Resea ch A icle
Cha ac e is ics and Ou comes o 79 Pa ien s wi h an Insulinoma:
A Na ionwide Re ospec i e S udy in Finland
Elina Pel ola,
1,2
Päi i Hannula,
3
Heini Huh ala,
4
Saa a Me so,
3
Ulla Ki iniemi,
3
Ma ine Vo nanen,
5
Juhani Sand,
6
Johanna Laukka inen,
1,7
Mi ja Tiikkainen,
8
Camilla Schalin-Jän i,
8,9
Johanna A ola,
10,11
Jukka Si én,
12
An i Pii oinen,
13
Minna Soinio,
14
Pi jo Nuu ila,
13,14
Mi a Söde s öm,
15
Hanna Hämäläinen,
16
Leena Moilanen,
17
Da id Laaksonen,
17
Elina Pi inen,
18
Fia Sundelin,
19
Tapani Ebeling,
19,20
Pasi Salmela,
20
Ma kus J. Mäkinen,
21,22
and Pia Jaa inen
1,2,3
1
Facul y o Medicine and Li e Sciences, Uni e si y o Tampe e, Finland
2
Di ision o In e nal Medicine, Seinäjoki Cen al Hospi al, Finland
3
Endoc inology, Depa men o In e nal Medicine, Tampe e Uni e si y Hospi al, Finland
4
Facul y o Social Sciences, Uni e si y o Tampe e, Finland
5
Fimlab Labo a o ies, Pa hology Depa men , Tampe e Uni e si y Hospi al, Finland
6
Päijä -Häme Join Au ho i y o Heal h and Wellbeing, Finland
7
Depa men o Gas oen e ology and Alimen a y T ac Su ge y, Tampe e Uni e si y Hospi al, Finland
8
Endoc inology, Abdominal Cen e , Helsinki Uni e si y Hospi al, Finland
9
Endoc inology, Abdominal Cen e , Uni e si y o Helsinki, Finland
10
Pa hology, HUSLAB Helsinki Uni e si y Hospi al, Finland
11
Pa hology, Uni e si y o Helsinki, Finland
12
Abdominal Cen e , Helsinki Uni e si y Hospi al, Finland
13
Facul y o Medicine, Uni e si y o Tu ku, Finland
14
Endoc inology, Depa men o In e nal Medicine, Tu ku Uni e si y Hospi al, Finland
15
Depa men o Pa hology, Tu ku Uni e si y Hospi al, Finland
16
Facul y o Heal h Sciences, School o Medicine, Uni e si y o Eas e n Finland, Finland
17
Depa men o Medicine, Kuopio Uni e si y Hospi al, Finland
18
Depa men o Clinical Pa hology, Kuopio Uni e si y Hospi al, Finland
19
Facul y o Medicine, Uni e si y o Oulu, Finland
20
Endoc inology, Oulu Uni e si y Hospi al, Finland
21
Resea ch Uni o Cance and T ansla ional Medicine, Depa men o Pa hology, Uni e si y o Oulu, Finland
22
Depa men o Pa hology, Oulu Uni e si y Hospi al, Finland
Co espondence should be add essed o Pia Jaa inen; pia.jaa inen@u a.fi
Recei ed 6 May 2018; Accep ed 9 Sep embe 2018; Published 23 Oc obe 2018
Academic Edi o : Thomas J. Fahey
Copy igh © 2018 Elina Pel ola e al. This is an open access a icle dis ibu ed unde he C ea i e Commons A ibu ion License,
which pe mi s un es ic ed use, dis ibu ion, and ep oduc ion in any medium, p o ided he o iginal wo k is p ope ly ci ed.
Objec i e. Insulinomas a e a e panc ea ic umou s. Popula ion-based da a on hei incidence, clinical pic u e, diagnosis, and
ea men a e almos nonexis en . The aim o his s udy was o cla i y hese aspec s in a na ionwide coho o insulinoma
pa ien s diagnosed du ing h ee decades. Design and Me hods. Re ospec i e analysis on all adul pa ien s diagnosed wi h
insulinoma in Finland du ing 1980–2010. Resul s. Se en y-nine pa ien s we e diagnosed wi h insulinoma o e he esea ch
pe iod. The median ollow-up om diagnosis o las con ol isi was one (min 0, max 31) yea . The incidence inc eased om
0.5/million/yea in he 1980s o 0.9/million/yea in he 2000s (p=0002). The median diagnos ic delay was 13 mon hs and did
no change o e he s udy pe iod. The mean age a diagnosis was 52 (SD 16) yea s. The o e all imaging sensi i i y imp o ed
Hindawi
In e na ional Jou nal o Endoc inology
Volume 2018, A icle ID 2059481, 10 pages
h ps://doi.o g/10.1155/2018/2059481
om 39% in he 1980s o 98% in he 2000s (p<0001). Se en y-one (90%) o he pa ien s unde wen su ge y wi h a cu a i e aim,
wo (3%) had pallia i e su ge y, and 6 (8%) we e inope able. The e we e no significan diffe ences in he ypes o su gical
p ocedu es be ween he 1980s, 1990s, and 2000s; umou enuclea ions comp ised 43% o he ope a ions, dis al panc ea ic
esec ions 45%, and panc ea icoduodenec omies 12%, o e he whole s udy pe iod. O he pa ien s who unde wen su ge y wi h
a cu a i e aim, 89% had a ull eco e y. Pos ope a i e complica ions occu ed in hal o he pa ien s, bu pos ope a i e mo ali y
was a e. Conclusions. The incidence o insulinomas has inc eased du ing he pas h ee decades. Despi e he imp o ed
diagnos ic op ions, diagnos ic delay has emained unchanged. To sho en he delay, clinicians should be in o med and ale o
conside he possibili y o hypoglycemia and insulinoma, when symp oma ic a acks a e in es iga ed in diffe en sec o s o he
heal hca e sys em. De eloping he su gical ea men is ano he majo a ge , in o de o lowe he o e all complica ion a e,
wi hou comp omising he high cu e a e o insulinomas.
