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European Journal of Endocrinology -17-0009 controlled studiestoinformpractice. other immunosuppressiveagents(e.g.azathioprine,rituximab)showbenefitinsomecases,butthereisaneed for strategies includingsurgeryandmedicaltherapy. Glucocorticoidsremainthemainstayofmedicaltreatmentbut Management ofhypophysitisincludescontroltheinflammatorypituitarymassusingavarietytreatment Hypophysitis usuallyresultsinacuteandpersistentpituitaryhormonedeficiencyrequiringlong-termreplacement. with likelyhypophysitis,includingexistingconventionaltechniquesandthoseintheresearch/developmentarena. for futuredevelopment.We describethepresentingfeatures,investigation anddiagnosticapproachofthepatient date withcurrentunderstandingofconditionspresentingashypophysitis,focussingonrecentadvancesandareas accuracy ofthediagnosispatientwithhypophysitis.Theobjectivethisreviewistobringreadersup-to- of hypophysitis.Modernimagingtechniques,histologicalclassificationandimmuneprofilingareimproving the consequence ofuseimmunemodulatorytherapyhasresultedinincreasedunderstandingthepathophysiology Traditionally consideredaveryrare condition,therecentrecognitionofIgG4-relateddiseaseandhypophysitisasa markers suchasanti-rabphilin3Aareyettoshowconsistentdiagnosticvalueandnotcommerciallyavailable. of currentlyavailableserumanti-pituitaryantibodiesarelimitedbylowsensitivityandspecificity. Newerserum histopathological andaetiologicalcriteria.Non-invasivediagnosisofhypophysitisremainselusive,theuse diseases, immunotherapyoralternativesella-basedpathologies).Hypophysitiscanbeclassifiedusinganatomical, commonly lymphocytic,granulomatousorxanthomatousdisease)assecondaryhypophysitis(asaresultofsystemic hypopituitarism andpituitaryenlargement.Pituitaryinflammationcanoccurasaprimaryhypophysitis(most Hypophysitis isarareconditioncharacterisedbyinflammationofthepituitarygland,usuallyresultingin Abstract King’s CollegeHospitalLondon,UK Endocrinology, KingsCollegeHospitalNHSFoundationTrust, London,UK,and 1 Mamta N Joshi Hypophysitis: diagnosisandtreatment MECHANISMS INENDOCRINOLOGY Department ofEndocrinology, Guy’s &St.Thomas’NHSFoundationTrust, London,UK, https://doi.org/ www.eje-online.org Review Review include clinical aspects of pituitary diseaseandinheritedendocrineconditions. include clinicalaspectsofpituitary developing particularinterests inpituitary, adrenalandthyroid disease.Hisresearch interests Dublinand trained in Endocrinology at St. Bartholomew’s and St. Thomas’ Hospitals in London Trust Senior Lecturer at Kings College London. He qualified from and Honorary Trinity College Paul Carroll Invited Author’s profile 10.1530/EJE 1 istheClinicalLeadforEndocrinologyatGuy’s andStThomas’NHSFoundation , Benjamin C Whitelaw -17-0009 3 © 2018EuropeanSociety ofEndocrinology M NJoshiandothers 2 , Printed inGreatBritain 3 and Paul V Carroll 3 Hypophysitis Faculty ofLifeSciences&Medicine, 1 Published byBioscientifica Ltd. , 3 2 Department of Downloaded fromBioscientifica.com at10/02/202103:32:52PM (2018) Endocrinology European Journal of [email protected] Email to PVCarroll should beaddressed Correspondence 179 179 :3 , R151–R163

R151 –R163 via freeaccess European Journal of Endocrinology www.eje-online.org common clinical entities such as immune checkpoint with emphasisondiscussion ofthenewerandless on thediagnosisandmanagement ofhypophysitis, evaluation (0.24–0.88%( to beof Neurosurgical centresreporthypophysitisprevalence by systemicpathologies has increasinglybeen recognised. IgG4-related diseaseandinvolvementofthehypophysis ( 9 million hypophysitis (all types combined) to be about 1 in Population-based studiesreportanincidence of and hypophysitisisstillconsideredararecondition. and comprehensivereviewarticles( the lastdecade,withcontributionsfromlargecaseseries understanding of hypophysitishas grown considerablyin was identified tohave anautoimmuneassociation ( ( beginning of thelastcentury infiltration oftheglandwasnotedasearly described casereportssuggeststhatlymphocytic ( pathologiesleadingtohypophysitis evaluate theprimary yearsthatwehavebeenabletobegin in thelast50 ( been documentedforoveracentury and emerging forms of hypophysitis are discussed in detail. and highlightsthediagnosticstrategy. Recentlyrecognised review guidesthereaderthroughclassificationsystems investigative features consistent with hypophysitis. This be consideredinthepatientpresentingwithclinicaland This highlightsthepotentiallybroaddifferentialthatmust processes (includingLangerhan’s cellhistiocytosis(LCH)). andneoplastic in usingthetermforbothinflammatory inconsistency intheclassificationandcommonlyoverlap gland.Therehasbeen inflammation ofthepituitary orsecondary conditions thatpresentwitheitherprimary term hypophysitishasbeenusedtodescribeanumberof gland.Intheexistingliterature, affecting the pituitary disorders has promptedincreasedinterestininflammatory inhibitors, ascancertherapieswithendocrineadverseeffects (IgG4-RD) andtheintroductionofimmunecheckpoint however, therecentrecognitionofIgG4-relateddisease conditions.Hypophysitisisararecondition; inflammatory to apredisposinglocal sella or multi-systemic or secondary entity infundibulum. Hypophysitis can occur as a primary glandand presenting withinflammationofthepituitary Hypophysitis isthecollectivetermforconditions Introduction 2 ). Histologicaldescriptionofsometheoriginally Review This reviewsummarises the currentliterature The overallprevalenceofthesediseasesremainslow Hypopituitarism relatedtoinfectiveconditionshas < 1% ofsellaandsuprasellalesionsreferredfor 4 ), butthisisanunderestimate,particularlyas 4 , 7 )). 1 ), and in the 1950s, this M NJoshiandothers 4 , 5 , 1 6 ), butitisonly ). 3 ). Our

