LukasKrhLukasKrh. Neuss . Neuss *HHU*HHU--DsdrfDsdrf..

SurgSurg..ClinicClinic 11 Med.Med.ClinicClinicInsulinoma & GEPInsulinoma & GEP--TU Center TU Center

Neuss / Düsseldorf Neuss / Düsseldorf

CAEK 2004 / WienCAEK 2004 / Wien

PANCREATIC HYPERINSULINISM

(increasing diversity and challenge of an „easy“ disease)

PANCREATIC HYPERINSULINISMPANCREATIC HYPERINSULINISM

((increasing diversityincreasing diversity andand challengechallenge of an „of an „easyeasy““ diseasedisease) )

P.E.Goretzki, H.Böhner, J.Terörde, **R.Köster, *A.Starke P.E.Goretzki, H.Böhner, J.Terörde, **R.Köster, *A.Starke

NEUROENDOCRINE TUMORS OF THE PANCREAS

Insulinoma 40%

Hormoninactive NEC 30-45%

Gastrinoma 15-25%

Vipoma

Glucagonoma -15%

Somatostatinoma

others

distribution of pancreatic NET/NEC

Insulinom inPancreatic tail

3 question. liver-metastases of NEC

Lukas Krh. Neuss

INSULINOMA - PATHOPHYSIOLOGYINSULINOMA INSULINOMA -- PATHOPHYSIOLOGYPATHOPHYSIOLOGY

Glc – uptake – ATP – K/Ca pump – Insulin secretionGlcGlc –– uptakeuptake –– ATP ATP –– K/Ca pump K/Ca pump –– Insulin Insulin secretionsecretion

INSULINOMA - DISTRIBUTIONINSULINOMA INSULINOMA -- DISTRIBUTIONDISTRIBUTION

author pat. adenoma Ca mult.tu

n n % n % n %

Pasieka 43 36 86 5 10 2 4

Böttger 36 29 84 6 14 1 2

Geughegan 34 30 88 2 6 2 6

Cryer 29 25 86 3 10 1 3

v. Heerden 20 19 95 1 5 - -

Total 162 139 87 17 10 6 3

authorauthor pat.pat. adenomaadenoma CaCa multmult.tu.tu

nn nn %% nn %% nn %%

PasiekaPasieka 4343 3636 8686 55 1010 22 44

BöttgerBöttger 3636 2929 8484 66 1414 11 22

GeugheganGeughegan 3434 3030 8888 22 66 22 66

CryerCryer 2929 2525 8686 33 1010 11 33

v. v. HeerdenHeerden 2020 1919 9595 11 55 -- --

TotalTotal 162162 139139 8787 1717 1010 66 33

Lukas Krh. Neuss

PANCREATIC HYPERINSULINISMPANCREATIC HYPERINSULINISM

authorauthor pat.pat. adenomaadenoma CaCa multmult././hyphyp..

NN NN %% NN %% NN %%

LiteratureLiterature 162162 139139 8787 1717 1010 66 33

HHUHHU--D 86D 86--0101 8383 6464 7777 88 1111 1111 1313

NE 2001NE 2001--0606 3535 1818 5151 5*5* 14 14 1212 3434

HHUHHU--D 1986D 1986--99 / LKH99 / LKH--N 2001N 2001--66 *plus 4 *plus 4 reoperationsreoperations

pgoretzki @lukasneuss.de

Whipple`s triadWhippleWhipple`s `s triadtriad

++

Lukas Krh. Neuss

PREVIOUS STRATEGY: organic hyperinsulinism

PREVIOUS STRATEGY: organic hyperinsulinism

72h fasting-test72h 72h fastingfasting--testtest

sulfonylureas; exogenes Insulin; inborn metabolic

diseases

sulfonylureassulfonylureas; ; exogenes Insulin; exogenes Insulin; inborn metabolic inborn metabolic

diseasesdiseases

familiarity, diabetesmellitus, other illnesses -

familiarity, diabetesmellitus, other illnesses ---

++

OPOP

localisationlocalisationtests priortests prior to to

OP ? / OP ? / --

no OPno OP

Insulinoma: localisation

Postoperative ASVS (Arterial Stimulatin Venous Sampling)

Calcium gluconate i.a.: delta insulin 100%

Intraoperative UltrasoundSensitivity 86-100%

Somatostatin Receptor ScintigraphySensitivity 60%

Endoscopic UltrasoundSensitivity 93% (Head 83%, Tail 73%)

UltrasoundSensitivity 9-63% (79%)

Biochemical diagnosis !!"Jamais l'image ne doit remplacer l'idee"

Proye C. 2001

«localisation can not substitute for a lack of clear endocrinologicdiagnosis»

EUS and SRS : Sensitivity 89%

Intraoperative US (IOUS) is moresensitive than palpation and shows surrounding structures(D.Wirsungianus, V.mesenterica etc.)

