Insulinoma

INTRODUCTION Low blood glucose concentrations were recognized as a feature of several diseases in the 1 th centur!" #owever$ it was not until insulin beca%e available for the treat%ent of diabetes %ellitus in the earl! 1 &'s that clinical events si%ilar to those arising fro% overtreat%ent with insulin were identified in nondiabetic (ersons" This observation led to the (ostulation of a new disease entit! called h!(erinsulinis% )1*" +u((ort for the e,istence of h!(erinsulinis% was (rovided b! finding a %alignant (ancreatic islet-cell tu%or in a (atient who had e(isodes of severe h!(ogl!ce%ia in 1 &. )&*" /,tracts of the tu%or caused %ar0ed h!(ogl!ce%ia in rabbits" The first cure of h!(erinsulinis% b! re%oval of an insulino%a was re(orted in 1 & )1*" The clinical features$ diagnosis$ and treat%ent of insulino%as will be reviewed here" The causes and evaluation of h!(ogl!ce%ia$ and the %anage%ent of %etastatic neuroendocrine tu%ors are discussed se(aratel!" 2+ee 3Diagnostic a((roach to h!(ogl!ce%ia in adults3 and see 3Overview of h!(ogl!ce%ic disorders3 and see 34anage%ent of %etastatic gastroentero(ancreatic neuroendocrine tu%ors3$ section on Treat%ent5" CLINIC6L 7/6TUR/+ The characteristic clinical %anifestation of an insulino%a is fasting h!(ogl!ce%ia$ with neurogl!co(enic s!%(to%s which %a! or %a! not be (receded b! s!%(athoadrenal 2autono%ic5 s!%(to%s" The longstanding recognition that (ost(randial h!(ogl!ce%ia %a! be a feature in so%e (atients with insulino%a and in the rare (atient the sole %anifestation of h!(ogl!ce%ia )8* continues to generate isolated case re(orts )9*" The h!(ogl!ce%ia in (ersons with insulino%a is (ri%aril! due to reduced he(atic glucose out(ut rather than increased glucose utilization ):*" /vidence suggests that insulino%as arise fro% cells of the ductular;acinar s!ste% of the (ancreas rather than fro% neo(lastic (roliferation of islet cells ).*" The %echanis% b! which insulino%as %aintain high levels of insulin secretion in the (resence of h!(ogl!ce%ia is un0nown" #owever$ one stud! re(orted that a variant of insulin %RN6 with increased translation efficienc! is (resent in high a%ounts in insulino%as when co%(ared to nor%al islets )<*" Incidence During a si,-decade (eriod of observation$ there were eight cases of insulino%a in residents of Ol%sted Count!$ 4innesota= the distributions of age and se, a%ong these cases were si%ilar to those of a large cohort described below ) *" The incidence was '"8 (er 1''$''' (erson-!ears 2or four cases (er %illion (er !ear5" 4a!o Clinic series Insulino%as are so rare that few institutions have accrued enough e,(erience to (rovide %eaningful data regarding their de%ogra(hic characteristics )1'$11*" This discussion will highlight the de%ogra(hic and incidence

data fro% the relativel! large nu%ber of (atients with insulino%as at the 4a!o Clinic and the co%(rehensive database for residents of Ol%sted Count! 2where the 4a!o Clinic is located5 )1&*" This cohort was seen over the :'-!ear (eriod fro% 1 &. to 1 <:" /ach (atient had an insulino%a re%oved at his or her first (ancreatic e,(loration$ which too0 (lace at the 4a!o Clinic" Reo(erated (atients$ regardless of where the initial surger! was (erfor%ed$ were e,cluded fro% this anal!sis ) *" The de%ogra(hic features re(orted fro% other centers have usuall! been si%ilar" Distribution of cases b! age and se, 7or the total cohort of &&8 (atients$ the %edian age 2and range5 at the ti%e of surger! was 8. !ears 2range < to <&5$ and 9 (ercent were fe%ale" There was no variation in age or se, distribution during the stud! (eriod or between %ale and fe%ale (atients with res(ect to age or !ear of diagnosis ) *" +!%(to%s The neurogl!co(enic s!%(to%s of insulino%a included confusion$ visual change$ and unusual behavior" The s!%(athoadrenal s!%(to%s included (al(itations$ dia(horesis$ and tre%ulousness )11*" 6%nesia for h!(ogl!ce%ia is co%%on" The %edian duration of s!%(to%s before diagnosis was less than 1"9 !ears in the 4a!o Clinic series" #owever$ a few (atients had (robabl! been s!