with checkpoint, infection, IgG4,granulomatous,xanthomatous,immune IgG4 granulomatous xanthomatous autoimmune, infundibulohypophysitis, autoimmuneinfection search terms We performedaPubMed-basedsearch ofarticlesusingthe Data collection patients presentingwithhypophysitis. guidance fortheclinicianinvestigatingandmanaging anticipated clinical developments. The review provides have alsoincludedareasoffutureresearch andfuture and wehavesummarisedtheavailableliterature.We hypophysitis and secondary treatment of bothprimary Little is known about the optimal diagnostic approach and therapy-related hypophysitisandIgG4hypophysitis. Traditionally infiltrativeconditionsincludingLCH and autoimmune polyglandular syndrome). erythematosus, include autoimmuneconditions (e.g.systemiclupus causes hypophysitis being less common. Secondary lymphocytic hypophysitiswithidiopathicgranulomatous conditionis hypophysitis. Thecommonestprimary structures)or secondary the hypothalamo-pituitary (affecting with conditions described aseitherprimary classify basedonaetiology(orpresumedaetiology); not beenpossibleforallpatients.Itisconventional to a solelyhistology-basedclassificationmechanism has the pathologyhasnotbeenpossible.Therefore,using findings. Inmanypatients,histological confirmation of aetiology, involvementandhistological patternofpituitary evolved tocategorisehypophysitis.Theseincludeusing hypophysitis. Anumberofclassificationsystemshave pituitary orsecondary as a result of either primary umbrella encompassingtheconditionsthatpresent In clinicalpractice,thetermhypophysitisisusedasan Classification ofhypophysitis articles. articles, 169werecasereportsand49otherjournal derived 271 articles. Of these, 53 articles were review filtering for mesh terms or text-words. The final search listing was done based on the relevance of the titles using duplicate articles resulting in 1074 articles. Further short- in English,articleswithavailablefulltextsandremoved original search, weused filterstoselectarticlesavailable Hypophysitis hypophysitis, hypopituitarism CTLA-4 hypophysitis, adenohypophysitis , PD1 Downloaded fromBioscientifica.com at10/02/202103:32:52PM , PD-L1 andcombinedthem , pituitary. Afterthe 179 :3 adenohypoph R152 via freeaccess , European Journal of Endocrinology predilection to ACTH, gonadotrophin, TSH, GH deficiencies predilection toACTH,gonadotrophin, TSH,GHdeficiencies aetiology. Lymphocytic hypophysitisisconsidered tohavea pattern ofendocrinedysfunction maybeinfluencedbythe serum prolactin(eitherhypoor hyperprolactinaemia( hormone deficiencies,diabetes insipidusandabnormal hypophysitis. is aconsistentlyreportedsymptominthepatientwith with ophthalmoplegiaisrarebutdescribed( acuity canalsooccur. Involvementofthecavernous sinus field defects butreduction incolour perception and visual ophthalmic consequences. These usually include visual compression oftheopticapparatuswithresultingneuro- gland canresultin infiltrative expansionofthepituitary or gland.Inflammatory enlargement ofthepituitary hormonedeficiencyand usually resultsinpituitary orsecondary) inflammation(eitherprimary Pituitary Clinical presentation ofhypophysitis are summarisedin predisposingfactors hypophysitisandsecondary primary by lackofdiagnostichistopathology. Theclassificationof Existing reports are mostly retrospective and are limited distinction betweentheseentitiesisnotalwayspossible. lymphocytic andxanthomatouslesionsmakingclear There isoverlapinthepresentationofgranulomatous, is usefulinguidingmanagementdecisionmaking. a successfulbiopsyhasbeenachieved,thisapproach conditions andideallymakeacategoricaldiagnosis.When to distinguishbetweenneoplasticandinflammatory appearances. Biopsy is most commonly performed hormone deficiency. but presentwiththeconsequencesofanteriorpituitary donothavediabetesinsipidus of theanteriorpituitary related toADHdeficiency. Thosewithpureinvolvement pan-hypophysitis typicallypresentwithdiabetesinsipidus with involvementoftheneurohypophysisandthose hormonedeficitsthatarise.Patients associated pituitary aetiology butdoeshaveimplicationsfordescribingthe limited asitdoesnotnecessarilyrelatetotheparticular stalk(PS)involvement.Thisapproachis and pituitary according to the pattern of the hypothalamic, pituitary recognised byoncologistsandendocrinologists. with CTLA-4 inhibitors, is a new entity increasingly category. Drugtherapy-inducedhypophysitis,especially sarcoidosis havebeenincludedinthehypophysitis Review Endocrine manifestations include anterior pituitary Endocrine manifestationsincludeanteriorpituitary Hypophysitis canalsobeclassifiedusinghistological Historically, hypophysitishasalsobeenjustclassified Tables 1 and 2 M NJoshiandothers . 