INSULINOMA - ENDOSCOPIC SURGERY -

FUTURE STANDARD

INSULINOMA INSULINOMA -- ENDOSCOPIC SURGERY ENDOSCOPIC SURGERY --

FUTURE STANDARDFUTURE STANDARD

AUTHOR YEAR N AD CONV. FISTULA

Gagner 1996 5 5 1 0/4

Berends 2002 10 10 4 2/6

Iihara 2002 7 7 1 3/6

Gramatica 2002 9 9 0 1/9

Ferna.-Cruz 2002 5 4 1 2/4

TOTAL 36 35 7/36 8/29(19%) (27%)

AUTHORAUTHOR YEARYEAR NN ADAD CONV. FISTULACONV. FISTULA

GagnerGagner 19961996 55 55 11 0/40/4

BerendsBerends 20022002 1010 1010 44 2/62/6

IiharaIihara 20022002 77 77 11 3/63/6

GramaticaGramatica 20022002 99 99 00 1/91/9

FernaFerna..--Cruz 2002Cruz 2002 55 44 11 2/42/4

TOTALTOTAL 3636 3535 7/36 7/36 8/298/29(19%)(19%) (27%) (27%)

PANCREATIC HYPERINSULINISM

localisation studies for insulinoma*

Tu (1.2cm)

• Endosonography / hCT of an insulinoms in pankreatic corpus/tail(Pat. O.S.,w, 39 J. MIC tail resection of the pancreas, OP 12.09.06)

- INSULINOMA -Importance of tumor size

-- INSULINOMA INSULINOMA --ImportanceImportance of of tumortumor sizesize

size pat. adenoma Cadiameter N N N (%)

< 1cm 13 13 0 -

1-1,9 cm 33 29 4 (12%)

2-2,9 cm 16 13 3 (19%)

> 3cm 7 3 4 (57%)

Gesamt 69 58 11 (16%)HHU-D 1986-99 / LKH-N 2001-4 *(in 69/86 pat. tumor size was defined)

sizesize pat.pat. adenomaadenoma CaCadiameterdiameter NN NN NN (%) (%)

< 1cm< 1cm 1313 1313 00 --

11--1,9 cm1,9 cm 3333 2929 44 (12%)(12%)

22--2,9 cm2,9 cm 1616 1313 33 (19%)(19%)

> 3cm> 3cm 77 33 44 (57%)(57%)

GesamtGesamt 6969 5858 1111 (16%)(16%)

HHUHHU--D 1986D 1986--99 / LKH99 / LKH--N 2001N 2001--4 *(in 69/86 pat. 4 *(in 69/86 pat. tumortumor sizesize was was defineddefined))

MALIGNANT INSULINOMA MALIGNANT INSULINOMA MALIGNANT INSULINOMA

THERAPY:Panc. tu resection, 12d afterw.3 chemoembolisations (right)- death in progr. liver failure

totally occluded r.hep.art

HISTORY.L.R., m, 64y, 1.2 years hypoglyc.increasing shock, unconciousness mental retardation and psychosis

Metast.

MALIGNANT INSULINOMA MALIGNANT INSULINOMA MALIGNANT INSULINOMA

Pat. K.A., m, 30yPat. K.A., m, 30y

1993 panc.LR - mal. Insulinoma i.v. STZ n=11999 reop. enl.LR + splenectomy; TACE n=12000 re hemihepatectomy TACP n=62003 intraper. metastases + rectalres. Octreotide 2004 reop.liver + intraper. metastases Glucagon

MALIGNANT INSULINOMA MALIGNANT INSULINOMA MALIGNANT INSULINOMA

Liv-fail.1.5 dead-3-Liver,lnLRM 64200411 Lasymp.2.222-Liver,lnLR, LNM 37200210 Sasymp.2.523-LiverLR, pHpxF 5020029 H

sepsis1.8 dead-6-Liver,lnbone

LR, pHpx, LN

F 3920018 Easymp.3.832-LiverLRF 5920017 Dasymp.4.66--liv.?,LNLR,LNF 6420006 Kp.embol1.8 dead-5-LiverLRF 5419965 Gasymp.9.313-LiverTRF 5619954 S

Octreo./glucag.

10.2 sympt.

611Liver, periton

LR, hHpxM 3619943 Ksuicide1.6 dead2-7LiverTR, hHpxM 8219932 Kweight7.5 dead-912LiverLRF 6319921 W

reason/therapy

Follow-up(years)

TA-CP(n)

TA-CE(n)

iv-STZ(n)

Metast.Tu / met. surgery

Sex/ age(years)

DiagnPat.