%(to%atic for decades" 6s %an! as &' (ercent of (atients had been %isdiagnosed with a neurologic or (s!chiatric disorder before the insulino%a was recognized )18$19*" +eizure disorder is another co%%on %isdiagnosis )11*" >eight gain was described in 1< (ercent of (atients )19*" 4/N1 6%ong the &&8 (atients in the total cohort$ 1. 2< (ercent5 had %ulti(le endocrine neo(lasia 24/N5 t!(e 1" The %edian age of these 1. (atients was &9 !ears 2range < to :15$ and 91 (ercent were fe%ale" 6ll had (ri%ar! h!(er(arath!roidis%$ three had (rolactino%as$ three had gastrino%as$ and one had Cushing?s disease" Ten 29 (ercent5 had %ulti(le islet tu%ors$ as co%(ared with onl! 9 (ercent in the rest of the cohort" Tu%or distribution Insulino%as can be single or %ulti(le$ and benign or %alignant" 6%ong the &&8 (atients in our cohort@ 1 8 2<. (ercent5 had single benign tu%ors 2one being ecto(ic5 1: 2seven (ercent5 had %ulti(le benign tu%ors 11 2si, (ercent5 had %alignant insulino%as$ defined as the (resence of %etastases One had islet h!(er(lasia )1:* The %edian age 2and range5 of (atients with %alignant insulino%a was 8< !ears 21< to :15$ and .. (ercent were %en" The tu%or distribution in another 1: (atients with insulino%a who underwent o(eration elsewhere or had an initial negative e,(loration at the 4a!o Clinic was si%ilar to that of the &&8 (atients as a whole" #owever$ the (atients who reAuired

additional surgical treat%ent at the 4a!o Clinic had an increased (revalence of 4/N 1 with %ulti(le tu%ors 2&9 (ercent5 and %alignant insulino%as 211 (ercent5" Insulino%as have been re(orted in (regnant wo%en$ (atients with t!(e & diabetes )1.$1<*$ in one (atient with t!(e 1 diabetes )1:* and in one (atient with renal failure )1 *" DI6BNO+I+ 6ND TU4OR LOC6LIC6TION The diagnosis of insulino%a in a (atient with fasting h!(ogl!ce%ia is established b! de%onstrating ina((ro(riatel! high seru% insulin concentrations during a s(ontaneous or induced e(isode of h!(ogl!ce%ia$ eg$ .&-hour fast or in the case of the (atient with solel! (ost(randial s!%(to%s$ the %i,ed %eal test" Dirtuall! all insulino%as are islet-cell tu%ors= there is one re(ort of an insulin-secreting s%all cell carcino%a of the cervi, )&'*" Other tu%ors can (roduce h!(ogl!ce%ia b! different %echanis%s$ such as the (roduction of insulin-li0e growth factor-II" 2+ee 3Diagnostic a((roach to h!(ogl!ce%ia in adults35" 6fter diagnosis$ i%aging techniAues are then used to localize the tu%or" 6ccurate (reo(erative localization of an insulino%a is desirable because so%e tu%ors %a! not be (al(able at the ti%e of surger!$ and (atients can be advised of the t!(e of surger! (lanned )&1*" The (rocedures available include s(iral CT$ arteriogra(h!$ ultrasonogra(h! 2transabdo%inal and endosco(ic5$ 111-In-(entetreotide i%aging$ and fluorine-1<-L-dih!dro,!(hen!lalanine (ositron e%ission to%ogra(h! 21<7-DOE6 E/T5 )&&$&1*" The choice of (rocedure de(ends u(on which tests are available and local radiologic s0ill" Transabdo%inal ultrasonogra(h! is our (referred initial test" Eentetreotide scintigra(h!$ the (referred test for other islet-cell tu%ors$ will %iss u( to 8' (ercent of insulino%as because these tu%ors do not e,(ress a sufficient nu%ber of subt!(e & so%atostatin rece(tors )&&$&8*" 2+ee 3Localization of (ancreatic endocrine tu%ors 2islet-cell tu%ors535" /ndosco(ic ultrasonogra(h! and arterial sti%ulation with he(atic venous sa%(ling are alternatives when an insulino%a cannot be localized b! noninvasive %eans )&9$&:*" The advantage of the latter is that it is also a d!na%ic test" In one re(ort of endosco(ic ultrasonogra(h! for 1 tu%ors 211 of which were insulino%as5 confir%ed b! surger! but not detected b! transabdo%inal ultrasonogra(h! or CT )&9*$ the sensitivit! for the detection was <& (ercent" In a second stud! of &< (atients with insulino%a$ the sensitivit! of endosco(ic ultrasonogra(h! was <9 (ercent )&8*" >e use this test when noninvasive (rocedures fail to localize the tu%or" 6rterial calciu% sti%ulation with he(atic venous sa%(ling involves selective inFection of calciu% gluconate into the gastroduodenal$ s(lenic$ and su(erior %esenteric arteries with subseAuent sa%(ling of the he(atic venous effluent for insulin )&:$&.*" This test is based u(on the observation that calciu% sti%ulates the release of insulin fro% insulino%as but not nor%al beta cells" Thus$ calciu% %a!

