European Journal of Endocrinology 10.1530/EJE-17-0523 structural subunits:twohydrophilic catalyticsubunits, electron transportchain.The complexconsistsoffour where ittransformssuccinate intofumarate,andthe complex II( the succinatedehydrogenase(SDH)ormitochondrial susceptibility genes,whichincludethoseencoding 10–15% showsomaticmutationsinthesameorother them arecausedbygermlinemutationsandanadditional tumors recorded to date ( (HNPGL). Thesetumorsarethemostcommonheritable the headandneckregion,namelyPGL (sPGL) andtumorsoftheparasympatheticganglia in catecholamine releasingtumors,namelysecretingPGL adrenal andextra-adrenalchromaffin,sympathetic, are rareneural crest-derived tumors( Pheochromocytomas (PHEO)andparagangliomas(PGL) Introduction clinicopathologic phenotypessuggestinganetiologicroleof genetic testingonbloodortumorsamplesshouldbeperformedinpatientsaffected byGISTs, RCCsorPAs with screening for prospective studiesassessingtheirfrequency, atpresent,theiroccurrenceseemstooinfrequenttosuggestsystematic carcinomas (RCCs)andpituitaryadenomas(PAs) havebeenassociatedwiththesesyndromes.Intheabsenceof paragangliomas (PGL).Recently, othersolidgrowths,suchasgastrointestinalstromaltumors(GISTs), renalcell cause thecorrespondingfamilysyndromescharacterizedbyoccurrenceofpheochromocytomas(PHEO)and Mutations inoneofthefivegenesencodingsuccinatedehydrogenase( Abstract 4 Medicine, UniversityofFlorence,Italy, 1 Serena Martinelli Massimo Mannelli paragangliomas mutations: beyondpheochromocytomas and DIAGNOSIS ofENDOCRINEDISEASE:SDHx Department ofSurgeryandTranslational Medicine,UniversityofFlorence,Italy Department ofExperimentalandClinicalBiomedicalSciencesand, https://doi.org/ www.eje-online.org Review SDH isfunctionallyinvolved inboththeKrebscycle, 101530/EJE-17-0523 5 ). SDHx

1 mutationcarriers.However, SDHBimmunohistochemistry(IHC)ontumortissuesor , Gabriele Parenti 1 , Letizia Canu 3 , © 2017EuropeanSociety2018 ofEndocrinology 4 ). Approximately 35% of M Mannelliandothers 1 , Tonino Ercolino 1 3 Azienda Ospedaliera-UniversitariaCareggi,Florence,Italy, and , 3 , Giuseppina De Filpo 2 ). Theycomprise Printed inGreatBritain 2 Department ofExperimentalandClinical 1 , Elena Rapizzi SDHx investigate ontumor’s SDHinsufficiency. testontumortissueto rapid andinexpensivepreliminary is retainedintumorswithother SDHmutations. with SDHB,in (IHC)whileSDHAislost, together immunohistochemistry enzymatic activity( of themitochondrialcomplex,withlossSDH encoded bythecorresponding responsible forflavinationofthecatalyticsubunitAand dehydrogenase complexassemblyfactor2(SDHAF2), Enzymatic activityrequiresafunctional unit, succinate subunits totheinnermitochondrialmembrane( by genes andtwohydrophobicsubunits,CD,encoded A andB,encodedbythecorresponding SDH-related tumors 1 Published byBioscientifica Ltd. and Consequently, SDHB IHC( Mutations inanyofthesefivegenescausedisassembly SDHC genes. Gabriella Nesi 2 , and SDHx SDHA SDHD ) ormitochondrialcomplexII 8 , -mutated tumors,butitsexpression 4 9 genesanchoringthecatalytic ) aswellofSDHBexpressionat Downloaded fromBioscientifica.com at09/30/202102:21:23PM SDHAF2 10 (2018) Endocrinology European Journal of [email protected] Email to MMannelli should beaddressed Correspondence ) hasbeenassumedasa 178 178 : 1 178 gene( :1 SDHx SDHA , R11–R17

7

and ). R11 –R17 SDHB 6 via freeaccess ).