Survival (years survived 2005 ; acc. to Kaplan-Meier plot)

0

0,2

0,4

0,6

0,8

1

1 2 3 4 5 6 7 8 9 10 11

Years

perc

enta

ge s

urvi

val

11 Patienten mit malignem Insulinom (1992-2005)

Mean 4.7 ± 3.3 ; Median 2.7 Years

pgoretzki @lukasneuss.de

PANC.HYPERINSULINIS PANC.HYPERINSULINIS -- DIAGNOSISDIAGNOSIS

0,8 cmadenoma

NIPHS

2,2cm adenoma

5 patients Mayo Clinic 1995-98

78 78 femalefemale

7272malemale

7272malemale

1616malemale

3737malemale

ageageM / WM / W

69696060828248488282blbl..glcglc 72h 72h fastingfasting testtest

12.712.716.816.83.33.30.840.844.24.2CC--peptidepeptide(ng/ml)(ng/ml)

1351351601607711114848insulininsulin(µU/ml)(µU/ml)

2 h2 h4 h4 h3.5 h3.5 h4 h4 h4 h4 hhypoglychypoglyc. . postpranpostpran..

yesyesyesyesyesyesyesyesyesyesWhippleWhipple`s `s triadetriade

40403636404036365050symptsympt. BZ. BZ

patpat 55patpat 44patpat 33patpat 22patpat 11

J.Service et al. NEJM 1999J.Service et al. NEJM 1999

NIPHS NIPHS –– HISTOLOGIEHISTOLOGIEpgoretzki @lukasneuss.de

Nesidioblastosis: 13Microadenomatosis: 4

PANCREAT. HYPERINSULINIS

Biochemical diagnosis

10/10 (100%)8/ 13 (66%)NIPHS74 / 75 (99%)Insulinoma

pathologic OGTTn(t)/n(path.t)

N (%)

patholog. 72h fast n(t)/n(path.t)

n (%)

HHU-D 1986-99LuKrh NE 2001-05

SASI-test (selective arterial secretagogue injection)SAVS-test (selective arterial stim.& venous sampling)

A. gastroduodenalisA. mesenterica sup. A. lienalis

01020304050

-30 0 30 60 90 120

Sek0

1020304050

-30 0 30 60 90 120

Sek0

1020304050

-30 0 30 60 90 120

Sek

(0.01 mval Ca2+ / kg b.w. ; BMI 39.4 kg / m2)

Zuverlässigster Nachweis (Lit. nur 1 falsch pos. Befund)pathologischer Insulinsekretion mit Lokalisation

PANCREAT. HYPERINSULINISMWITHOUT INSULINOMA (NIPHS)

normoglycemiaDiabetes mellitus

nono

left (80%)left (80%)

SAVSOGTT

w; 74 Jw; 39 J

20052006

12)S.K.13)J.I.

Diabetes mellitusre-res. (~90%)(1y)Whipple` OP.SAVSw; 30 J200511)R.S.

normoglycemianoleft (80%)OGTTw; 42 J200410)F.R.

normoglycemianoleft (80%)72h fastw; 45 J20049) B.F.

normoglycemianoleft (80%)72h fastw; 44 J20038) R.A.

normoglycemianoleft (80%)SAVSw; 43 J20027) B.S.

normoglycemiaWhipple` OP (80%)diagnost. PESAVSw, 67 J20026) B.C.

normoglycemianoleft (80%)72h fastw, 34 J20015) S.S..

normoglycemialeft (70%)(1/2 y)tail 72h fastw; 31 J19984) B.E.

normoglycemianoTail+head72h fastm; 48 J19963) L.H.

normoglycemia80% left (10y)tail72h fastw; 30 J19942) B.M.

Diabetes mellitus90% resektion(1m)diagnost. PEPostop.m; 18 J19941) S.B.

resultsre-operation dt(m/y)

1.-sperationgiagnosis

Sex andAge (y)

Year ofdiagnosis

patient

SURGICAL THERAPY FOR PANCREATIC HYPERINSULINISM

Insulinoma resected withpancreatic tail Somatostatin as an

alternative to surgery

Which therapy is indicated for pancreatic hyperinsulinism without

an insulinoma ??

subtotal pancreatectomy

Spleen preserving subtotale pancreatectomy for pancreatichyperinsulinism without insulinoma (NIPHS)

pancreas

splenic v.