sti%ulate insulin release in the sa%e arterial territor! as the tu%or 2show table 15" >e reserve this test for co%(le, cases" Overall$ with a((ro(riate (reo(erative localization studies (lus intrao(erative ultrasonogra(h! and (al(ation$ a tu%or 2or tu%ors5 can be identified in < (ercent of (atients with insulino%as" Differential diagnosis There are three rare disorders in which the bioche%ical findings si%ulate those of an insulino%a because the! are also associated with (ri%ar! over(roduction of insulin@ fa%ilial (ersistent h!(erinsuline%ic h!(ogl!ce%ia= (ri%ar! islet-cell h!(er(lasia 2also called nesidioblastosis5$ and noninsulino%a (ancreatogenous h!(ogl!ce%ia which has the characteristic feature of (roducing (ri%aril! (ost(randial h!(ogl!ce%ia"

TR/6T4/NT Initial surger! +urgical re%oval of the insulino%a is the treat%ent of choice" The following (rocedures were (erfor%ed in the 4a!o Clinic cohort ) *@ /nucleation of the insulino%a 11' (atients Eartial distal (ancreatecto%! .1 (atients /nucleation of the insulino%a and (artial (ancreatecto%! nine (atients 6 >hi((le (rocedure 2re%oval of the head of the (ancreas$ gastrecto%!$ duodenecto%!$ and s(lenecto%!5 one (atient Total (ancreatecto%! one (atient The surgical (rocedure was chosen b! the surgeon$ and none of the o(erations in this series was done via the la(arosco(e" The rate of surgical co%(lications was a((ro,i%atel! 1' (ercent" In addition$ eight (atients with %alignant insulino%as underwent bio(s! of %etastatic lesions$ and the tu%or was found at auto(s! after (erio(erative death in one (atient" #istologic e,a%ination of this tu%or revealed a %alignant islet cell tu%or that stained intensivel! for insulin 2show histolog! 16-1G5" Outco%e The following results were noted after surger!@ 1 : (atients were cured$ as defined b! being totall! free of s!%(to%s for at least si, %onths after re%oval of the insulino%a 1 (atients 21' with benign insulino%as$ eight with %alignant insulino%as$ and one with islet-cell h!(er(lasia5 had (ersistent h!(ogl!ce%ia 7ive develo(ed diabetes %ellitus 7our died (erio(erativel!= all four were o(erated on before 1 81 6%ong the 1' (atients who had benign insulino%as and (ersistent h!(ogl!ce%ia after initial surgical treat%ent$ si, had %ulti(le tu%ors 2four due to 4/N 15" 7ive of these si, (atients underwent reo(eration" Three of the five were found to have

additional %ulti(le tu%ors= one was cured and two develo(ed diabetes %ellitus after the second o(eration" Two (atients with single tu%ors at initial o(eration had (ersistent h!(ogl!ce%ia after the second o(eration because additional insulino%as were not identified" 7or (atients with insulino%a related to 4/N1$ so%e e,(erienced surgeons reco%%end local e,cision of an! tu%ors found in the head of the (ancreas (lus a distal subtotal (ancreatecto%! )&<*" This a((roach differs fro% that in (atients with s(oradic insulino%as$ who t!(icall! have a solitar! tu%or and in who% enucleation is usuall! successful" La(arosco(ic surger! In so%e centers$ la(arosco(ic (ancreatic surger! is so%eti%es (erfor%ed for s%all$ solitar! insulino%as that have been localized (reo(erativel! )& $1'*" Intrao(erative la(arosco(ic ultrasound %a! hel( %ini%ize the need for conversion to o(en (ancreatic surger!" /valuation for %issed insulino%a Reo(eration for %issed insulino%a (resents uniAue (roble%s" 7irst$ the diagnosis %ust be confir%ed" +econd$ one or %ore localizing (rocedures should be done" Reo(eration for insulino%a should onl! be (erfor%ed b! a surgeon e,(erienced with this situation and acco%(anied b! highl! e,(erienced endocrinologic and radiologic su((ort" >ith rare e,ce(tions$ blind (ancreatic resection should not be (erfor%ed if a tu%or is not identified" Ris0 of recurrence 6s noted above$ 1 : (atients in our series were in re%ission soon after surger! 