8 ). Headache 6 ). The ). The (b) Basedonhistology (a) Basedonanatomy modified from( Table 1 • • • Infection • • Local tumoureffect (Sellardiseases) • • Infiltrative lesions • • Drug induced • • • • Systemic inflammatorydisorders • • Autoimmune conditions hypophysitis. Table 2 cavernous sinus involvement ( large casestudies( and visualdisturbancesarecommon,asdescribedin the acute phase of the lymphocytic hypophysitis, and the acutephaseoflymphocytichypophysitis,and hyperprolactinemia isafeaturepredominantlyseenin inhibitor-related hypophysitis.Ithasbeensuggestedthat deficits maydifferinIgG4-RDandimmunecheckpoint rare, havebeenreported( in thissequence,butisolatedhormonedeficienciesthough anterior pituitary hormonedeficiency). anterior pituitary to present with diabetesinsipidus (the latter including glandandstalk(pan-hypophysitis)aremorelikely pituitary (infundibulo-hypophysitis) andentireinvolvementofthe may bepresent( simultaneously, enlargement othersymptomsofpituitary Hypophysitis Mixed forms(lymphogranulomatous, Necrotising hypophysitis Plasmacytic/IgG4-related hypophysitis Xanthomatous hypophysitis Granulomatous hypophysitis Lymphocytic hypophysitis Lymphocytic pan-hypophysitis Lymphocytic infundibuloneurohypophysitis Lymphocytic adenohypophysitis Fungal infections Syphilis Tuberculosis Germinoma Rupture ofRathke’s cleftcyst Erdheim–Chester disease Langerhans cellhistiocytosis Interferon Immune checkpointtherapy(CTLA4Ab,PD-1Ab) disease) Other granulomatous(Crohn’s, Takayasu’s, Castlemans’ IgG4-disease Granulomatosis withpolyangitis Sarcoidosis Autoimmune polyglandularsyndrome(APS) Systemic lupuserythematosus(SLE) xanthogranulomatous) Headache with or without nausea, vomiting ( Classification ofprimaryhypophysitis(adaptedand Conditions predisposingtothedevelopmentof α 91 )). 6 5 , ). Involvement of PS in isolation ). InvolvementofPSinisolation 10 Downloaded fromBioscientifica.com at10/02/202103:32:52PM ). Cranial nerve palsies( ). Cranialnerve 4 , 9 ). The pattern of hormone ). Thepatternofhormone 10 ), intracavernous carotid 179 www.eje-online.org :3 10 R153 > , 50%) 11 via freeaccess ), European Journal of Endocrinology Other infiltrative/infectiousaetiologies Germinoma (ifconsideredasdifferential tohypophysitis) Langerhan cellhistiocytosis(LCH)/Erdheim–Chesterdisease(EDH) IgG4-related disease Granulomatous lesions Lymphocytic hypophysitis Suspected conditions Table 3 www.eje-online.org 2. 1. with hypophysitis Investigation ofthepatient highlighting therelevanceofabroaddifferential( pathologies(20%), more commonthaninflammatory 152 PSlesionsreportedneoplastic(32%)were as recognisedadverseeffects.Alargecaseseriesof ipilimumab, result in hypophysitis and thyroiditis therapy. Immunecheckpointinhibitors,mostcommonly when neweroncologymedicationsareusedasimmune mayberelevant,especially bone disease.Drughistory or LCH might manifest with symptoms of respiratory and examination. Conditions such assarcoidosis or disorder, itisimportanttoconsiderabroadhistory toasystemicconditionoraninfiltrative secondary evidence tosupportadiagnosisoflymphocytichypophysitis. (particularly thirdtrimesterorearlypost-partum)provides the aetiologyofhypophysitis.Arelationshipwithpregnancy conditions andtheirtreatmentsareimportanttoidentify and featuresofassociatedautoimmuneconditions( reported inarecentGermanstudyincludeweightgain Amongst the other common non-endocrine symptoms apoplexy-mimic ( occlusion( artery

Review profile includingcortisol,ACTH,IGF-1,GH,oestradiol hormonal A fullearlymorningpituitary-related Biochemistry Given thepossibilitythathypophysitismaybe The relationshiptopregnancyandknownexisting Investigations forsuspectedhypophysitis(excludinghistology). 11 12 , 14 ), meningitis-mimic( ) presentations have been reported. M NJoshiandothers

13 ) andeven 15 10 ). ). 4. 3. Hypophysitis CSF analysis(cytology, oligoclonalbands) Imaging LDH (lacticaciddehydrogenase), urineanalysis Serum andCSFAFP(alpha-fetoprotein) andHCG(human FDG PETfordiseaseactivity Skeletal survey, wholebodybonescan FDG PETfordiseaseactivity Immunoglobulin levels,particularlyIgG4 CT andscintigraphy CSF analysisforglucose,protein,oligoclonalbands,ACE ANCA antibodies Serum ACElevelsifsarcoidosissuspected Chest X-ray, interferongammaassayifhistoryoftraveland Pituitary antibody Anti-Ro, anti-La,anti-SSa,anti-Ds-DNA(ifconcomitant Anti-nuclear antibody Thyroid antibodies(TPO) Investigations chorionic gonadotropin) tuberculosis suspected autoimmune featurespresent) and immune checkpoint therapy-related hypophysitis and immunecheckpointtherapy-relatedhypophysitis classical lymphocytic hypophysitis. IgG4 hypophysitis features aremostprominentinthepatientwith as the preferred radiologic investigation of choice as thepreferredradiologicinvestigationofchoice MRI is considered Gadolinium-enhanced pituitary Radiology Table 3 investigations canbeconsidered,assummarisedin diagnosis, furtherbiochemicalandradiological process. Basedontheclinicalsuspicionordifferential provide subtlecluestothenatureofsystemic sedimentation rate (ESR) can (CRP), erythrocyte smear, renal,liverandboneprofile,C-reactiveprotein investigations such asfullbloodcount,peripheral should bemeasured,wherefeasible.Routinebaseline diabetes insipidus, levels of anti-diuretic hormone with normalmenstruation.Inpatientssuspected axis may not be indicated in a pre-menopausal female up. Biochemical evaluation of the gonadotrophin electrolytes shouldbeapartofthehormonalwork thyroxine, TSH,prolactin,plasma/urineosmolality, (pre-menopausal females)/testosterone,LH,FSH,free of theadjacentdurareferredas‘duraltail’( symmetrical suprasellaextensionandenhancement insipidus. Thelesionsarecommonlyassociatedwith spot, particularly, inpatientspresentingwithdiabetes bright supported by the absenceofposteriorpituitary gland withnoobviousstalkdeviation.Thisisfurther a prompt,intenseandhomogenouslyenhancing radiological featuressuggestiveofhypophysitisinclude anatomy and appearances. The to define pituitary . Downloaded fromBioscientifica.com at10/02/202103:32:52PM 179 :3 16 ). These ). These R154 via freeaccess European Journal of Endocrinology 8. 7. 6. 