1. In oduc ion
Insulinomas a e he mos common unc ioning endoc ine
neoplasms o he panc eas wi h an es ima ed incidence o
1–4 pe million pe yea . Less han 10% a e epo ed o me as-
asize [1, 2]. Du ing he pas ew decades, he incidence o all
neu oendoc ine neoplasms (NENs) has inc eased apidly
compa ed wi h he gene al incidence o cance s [3, 4]. The
inc ease may in pa be explained by imp o ed diagnos ics,
including mo e sensi i e imaging me hods [4, 5]. Whe he
he incidence o insulinomas has ollowed he inc easing
end o NENs in gene al is p esen ly unknown.
In pa ien s wi h insulinoma, episodes o hype insuline-
mic hypoglycemia cause a ious au onomic and neu oglyco-
penic symp oms, which usually eme ge in he as ing s a e.
Documen a ion o he so-called Whipple’s iad, i.e., symp-
oms consis en wi h hypoglycemia, a low plasma glucose
measu ed a he ime o he symp oms, and immedia e elie
o he symp oms a e adminis a ion o glucose, is he co -
ne s one o insulinoma diagnos ics [6–8]. Demons a ion o
a low plasma glucose concomi an wi h inapp op ia ely high
se um insulin and C-pep ide le els in a symp oma ic pa ien
cons i u es he basis o he biochemical diagnosis, wi h he
exclusion o o he causes o hype insulinemic hypoglycemia
[7]. β-Hyd oxybu y a e le els o 2.7 mmol/li e o less, an
inc ease in plasma glucose o a leas 1.4 mmol/li e a e i
glucagon, and a nega i e sc een o o al hypoglycemic agen s
dis inguishendogenoushype insulinemichypoglycemia om
ha caused by o he mechanisms [7]. A 72-hou as ing es
wi h plasma glucose, insulin, and C-pep ide measu emen s
is conside ed he gold s anda d o he biochemical diagnosis
o insulinoma [7]. Gadolinium-enhanced dynamic magne ic
esonance imaging (MRI), 3-phase compu ed omog aphy
(CT), and endoscopic ul asonog aphy (EUS) ha e been
ega ded as he mos use ul imaging modali ies o insuli-
noma e alua ion [8]. In expe ienced hands, he sensi i i y
o EUS is 70–95%, and combined wi h 3-phase CT, sensi i -
i ies up o 100% ha e been epo ed [8, 9]. Con en ional US,
CT, and MRI a e widely a ailable and hus o en applied as
he fi s -line imaging me hods, bu hei success a es emain
a 10–40% in many s udies [9]. Du ing he pas 10 yea s,
new unc ional nuclea imaging me hods (such as
18
F-
DOPA-PET/CT,
68
Ga-DOTA-NOC-PET/CT, and ecen ly,
GLP-1-analogue-PET/CT) ha e also become a ailable, and
p omising esul s ha e been epo ed wi h sensi i i ies
exceeding 90% [10–13]. These unc ional imaging me hods
ha e la gely eplaced he p e iously mo e commonly used
diagnos ic angiog aphy (based on de ec ion o a hype as-
cula lesion consis en wi h an insulinoma) and oc eo ide
scin ig aphy, wi h gene al sensi i i ies o 60 and 50%,
espec i ely [9]. Lapa oscopic su ge y has de eloped, and
panc eas-p ese ing su gical me hods ha e become mo e
common in many cen e s, o a oid he ad e se effec s o
ex ensi e panc ea ic esec ions, such as exoc ine dys unc-
ion and insulin-dependen diabe es [14].
Because p e ious epo s on single-cen e coho s ha e
sugges ed changes in he clinical pic u e, diagnos ics, and
ea men o insulinoma [10, 15–18], we wan ed o cla i y
hese aspec s in an unselec ed, na ionwide coho o pa ien s
wi h insulinomas, diagnosed o e a 3-decade pe iod. Mo e-
o e , no p e ious popula ion-based da a exis on changes
in he incidence o insulinomas, al hough an inc ease in
he o e all incidence o NENs has been no ed wo ldwide.
We ha e p e iously epo ed a pilo s udy o 23 insulinoma
pa ien s included in he p esen s udy, diagnosed a one
o he pa icipa ing cen e s (Tampe e Uni e si y Hospi al,
Finland) [19].
2. Subjec s and Me hods
2.1. Pa ien Popula ion. A e ospec i e analysis was pe -
o med on adul (≥18 yea s) pa ien s diagnosed wi h an insu-
linoma in Finland du ing 1980–2010. To find all he Finnish
insulinoma pa ien s, a comp ehensi e sea ch was ca ied ou
in he pa ien eco d and pa hology egis ies in all he fi e
uni e si y hospi als, as well as a he Finnish Cance Regis y.
In Finland, he diagnos ics and ea men o insulinomas a e
cen alized in he Uni e si y Hospi als. Diagnosis codes o
benign and malignan panc ea ic umou s, as well as hypo-
glycemia, we e sea ched o in he pa ien eco ds o all he
fi e Finnish Uni e si y Hospi als (de ailed sea ch s a egy
in Supplemen a y Ma e ials (a ailable he e)). To double-
check he sea ch esul s o su gically managed insulinomas,
pa hology egis ies o he Uni e si y Hospi als we e sea ched
o he e m insulinoma∗. In addi ion, a sea ch in he Finnish
Cance Regis y, a na ionwide da abase on all cance s diag-
nosed in Finland, was pe o med wi h ICD-O-3 mo pholog-
ical codes 8150 Panc ea ic endoc ine umou and 8151
Insulinoma. The case his o ies o all he pa ien s iden ified
by he sea ches desc ibed abo e we e e iewed o e i y i
he inclusion c i e ia o he p esen s udy we e ulfilled.