2defined as a si,-%onth (eriod free of s!%(to%s after initial re%oval of an insulino%a5" 6%ong these (atients$ 11 2si, (ercent5 had recurrent h!(ogl!ce%ia" /ight of these (atients underwent re(eat e,(loration of the (ancreas@ si, had (athologic confir%ation of recurrent insulino%a$ one had (ersistent h!(ogl!ce%ia des(ite total (ancreatecto%!$ and one died intrao(erativel!" Eancreatic ree,(loration was not (erfor%ed in the other three (atients because of age and concerns about diabetes" Recurrence of h!(ogl!ce%ia within four !ears of the successful re%oval of an insulino%a suggests regrowth of residual insulino%a tissue left behind as a result of fracturing of the original tu%or" In this case$ the tu%or is at the sa%e site as the original tu%or )11*" The recurrences occurred fro% 8 to 1<"9 !ears after the initial o(eration" The cu%ulative incidence of recurrence was si, (ercent at 1' !ears and eight (ercent at &' !ears" Recurrences were %ore co%%on in the (atients with 4/N 1= the cu%ulative 1'- and &'-!ear recurrence rates were &1 (ercent at both ti%es co%(ared to 9 and . (ercent in those without 4/N 1 2(H'"''15 ) *" 6%ong four (atients with %alignant insulino%a who were s!%(to%-free for si, or %ore %onths after the initial o(eration$ two (atients had recurrences at four and nine !ears"

Eatient survival The overall survival rate of (atients with insulino%a did not differ fro% that e,(ected in the general (o(ulation" +urvival$ however$ was significantl! worse in the (atients with %alignant insulino%as 2but better than in (atients with acinar (ancreatic carcino%a5$ in older (atients$ and in those diagnosed earl! in the (eriod of observation 21 &. through 1 <:5 ) *" +o%e (atients with %alignant insulino%a a((ear to have a (rolonged natural histor!" In a series of 1' (atients treated at the National Institutes of #ealth over a &'-!ear (eriod for %etastatic insulino%a$ nine re%ained alive long-ter% 2u( to &9 !ears5$ three with liver %etastases )1&*" 7our had develo(ed %etastatic disease fro% 8 to 1& !ears after initial diagnosis$ while four had resected l!%(h node %etastases as the onl! site of disease" Darious treat%ent %odalities were used to control h!(ogl!ce%ia" In this series$ short-ter% benefits were %ost often achieved with e%bolization and diazo,ide$ and less often with radiofreAuenc! ablation$ radical debul0ing surger!$ vera(a%il$ octreotide$ and che%othera(!" 4edical thera(! to control s!%(to%atic h!(ogl!ce%ia 4edical thera(! should be considered in the (atient whose insulino%a was %issed during (ancreatic e,(loration$ who is not a candidate for or refuses surger!$ or who has unresectable %etastatic disease" The thera(eutic choices to (revent s!%(to%atic h!(ogl!ce%ia include@ Diazo,ide 2which di%inishes insulin secretion and is given in divided doses of u( to 1&'' %g;da!5 so%eti%es used for controlling h!