European Journal of Endocrinology www.eje-online.org embedded tumortissue.Tumors havebeenlabeledas‘SDH retrospective studiesperformedbySDHBIHConparaffin- role of SDH in the pathogenesis of these tumors report mutation carriersandmostofthepapersevaluating tumors have been sometimes found incidentally in SDHx tumors otherthan PHEO/PGL. These additionalsolid mutation carrierstodefinethetrueprevalenceofsolid systematic prospectivestudyhasbeenconductedin adenomas (PAs)and pituitary ( RCC, Renalcellcarcinoma. HNPGL, headandneckparagangliomas; PA, Pituitaryadenoma; PHEO,pheochromocytomas;PGL,paragangliomas;PTC,Papillary ThyroidCarcinoma; SDHA SDHAF2 SDHC SDHB SDHD Gene Table 1 tumors (GISTs) ( beyond PHEO/PGL,suchasgastrointestinalstromal have beenrarelyassociatedwithothersolidtumors PHEO/PGL ( aspects, but they are all characterized by the presence of clinical pictureofthesefivePGLsyndromesdiffersinsome familial syndromes,namelyPGL2toPGL5( germline mutationsareassociatedwiththecorresponding PHEO/PGL susceptibilitygenes( ( characterized bythepresenceofbothsPGLandHNPGL known asfamilial paragangliomatosis type1(PGL1) mutations resultinaninheritedfamilialsyndrome, for theoccurrenceofPHEO/PGL. SDH insufficiencyintumortissue( therefore becomearapidandinexpensivetoolfortesting mutations ( whereas loss of SDHA expression is only detected in of SDH enzymatic activity and loss of SDHB expression, PGL5 PGL2 PGL3 PGL4 PGL1 11 Review ). Subsequently, other In recentyears,germlinemutationsin In 2000, Baysal Mutations inanyofthefiveSDHgenesareresponsible Mutations inanyofthesefivegenescauseimpairment Clinical characteristicsoftheSDHx-relatedsyndromes. 8 16 , 9 Abdominal PGL HNPGL Abdominal PGL HNPGL PHEOs HNPGL Abdominal PGL PHEO Abdominal PGL Thoracic PGL HNPGL Lesions , ). SDH immunohistochemistry (IHC) has ). SDH immunohistochemistry 17 21 , 18 ), renalcellcarcinomas (RCC) ( t al et , 19 . ( , SDHx 20 5 ) demonstrated that ). 23 genesalsoprovedtobe 12 M Mannelliandothers ). To our knowledge, no , 10 Rare Rare Rare Yes (rare) Yes Multiple lesions 13 ). , 14 , 15 Table 1 SDHx ), andtheir genes SDHD ). The SDHA Unknown Unknown Unknown Low High Penetrance SDHx 22 )

of 1p36.1-p35 and loci ( 1p andlessfrequentlyinthe14q22chromosomal genomic hybridizationhasshownalterationsinthe1q, chondromasinCarneytriad. and pulmonary with PGL( due togermlineSDHxmutations,GISTs areassociated In Carney-Stratakissyndrome,dominantlyinheritedand these cases,whiletheremaining50%provenegative in NF1( labeled as‘wildtype’,mainlyaffectchildren.Mutations 10–15% non- mutations of with anincidenceof6.8–20permillion( gastrointestinal tract( GISTs arethemostcommonmesenchymaltumorsof Gastrointestinal stromal tumors(GISTs) characteristics. somatic orgermlinemutations. genetic analysislookingforthecorrespondent not allthetumorsorpatientshavethenundergone deficient’ incaseof negative SDHB immunostaining but i.e. Carney-Stratakis( GISTs. Theycanbesporadicorpartoftwosyndromes, for SDHBonIHC,andarereferredtoasSDH-deficient SDH-related tumors SDHx

In 85–90%ofcases,GISTs resultfromactivating Etiology ofCarneytriadisuncertain( This paperreviewsthesetumorsandtheir Unknown Unknown Unknown Frequent Very rare Malignancy 38 ). Although geneshaverarelybeenfound.Nonetheless,the 30 35 , 31 , KIT KIT 36 ) orBRAF( SDHC ), whereastheyareassociatedwithPGL

or No Yes No No Yes Paternaltransmission / PDGFRA 33 24 PDGFRA SDHB on1q21-q23.3,germlinemutations ) syndromeandCarneytriad( ), occurringassporadicorfamilial Downloaded fromBioscientifica.com at09/30/202102:21:23PM 32 islocatedonchromosome -mutated GISTs, incorrectly ) genesaccountfor50%of genes( 178 PA GIST PA PA RCC GIST PTC (?) PA RCC GIST PTC (?) RCC PA GIST Associated neoplasms 28 :1 37 , 25 29 ). Comparative , 26 ). Theother , 27 ). R12 SDHx 34 via freeaccess ).