2.2. Inclusion C i e ia. The diagnosis o insulinoma was
based on documen a ion o he Whipple’s iad and/o
2 In e na ional Jou nal o Endoc inology
hype insulinemic hypoglycemia oge he wi h his opa ho-
logical e ifica ion o an insulinoma. His opa hology was
ega ded as posi i e, i he diagnosis was panc ea ic neu o-
endoc ine umou and insulin s aining (i pe o med) was
posi i e. In pa ien s wi hou his opa hological e ifica ion,
he diagnosis equi ed documen a ion o he Whipple’s iad
o hype insulinemic hypoglycemia, as well as imaging find-
ings o a panc ea ic umou compa ible wi h an insulinoma.
2.3. Da a Collec ion. Da a was collec ed on he clinical pic-
u e, labo a o y findings, imaging, pa hology, ea men ,
and ollow-up o insulinomas. The symp oms we e classified
as neu oglycopenic and au onomic. Labo a o y findings eg-
is e ed we e he lowes inciden al blood glucose concen a-
ion, measu emen s o glyca ed hemoglobin (HbA1c), and
he esul s o as ing es s and p olonged (5-hou ) OGTTs.
The as ing es s we e analysed acco ding o he Endoc ine
Socie y 2009 Guideline c i e ia o hype insulinemic hypo-
glycemia [7] (Table 1). The blood glucose alues we e mul i-
plied by 1.15, o be compa able wi h he plasma glucose
measu emen s. Any medica ion po en ially affec ing insulin
sec e ion o insulin sensi i i y was documen ed. The numbe
and he size o insulinomas, he ype o ope a ion, su gical
complica ions, and he his opa hological diagnosis we e eg-
is e ed. Pos ope a i e hospi al mo ali y was eco ded. Pos -
ope a i e su gical complica ions we e classified acco ding
o he Cla ien-Dindo (CD) classifica ion [20, 21]. The inci-
dence o insulinoma was calcula ed acco ding o he popula-
ion s a is ics p o ided by S a is ics Finland [22].
The e hical commi ee o Tampe e Uni e si y Hospi al
and he Na ional Ins i u e o Heal h and Wel a e app o ed
he s udy p o ocol.
2.4. S a is ical Analysis. The s a is ical analysis was con-
duc ed wi h he IBM SPSS S a is ics o Windows, Ve sion
22.0 (IBM Co p., A monk, NY, USA). The nume ical esul s
a e p esen ed as mean (s anda d de ia ion, SD) o no mally
dis ibu ed a iables, median (minimum, maximum) o
o he con inuous a iables, and numbe (%) o ca ego ical
a iables. Diagnos ic delay was calcula ed om he fi s p e-
sen a ion o hypoglycemic symp oms up o he clinical diag-
nosis o insulinoma, as documen ed in he pa ien eco ds.
Diffe ences we e analysed be ween insulinomas diagnosed
in he 1980s, 1990s, and 2000s. Ca ego ical a iables we e
analysed by he chi-squa e es o he Fishe exac es , as
app op ia e. Nume ical a iables we e assessed by he
Mann-Whi ney U es , S uden - es , o K uskal-Wallis es ,
as app op ia e. A wo-sided p alue below 0.05 was conside ed
s a is ically significan . The changes in he incidence o insu-
linomas we e assessed wi h Poisson eg ession, conduc ed
wi h STATA S a is ical So wa e: Release 13 (S a aCo p LP,
College S a ion, TX, USA).
3. Resul s
3.1. Pa ien Cha ac e is ics and Incidence o Insulinomas.
Al oge he , 79 insulinoma pa ien s we e iden ified, 55 (70%)
o hem emale. In 73 pa ien s, he diagnosis was confi med
his opa hologically, whe eas in 6 pa ien s, he diagnosis
was based on documen a ion o he Whipple’s iad o
hype insulinemic hypoglycemia and imaging findings com-
pa ible wi h an insulinoma. O hese 6 pa ien s wi hou his-
opa hologic e ifica ion, 4 we e inope able (2 malignan
insulinomas wi h dis an me as ases and 2 clinically classi-
fied as benign bu inope able due o o he diseases). One
pa ien wi h hypoglycemic symp oms, confi med hype insu-
linemic hypoglycemia, and imaging esul s consis en wi h
an insulinoma died o bleeding complica ing he panc ea ic
su ge y, and his opa hological e ifica ion o he insulinoma
was no ob ained. In one pa ien , diagnosed in he 1980s, no
insulinoma could be localized in he p ima y su ge y,
despi e he p eope a i e anshepa ic po o enous sampling
(THPVS) findings compa ible wi h an insulinoma loca ed
in he body o he panc eas. As he hypoglycemic symp oms
p og essed, a diagnos ic angiog aphy was pe o med o
localize he umou . As a complica ion o his angiog aphy,
le hal in aabdominal bleeding de eloped, and no his opa h-
ological e ifica ion o he umou was ob ained.