5. Review pituitary gland-specific factors(PGSF1aandPGSF2 pituitary ( antigens such as alpha enolase ( over theyearshavereported presenceofpossible have been unsuccessful ( can beimplicatedinthecausationofhypophysitis Attempts to consistently identify autoantigens that Immunology related diseaseandLCH( biopsyinpatients withIgG4- the needforpituitary helpful inconfirmingmultisitediseaseandavoiding diagnosis. TheintroductionofFDGPET-CT hasbeen or whenmalignancyisapotentialdifferential potential sarcoidosis, TB, connective tissue disorders chest, abdomenandpelvis is usefulinpatients with helpful toidentifyotherinvolvedsitesofdisease.CT related tosystemicpathology, additionalimagingis hypophysitis In patientssuspectedtohavesecondary biopsy.thickness asaguidetoconsiderpituitary ( out of37PSlesionsoverameanfollow-up4.2 years et al. A significant proportion of lesions willprogress. Jian a suspectedmalignantlesionhasnotbeenruledout. are used.Acloserfollow-upmaybepreferredwhen monthlyorannualscans then follow-upwith3–6 is the preferred initial management, If surveillance not differentiatebetweenaetiologies( tumours ormetastases,butimaginginisolationdoes common inLCH,lymphocytichypophysitis,germcell al. et difficult ( scoring, thedifferentiationcontinuestoremain of score of the score ( stalk sizeandmucosalswellingforthecalculationof brightspotpresence, administration, posteriorpituitary and signalintensityhomogeneityaftergadolinium massvolumeandsymmetry,pituitary signalintensity scoring system( hypophysitis, Gutenberg To adenomaand aiddistinctionbetweenpituitary process( response oftheburntoutinflammatory of an‘emptysella’hasbeenconsideredastheatrophic in awidedifferential.Notuncommonly, thepresence andgenerallyresults based massisnotstraightforward categorisation. Thecharacterisationoftheunusualsella- radiological characteristics that facilitate clear have notbeenreportedtouniqueordistinctive 23 19 ≤ ), chromosome14openreading frame166( ). Theyrecommendedusingprogressionofstalk 0 suggested hypophysitis. Despite the systematic 0 suggested hypophysitis. Despite the systematic demonstrated changes to baseline images in 21 demonstrated that isolated PS lesions are more demonstratedthatisolatedPSlesionsaremore ≥ 1 was suggestive of adenoma, whereas a score 1 wassuggestiveofadenoma,whereasascore 5 18 ). Inarecentsystematicreview, Catford ). The score ranges from 18 ). Theyusedrelationtopregnancy, 20 6 t al. et , , 9 21 M NJoshiandothers ). Numerous researchers ). derived a radiologic derivedaradiologic 22 ), secretogranin II 20 − 13 to +8 and a 13 to +8 anda ). 24 17 ), ). ). 9. 13. 12. 11. 10. Hypophysitis MRI, withouthypothyroidismorassociatedwith adenomaat hyperprolactinemia withoutpituitary with otherautoimmunediseases,inpatients as patientswithapparentlyidiopathichypopituitarism antibodies maybehelpfulinselectivesituationssuch recently suggestedthatlookingforanti-pituitary antibodies( of pituitary and providedhelpfulguidanceintheidentification using immunofluorescence-basedtestingmethods be oflimiteduse.Ricciuti and specificitythereforearenormallythoughtto antibodieshavealowsensitivity Serum anti-pituitary future diagnosticbiomarker( neurohypophysitis, suggestingapotentialroleas central DIandsuspectedlymphocyticinfundibular rabphilin-3A antibodyin76%(22/29)patientswith not beenconfirmed.Onestudydemonstratedanti- ( ( (leukocyte commonantigen), CD3(T-cells), CD20 cells anduseoftissue(suchasCD45 inflammatory nature ofthedisease.Histologic stainstoidentify specimen provides valuable information about the When available,evaluation ofthehistological patient consent. such assteroidtherapyordifficultyinobtaining regression, responsetoinitialmedicalmanagement other reasons,includingspontaneousresolutionor a tissuesamplemightalsonotbepracticalfor potentially involvessignificantmorbidity. Obtaining or resectionofsellasuprasellatissue,andthis obtaining histologywillrequireneurosurgicalbiopsy robust and definitive method of diagnosis. However, classification ofhypophysitisandthereforeisthemost Histological assessmentwillprovideconfirmationand Histology autoimmune hypophysitis( co-associate) presentinonly8%ofpatientswith with autoimmunethyroiddisease(thecommonest in thepatientwithhypophysitisisuncommon that demonstrable co-existing autoimmune pathology suggest Data fromtheHopkinsHypophysitisRegistry hypophysitis. be usefulintheassessmentofsecondary specific antibodies(suchasANA,ds-DNA,ANCA)may not currently part of routine practice. Other disease- autoimmune process ( or pituitary presenting condition with a selective hypothalamic antibodies mayhelptoestablishassociationofthe ( iatrogenic causesorinpatientswithemptysella 26 25 5 ). Furthermore, in select cases,anti-hypothalamus ), butthepathogenicityoftheseantigenshas transcriptionalfactor1 ) andpituitary-specific Downloaded fromBioscientifica.com at10/02/202103:32:52PM 28 ). HoweverBellastella et al. 4 27 ). ). reviewed122articles 179 5 www.eje-online.org :3 ). These tests are R155 et al. via freeaccess