European Journal of Endocrinology common arethosedueto RCCs athistology. OftheSDH-deficientRCCs,most essentially indistinguishable fromothernon-SDH-related has beenpreviouslydescribed ( ( entity inthe2016WHOclassificationofrenaltumors tumor histologywasvariable( most tumorsexhibited‘oncocytic’featuresalthoughrenal et al inclusions werefocalandnoteasytoidentify. Ricketts flocculent material( like spacescontainingeitherpaleeosinophilicfluid or was thepresenceofcytoplasmicvacuolesandinclusion- and concludedthatthemostdistinctivehistologicfeature morphology of36SDH-deficientRCCsfrom27patients variably solidornestedarchitecture. with granular-eosinophilic cytoplasm arranged in a and werecomposedofamixtureclearcells originate fromtheepithelialcellsofproximaltubule diagnosed inthese was by Vanharanta mutated patientsaffectedbybothPHEO/PGLandRCCs for 0.05–0.2%ofallRCCs( SDHx mutatedRCCsareraretumors,estimatedtoaccount Renal cellcarcinomas (RCCs) the patientandofhis/herfamilymembers. important consequencesontheclinicalmanagementof performed. Indeed,thediagnosisofafamilialformhas SDHx PHEO/PGL, SDHBimmunostainingofthetumoror for histology or a positive personal or family history gastric location,multiplelesions,nodular/plexyform a GISTshowingcharacteristicssuchaschildhoodonset, does notseemtobecost-effective.However, inthecaseof carriers andthereforesystematicscreeningforthesetumors indolent course( lymph nodes,butgenerallypresentaprotractedand and frequentlymultinodular, theymaymetastasizeto Nearly allarelocatedinthestomach,usuallymultiple, promoter ( somatic lossesorbyepigeneticsilencingofSDHC for SDHB ( GISTs fromCarneytriaddisplaylossofimmunoreactivity 44 Review , SDH-deficient RCC has been recognized as novel In amorerecentpaper, Gill In summary, GISTs occurrarelyinSDHxmutation SDH-deficient GISTs account for 5–7.5% ofall GISTs. . alsoreportedthatin21casesofSDH-deficientRCC, 45 genetictestingonpatientortumorDNAshouldbe ). Itmayshowamorphologic spectrumwiderthan 40 39 ). ). This finding can be explained by SDHx 35 , 42 et al SDHB 37 ). Nonetheless, in somecases,these , 41 . in 2004 ( mutationcarriersappearedto SDHB ). 42 ). Thefirstreporton 43 46 mutations. ). M Mannelliandothers ) andsomecasesmaybe 22 t al et ). The renal cancers . evaluatedthe SDHB - et al affected byasingleHNPGLandPA wasbyLopez-Jimenez The firstreportofan Pituitary adenomas(PAs) ofPHEO/PGL,GISTsfamily history orRCCs. or recurrenttumors,inthecaseofapositivepersonal asmultiple occurring inpatientsyoungerthan40 years, genetic testingshouldhoweverbeconsideredinRCCs effective in RCCs seemstomaketheirsystematicresearch non-cost- in 30%ofpatientsatlong-termfollow-up. (range 22–72).Multifocalorbilateraltumorsaredetected the seriesofWilliamson ( (range14–76)whilein present atameanageof37 years both PHEO/PGLandPA havebeenreportedsofar( SDHD PAs, 4alsopresentedPHEO/PGL,2were carrier. Conversely, inthegroup ofpatientswithfamilial PHEO/PGL, butnoneofthemwasan sporadic and22werefamilial. testing on168patientsaffectedbyPA, ofwhich146were Subsequently, Xekouki PA astheresultofadoubleSDHAsomaticmutation. assessed 309 PAs detectingonlyone SDHA-negative the settingofgermline IHC. In 2013, Dwight downregulation ofSDHDproteinatimmunoblottingand and abdomenaGH-secretingPA exhibitingLOHand carrier whopresentedmultiplePGLintheneck,thorax published thecaseofa37-year-oldmale D first descriptionof PAs relatedtoan of thePA sincethetumortissuewasnotavailable.The (LOH) intheHNPGLbutcouldnotverify SDH deficiency (5 patients), (4 patients), be mutatedforasusceptibility gene,suchasmenin and21 (29%) were found to personal or family history syndrome, 28(39%)hadno mutationsandnosuggestive endocrine suggestiveofahereditary or familyhistory ( Of the72patientscollectivelyanalyzedbyO’Toole SDH-related tumors 52 ) mutationwasbyXekouki ), 23(32%)harborednomutationsbuthadapersonal . in2008( In summary, lowprevalenceofSDH-deficient thevery According toGill( To thebestofourknowledge,74patients affectedby Among thepatientswithsporadicPAs, 3alsodisplayed In 2014Gill germlinemutationcarriers. SDHx SDHC 48 RET ). Theauthorsfoundlossofheterozygosity (1patient), mutationcarriers.SDHIHCor (1patient)and t al et SDH et al 42 SDHA Downloaded fromBioscientifica.com at09/30/202102:21:23PM ), SDH-deficientRCCscommonly . ( t al et (inthiscase . reported a case of PA arising in 47 50 mutation( ,tema g s4 years ), themeanageis40 . ( ) immunohistochemically SDHB t al et 51 ) performed genetic . in2012( SDHAF2 (6patients), 178 C SDH www.eje-online.org ) mutationcarrier :1 49 SDHD SDHx ). (inthiscase SDHB (1patient). mutation mutation 23 ). They 52 and1 SDHD R13 SDHx , et al 53 via freeaccess ). .