The median leng h o ollow-up om he clinical diagno-
sis o insulinoma up o he las con ol isi a he Uni e si y
Hospi al was one (0, 31) yea . MEN1 synd ome was diag-
nosed in wo pa ien s, bo h o hem associa ed wi h a soli a y
insulinoma. The mean age a he ime o diagnosis was 52
(SD 16) yea s. The MEN1 pa ien s we e younge a he diag-
nosis (mean age 42 yea s in MEN1 s. 52 yea s in spo adic
cases), bu he diffe ence was no s a is ically significan
(p=0368). The median age a he ime o diagnosis did no
diffe be ween malignan [55 (39, 76) yea s] and nonmalig-
nan (insulinomas classified as benign o unde e mined)
insulinomas [51 (21, 84) yea s, p=0098]. The median BMI
a diagnosis was 27 (20, 51) kg/m
2
.
The incidence o insulinoma o e he whole esea ch
pe iod was 0.6 pe million adul s pe yea and inc eased
ema kably du ing he s udy pe iod (0.5, 0.4, and 0.9/mil-
lion/yea in he 1980s, 1990s, and 2000s, espec i ely). In
Poisson eg ession analysis, he yea ly incidence a e a io
was 1.043, and he inc ease in incidence was s a is ically sig-
nifican (p=0002). The inc easing incidence o insulino-
mas is p esen ed in Figu e 1. The median diagnos ic delay
was 13 mon hs (17, 11, and 17 mon hs in he 1980s,
1990s, and 2000s, espec i ely). Thi y-one o 79 pa ien s
we e fi s examined o hei symp oms by speciali ies o he
han endoc inology, mos o en by neu ology, neu osu ge y,
o ca diology.
3.2. Symp oms. All bu wo pa ien s had hypoglycemic
symp oms be o e he insulinoma diagnosis (Table 2). The
Table 1: The c i e ia o endogenous hype insulinemic hypoglycemia
acco ding o he Endoc ine Socie y Guideline 2009 [7].
Symp oms and signs, o bo h, consis en wi h hypoglycemia wi h
concomi an plasma concen a ions o
Glucose <3.0 mmol/l
Insulin ≥18 pmol/l
C-Pep ide ≥0.2 nmol/l
P oinsulin ≥5.0 pmol/l
3In e na ional Jou nal o Endoc inology
symp oms we e usually p og essi e, p o oked by as ing, and
a wo s , occu ed daily o weekly. 96% o he pa ien s had
neu oglycopenic symp oms, and 77% had au onomic symp-
oms. The mos common p esen ing symp oms we e con u-
sion (86%), d owsiness (58%), and excessi e swea ing (57%).
Weigh gain was documen ed in 56% o he pa ien s, o whom
one- hi d gained weigh mo e han 10 kilog ams.
O he wo pa ien s wi hou hypoglycemic symp oms
p io o he diagnosis o insulinoma, one was ound in con-
nec ion wi h he MEN1-in es iga ions o he pa ien ’s sibling,
and he symp oms ela ed o hypoglycemia fi s appea ed 3
yea s a e he diagnosis. The o he pa ien p esen ed wi h
jaundice and dia hea ela ed o a panc ea ic umou . The
umou was ope a ed on, and hypoglycemic symp oms and
e ified hype insulinemic hypoglycemia did no occu un il
8 mon hs a e he p ima y ope a ion, when li e me as ases
we e de ec ed.
3.3. Labo a o y Findings. In all excep he wo pa ien s
desc ibed abo e, hypoglycemia had been de ec ed, ei he
spon aneously o in a as ing es , p io o he insulinoma
diagnosis. The median lowes spon aneous plasma glucose
was 2.0 (1.3, 4.9) mmol/l (n=62). The median glyca ed
hemoglobin (HbA1c) alue a diagnosis was 4.9% (3.7, 5.7;
n=31). Hype insulinemic hypoglycemia was e ified in 65
(82%) o he pa ien s, ei he spon aneously, du ing a as ing
es , o du ing a p olonged OGTT.
Six y-fi e pa ien s unde wen a as ing es , aiming a a
24, 36, o 72-hou as ing ime. Da a o analysis was a ail-
able on 64 pa ien s. In he as ing es , he median plasma
glucose nadi was 2.2 (0.8, 4.5) mmol/l (n=64), and he
co esponding se um insulin 16 (1.5, 154) mU/l (n=55)
and C-pep ide 0.9 (0.3, 4.4) nmol/l (n=44). The c i e ia
o endogeneous hype insulinemic hypoglycemia by he
Endoc ine Socie y [7] we e me in 92% o he es s, a e a
median as ing ime o 14 (0, 36) hou s. In 5 pa ien s, he
c i e ia we e no me , bu in h ee o hem, he es was
in e up ed p ema u ely. Ele en (14%) pa ien s unde wen
a p olonged OGTT, and h ee o hese es s e ified hype -
insulinemic hypoglycemia.
3.4. Imaging Me hods. The umou was localized p eope a-
i ely in 59 (75%) o he pa ien s. In 9 (11%) o he pa ien s,
he imaging esul s we e indefini e, and in 11 (14%) nega i e.
A median o 3 imaging modali ies was used pe pa ien (1, 7).
The mos equen ly used imaging modali ies we e CT scan,
angiog aphy, MRI, EUS, and
18
F-DOPA-PET/CT, o which
EUS,
18
F-DOPA-PET/CT, and MRI we e he mos success ul
ones, wi h o e all sensi i i ies o 78, 55, and 50%, espec-
i ely. A CT scan was pe o med on 90% o he pa ien s,
and he sensi i i y o CT scanning imp o ed ema kably
unde he s udy pe iod, om 6% in he 1980s o 51% in he
2000s (p=0001). The o e all imaging sensi i i y imp o ed
du ing he s udy pe iod om 39% in he 1980s o 98% in
he 2000s (p<0001) (Table 3). EUS had he bes sensi i i y
(78%) o de ec ing small umou s (diame e o 1 cm o
less), while he sensi i i ies o o he modali ies we e 43%
o
18
F-DOPA-PET/CT, 40% o MRI, 33% o oc eo ide
scin ig aphy, 23% o CT, and 0% o ansabdominal US.