(ogl!ce%ia )1&-18*" #owever$ it can cause %ar0ed ede%a 2which %a! reAuire high doses of loo( diuretics5 and hirsutis%" Octreotide$ an analog of so%atostatin 2growth hor%oneinhibitor! hor%one5$ inhibits B# secretion$ but in large doses$ also inhibits the secretion of T+#$ insulin$ and glucagon" >hile octreotide is highl! effective in controlling the s!%(to%s associated with glucagono%as$ DIEo%as$ and carcinoid tu%ors$ efficac! is less (redictable for s!%(to%atic (atients with insulino%a )1&$191<*" Nevertheless$ it is a reasonable choice for (atients with (ersistent h!(ogl!ce%ia that is refractor! to diazo,ide" Lanreotide$ another so%atostatin analog which is available internationall! but not in the U+$ a((ears to have si%ilar clinical efficac! as octreotide$ and is also available in a long-acting de(ot for% 2Lanreotide-+R5" 2+ee 34anage%ent of %etastatic gastroentero(ancreatic neuroendocrine tu%ors3$ section on Octreotide and lanreotide5" Dera(a%il )1&* and (hen!toin )1 * have also been used with so%e success" #owever$ none of these drugs is as effective as tu%or resection" Liver-directed thera(! for %etastatic disease The liver is the %ost co%%on site of %etastatic disease" Resection #e(atic resection is indicated for the treat%ent of %etastatic liver disease in the absence of diffuse bilobar involve%ent$ co%(ro%ised liver function$ or e,tensive e,trahe(atic %etastases 2eg$ (ul%onar!$ (eritoneal5" 6lthough the

%aForit! of cases will not be cured b! surger!$ (rolonged survival is often (ossible$ given the slow-growing nature of these tu%ors" In general$ resection should be considered onl! for (atients with a li%ited nu%ber of he(atic %etastases and is %ost successful when underta0en with curative intent" #e(atic arter! e%bolization Liver %etastases derive %ost of their blood su((l! fro% the he(atic arter!$ whereas health! he(atoc!tes derive %ost of their blood su((l! fro% the (ortal vein" This (rovides the rationale for thera(eutic e%bolization of the he(atic arter!$ with the goal of inducing necrosis of the %etastases with %ini%al da%age to nor%al liver (arench!%a" #e(atic arterial e%bolization with or without selective he(atic arter! infusion of che%othera(! is freAuentl! a((lied as a (alliative techniAue in (atients with s!%(to%atic he(atic %etastases who are not candidates for surgical resection" Res(onse rates$ as %easured b! a decrease in hor%onal secretion or b! radiogra(hic regression$ are generall! over 9' (ercent" R76 and cr!oablation Other a((roaches to the treat%ent of he(atic-(redo%inant disease include radiofreAuenc! ablation 2R765 and cr!oablation$ either alone or in conFunction with surgical debul0ing" These (rocedures$ which can be (erfor%ed using (ercutaneous or la(arosco(ic a((roaches$ a((ear to be less %orbid than either he(atic resection or he(atic arter! e%bolization" #owever$ both techniAues are a((licable onl! to s%aller lesions$ and their long-ter% efficac! is uncertain" Liver trans(lantation The nu%ber of (atients with liver-isolated %etastatic disease in who% orthoto(ic liver trans(lantation 2OLT5 has been atte%(ted is s%all$ and follow-u( data are insufficient to Fudge whether co%(lete cure has trul! been achieved" The li%ited availabilit! of donor organs in %an! regions has restricted investigation of this (rocedure" Until %ore data beco%e available$ %ost clinicians consider that liver trans(lantation is an investigational a((roach for %etastatic islet cell tu%ors$ including insulino%a" Che%othera(! and novel treat%ent a((roaches /,(erience with s!ste%ic che%othera(! is li%ited" The traditional regi%en of choice has been stre(tozocin and do,orubicin" 6lthough obFective res(onse rates as high as : (ercent were initiall! re(orted for %etastatic islet cell tu%ors$ the true radiologic res(onse rate is (robabl! lower$ between 1' and 8' (ercent" Uncertaint! as to efficac!