European Journal of Endocrinology www.eje-online.org medical management.Numerous authorshaveconfirmed ( in additiontoreplacement ofendocrineinsufficiencies ofhypophysitiscanbeused or headache,surveillance of hypophysitis.Incaseswithoutsignificantmasseffect resection. after grosstotalresectioncomparedtobiopsyorpartial insufficienciesandwasparticularly frequent pituitary Post-operative follow-upshowedthedevelopment of wasreportedtobe 11–25% ( lesion aftersurgery disturbances ( resolution ofsymptomssuchasheadachesandvisual for hypophysitis resulted in significant cohort, surgery impairment due to the lesion ( also reliablyandquicklytreatsmasseffectsvisual management andexcludesthediagnosisoftumour. It that itprovidesahistologicaldiagnosistoguidefuture are is significantmasseffect.Theadvantagesofsurgery remains thepreferredmethodofchoice( management andradiotherapy. Historically, surgery surgery, medicaltherapy, anti-inflammatory conservative hypophysitis falls into four categories which include: treatmentofthe mass-related consequences.Primary enlargementwithassociated pituitary inflammatory hormonedeficienciesandtoreducethe pituitary conventional recommendations( and diabetes insipidus should be treated according to of hypopituitarismisneeded( a chronicorburntoutphaseduringwhichonlytreatment treatment; and hypophysitis, which may require primary Bellastella inhibitor treatment)willemergewithfuturestudies. responses (e.g.IgG4-relateddisease,immunecheckpoint of thespecificcausalconditionsandtheirtreatment recommendations. Itislikelythatincreasedunderstanding there isnostrongevidencebaseformanagement ofhypophysitisisvariable,and The naturalhistory Treatment ofhypophysitis 31 Review , inflammatory lesions. inflammatory essential to confirm specific subtypes of pituitary presence ofhistiocytes,granulomasxanthomasare to delineatedifferenttypesofhypophysitis( cells)) andhormone-specificimmunestaininghelps (B cells),CD68(macrophages)andCD138(plasma There arelimitedreportsofspontaneousresolution The mainobjectivesoftreatmentaretomanage Glucocorticoid therapyforms thecornerstoneof 34 ). t al. et 31 distinguish between the acute phase of , 32 , 33 ). Therateofrecurrencethe M NJoshiandothers 31 30 ). In a large German ). 7 ). Hypopituitarism 4 ) whenthere 29 31 ). The , 32 ). 2. 1. Specific conditionscausinghypophysitis agonists forinducingtreatmentresponse( modulating autoimmunityandtheuseofdopamine Some authorshavereportedthepossibilityofprolactin is likely we will see more focussed monoclonal antibody- suppressive agentatpresent,whileinthecomingyears,it ( of immunosuppressive therapies for resistant lesions therapies. Thelastfewyearshaveseenariseintheuse ofthepapersreportingusesteroid-sparing summary data 4 Table Supplementary used, andexperienceoftenreportedascasereports. have beenconsidered.Avarietyofagents alternative immune-suppressiveagentsorradiotherapy or recurrentdiseasesteroid-sparingoptionssuchas limits theuseofthisstrategy( long-term steroidsleadstoincreasingadverseeffectsand a recentlargecohort( to 38% patients developed relapse on steroid therapy, in highlights thelimitationsofthistreatment( overall recurrenceratehasbeenreportedtobehighand an initialgoodresponseto‘steroidtherapy’,butthe patient withsuspectedhypophysitisisoutlinedin hypogonadism if present). The approach to managing the to provide symptomatic relief (from galactorrhoea and/or bromocriptine inhyperprolactinaemicpatientsislikely treatment isstilluncertain( the beneficial effect of long-term dopamine agonist inflammation( in theacutephaseofpituitary directed therapysuchasrituximab( Hypophysitis 36 ). Azathioprineisthemostcommonlyusedimmune- ( gland andstalk disease thatinvolvesthepituitary hypophysitis) isarareinflammatory/autoimmune Lymphocytic hypophysitis(LH,autoimmune Lymphocytic hypophysitis ADH) and decision making regarding conservative, ADH) anddecisionmaking regardingconservative, replacement of hormone deficiency (including cells, histiocytesandfibrosis. Treatment includes withlymphocyticinfiltration,plasma normal pituitary is confirmed histologically and the features include pregnancy orearlypost-partum( but theconditionisclassicallyidentifiedduring be present.Bothgendersandallagesmayaffected insipidus. Masseffectwithvisualconsequencemay degrees ofhypopituitarismandfrequentlydiabetes Hyperprolactinaemia affectsaminorityofcases givenattheendofthisarticle)providesabrief 1 ). Theclinicalfeaturesincludeheadache,variable 31 (seesectionon Downloaded fromBioscientifica.com at10/02/202103:32:52PM ). Asisexpected,treatmentwith 31 5 ), theuseofcabergoline/ ). Incaseswithprogressive 31 179 ). 2 :3 ). Thediagnosis supplementary supplementary 37 , 33 38 , ). While 35 R156 Fig. 1 ). Up 5 via freeaccess . ). European Journal of Endocrinology 4. 3. effect despitecorticosteroids suspicion forrecurrence.Considerescalatingtoimmunosuppressionorradiotherapyifpersistentsymptomscontinuing mass Early assessmentfortreatmentresponsewithpituitaryMRI.Followserialimaginguntilclearstability, maintainclinical Figure 1 Review the presenceofmultinucleated giantcells,histiocytes, partum state( condition, fivehavebeen associatedwiththepost- less thanahundredreported casesoftheprimary (previously knownasWegener’s granulomatosis).In tuberculosis orgranulomatosiswithpolyangitis toasystemicpathologysuchassarcoidosis,secondary granulomatoushypophysitis) or idiopathic primary entity (known as disease can be seen as a primary hypophysitis( type ofprimary Granulomatous hypophysitisisthesecondcommonest Granulomatous hypophysitis ( LH andwehavepurposefullylimitedthediscussion treatment. Therehavebeencomprehensivereviewsof of diseaseandsomepatientsrequiremulti-modal Radiotherapy may be useful when there is relapse or whenatissuediagnosisisconsideredimportant. non-responders, masseffect,headache,visualfailure isindicatedfor treatments havebeenused.Surgery therapy butavarietyofimmunosuppressive glucocorticoid remainsthecornerstoneofmedical medical andsurgicaltherapies.High-dosesuppressive 1 , 3 , 4 , 5 ) inthisreview. 39 ). Thehistologyischaracterised by ± surgery. M NJoshiandothers 10 ). Granulomatous 6. 