In aope a i e US was pe o med in 19 pa ien s, wi h an
o e all success a e o 79%.
3.5. Medical T ea men . Fi y-fi e (70%) o he pa ien s used
p eope a i e medica ion: 47 (59%) used diazoxide, 10 (13%)
1985-89 1990-94 1995-99 2000-04 2005-101980-84
0
0.2
0.4
0.6
0.8
1
1.2
1.4
Incidence (/1.000.000/yea )
Figu e 1: The incidence o insulinomas in Finland 1980–2010. In Poisson eg ession analysis, he yea ly incidence a e a io was 1.043, and
he inc ease in incidence was s a is ically significan (p=0002).
Table 2: The p esen ing symp oms o he 79 pa ien s diagnosed
wi h an insulinoma in Finland 1980–2010.
Symp om n%
Au onomic symp oms 61 77
Swea ing/diapho esis 45 57
T emo 21 27
Anxie y, agg essi eness 16 20
Palpi a ions 14 18
Neu oglycopenic symp oms 76 96
Con usion 68 86
D owsiness 46 58
Visual dis u bances 41 52
Amnesia 35 44
Unconsciousness 36 46
Ligh headedness 26 33
Hunge 24 30
Pa es hesias 20 25
Headache 16 20
Seizu es 15 19
4 In e na ional Jou nal o Endoc inology
used a soma os a in analogue, and 4 (5%) used bo h com-
pounds. The median main enance dose o diazoxide was
150 (25, 600) mg/day, and a a o able esponse ( elie o
symp oms and/o imp o emen o plasma glucose le els) o
diazoxide was documen ed in 19 (63%) o he 30 pa ien s
wi h da a a ailable.
3.6. Su ge y. Se en y-one o he 79 (90%) pa ien s unde wen
panc ea ic su ge y wi h a cu a i e aim, wo (3%) had pallia-
i e su ge y o he p ima y umou , and six cases (8%) we e
inope able. The ope a ions included 31 enuclea ions (43%),
33 dis al esec ions (45%), and 9 panc e icoduodenec omies
(PDs; 12%). In one o he wo pa ien s wi h pallia i e panc e-
a ic su ge y, also li e esec ions we e pe o med, o educe
he umou load.
The median umou diame e o enuclea ions ended o
be smalle [10 (5, 28) mm] han o dis al esec ions [15 (7,
60) mm] o PDs [15 (5, 26) mm], (p=0073). Enuclea ions
became sligh ly mo e common du ing he s udy pe iod, bu
he e was no s a is ically significan diffe ence in he dis ibu-
ion o su gical p ocedu es be ween he 1980s, 1990s, and
2000s in he whole coho (Table 4, p=0355). In Helsinki
Uni e si y Hospi al, whe e mos o he insulinoma ope a-
ions we e pe o med, he enuclea ion a e inc eased om 0
in he 1980s o 44% in he 2000s, and he dis al esec ion a e
dec eased om 100 o 56%, espec i ely (p=0021).
Pos ope a i e hospi al mo ali y was 3% (2/73). Pos op-
e a i e complica ions, g aded acco ding o he Cla ien-
Dindo classifica ion [20, 21], occu ed in 51% o he pa ien s
(Figu e 2); CD g ade I in 3% and significan CD g ades II–IV
complica ions in 45%. The mos common pos ope a i e
complica ions we e panc ea ic fis ula (19%), panc ea i is
(10%), in a-abdominal abscess (14%), and wound in ec ion
(10%). Panc ea ic fis ulas occu ed in 19% o he pa ien s
(23% a e umou enuclea ions, 12% a e dis al esec ions,
and 33% a e PDs, wi hou a significan diffe ence be ween
he su gical me hods (ns; p=0293)). O e all majo compli-
ca ions (CD g ades III–V) occu ed in 16% o enuclea ions,
24% o dis al esec ions, and 56% o PDs (p=0062). The e
was no diffe ence in he Cla ien-Dindo g ade be ween he
1980s, 1990s, and 2000s (p=0894), be ween he su gical
cen e s (p=0079) o be ween he insulinomas classified as
malignan and hose classified as nonmalignan (p=0488).
The pos ope a i e mo ali y o insulinoma enuclea ion was
3%, o dis al esec ion 3%, and o PD 0% (p=100). Two
pa ien s died du ing he pos ope a i e hospi aliza ion, bo h
because o su gical complica ions. One pa ien wi h a single
insulinoma loca ed in he panc ea ic ail died because o
bleeding du ing ail esec ion. One pa ien died du ing a
eope a ion because o a panc ea ic fis ula, se e e panc ea i-
is, and sepsis a e p ima y enuclea ion o a benign insuli-
noma in he head o he panc eas.
Table 3: The imaging me hods used and hei sensi i i ies in he localiza ion o insulinomas in Finland 1980–2010.
Localizing me hod 1980–1989 (n=18) 1990–1999 (n=18) 2000–2010 (n=43)
Ra io
a
% Ra io % Ra io %
Abdominal US 1/12 8 1/12 8 4/11 36
Angiog aphy 3/14 21 3/9 33 7/11 64
CT scan 1/17 6 3/17 17 19/37 51
EUS NA 4/6 67 14/17 82
ERCP 0 0 0/2 0 NA
MRCP NA NA 1/1 100
MRI NA 2/6 33 12/22 55
Oc eo ide scin ig aphy NA 2/6 33 1/9 11
THPVS 3/4 75 NA NA
18
F-DOPA-PET/CT NA 0/1 0 11/19 58
18
F-FDG-PET/CT NA NA 0/1 0
O e all de ec ion 7/18 39 10/18 56 42/43 98
a
Ra io indica es he p opo ion o pa ien s in whom he imaging me hod was success ul in localizing he insulinoma. US indica es ul asonog aphy; CT:
compu ed omog aphy; EUS: endoscopic ul asonog aphy; ERCP: endoscopic e og ade cholangiopanc ea og aphy; MRCP: magne ic esonance
cholangiopanc ea og aphy; MRI: magne ic esonance imaging; THPVS: anshepa ic po o enous sampling;
18
F-DOPA-PET:
18
F-dihyd oxyphenylalanine
posi on emission omog aphy;
18
F-FDG-PET:
18
F-fluo odeoxyglucose posi on emission omog aphy; NA: no applicable.