$ as well as the to,icit! of this regi%en 2nausea$ (rolonged %!elosu((ression$ renal failure5$ has (revented its wides(read acce(tance as a standard first-line thera(!" 6ntitu%or activit! has also been shown for regi%ens containing the orall! active al0!lating agent te%ozolo%ide" In the absence of co%(arative trials$ the choice of first-line stre(tozocin;do,orubicin or a te%ozolo%ide-based regi%en %ust be individualized$ ta0ing into account the convenience of oral rather than intravenous

treat%ent$ (erfor%ance status$ and the antici(ated side effect (rofile of both co%binations" The %odest efficac! of conventional c!toto,ic che%othera(! has (ro%(ted the develo(%ent of novel thera(eutic a((roaches for (atients with advanced islet cell tu%ors" These include the use of targeted radiothera(!$ as well as regi%ens incor(orating inhibitors of angiogenesis and s%all %olecule t!rosine 0inase inhibitors" These to(ics are discussed in detail elsewhere" +U446RI 6ND R/CO44/ND6TION+ Insulino%as are rare (ancreatic islet cell tu%ors not li%ited to an! ethnic grou( 2incidence of 1 case (er &9'$''' (erson-!ears5= while %ost are s(oradic$ so%e are associated with the 4/N1 s!ndro%e" The characteristic clinical %anifestation of an insulino%a is fasting h!(ogl!ce%ia$ 2although so%e (atients also have (ost(randial h!(ogl!ce%ia5$ with neurogl!co(enic s!%(to%s which %a! or %a! not be (receded b! s!%(athoadrenal 2autono%ic5 s!%(to%s" 4ost insulino%as are solitar! and benign" 4ulti(le insulino%as are less co%%on$ and tend to be associated with 4/N1" 4alignant insulino%as are also less co%%on" The diagnosis of insulino%a is established b! de%onstrating ina((ro(riatel! high seru% insulin concentrations during a s(ontaneous or induced e(isode of h!(ogl!ce%ia 2eg$ .&-hour fast5" I%aging techniAues are then used to localize the tu%or" 6ccurate (reo(erative localization of an insulino%a is desirable" The (rocedures available include s(iral CT$ arteriogra(h!$ ultrasonogra(h! 2transabdo%inal and endosco(ic5$ and 111-In(entetreotide i%aging" Transabdo%inal ultrasonogra(h! and CT are our (referred initial test$ followed b! endosco(ic ultrasonogra(h! or arterial sti%ulation with he(atic venous sa%(ling when an insulino%a cannot be localized" Treat%ent 7or initial thera(! of (atients with benign$ solitar! insulino%as$ we reco%%end surgical e,cision of the tu%or 2Brade 165" The a((roach and e,tent of surger! should be deter%ined based u(on tu%or location" 2+ee 3Initial surger!3 above5" 7or (atients with %ulti(le insulino%as 2t!(icall! in the setting of 4/N15$ we reco%%end local e,cision of an! tu%ors found in the head of the (ancreas (lus a distal subtotal (ancreatecto%! 2Brade &G5" 2+ee 3Initial surger!3 above5" 7or (atients with (ersistent h!(ogl!ce%ia after surger! in who% solitar! or %ulti(le tu%ors are identified after additional localization (rocedures$ we reco%%end re(eat o(eration 2Brade 165" 2+ee 3Initial surger!3 above5" 7or (atients whose insulino%a cannot be located during (ancreatic e,(loration$ who are not candidates for or refuse surger!$ we suggest diazo,ide thera(! for the %edical %anage%ent of h!(ogl!ce%ia 2Brade &C5" 7or (atients with (otentiall! resectable liver-isolated %etastatic insulino%a$ we reco%%end surgical resection of the he(atic %etastases along with the (ri%ar! tu%or 2Brade 1G5" 6lthough the %aForit! of cases will not be