5. Hypophysitis be therarestofhistological types.Only18cases Xanthomatous hypophysitis (XH)isconsideredto Xanthomatous hypophysitis resolution ( ( therapy appearstobelesseffectivecomparedwithLH granulomatous disease( systemic conditionscanhelpidentifythesecondary types. Thepresenceofimmunologicalmarkers does nothelpdifferentiatebetweendifferent presentation ( and vomitingwerereportedtocorrelatewithearlier ( present in 100% cases with granulomatous disease al. et LH ( higher incidenceofvisualsymptomscomparedto clinical presentationtendstobemoreseverewith in asystematicreviewofidiopathiccases( ( processes continuum ofthelymphocyticinflammatory It isstillunclearifgranulomatouschangesforma lymphocyte infiltration along with plasma cells ( 33 33 33 ) whilesurgicalresectionleadstobettersymptom ). Systemicsymptomssuchasafever, nausea ). Therehasbeenreportedfemalepredominance 10 identifiedthatgonadotrophindeficiencywas , 40 ). Inareviewof31patients,Gutenberg 40 ). 40 ). Theradiologicalappearance Downloaded fromBioscientifica.com at10/02/202103:32:52PM al 3 Table 179 ). Glucocorticoid www.eje-online.org :3 40 R157 ). The 40 via freeaccess ). European Journal of Endocrinology www.eje-online.org 9. 8. 7. Review Della Torre has beenfrequentlyreported ( association withautoimmune andatopicconditions While theexactaetiology still remainsunclear, an cohort withinthehypophysitis spectrumofdiseases. understand whetherIgG4-RDrepresentsasubstantial that furtherretro-andprospectivestudieswillhelpus hypophysitis’ mayinfactreflectIgG4-RD.Itislikely previously classifiedas‘hypophysitis’or‘lymphocytic lack ofrecognitionthisaetiology indicates thatcases reclassified asIgG4hypophysitis( to demonstrate LH showed that 41% (12/29) were histological review of cases, previously thought ( IgG4-related hypophysitiswasfirstreportedin2004 IgG4-related disease seldom recover( mass effectofsymptoms,butendocrinedeficiencies fromvaries fromcomplete,partialornorecovery diagnostic purposes( with surgery, ifnotalreadyoperatedonfor of medical management, most lesions are treated established. Given the reported lack of effectiveness experience is extremely limited this is yet to be steroid therapy, ascomparedtoLHbutclinical been suggestedthatXHmaybelessresponsiveto macrophage-related pathology ( glycoprotein and can be utilised as tool to mark tissue. Immunostaining highlights CD68pituitary xanthoma cellsorlipid-ladenmacrophagesinthe is onlyconfirmedontissuesectionsdemonstrating crystals ( fluid withfloating appears asacystfilledwiththickorangecoloured post-gadolinium contrast images. The grosslesion cystic sellarmassesonMRIandenhancethe Xanthomatous lesionspresentradiologicallyas rarely reportedwithxanthomatouspresentation( to othertypesofhypophysitis( present foralongerdurationinthepatientscompared 43 LH, but visual symptoms are considered to be rare ( The clinicalpresentationisthoughttobesimilar has beenmorecommonlyreportedinfemales( to chronic inflammation ( activation secondary xanthomatous infiltrationresultsfrommacrophage lesions elsewhereinthebody, itispostulatedthat or lymphocyticspectrum.Asseenwithxanthomatous entity orisapossibleextensionoftheautoimmune ( have beenreportedsincethefirstpublishedin1998 41 46 ). Theclinicalsymptomsappeartobemilderand ). Itisbelieved to berare but arecent retrospective , 42 ). ItisunclearifXHconstitutes a distinct et al. debated against the role of atopy in 44 , 45 42 ). ). Theresponsetotreatment M NJoshiandothers 48 42 , , 49 33 43 ). Inarecentpaper, 47 42 ). Similarly, DIis ). Thediagnosis ). Theprevious , 43 ). It has 42 33 43 ). It 33 ). ). , 11. 10. 12. Hypophysitis but recovery ofendocrine function is thought to be but recovery mainstay oftreatmentwitha beneficialearlyresponse, systemic involvement of tissues. Steroids form the of FDG PET in IgG4-related disease to characterise of hypophysitis.Thereisan evolvingroleoftheuse radiologic featuresarenotdistinctfromothertypes to othertypesofhypophysitisisuncertain. The The significanceofthefindingoritsapplicability In arecentreport,Landek-Salgado obliterative phlebitis. There have been other disease- lymphoplasmacytic infiltrate,storiformfibrosisand with twooutofthethreefeaturesnamely, dense of IgG4-relateddiseaseandaprerequisitecriteria A consensusstatementdescribedhistologicalfindings retroperitoneal fibrosis( diseaseis related pathologyassociatedwithpituitary predominance ( suggested a distinct subset of IgG4 disease with female ( and elderlypopulations,withmalepredominance has beenmorecommonlyreportedinmiddle-aged of multiple organs ( lesions withIgG4-dominantplasmacyticinfiltration The condition commonlypresents as pseudo-tumour phenomenon( the inflammatory elusive, and it may well be considered a ‘bystander’ in 50 IgG4 disease,whichremainstobeconfirmed( in abiopsyprovenIgG4-hypophysitispatient( autoantigens againstgrowthhormoneandPOMC subset of patients with multi-organ involvement ( that thosewithelevatedserumIgG4couldrepresenta prozoning (hook)effect( reporting IgG4shouldconfirmfreedomfrom tool ( steroid therapymakingthemlessusefulasdiagnostic IgG4-RD andelevatedlevelstendtonormalisewith Serum levelsofIgG4arenotsensitiveorspecificfor have beendebatedbyothers( confirmed IgG4hypophysitis( cells ofmorethan40%wasnotedinallpatientswith high powerfieldandaratioofIgG4/IgG-positive presence ofmorethantenIgG4-positivecellsper used asaprerequisitetotestforIgG4staining.The presence oflymphoplasmacyticinfiltrateshouldbe hypophysitis, Bernreuther the disease ( disease-specific diagnosticcriteriaforconfirmationof guidelines ( specific guidelines, which report exceptions to these 48 ). Theexact role ofIgG4inpathogenesisremains , 54 56 , , 55 58 ), exceptforarecentstudywhereauthors 47 52 ). Itisrecommendedthatlaboratories , ). In a retrospective review of primary ). In a retrospective review of primary 57 47 ). Leporati ). Thecommonestco-existentIgG4- Downloaded fromBioscientifica.com at10/02/202103:32:52PM 52 , 56 53 59 ). , ). Wallace et al. 54 t al. et 58 ). IgG4-related disease ). suggested a pituitary suggested a pituitary 47 179 51 et al. ). Thesefindings ). suggestedthat :3 et al. demonstrated suggested R158 61 60 49 via freeaccess ). ). , European Journal of Endocrinology 15. 