Table 4: Su gical ea men o insulinoma pa ien s in Finland 1980–2010.
Su gical p ocedu e
1980–1989
(n=13)
1990–1999
(n=19)
2000–2010
(n=41)To al (n=73)
n%n%n%n%
Tumou enuclea ion 4 31 11 58 16 39 31 43
Dis al esec ion 8 61 5 26 20 49 33 45
Panc ea icoduodenec omy 1 8 3 16 5 12 9 12
5In e na ional Jou nal o Endoc inology

3.7. Tumou Cha ac e is ics. Se en y- h ee o he 79 pa ien s
had a soli a y insulinoma, and 5 had mul iple umou s (da a
no a ailable o one pa ien ). In 44% o he pa ien s, he
umou was loca ed in he head o he panc eas, while
umou s in he panc ea ic ail and body accoun ed o 27%
and 18%, espec i ely. In 8 pa ien s, he localiza ion o he
insulinoma was no documen ed. The median umou diam-
e e was 14 (5, 60) mm.
In he pa ien eco d and pa hology egis y da a, he
insulinomas we e classified as benign in 58 (73%), malignan
in 11 (14%), and unde e mined in 6 (8%) pa ien s, using he
con empo a y classifica ions o PNENs. Dis an me as ases
we e documen ed in 9 (11%) pa ien s. In he wo pa ien s
wi hou dis an me as ases, he malignan classifica ion
was based on a locally in asi e g ow h o he umou and
a ela i ely high Ki-67 labeling index (9%). Insulin s aining
was pe o med in 59 specimens and was posi i e in all o
hem. The umou s we e also s ained posi i ely wi h o he
neu oendoc ine ma ke s, e.g., ch omog anin A (39 posi i e/
42 es ed) and synap ophysin (32/35). Ki-67/MIB-1 s aining
was pe o med in 29 specimens and was ≤2% in 20 (69%)
and ≥5% in 7 (24%) o he es ed specimens (min <1%,
max 50%).
3.8. Managemen and Ou come o Insulinomas Classified as
Benign o Unde e mined. The median leng h o ollow-up
o insulinomas classified as benign was 0.7 (0.1, 26) yea s
and 1.6 (0.2, 31) yea s o hose classified as unde e mined.
A o al o 66 o he 68 pa ien s wi h nonmalignan insulino-
mas unde wen su ge y, and 62 o hem had a ull eco e y.
Two pa ien s, as desc ibed abo e, died o su gical complica-
ions and one o complica ions in a diagnos ic angiog aphy.
In one pa ien , umou ecu ence was de ec ed 10 yea s a e
he p ima y enuclea ion o a single benign umou , loca ed in
he head o he panc eas. This pa ien was ea ed wi h
soma os a in analogues and a eope a ion, and no ecu ence
was de ec ed du ing 7.5 yea s o ollow-up a e he eope a-
ion. Two pa ien s wi h benign insulinomas we e inope able
Tumou enuclea ion Pa ial esec ion Panc ea icoduodenec omy
V
IV
III
II
I
0
G adea
n = 31 n = 33 n = 9
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Figu e 2: Pos ope a i e o e all complica ions g aded acco ding o he Cla ien-Dindo classifica ion [20, 21] in he 73 insulinoma pa ien s
ope a ed in Finland 1980–2010.
a
Complica ion g ade (0–V) acco ding o he Cla ien-Dindo classifica ion, whe e 0 indica es no
complica ions and V indica es dea h o he pa ien . The e was no s a is ically significan diffe ence in he Cla ien-Dindo g ades be ween
he su gical me hods (p=0218, Fishe exac es ).
6 In e na ional Jou nal o Endoc inology
due o o he diseases: one o hem was ea ed wi h diazoxide,
and he symp oms did no p og ess du ing he 6-yea ollow-
up. The o he pa ien was ea ed by equen meals only,
du ing 13 yea s o ollow-up.
3.9. Managemen and Ou come o Insulinomas Classified as
Malignan . The median leng h o ollow-up o he insulino-
mas classified as malignan was 3 (1, 27) yea s. O he 11
pa ien s wi h a malignan insulinoma, 5 unde wen su ge y
wi h a cu a i e aim. Two o hem had immedia e disease p o-
g ession due o dis an me as ases (li e and lung, li e and
jejunal mesen e y): one o hem was ea ed wi h a soma o-
s a in analogue and he o he one wi h diazoxide, p edniso-
lone, and s ep ozo ocin. Two pa ien s had elapses, 1 yea
and 5 yea s a e he p ima y su ge y. The fi s one was ope -
a ed on he li e me as ases, as well as ea ed wi h diazoxide,
soma os a in analogues, 5-fluo ou acil-s ep ozo ocin, epi u-
bicin, and in e e on alpha, and he o he one was ea ed
wi h diazoxide, low-dose in e e on, and chemoemboliza ion
o he li e me as ases. One o he insulinomas classified as
malignan was cu ed by su ge y. This insulinoma had no dis-
an me as ases, bu he his opa hologic diagnosis o malig-
nancy was based on he local in asion and he ela i ely
high Ki-67 index (9%) o he umou .