Pat.M.B.-S., w, 43J

NIPHS NIPHS -- RERE--RESEKTION AFTER RESEKTION AFTER „WHIPPLE´S“ (PPPD)(80„WHIPPLE´S“ (PPPD)(80--90% Res.)90% Res.)

pgoretzki @lukasneuss.de

Pat. R.S, w, 30J1.OP 04/ 2.OP 05

NIPHS - SURGERY

literature:

(14)9(22)14(47)30(31)20(100)64total

--(82)9--(18)2(17)11>90%

(4)1(14)4(50)14(36)10(44)2870-85%

(32)8(4)1(64)16(32)8(39)25< 60%

(%)reop. (n)(%)

DM (n)(%)

pers./rec. (n)(%)

cure (n)(%)

pat. (n)

Extent of resect.

own experience:

(31)4233(--)0(77)10(100)13~80%(%)

reop.* (n)(%)

DM (n)(%)

pers./rec(n)(%)

cure (n)(%)

pat(n)

Extent of res.

including reoperations: cure rate with DM 13/13 (100%)literature 34/64 ( 43%)

MENMEN--1 1 associatedassociated pancreaticpancreatic--tumorstumors((withwith InsulinInsulin--productionproduction))

0022NonsenseNonsensepituitarypituitaryHPTHPTpancrpancr..yesyesmmR.M. 36R.M. 360033FrameshiftFrameshiftpancrpancr..HPTHPTyesyesmmH.M. 32H.M. 320033FrameshiftFrameshiftlungslungspancrpancr..HPTHPTyesyesmmH.J. 34H.J. 340033NonsenseNonsenselipomaslipomaspancrpancr..HPTHPTnonoffG.H. 27G.H. 27yesyes77Splice variSplice vari..pituitarypituitaryHPTHPTpancrpancr..yesyesffH.C. 38H.C. 38yesyes77Splice variSplice vari..pancrpancr..HPTHPTnonoffB.H. 42B.H. 42yesyes22Nonsense Nonsense pancrpancr..adrenaladrenalHPTHPTyesyesffD.S. 32D.S. 32

yesyes22Nonsense Nonsense pancrpancr..HPTHPTyesyesmmH.S. 34H.S. 34yesyes22Frameshift Frameshift pituitarypituitarypancrpancr**HPTHPTyesyesffB.J. 65B.J. 65yesyes????pancrpancr..adrenaladrenalHPTHPTnonoffK.L. 35K.L. 35yesyes????HPTHPTpancrpancr..nonommG.M. 61G.M. 61

clinicclinicExExonon

mutationmutation3.OP3.OP2.OP2.OP1.OP1.OPfamfamsexsexpat. agepat. age

Organic hyperinsulinismOrganic hyperinsulinism

endocrine pancreatic tuswith family history (MEN-1)endocrineendocrine pancreaticpancreatic tustus

withwith family historyfamily history (MEN(MEN--1)1)

primäryprimäry OPOP nn recurrence recurrence 2.2.operationoperation

enucleationenucleation 33 3 (100%)3 (100%) 1xleft res.1xleft res.2xsubtot.PX2xsubtot.PX

left resectionleft resection 55 1 ( 20%)1 ( 20%) 1xWhipple`s1xWhipple`s

subtotsubtot. . pankreatectpankreatect.. 3*3* 0 0 ----

total total pancreatectpancreatect.. 11 0 0 ----

* mal.Tu + LN-metastases

subtotal pancreatectomy in MEN-1 with LN-dissection

PANCREAT. HYPERINSULINISM

6 ( 5)16 (14)44 (39)52 (46)total (n=118 pat)6 (46)5 (39)2 (15)0 (---)malignancy (n=13 pat.)0 (---)9 (69)4 (31)0 (---)NIPHS (n=13 pat.)0 (---)1 (10)2 (20)7 (70)mult.ad./ MEN-1 (n=10 pat.)0 (---)1 ( 1)36 (44)45 (55)adenoma (n=82 pat.)

multivisc.r*n (%)

PX+ sPXN (%)

part.resect.N (%)

enucleat. N (%)

Diagnosis

*(plus LN/liver/lung etc.) HHU-D 1986-99LuKrh NE 2001-05

PANCREATIC HYPERINSULINISM PANCREATIC HYPERINSULINISM PANCREATIC HYPERINSULINISM

1) It may be difficult to be diagnosed (NIHPS!)

2) It may be impossible to be located (preoperatively)

3) It may be part of a MEN-1 syndrome

4) Malignant tumors prim. cause metabolic problems

AND You will need the whole spectrum of endocrine

knowledge and experience in pancreatic + liver

surgery

1)1) It may be difficultIt may be difficult toto be diagnosedbe diagnosed (NIHPS!)(NIHPS!)

2)2) It may be impossibleIt may be impossible toto be locatedbe located ((preoperativelypreoperatively))

3)3) It may be partIt may be part of a MENof a MEN--11 syndrome syndrome

4)4) Malignant tumorsMalignant tumors prim. causeprim. cause metabolic problemsmetabolic problems

ANDAND YouYou willwill need the whole spectrumneed the whole spectrum ofof endocrine endocrine

knowledgeknowledge andand experienceexperience inin pancreaticpancreatic ++ liver liver

surgerysurgery