cured b! surger!$ given the slow-growing nature of the tu%or$ e,tended survival is so%eti%es (ossible" Other treat%ent o(tions for (atients with unresectable he(atic(redo%inant s!%(to%atic %etastatic disease include e%bolization$ che%oe%bolization$ R76$ and cr!oablation" The efficac! of so%atostatin analogs for (atients with diazo,ide-refractor! s!%(to%atic h!(ogl!ce%ia is un(redictable$ but so%e (atients %a! benefit" Octreotide$ as well as other s!ste%ic thera(! a((roaches 2interferon$ che%othera(!$ targeted radiothera(!5 are discussed in detail elsewhere"

R/7/R/NC/+
1" #arris$ +" #!(erinsulinis% and d!sinsulinis%" J646 1 &8= <1@.& " &" >ilder$ R4$ 6llan$ 7N$ Eower$ 4#$ et al" Carcino%a of the islands of the (ancreas" J646 1 &.= < @18<" 1" #owland$ B$ Ca%(bell$ >R$ 4althb!$ /J$ et al" D!sinsulinis%@ Convulsions and co%a due to islet cell tu%or of (ancreas$ with o(eration and cure" J646 1 & = 1@:.8" 8" +ervice$ BJ$ Tho%(son$ BG$ +ervice$ 7J et al" #!(erinsuline%ic h!(ogl!ce%ia with nesidioblastosis after gastric-b!(ass surger!" N /ngl J 4ed &''9= 191@&8 " 9" Kar$ E$ Erice$ E$ +awers$ +$ et al" Insulino%as %a! (resent with nor%ogl!ce%ia after (rolonged fasting but glucose-sti%ulated h!(ogl!ce%ia" J Clin /ndocrinol 4etab &'':= 1@8.11" :" Rizza$ R6$ et al" Eathogenesis of h!(ogl!ce%ia in insulino%a (atients@ su((ression of he(atic glucose (roduction b! insulin" Diabetes 1 <1= 1'@1.." ." Dort%e!er$ 6O$ #uang$ +$ Lubens0!$ I$ Chuang$ C" Non-islet origin of (ancreatic islet cell tu%ors" J Clin /ndocrinol 4etab &''8= < @1 18" <" 4inn$ 6#$ Ka!ton$ 4$ Lorang$ D$ et al" Insulino%as and e,(ression of an insulin s(lice variant" Lancet &''8= 1:1@1:1" " +ervice$ 7J$ 4c4ahon$ 44$ O?Grien$ EC$ Gallard$ DJ" 7unctioning insulino%a-incidence$ recurrence and long-ter% survival of (atients@ a :'-!ear stud!" 4a!o Clin Eroc 1 1= ::@.11" 1'" Kavlie$ #$ >hite$ TT" Eancreatic islet beta cell tu%ors and h!(er(lasia@ e,(erience in 18 +eattle hos(itals" 6nn +urg 1 .&= 1.9@1&:" 11" Cullen$ R4$ Ong$ C/" Insulino%a in 6uc0land 1 .'-1 <9" N C 4ed J 1 <.= 1''@9:'" 1&" Kurland$ LT$ 4olgaard$ C6" The (atient record in e(ide%iolog!" +ci 6% 1 <1= &89@98" 11" Dizon$ 64$ Kowal!0$ +$ #oogwerf$ GJ" Neurogl!co(enic and other s!%(to%s in (atients with insulino%as" 6% J 4ed 1 = 1':@1'." 18" +ervice$ 7J$ Dale$ 6J$ /lvebac0$ LR$ Jiang$ N+" Insulino%a@ clinical and diagnostic features of :' consecutive cases" 4a!o Clin Eroc 1 .:= 91@81." 19" #arrington$ 4B$ 4cBeorge$ 6E$ Gallant!ne$ JE$ et al" 6 (ros(ective surve! for insulino%as in a neurolog! de(art%ent" Lancet 1 <1= 1@1' 8" 1:" Grennan$ 4D$ +ervice$ 7J$ Car(enter$ 64$ et al" Diagnosis of (ancreatic islet h!(er(lasia causing h!(ogl!ce%ia in a (atient with (ortacaval anasto%osis" 6% J 4ed 1 <'= :<@ 81" 1." Kane$ L6$ Brant$ C+$ Ni((oldt$ TG$ et al" Insulino%a in a (atient with NIDD4" Diabetes Care 1 1= 1:@1& <" 1<" +vartberg$ J$ +tridsberg$ 4$ >ilander$ /$ et al" Tu%our-induced h!(ogl!cae%ia in a (atient with insulin-de(endent diabetes %ellitus" J Intern 4ed 1 := &1 @1<1"