In wo pa ien s wi h malignan insulinoma, dis al panc e-
a ic esec ions we e pe o med as pallia i e su ge y. In bo h o
hem, he disease p og essed, and he pa ien s died 1.3 yea s
and 4.2 yea s a e su ge y. O he ou inope able malignan
insulinomas, all p og essed. Medical ea men o hese inop-
e able pa ien s and he pa ien s wi h pallia i e su ge y
included diazoxide (n=4), soma os a in analogues (n=5),
adia ion he apy o me as ases (n=2), 5-fluo ou acil-
s ep ozo ocin (n=3), suni inib (n=1), doxo ubicin (n=1),
doxo ubicin-daca bazine (n=1), in e e on alpha (n=3),
pe o al co icos e oids (n=4), dea e ializa ion and emboli-
za ion o li e a e ies (n=1), chemoemboliza ion o li e
me as ases (n=1), esec ion and he moabla ion o li e
me as ases (n=1), and supe selec i e emboliza ion o a
b anch o he gas oduodenal a e y (n=1).
4. Discussion
In his s udy, we demons a e an almos wo- old inc ease in
he incidence o insulinomas in Finland, om 0.5/million/
yea in he 1980s and 0.4/million/yea in he 1990s o 0.9/
million/yea in he 2000s. In spi e o he imp o ed diagnos ic
me hods a ailable, he delay om he fi s symp oms o he
diagnosis has emained unchanged o e he las h ee
decades (median delay ca. 13 mon hs). P eope a i e imaging
has imp o ed ema kably, and in he 2000s, all he insulino-
mas excep o one we e localized p eope a i ely. Eigh y-nine
pe cen o he pa ien s who unde wen su ge y wi h a cu a-
i e aim had a ull eco e y, bu pos ope a i e complica ions
occu ed in hal o he pa ien s.
The obse ed incidence o 0.4–0.9/million adul s/yea is
sligh ly lowe han he es ima ed incidence o 1–4/million/
yea sugges ed in ea lie s udies [1, 2]. Ea lie es ima es o
he incidence o insulinoma migh be inco ec ly high
because o he selec ed da a o single-cen e coho s o da a
om a limi ed a ea. Fo example, in he la ge Mayo Clinic
s udy o 224 insulinoma pa ien s ea ed be ween 1927
and 1986, he incidence o insulinoma was calcula ed
based on eigh de ec ed insulinomas among he esiden s
o Olms ed Coun y [2]. In ou s udy, he incidence o insuli-
noma inc eased app oxima ely wo- old du ing he s udy
pe iod, being 0.9/million adul s/yea in he 2000s. This may
be explained by imp o ed diagnos ic me hods, especially
imaging. An ac ual inc ease in he incidence o insulinomas,
howe e , canno be excluded.
In his coho , all excep wo pa ien s had symp oma ic
hypoglycemia be o e he diagnosis o insulinoma; in he
emaining wo pa ien s, he symp oms eme ged only a e
he diagnosis. The median du a ion o hypoglycemic symp-
oms be o e he diagnosis was 13 mon hs, which is sligh ly
sho e han he 18 mon hs epo ed in p e ious s udies
[2, 16]. Thi y-one (39%) o he pa ien s we e fi s examined
by o he speciali ies, eflec ing he di e se symp oms associ-
a ed wi h insulinomas. The episodic symp oms we e o en
in e p e ed as ce eb o ascula diso de s, epilepsy, o psychi-
a ic diso de s.
In he p esen coho , he c i e ia o hype insulinemic
hypoglycemia we e me in 91% o he as ing es s, and all
he posi i e findings we e de ec ed wi hin a 36-hou as .
Ou esul s suppo he sugges ion ha he diagnosis o
endogeneoushype insulinemichypoglycemiacanbeachie ed
in o e 90% o cases wi hin 48 hou s, and a 48-hou as could
eplace he cu en 72-hou as as he diagnos ic s anda d
[23]. Acco ding o a Mayo clinic s udy, 20% o insulinoma
pa ien s ha e addi ionally and 6% exclusi ely pos p andial
symp oms [24]. In pa ien s wi h pos p andial symp oms
only, he co esponding plasma measu emen s can be pe -
o med pos p andially o du ing a p olonged o al glucose
ole ance es (OGTT) [1, 7, 25]. In he p esen coho , pos -
p andial symp oms we e documen ed in 6 (8%) pa ien s, bu
all o hem had also symp oms p o oked by as ing.
In he p eope a i e localiza ion o insulinomas, nonin a-
si e imaging me hods, p ima ily CT and MRI, a e p e e ed.
The lowe sensi i i y and limi ed u ili y in p o iding addi-
ional in o ma ion ha e educed he use o ansabdominal
US as a diagnos ic modali y [14]. In asi e localizing me hods,
including selec i e angiog aphy, EUS, and selec i e a e ial
calcium s imula ion (SACS) es , a e applied when he nonin-
asi e s udies ail o localize an insulinoma. Blind panc ea ic
esec ion is no ecommended because o a low cu e a e and
a high isk o complica ions [26]. In his s udy coho , all he
a o emen ioned localizing me hods we e applied, excep o
he SACS es , which has also p o ed o be a sensi i e me hod
o localizing insulinoma [27]. Du ing he s udy pe iod, he
p eope a i e localiza ion o insulinomas imp o ed ema k-
ably, and in he 2000s, up o 98% o he umou s we e local-
ized p eope a i ely. In he 2000s, he mos sensi i e imaging
me hods we e EUS (sensi i i y 82%), selec i e angiog aphy
(64%),
18
F-DOPA-PET/CT (58%), MRI (55%), and CT
(51%), in acco dance wi h he sensi i i ies epo ed in a
ecen sys ema ic e iew [14].
