doi: https://doi.org/10.5114/pjp.2017.69684 pol j pAthol 2017; 68 (2): 97-101 Review papeR The diagnosis and managemenT of congeniTal and adulT-onseT hypeRinsulinism (nesidioblasTosis) – liTeRaTuRe Review AdAm m. KowAlewsKi1, Łukasz szylberg1, AnnA KAsperska1, Andrzej mArszałeK1,2,3 1ChairandDepartmentofClinicalPathomorphologyCollegiumMedicuminBydgoszcz,NicolausCopernicus UniversityinTorun,Poland 2ChairandDepartmentofOncologicPathologyandProphylactics,PoznanUniversityofMedicalSciences,Poland 3DepartmentofOncologicPathology,GreaterPolandCancerCenter,Poznan,Poland Congenitalandadult-onsethyperinsulinism(CHI)mustbetakenunderconsid- erationinthedifferentialdiagnosisofhypoglycaemiasymptomswithendogenous hyperinsulinism,especiallyincasesinwhichtherewasfailuretofindaninsulinoma. Histologicalexaminationisnecessaryforadefinitivediagnosis.CHIisadisorder withthreehistopathologicalvariants:focalCHI,diffuseCHI,andatypicalCHI. Thesevariantsareclinicallyindistinguishable.Accordingtopublishedstatistics, 0.5to5%ofnesidioblastosiscasesoccurinadults.Clinicalmanifestationranges frommildlysymptomaticuptolife-threateninghypoglycaemia.Earlydiagnosis andtreatmentareimportantinyoungandveryyoungpatientsbecauseearlytreat- mentaccountsforfavourablementaloutcomes. Key words:congenital,adult,hyperinsulinism,nesidioblastosis,diagnosis,man- agement. Introduction edwithmonogenicformsofCHI,aswellasseveral genetic forms of CHI related to clinical syndrome ThetermnesidioblastosiswascoinedbyLaidlawin (e.g. Beckwith-Wiedemann, Kabuki, and Turner 1938.Heusedittodescribethediffuseproliferation syndromes)[4].Geneticdiagnosisispossibleforap- ofcellsthatdifferentiatefromtheductepitheliumto proximately50%ofpatientswithfullclinicalpres- build islets of Langerhans [1]. Since then the term entation[5].Accordingtopublisheddata,mutations evolved. Morphologically similar lesions are called: inthesulfonylureareceptorandaninwardlyrectify- islethyperplasia,endocrinecelldysplasia,isletcellad- ingpotassiumchannelarethemaincausesofCHI. enomatosis,andductoinsularproliferation[2,3].The Moreover,alinkwasfoundbetweengestationaldia- currentdefinitionofnesidioblastosisiswiderandisat- betes,diabetesmellitus,andCHIinafamilycarrying tributedtocongenitaloracquiredexcessivefunction theinactivatingABCC8E1506Kmutation[6,7].In ofabnormalpancreaticβ-cellsresultinginpersistent suchcasestheneteffectisfailuretoreducepancreat- hypoglycaemia.Acquirednesidioblastosisisextreme- icinsulinsecretioninthepresenceofhypoglycaemia lyrare.Nowadaysthetermcongenitalhyperinsulin- (serumglucoselevelbelow60mg/dl)[8,9]. ism(CHI)referstonesidioblastosisininfants. Clinical manifestation ranges from mildly symp- TheincidenceofCHIis1/50,000livebirths(but tomatictolife-threateninghypoglycaemia[10].The upto1/2500inSaudiArabiaduetoahighrateof riskofpermanentbraininjuryininfantswithCHI consanguinity)[2].Currently,11genesareassociat- continuestobeashighas25-50%duetodelaysin 97 AdAm m. KowAlewsKi, Łukasz szylberg, AnnA KAsperska, et al. diagnosisandinadequatetreatment[4].Thesepoor acinarnuclei(Figs.1and2)[2].Well-developeden- outcomes have not changed much since the 1970s doplasmic reticulum and Golgi complex (best ob- despite tremendous advances in the field of under- servedonultrastructuralstudies)suggestahighlevel standing this condition [11]. This heterogeneous ofproteinsyntheticactivity.Immunostainingshows disorderleadstoincreasedsecretionofinsulinfrom an increased proportion of insulin-containing cells. pancreatic β-cells [10, 12]. Such symptoms could FocalCHIdoesnotinvadetheneighbourtissuenor be observed in neonates, predominantly shortly af- has a pushing margins. There is no pseudocapsule. ter birth. The panel of diagnostic methods include Typically, outside the focal lesion, the pancreas ap- laboratorystudies,ultrasonography,CT,MRI,PET, pears histologically and functionally normal [24]. portalandpancreaticvenoussampling,intra-arterial Although most patients have a solitary lesion, one calciumstimulation,andmicroscopicexaminationof fourthofcasesaremultifocal[23]. pancreatictissuesamples. Familialcasesoccursporadically[25].Thesehave CHIisadisorderwiththreehistopathologicalvar- twomainpatterns.Firstistheinheritanceofapa- iants:focalCHI,diffuseCHI,andatypicalCHI[13]. ternal mutation of ABCC8 or KCNJ11. Second is These variants are clinically indistinguishable. Sur- thesomaticlossofthematernal11palleleinvolving geryisthemaintreatmentmethodforthisdisease; the ABCC8 and KCNJ11 region [26]. Both result however,asthemolecularknowledgeofCHIhasim- inhigherproliferationofβ-cellsevolvingintoafo- proved,newtherapiesarebeingdeveloped,suchas caladenomatoushyperplasia[27].FocalCHIcanbe GLP-1 receptor antagonists [14], mTOR inhibitors completely cured by surgical removal of the lesion [15],andlonger-actingsomatostatinanalogues[16]. [21,22]. Accordingtopublishedstatistics,0.5to5.0%of In the diffuse form of CHI, similar changes are nesidioblastosiscasesoccurinadults[17].Thesecas- found throughout the pancreas (Table I). All the esarerarebutwelldocumented[18,19,20]. β-cellsoftheisletsofLangerhansareaffectedbutthe intensityofabnormalitiesvariesthroughouttheor- Types of congenital hyperinsulinism gan[2,3].