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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