ImagingofNeuroendocrineTumors and ObstaclestoDiagnosis

EricLiu,M.D. VanderbiltNeuroendocrineCenter DivisionofSurgicalOncologyandEndocrineSurgery DepartmentofSurgery VanderbiltUniversityMedicalCenter

Overview
BackgroundonNeuroendocrine CrossSectionalImaging NuclearImaging NewImagingTechniques FollowupImaging Choosingtherightimagingtechnique ObstaclestoDiagnosis

BasicsofNeuroendocrineCells
Foundinbronchial,gastroenteropancreatic tract Secretehormones
Serotonin Insulin Gastrin Glucagon VIP Somatostatin Histamine

ExpressSOMATOSTATINRECEPTORS
Liu and Oberg, Endo Meta Clin N Am, 39(4):697-71, 2010

Terminology
Carcinoid APUDoma IsletCellTumors Neuroendocrine carcinoma

Modlin et al, Hum Pathol 12:1440-51, 2004

Definitions
SiegfriedOberndorfer Carcinoid slow growing tumor of the GI and bronchial tracts that derives from enterochromaffin cells that frequently secrete serotonin Neuroendocrine Tumors tumors derived from GI endocrine cells that can secrete many hormones Insulin glucagon gastrin VIP

Express somatostatin receptor

Incidence of neuroendocrine tumors

2.55.0/100,000inhabitants

Modlin, I. M. et al. J. Natl. Cancer Inst. 2008 100:1282-1289; doi:10.1093/jnci/djn275

Incidence of neuroendocrine tumors

2.55.0/100000inhabitants

Modlin, I. M. et al. J. Natl. Cancer Inst. 2008 100:1282-1289; doi:10.1093/jnci/djn275

Incidence of neuroendocrine tumors

Surveillance,EpidemiologyandEndResults(SEER),USpopulation19742005
Lung

Smallintestine Rectum

GEPNET ~75%

Yaoetal.,JCO,2005.Modlinetal.,LancetOncol.2008

Neuroendocrine Tumors are highly Prevalent

Prevalence in the United States

120000 100000 80000 60000 40000 20000 0

HBC Esophageal Pancreatic Gastric NET
Modlinetal.,LancetOncol.2008

Survivalofpatientswithmetastaticcarcinoid
1 0.9 0.8 Survival probability 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 48 60 72 84 96 108 120 Survival time (months)

1988-99 n=892 SEER data base. Median survival 37 mo 1973-87 n=787 SEER data base. Median survival 17 mo 1974-2004 SEER. Median survival 33 mo
Yaoetal.,JCO,2005.

SurvivalChangesBasedonLocation andDifferentiation
Well/ModeratelyDifferentiated PoorlyDifferentiated

Yaoetal,JCO,2005.

ClinicalPresentations
Carcinoid:diarrhea,flushing,abdominal cramping Insulinoma:WhipplesTriad Glucagonoma:diabetes,anemia,diarrhea, necrolyticmigratoryerythema Gastrinoma(ZES):resistantulcers,abdominal pain,diarrhea VIPoma(WDHA,VMS):waterydiarrhea, hypokalemia,achlorhydria,vasodilation

BiochemicalTesting
Hormonelevels
5HIAA Gastrin Insulin/C peptide/Proinsulin Glucagon VIP Serotonin Andothers

Biomarkers
ChromograninA ChromograninB Pancreastatin Neuronspecificenolase Ghrelin PancreaticPolypeptide SubstanceP Andmore

TheImportanceofImaging
Diagnosis
Incidentalfinding Stagingformetastaticdisease Determinationofresectability

Followup
Diseaseprogression Symptomatology

TheImportanceofImaging
Resectionofprimary7.4vs.4.0 years;p<0.001 CUTITOUT LNmetsresected:7.9vs.6.2 years;p<0.001 Livermets:p<0.001
(+)4.9yrs ()10.1yrs

CUTITOUT

CUTITOUT

Livermets()&LNresection12.4 yrs vs.~7.6,p<0.01

Hellman, et al. World J Surg 2002;26:991-7.