β-cellsaretypicallyenlargedbecauseofan abundantcytoplasm.Easilyvisible3-4timeslarger Focalformsaccountforonefourthtoonethirdof nucleisuggestsdistincthyperfunctioning[13]. cases.Theyareusuallyrestrictedtoasmallarea(2.5 MutationsinABCC8andKCNJ11genesarethe to7.5mmindiameter)ofthepancreas[2].Dueto mostcommoncausesofdiffuseCHI[28,29].Itis thesmallsizeofthelesion,identificationonstand- worthmentioningthatnochangesarenotedonmac- ard imaging studies or palpation during surgery is roscopicexamination[23]. oftenimpossible.However,itcanbesimplyidenti- Sufficient reduction of hyperinsulinemia requires fiedby18F-PET/CT[21,22].Thetailandbodyof neartotalpancreatectomy,whichinturnimplicates the pancreas are the most common locations [23]. theriskofeitherpersistenthypoglycaemiaorinsu- Onmicroscopicstudies,thelesionscontainclusters lin-dependentdiabetes[2,30,31]. oflargeendocrinecellswithcharacteristicgiantnu- Recently, a new atypical form of CHI has been cleiofirregularandangularshape.Abnormalnuclei characterised by morphologic mosaicism. Mosaic aremorethan3to5timesthesizeofnearbyfound patternreferstothepresenceoftwostrikinglydif- Fig. 1.Microscopicimageoffocalcongenitalhyperinsulin- Fig. 2.Microscopicimageoffocalcongenitalhyperinsulin- ism.Originallensmagnification10× ism.Abnormalnucleiaremorethan3to5timesthesize ofnearbyacinarnuclei.Originallensmagnification40× 98 Congenital and adult-onset hyperinsulinism (nesidioblastosis) Table I.Keyfetauresofnesidioblastosisvariantsandinsulinoma pRoperties chi (nesidioblasTosis) insulinoma focal diffuse adulT onseT Age <1year <1year 5thdecade 5thdecade Typeoflesion Benign Benign Benign Mostlybenign Mainlocalization Bodyandtail Entirepancreas Entirepancreas Equallydistributedto head,bodyandtail Leadingetiology Sporadic Genetic Gastricbypasssurgery Sporadic(geneticin MEN1) Hyperinsulinemic + + + + hypoglycemia Grossfindings – – – Solitary,encapsulated tumor <2cminsize Microscopic Oftenunifocal Diffusewithdifferent Diffusewithdifferent Solidorgyriformpat- findings prevalence prevalence terns,usuallywithout glands Ductoinsular Ductoinsular Ductoinsular Amyloiddepositions complexes complexes complexes inβ-cells Hypertrophiedβ-cells Hypertrophiedβ-cells Hypertrophiedβ-cells Associatedwith withgiantnuclei withgiantnuclei withgiantnuclei nesidioblastosis Immunohisto- Increasednumberof Increasednumberof Increasednumberof Cellscontainless chemistry insulin-containing insulin-containing insulin-containing insulinandsecretory cells cells cells granulesthannormal β-cellsbuthigher levelsofproinsulin MEN 1 – multiple endocrine neoplasia type 1 ferenttypesofislets.Largeisletswithcytoplasm-rich small,scatteredclusters.Ductsformingintoisletsare β-cellsandenlargednucleicoexistwithshrunkenis- seenasductuloinsularcomplexes[18]. letswithβ-cellsshowinglittlecytoplasmandsmall As in diffuse CHI, near-total pancreatectomy is nuclei[32].Thesehyperactiveisletsusuallyarecon- needed.Performedpancreaticresectionsrangingfrom finedtoonelobule.Thatgivesapotentialchancefor 30%to95%ofanorganhavebeenreportedsofar. complete clinical symptom withdrawal after partial Butbecauseitleadstobroadmorphologicalchanges pancreatectomy. Hence, there is great relevance of typetheirresultsvarywidely.Someauthorssuggest proper diagnosis of the disease by pathologists on conservativeresectionwithpossiblereoperationifap- intraoperativefrozensections,ifperformedbyasur- propriateglycaemiccontrolisnotachieved[23]. geon. In such cases the surgery would be curative [33]. In atypical form the genetic mechanism may Insulinoma involvemutationsofGCKbutithasbeenreported inonlyonepatientsofar[28]. In the differential diagnosis, insulinoma should Acquiredadult-onsetnesidioblastosisoccursmain- definitely be taken into consideration. Insulinoma lyafterRoux-en-Ygastricbypasssurgery.Thisinter- (β-celltumour)occursattherangefrom1to4cas- vention increases levels of a β-cell-trophic polypep- es/1,000,000peryear[34].Fourpercentofinsulino- tide,suchasglucagon-likepeptide1,thatcontribute masareassociatedwithmultipleendocrineneoplasia tothehypertrophyofpancreaticβ-cells[14].Annual type1(MEN1).Nevertheless,itisthemostcom- incidenceofadult-onsethyperinsulinaemichypogly- moncauseofendogenoushyperinsulinismresulting caemiais0.09/100,000andmeanpatientageis47 inhypoglycaemia.Themeanageatdiagnosisisap- years[3,18]. proximately47yearswiththeexceptionofinsulino- Diffusechangesarefoundthroughoutthepancre-