14. 13. Review radiological abnormalities( adenoma) resultsinpartial or transientresolutionof ( maintenance therapytoreduce theriskofreactivation 6-week inductionregimenis followedby12 months of by theHistiocyteSocietyGuidance( based therapyaresuggestedasthefirst-lineoptions the diagnosisisestablished.Vinblastine andsteroid- replacement therapiesshouldbeinitiatedassoon been standardisedforadultpatients( radiotherapy andunlikeinchildren,ithasnotyet immune-suppressive regimen,chemotherapyor gland.Treatmentpituitary commonlyinvolvesan sites ofdiseasemoreamenabletobiopsythanthe allowing clarificationofthediagnosisbyidentifying identification of active disease ( imaging maybeusedtoguideresponsetherapyor involvement haveallbeendescribed( enlargement,emptysellaandhypothalamic pituitary common, otherfeaturessuchasstalkthickening, brightspotismost absence ofposteriorpituitary involvementhavebeenreported.While pituitary are notspecifictoLCH,anddifferentpatternsof the first-lineimaginginvestigations( ( based onhistologicalandimmunologicalcriteria insipidus. Whileconfirmationofthediagnosisis multisystem featuresorthepresenceofdiabetes Diagnosis issuspectedwhenthereareother DI associatedwithmultipleendocrineinsufficiencies. with multisysteminvolvementaremorelikelytohave of stalk involvement ( Prolactin elevationisconsideredasapossibleresult deficiency, asreportedinpaediatricstudies( is mostcommon,followedbygonadotrophin 20% of patients ( but nonethelesshavebeenreportedinapproximately ( axis for involvementofthehypothalamic–pituitary the earliest manifestations, denoting the predilection progressive form( often rangingfromaself-limitingcoursetorapidly is stilldebated.Ithasavariableunpredictablecourse, population. The exact pathogenesis of the condition it ismorecommonlyreportedinthepaediatric of 1–2casespermillioninadults( disease,withanincidence LCH isarareinflammatory Langerhans cellhistiocytosis of B-cell-depletingtherapies( uncommon ( Table 3 65 70 ). Radiotherapy (lower doses than for pituitary ). Radiotherapy(lowerdoses thanforpituitary deficiencies are less common, ). Anterior pituitary ), a skeletal survey andchestX-raycouldbe ), askeletalsurvey 56 ). Thereisapotentialrolefortheuse 66 66 ). Oftendiabetesinsipidusisoneof ). Growth hormone deficiency 69 ), with disinhibition. Patients 65 M NJoshiandothers 62 ). Whiletheradiological 66 , 63 ). It also has a role in ). 66 64 70 ). MRIfindings 66 , ). Aninitial 65 ). Hormone ), though 65 67 ). PET , 68 ). 17. 16. 18. Hypophysitis elderly, unlikeLH( appears tohaveahigherincidenceinmalesandthe with immunecheckpointinhibitor-relatedtherapies side effectoftheseagents( metastatic malignancies.Hypophysitisisarecognised combination therapiesarebeingusedforanumberof antibody), pembrolizumab(PD1antibody)and melanoma ( checkpoint inhibitorlicensedfortheuseinmalignant Ipilimumab (CTLA4antibody)wasthefirstimmune rise ofimmune-mediatedsystemicadverseevents. therapy foravarietyofcancers,therehasbeen With theintroductionofnovelimmunetargeted hypophysitis Immune checkpointtherapy-related might beasignofreactivationthedisease( a patientpreviouslyconsideredtobeinremission, endocrine deficienciesisrare( of lesion seemstoregresswithtreatment,recovery can precede clinical diagnosis by several weeks ( and as has been reported, the radiological findings anddrug-induced hypophysitis differentiate primary There arenoobviousradiologicalpatterns,which hypophysitis ( rare in CTLA-4-induced ACTH insufficiency is very of hypophysitis, recovery variable inmostprimary isvery about GHstatus.Whilethetrendtorecovery well as corticotroph insufficiency ( include highratesofthyrotrophin,gonadotrophinas deficiencies arenotedinmorethan70%patientsand insipidus isextremelyrare( ( (lymphocytic)hypophysitis hypophysitis andprimary immune checkpointtherapy(CTLA-4)-induced have recentlysummarisedthedifferencesbetween weeks( therapy, withameandurationof9 from theonset of the oncological from 5 to 36 weeks noted priortothethirdcycleoftreatmentandranges detection ofhypophysitis, pancreatitis,adrenalitis Numerous casereportshighlighted theincidental additional sitesofimmune-mediated adverseeffects. a potentialtoidentifyradiological evidenceof The useofFDGPETinthese oncologypatientshas for thelikelihoodofhypophysitis( or suspectedcortisoldeficiencyshouldbeevaluated immune checkpoint therapy with new onset headache been reportedinseveralstudies.Allpatientsreceiving requires a high index of suspicion. Headache has of hypophysitis,inrelationtothesymptomsand The clinicalpresentationissimilartootherforms 76 ). Theincidenceofvisualdisturbancesanddiabetes 72 76 ). Morerecentlynivolumab(PD1 , 77 74 Downloaded fromBioscientifica.com at10/02/202103:32:52PM ). ). Theincidenceiscommonly 73 ). Pituitary inflammation ). Pituitary 71 73 179 ). New-onsetDI,in 77 76 , www.eje-online.org :3 ). Little is known ). Caturegli 76 ). Endocrine 65 R159 ). et al. 74 75 via freeaccess ). ).

