET/MRI shortly beforethe
trialformallystartedandwereincludedretrospectivelyafterproviding
informedconsent.TheindicationsandPET/MRIitselfwereidentical
to(therestofthe)studycohort.
Consent for Publication The participants signed consent regarding
publishingtheirdataandphotographs.
Competing Interests M.J.BrunoreceivedresearchfundingfromBos-
tonScientic,CookMedical,PentaxMedical,InterScope,andMylan;
he is a consultant to Boston Scientic, Cook Medical, and Pentax
Medical. The remaining authors (D.M. de Jong, K. Chehin, T.L.N.
Meijering, M. Segbers, L.M.J.W. van Driel, B. Groot Koerkamp,
J.N.M.IJzermans,F.A.Verburg,Q.G. deLussanetde laSabloniere,
R.S.Dwarkasing)declarethattheyhavenotconictsofinterest.
Declaration of Generative AI in Scientic Writing Duringtheprepara-
tionofthisworktheauthorsdidnotusegenerativeAIandAI-assisted
technologies. The authors take full responsibility for the content of
thispublication.
Preprint sharing Notapplicable.
Open Access  This article is licensed under a Creative Commons
Attribution 4.0 International License, which permits use, sharing,
adaptation, distribution and reproduction in any medium or format,
aslongasyougiveappropriatecredittotheoriginalauthor(s)andthe
source,providealinktotheCreativeCommonslicence,andindicate
ifchangesweremade.Theimagesorotherthirdpartymaterialinthis
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