European Journal of Endocrinology www.eje-online.org female Renella lymphoid malignancieshas beenrecentlyreportedby adenomatoid adrenaltumors. 47 neuroblastictumors,50testicularseminomasand10 authors didnotfindanySDHB-negativetumoramong study provedimmunoreactiveforSDHB.Similarly, the deficient state( argued againstapositivelinkbetweenPTCandSDH- in theclinicalpresentationofDTC,Papathomas Although these findings identify with earlierdiseaseonsetandhigherpathologicstage. consistent lossof However, andfollicularthyroidtumorsshowing papillary patients, butweregenerallyclassifiedasnon-pathogenic. Germline cancers (DTC)wasevaluatedbyNi was notinvestigated. mutation carriers,althoughthetumorSDHdependency SDHB mutationcarriersandinoneoutof47SDHD thyroidcarcinomaof papillary (PTC)inoneoutof53 been foundtoberelatedSDHdeficiency. germline mutationcarriers;however, fewcases have very been reportedtobeassociatedwithPHEO/PGLin In additiontoGISTs, RCCsandPAs, othertumorshave Other tumors forPHEO/PGL. family history PAs, early-onsetPAs orpatientswithapositivepersonal PAs, phenotypicallyaggressiveand/ortherapy-resistant testing or SDHB IHC is advisable in the case of familial not seemtoberecommended.Conversely, mutation carriers is rare, and systematic screening does determined. as chromophobic,andin5(6.9%),thesecretionwasnot secreting adenoma.In1(1.4%)patient,PA wasdiagnosed an ACTH-secretingtumorand1(1.4%)amixedGH/PRL- 13 (18.1%)patientshadanon-functioningPA, 2(2.8%) (27patients, 37.5%)andPRL(23patients31.9%).Overall, and in27(37.5%),thesizeofPA wasunavailable. presented amacroadenoma,11(15.3%)microadenoma Of the72patients,34(47.2%) with ameanof44 years. The patientageatdiagnosisrangedfrom15to84 years Review The causalroleofSDHindifferentiatedthyroid In 2004,Neumann In summary, theoccurrenceofPAs inSDHgermline PA secretionvariedbutconsistedmainlyofGH An associationbetween SDHB et al SDHx . ( mutation carrier was affected with abdominal 56 55 missensevariantswerefoundin48(6%) ) intwofamilies.Inonefamily, ayoung SDHC/D ). Indeed,allthe60casesofPTCunder et al geneexpressionwereassociated . ( 16 ) reportedtheoccurrence M Mannelliandothers SDHx SDHx et al mutationsand . ( as modifier genes 54 ) in754cases. SDHx genetic SDHx t al et .