68
Ga-NOTA-Exendin-4 PET/
CT, a no el echnique o localizing insulinomas wi h a
epo ed sensi i i y o 97%, was no a ailable du ing he
s udy pe iod [28].
7In e na ional Jou nal o Endoc inology
Mos pa ien s unde wen su ge y wi h a cu a i e aim, and
3% had pallia i e su ge y. Typical complica ions in panc ea ic
su ge y a e fis ulas, hemo hages and, delayed gas ic emp y-
ing [29–31]. Cla ien-Dindo classified o e all pos ope a i e
complica ionsoccu edin51%o hepa ien s,whichissligh ly
mo e han he complica ion a e o 33–35% p esen ed in a
ecen sys ema ic e iew [14], bu simila o he o e all com-
plica ion a es in panc ea ic su ge y. Pos ope a i e mo ali y
was 3%, which is accep able and simila o he pe cen ages
epo ed in he sys ema ic e iew (3.7% o open app oach
and 0% o lapa oscopic app oach) [14]. Eigh y-nine pe cen
o he pa ien s who unde wen cu a i e su ge y had a ull
eco e y. The ecu ence a e (8%) was compa able o he
p e iously epo ed 7.2% [14]. O no e, cu en guidelines
sugges enuclea ion o spo adic small insulinomas (<2 cm),
i s uc u al in eg i y o he panc ea ic duc can be main-
ained [32]. Lapa oscopic enuclea ion is cu en ly conside ed
easible e en in challenging loca ions, such as he pos e io
su ace o he panc ea ic neck [33, 34]. The complica ion isk
associa ed wi h enuclea ions is compa able o e en highe
han wi h dis al esec ions and PDs [35, 36]. Fo MEN1
pa ien s, dis al o sub o al panc ea ec omy mus be consid-
e ed in mul i ocal disease, when o he panc ea ic NENs a e
p esen , and in cases wi h po en ially malignan disease.
A majo s eng h o his s udy is he na ionwide da a
including all insulinomas diagnosed in Finland o e h ee
decades. In con as o many p e ious s udies, we also
included inope able cases, which cons i u ed 6% o he coho .
Collec ing na ionwide da a enabled us o assess he incidence,
as well as he e ol ing me hods o diagnos ics and ea men
o insulinomas, in an unselec ed coho o pa ien s.
The e a e, howe e , some limi a ions o his s udy. Due o
he e ospec i e, egis e -based design o he s udy, he e
was incomple eness in he da a, ega ding, e.g., he clinical
pic u e and he esponse o he medical ea men o insuli-
nomas. As he sea ch o insulinomas was ca ied ou on
pa ien and pa hology egis ies and hus depends on co ec
en olling o he diagnoses, we may no ha e ound all he
insulinomas, especially om he ea lie yea s o he s udy
pe iod. To minimize he loss o cases, a comp ehensi e
sea ch was pe o med on h ee sepa a e da abases, and all
he po en ial cases ound we e e iewed. Ano he limi a ion
is he sho ollow-up, as pa ien s wi h a benign insulinoma
a e ollowed up a he Uni e si y Hospi als only o a sho
ime a e a success ul ope a ion. In case o a possible elapse
o disease p og ession, howe e , an insulinoma pa ien
would mos likely ha e ended up a one o he fi e Finnish
Uni e si y Hospi als wi h a new e e al, and he elapse/p o-
g ession would ha e been egis e ed in ou s udy. Thi dly, as
pa ien eco d da a om p ima y heal h ca e was no a ail-
able, we could no dis inguish he heal h ca e sys em delay
( ime om he fi s consul a ion o heal h ca e p o ide s o
he diagnosis) om he o al diagnos ic delay ( om he onse
o symp oms) calcula ed in his s udy.
5. Conclusions
The incidence o insulinomas has inc eased du ing he pas
h ee decades. The diagnos ic delay has emained unchanged
since he 1980s, despi e imp o ed imaging. To sho en he
diagnos ic delay, clinicians should be in o med o conside
he possibili y o hypoglycemia and insulinoma, when symp-
oma ic a acks a e in es iga ed in any heal h ca e uni .
De eloping he su gical ea men is ano he majo a ge
in he managemen o insulinomas, o lowe he o e all com-
plica ion a e, while ensu ing he high cu e a e.
Da a A ailabili y
The da ase s gene a ed and analysed du ing he cu en s udy
a e no publicly a ailable, in o de o p o ec pa ien p i acy,
as i migh be possible o iden i y he esul s o an indi idual
pa ien om his limi ed g oup o pa ien s.
Disclosu e
The unding o ganiza ions had no ole in he design, con-
duc , epo ing, o publishing o his esea ch. The esea ch
was pe o med as pa o he employmen o he fi s au ho
Elina Pel ola as a doc o al (Ph.D.) s uden a he Uni e si y o
Tampe e, Facul y o Medicine and Li e Sciences.
Con lic s o In e es
The au ho s decla e ha he e is no conflic o in e es
ega ding he s udy o i s publica ion.
Acknowledgmen s
The au ho s hank Esko Väy ynen, M.A., o e ising he
language o he manusc ip . This wo k was financially
suppo ed by he Compe i i e Resea ch Funding o he
Special Responsibili y A ea o Tampe e Uni e si y Hospi al
(9U012) and by he Finnish Medical Founda ion.
Supplemen a y Ma e ials
Diagnosis-based sea ch s a egy on pa ien eco ds 1980–
2010. (Supplemen a y Ma e ials)
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9In e na ional Jou nal o Endoc inology