1 " Gasu$ 6$ +heehan$ 4T$ Tho%(son$ BG$ +ervice$ 7J" Insulino%a in chronic renal failure@ a case re(ort" J Clin /ndocrinol 4etab &''&= <.@8<< " &'" +ec0l$ 4J$ 4ulholland$ EJ$ Gisho($ 6/$ et al" #!(ogl!ce%ia due to an insulin-secreting s%all-cell carcino%a of the cervi," N /ngl J 4ed 1 = 181@.11" &1" 7edora0$ IJ$ Ko$ TC$ Bordon$ D$ et al" Localization of islet cell tu%ors of the (ancreas@ a review of current techniAues" +urger! 1 1= 111@&8&" &&" 4odlin$ I4$ Tang$ L#" 6((roaches to the diagnosis of gut neuroendocrine tu%ors@ the last word 2toda!5" Bastroenterolog! 1 .= 11&@9<1" &1" Kauhanen$ +$ +e((anen$ 4$ 4inn$ #$ et al" 7luorine-1<-L-dih!dro,!(hen!lalanine 21<7DOE65 (ositron e%ission to%ogra(h! as a tool to localize an insulino%a or beta-cell h!(er(lasia in adult (atients" J Clin /ndocrinol 4etab &''.= &@1&1." &8" 4irallie$ /$ Eattou$ 7$ 4alvau,$ E$ et al" )Dalue of endosco(ic ultrasonogra(h! and so%atostatin rece(tor scintigra(h! in the (reo(erative localization of insulino%as and gastrino%as" /,(erience of 98 cases*" Bastroenterol Clin Giol &''&= &:@1:'" &9" Rosch$ T$ Lightdale$ CJ$ Gotet$ J7$ et al" Localization of (ancreatic endocrine tu%ors b! endosco(ic ultrasonogra(h!" N /ngl J 4ed 1 &= 1&:@1.&1" &:" Do((%an$ JL$ 4iler$ DL$ Chang$ R$ et al" Insulino%as@ localization with selective arterial inFection of calciu%" Radiolog! 1 1= 1.<@&1." &." Eereira$ EL$ Roche$ 6J$ 4aier$ B>$ et al" Insulino%a and islet cell h!(er(lasia@ value of the calciu% intraarterial sti%ulation test when findings of other (ros(ective studies are negative" Radiolog! 1 <= &':@.'1" &<" De%eure$ 4J$ Klonoff$ DC$ Kara%$ J#$ et al" Insulino%as associated with %ulti(le endocrine neo(lasia t!(e I@ the need for a different surgical a((roach" +urger! 1 1= 11'@ <" & " 6ssalia$ 6$ Bagner$ 4" La(arosco(ic (ancreatic surger! for islet cell tu%ors of the (ancreas" >orld J +urg &''8= &<@1&1 " 1'" 6!av$ 6$ Gresler$ L$ Grunaud$ L$ Goissel$ E" La(arosco(ic a((roach for solitar! insulino%a@ a %ulticentre stud!" Langenbec0s 6rch +urg &''9= 1 '@118" 11" +ervice$ 7J" Recurrent h!(erinsuline%ic h!(ogl!ce%ia caused b! an insulin-secreting insulino%a" Nat Clin Eract /ndocrinol 4etab &'':= &@8:." 1&" #irshberg$ G$ Cochran$ C$ +0arulis$ 4C$ et al" 4alignant insulino%a" Cancer &''9= 1'8@&:8" 11" Bill$ BD$ Rauf$ O$ 4ac7arlane$ I6" Diazo,ide treat%ent for insulino%a@ a national UK surve!" Eostgrad 4ed J 1 .= .1@:8'" 18" Boode$ EN$ 7arndon$ JR$ 6nderson$ J$ et al" Diazo,ide in the %anage%ent of (atients with insulino%a" >orld J +urg 1 <:= 1'@9<:" 19" +ervice$ 7J" #!(ogl!ce%ia including h!(ogl!ce%ia in neonates and children" In@ /ndocrinolog!$ 1d ed$ DeBroot$ LJ 2/d5$ >G +aunders$ Ehiladel(hia 1 9" ("1:'" 1:" Ro%eo$ +$ 4ilione$ 4$ Batti$ 6$ et al" Co%(lete Clinical Re%ission and Disa((earance of Liver 4etastases after Treat%ent with +o%atostatin 6nalogue in a 8'-Iear-Old >o%an with a 4alignant Insulino%a Eositive for +o%atostatin Rece(tors T!(e &" #or% Res &'':= :9@1&'" 1." Ricci$ +$ 6ntonuzzo$ 6$ Balli$ L$ et al" Long-acting de(ot lanreotide in the treat%ent of (atients with advanced neuroendocrine tu%ors" 6% J Clin Oncol &'''= &1@81&" 1<" 6(aricio$ T$ Ducreu,$ 4$ Gaudin$ /$ et al" 6ntitu%our activit! of so%atostatin analogues in (rogressive %etastatic neuroendocrine tu%ours" /ur J Cancer &''1= 1.@1'18" 1 " #ofeldt$ 7D$ Di((e$ +/$ Levin$ +R$ et al" /ffects of di(hen!lh!dantoin u(on glucoseinduced insulin secretion in three (atients with insulino%a" Diabetes 1 .8= &1@1 &"