PathologicalClassificationofNETs
Histology Appearance Prognosis MitoticRate Ki67 Necrosis WellDifferentiated Uniform Good <2 <2% Absent Intermediate Moderately Poor >10 > 20% Present Poorly Pleomorphism

Ultrasound
LowCost HighResolution ExaminationoftheLiverandBiliary USER DEPENDENT Best when attached to an endoscope or biopsy needle

Imagefromhttp://www.hopkinscoloncancercenter.org

Sundin etal,2009

ComputedTomography(CT)
Workhorse Readilyavailable Fast CTAbdomen liverandpancreasprotocol CTNeckandChest

ScanningProtocols 64sliceMDCT
PancreasProtocol
Slices13mm OralContrast(negative contrast) LateArterialPhase(25 30sec) PancreaticPhase(40 sec) VenousPhase(7090 sec) BolusTracking

LiverProtocol
Slices3mm OralContrast Noncontrast ArterialPhase(1525 sec) LateArterialPhase(25 30sec) VenousPhase(7090 sec) BolusTracking

SensitivityandSpecificityofCT

Sundin etal,2009

FeaturesofNETsonCT
Mass Relationshiptostructures Calcifications Lymphnodemetastases LiverMetastases Carcinomatosis

RadiationExposure

MagneticResonanceImaging
SpecificOrganSystem
Liver Pancreas Bones Pelvis

ContrastAgents
Gadolinium EOVIST/PRIMAVIST

MRCholangiogram

MRProtocols
T1weighted(fatbright,waterdark) T2weighted(fatdark,waterbright) ContrastEnhancedforvasculature (Gadolinium) LiverParenchyma
Gadoxetate(Eovist/Primovist)

DuctalSystem

AppearanceofNETonMRI
T1lowsignal T2highsignal Goodforsmalllesions

Sundin etal,2009

CTvs.MRI

MRImaypickup~20%morelesions
Giesel etal,2011,Dromain,etal,2005

FunctionalImaging
ColorPictures DescribeBiology Octreoscan 111InPentetreotide 131I/123I MIBG 18FDGPET 11CHTP 18FDOPA 68GaDOTATATE

Octreoscan
SinglePhotonEmissionTomography(SPECT) ImagesSomatostatinReceptor Octreotidepeptidechelated to111Indium Inject185222MBq FourHourScan 24hourscan

Octreoscan

Octreoscan

Octreoscan

Octreoscan

Octreoscan

Kwekeboom,etal,2009.

123/131IMIBG

Pheochromocytoma Neuroblastoma Paraganglioma

metaiodobenzylguanidine

Sensitivity8288% Specificity8224%

Wisemanetal,2009

FDGPET

Tends to accumulate in poorly differentiated tumors Adamsetal,EJNM,1998

Pasquali, World J Surg, 1998

11CHTPPET

Orlefors etal,2005

18FDOPAPET

Koopmansetal,2008.

68Gallium

DOTATATEPET

Patientwastold shehadonly twolesionsby CT,MRI, octreoscan

Otherpeptides: DOTATATE DOTATOC DOTANOC

DirectComparisonCTvs.MRIvs.SRS
21%betterthanCT 93%betterthanSRS

Dromain etal,JCO,2005

STRONGSSTR2Staining

WEAKSSTR2Staining

DirectComparisonCTvs.MRvs.PET

CT ArterialPhase

CT PortalPhase

MRIwithcontrast

PET 68GaDOTATOC

Giesel etal,EJR,2012.

CTvs.MRI

Giesel etal,EJR,2012.

EffectiveImaging

Modlin, 2007

ChoosingtheRightImagingTechnique

CT resolution MRI sensitivityinorgans Ultrasound biopsy Octreoscan SSTR/Distant FDGPET PDNEC

FollowupImaging
EarlyStages:36months LateStages:1224months ChangesinTumorMarkers ChangesinSymptoms

Obstaclesinthediagnosisfortheclinician
Whatdothesemarkersmean? Whendoyoustartthehunt? Howfardoyougo? WhatifIcantfindit? WhatifImissit?

Vinik etal,2010

GUIDELINES
NORTHAMERICANNEUROENDOCRINETUMOR SOCIETY(2010) www.nanets.net EUROPEANNEUROENDOCRINETUMORSOCIETY (2009) www.enets.org