European Journal of Endocrinology www.eje-online.org suspected tohaveLH.There isa23.1-foldincreaseinthe for DQ8andDR53could be usedtoidentifypatients ( LH, eveninpatientsnotpresenting withACTHdeficiency tissue hasbeenidentifiedas apossibleantigenictargetin exact pathogenesis( process, but further studies are needed to establish the considered tobeacytotoxicTcell-mediatedautoimmune prolactin withdetectableanti-Pit1antibody( an acquireddeficiencyofgrowthhormone,TSHand syndrome’ hasbeenrecognised( In recentyears,anovelentitycalled‘Anti-Pit1antibody and immunomarkers hypophysitis: imagingmodalities Recent advancesintheunderstandingof 20. 19. 87 Review ). Heaney checkpoint therapies. manage acuteandchroniccomplicationsofimmune local guidelinestohelpcliniciansidentifyiRAEsand consideration ( and discontinuationoftheoncologytherapyneeds life-threatening cases,theroleofhigh-dosesteroids hormone deficiency asstandard( dysfunction, thetreatmentinvolvesreplacing grading systeminoncologytrials( the clinicalpresentationsgradedbyCTCAE related hypophysitisdependsontheseverityof The managementofimmunecheckpointtherapy- for immunetherapy-relatedhypophysitisisrequired. precise pathophysiologicalmechanism(s)responsible of thisreviewandincreasedunderstandingthe Further detailsofthemechanismarebeyondscope cellshasnotbeeninvestigated. expression onpituitary mount asimilarADCC-mediatedresponse( IgG4-based PD1antibodiesandlesslikelytobeable activation ( activation (ADCC)astheunderlyingmodelofimmune tissue andsuggestantibody-dependentcomplement first toreportthepresenceofCTLA-4Aginpituitary type IVhypersensitivityreaction.Iwama 4-related hypophysitisislargelyaresultoftypeIIand activation confirmingthatthemechanism ofCTLA- fixation, macrophage infiltration and lymphocyte demonstrated pathologicalfindingsofcomplement of CTLA-4relatedhypophysitis( Caterugli purposes ( and thyroiditis, when PET was used for surveillance et al. 78 t al. et 82 , 79 have suggested that use of HLA markers ). Nivolumab and pembrolizumab are 73 havedescribedthebiopsyfindings , 86 80 , 84 ). Similarly antibody to pituitary ). Similarlyantibodytopituitary , 81 ). Manycentresaredeveloping ). M NJoshiandothers 85 73 ). Thispresentsas ). Butinsevereor 76 73 ). Theyhave ). Formilder et al. 26 83 werethe ). Itis ). PD1 and facilitatedecisionmaking( determine, whichlesionsarelesslikelytobeinflammatory region ofinterestcouldbeusedasaguidingtoolto certainty. The distribution of the grey levels in the given neoplastic andnon-neoplasticPSlesionswithmore called texturalanalysishasbeensuggestedtodifferentiate The useofsoftware-based image processing technology facilitating lessinvasivetissuebiopsyinmultisitedisease. conditions, oftenallowingdiagnosistobemadeby pituitary assessment ofthepatientwithinflammatory FDG PEThasbecomeanincreasinglyusedtoolinthe were significant predictors of IgG4-related disease ( that patternofuptakeandmulti-organinvolvement et al. conditionshasbeenevolving.RecentlyLee inflammatory lesions( those withotherpituitary levels ofDQ8inthepatientswithLHascomparedto perceived asprejudicingtheimpartiality ofthisreview. The authorsdeclarethatthereis no conflictofinterestthatcouldbe Declaration ofinterest EJE-17-0009 This is linked to the online version of the paper at Supplementary data for thepatientwithhypophysitis. are requiredtodefinetheoptimaltreatmentapproaches disorders. Collaborativemulti-centreprospectivestudies consistent and specific treatments for this rare group of hypophysitis andleadtomore andsecondary primary The nearfuturewilllikelyseemoreaccuratediagnosis of to emerge and non-invasive diagnostics will improve. classification of disease. New serological markers are likely result innewdiagnosticalgorithmsandmoreaccurate of disease.Theseincreasesinunderstandingwilllikely provides insight into the pathophysiological mechanisms experience withhypophysitisforendocrinephysiciansand checkpoint inhibitionhasmeantanincreaseinclinical as LH(oftenwithoutbiopsy).Theadventofimmune both innewprospectivecasesandhistoriconeslabelled hypophysitis and clinicians areconsidering this diagnosis has promptedreconsiderationoftheclassification gland hasincreasedinrecentyears.RecognitionofIgG4-RD disorders affecting the pituitary Interest in inflammatory Anticipated future developments Hypophysitis The useofnuclearmedicineinthediagnosis usedFDGPETinIgG4-relateddiseases.Theyreported . Downloaded fromBioscientifica.com at10/02/202103:32:52PM 90 88 ). Inclinicalpractice, 179 ). https://doi.org/10.1530/ :3 R160 89 via freeaccess ). European Journal of Endocrinology References the public,commercialornot-for-profit sector. 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Accepted 6June2018 Revised versionreceived6June2018 Received 6January2017

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