tumors seems to be very rare,althoughthecasesreported tumors seemstobevery mainly GISTs, RCCsandPAs. responsible fortheoccurrenceofothersolidtumors, In additiontoPHEO/PGL, Discussion with oligodendrogliomaandmultipleHNPGL( reported inan SDHB negativity, SDHApositivityandLOHhasbeen specimen wasnotavailableforIHC. diagnosed withstageIV-B Hodgkinlymphomawhose metastatic GIST/PHEOanda24-year-oldmaternalaunt family includeda15-year-old lymphoma stainingforSDHB.Thepedigreeoftheother PGL andnodularlymphocyte-predominantHodgkin of SDHactivityintumortissue. expression bywesternblot analysis orthemeasurement tools aimedatprovingtumor SDHimpairmentareSDHB for SDHxmutationsshould beperformedforfirst.Other germline orsomatic.Whenavailable, tumorDNAanalysis detect thetypeofmutationandwhether is by geneticanalysisonbloodand/ortumorDNA to of SDHexpression.Thisresultshouldthenbeconfirmed immunostaining provesthatthetumordependsonaloss SDHD-mutated tumors( in weakly diffuseSDHBstaining)sometimesobserved caution, duetopossiblefalsepositive(i.e. or be recalledthatSDHBIHCshouldinterpretedwith However, when testing tumor tissue by IHC, it must SDHx thereby recommendingSDHBIHContumortissueor or histologicfeaturessuggestiveof Nevertheless, thesetumorsmayattimespresentclinical studies aimed at establish their frequency are necessary. carriers does not seem advisable although prospective neoplasms otherthanPHEO/PGLin abdomen orheadandneckrespectively. screening procedures,byCTorMRI,carriedoutonthe like RCCandPA shouldbediagnosedduringradiological of HNPGLaswellPHEO/PGLandthereforetumors enrolled inalifelongscreeninglookingfortheoccurrence SDHx been performedinSDHxmutationcarriers.Nevertheless, systematic studiesaimedatdiagnosingthesetumorshave in theliteraturemayresultunderestimatedasno SDH-related tumors The frequencyofthesenon-neural-crest-derived Finally, apancreaticneuroendocrinetumorshowing Therefore, atpresent,asystematicsearch for genetic testing on patient’s blood ortumor DNA. mutationcarriersaregenerally(andhopefully) SDHD mutation carrier who was also affected mutationcarrierwhowasalsoaffected Downloaded fromBioscientifica.com at09/30/202102:21:23PM 57 ). Asawhole,negativeSDHB SDHC SDHx genemutationsare mutationcarrierwith 178 SDHx :1 SDHx dependency, 53 mutation ). R14 via freeaccess European Journal of Endocrinology References Network fortheStudyofAdrenalTumors). M M;LC,TE,ER,SandaremembersoftheENS@T(European Fondazione CassadiRisparmioPistoiaePescia(Prot.2016.0241/gi)to This workwassupportedbytheParadifference Foundationandbythe Funding perceived asprejudicingtheimpartialityofreviewreported. The authorsdeclarethatthereisnoconflictofinterestcouldbe Declaration ofinterest case aswellforthefamilymembers. genetic syndromeisclinicallyrelevantbothfortheindex the occurrence of PHEO/PGL. Indeed, the diagnosis of a searchingan accuratepersonalandfamilyhistory for affected byGISTs, RCCsorPas,cliniciansshouldcollect associated toGISTs, RCCsorPAs. Conversely, inpatients clinicians shouldaccuratelyinquireonsignsorsymptoms than PHEO/PGL,whenscreening 9 8 7 6 5 4 3 2 1 Review Rapizzi E, Ercolino T, Canu L,Giaché V, Francalanci M,Pratesi C, Gimenez-Roqueplo AP, Favier J,Rustin P, Mourad JJ, Plouin PF, Ghezzi D, Goffrini P, Klopstock T, Uziel G,Horvath R, Lochmüller H, complexII:roleincellularphysiologyand Cecchini G. Respiratory Baysal BE, Ferrell RE,Willett-Brozick JE, Lawrence EC,Myssiorek D, Welander J, Soderkvist P&Gimm O.Geneticsandclinical Dahia P. Pheochromocytomaandparagangliomapathogenesis: ofpheochromocytoma:history,Manger WM. Anoverview current Lenders JW, Eisenhofer G,Mannelli M&Pacak K. pheochromocytoma/paraganglioma ofsuccinatedehydrogenase Valeri A &Mannelli M.Mitochondrialfunctionandcontentin 1186–1197. the hypoxiapathway. chainandactivates of complexIIinthemitochondrialrespiratory paraganglioma abolishestheenzymaticactivity gene inhereditary Corvol P, Rotig A&Jeunemaitre X.TheR22XmutationoftheSDHD 654–656. 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