AHistoryof PituitarySurgery JohnA. Jane, Jr., MD,Kamal Thapar, MD,PhD,andEdward R.Laws, Jr., MD For the last 30 years, the transsphenoidal approachhas been the principal corridor for the treatment ofpituitary tumors.However, transsphenoidalsurgerydidnotreachthispositioninisolation. Significant contributionsin the field of endocrinology andradiol- ogy,notonlyat theti meofthefi rst transsphenoidaloperations butalsoduringitsresurgence,allowedtheproceduretoevolve andlater flourish. Copyright2002,Elsevier Science(USA). Allrightsreserved. T he20t hcent ur ygave risetosignificanttechnicaladvances inpi t ui t arysurgery. Theseadvances, however, didnot oc- curinisolation.Equallysignificantprogresswasmadeinthe fieldsof endocri nol ogyandradiology.Atthet urnof the19th cent ury, the bur geoni ngof these fields al l owed surgeonsto first recogni zet hepi t ui t aryasasourceofdisease.Thet ranssphe- noi dalcorri dor was used f r om the very out setof pi t ui t ary t umorsurgerybut l ost favorint helate1920s.Fur t her evol ut i onof endocr i nol ogyandradi ol ogyallowedt ranssphenoi dal surgery tore-emergeasthefirst-linet r eat ment formost pi t ui t arytu- mors.For thisreason, thisdi scussi onofthehi st oryofpi t ui t ary surgery at t empt stodescribethecont ext fortwodifferentperi- ods:thet urnofthelastcent ury, atthebegi nni ngof pi t ui t ary surgery, andthe late1960sandearly 1970s when t ranssphenoi - dalsurgery experi enceditsrenaissance. Thei nf or mat i onis notal t oget hernew. Excel l ent hi st ori cal revi ews have beenwri t t en onthesesubjects, reviewsessentialtothewri t i ngof thischap- t er .109,110,137,167,200 ContextoftheBirthofPi tui tarySurgery Statusof Endocrinology ExistenceoftheEndocrineSystem.The19thcent ur yis mar kedbytherecogni t i onofhor mones andtheendocri ne system. In1855ClaudeBernardemphasi zedt hat al t houghthe liverpr oducedanext ernal secret i on(bile),italsoemi t t edan i nt ernal secret i ondirectlyintothebl oodst ream.334 Inthelate 1880svonMet i ngandMi nkowski publ i shedfindingst hat are consi deredthecornerst oneof endocrinology.198Thesetwo sci- entistsobservedt hat diabetesdi dnot followsi mpl eligationof thepancreat i cduct ligationbut woul doccur ifthepancreas wereresected.Thi sexper i ment pr ovedt hat thepancreasacted as a"ductless gland."Bayliss and Starling furt her el uci dat edthe Department of Neurosurgery, University of Virginia, Charlottesville,VA, USA andDivision ofNeurosurgery, University of Toronto, Toronto, On- tario. Addressreprintrequests toEdward R.Laws, Jr., MD,Professor of Neurosurgery,UniversityofVirginia, Health Sciences Center,Box 800212, Charlottesville, VA 22908; el5g@virginia.edu Copyright 2002, Elsevier Science (USA). All rights reserved. doi:l 0.1053/otns.2002.32494 concept ofthehor moneatthet urnofthe19thcent ury.12 Gl andswereknowntosecretehor mones intothebl oodandto havetheireffect di st ant tothesiteof secretion.Treatment of other endocrinedisorders.The cont extnotonl y inwhi chthepi t ui t aryglandwasfirst recogni zedasasourceof diseasebut alsoinwhi chpi t ui t arydi sordersmaybet reat ed surgicallyissignificant.Pat hol ogyofot hergl andswasrecog- ni zedbeforet hoseofthepituitary. Thet hyroi dwasthefirst endocri neorgan whose hypof unct i on was recogni zed to cause a disease.Buildingontheobservat i ons of Wi l l i amGullandEmi lKocher inthe1870s,bet ween1883and1886,FelixSemon and SirVictorHorsl eypr ovedt hat hypot hyr oi di smcausedmyxo-edema.68,91,92.1os.lo6dm Therecogni t i onof gl andul arhyper secr et i onwasrecogni zed onl ylater.Al t houghtheclinicaldescri pt i onof Grave' s disease wasr epor t edin1835,itwasnot until1886t hat PaulMoebi us correl at edt hyroi dhyperact i vi t ywi t hexopht hal mi cgoiter. 141 Successfulsurgeri esonthet hyroi dforgoiterhadbeende- scri bedsincetheearly tomi d1800s. 4r,1~ Theeffectofthisrecogni t i onwaspr of ound. Surgeonsreal- izedt hat if onegl andcoul dbethesourceof diseaseandame-nabl etosurgery, others, namel ythepi t ui t ary, mi ght aswell. Thi spoi nt iswelli l l ust rat edbyCushi ng' sopeni ngst at ement s inhis1909Ameri canMedicalAssociationorat i oninwhi ch,before discussingthemanagement of pi t ui t aryhyper-or hypo-funct i on, he pai d homage to theexper i ment alandclinical wor k onthet hyroi dandparat hyroi d.3~ Few chapters inthe history of medicine tell a more creditablestory than that which relatesour progress toward a better understanding of thethyroidandparathyroidgl ands. . , whosenormal activities prove to be so essentialtothemaintenance of physiologic equilib- rium.Myxoedema,cretinism,exophthalmicgoi t er . . , havecome tobeunderstandablemaladies,definitelyamenabletorational methods of treatment- and organotherapy, when glandular activity is subnormal, or partial surgicalremoval to correct functional over- activity. PituitaryasPart of theEndocrineSystem.Atthebegi nni ng of the20t hcent ury, thephysi ol ogi cal roleof thepi t ui t ary was largelyunknown. Therehadbeenal ongdelayintheunder -st andi ngof thepi t ui t arypart l y because itsinaccessibility made itdifficulttostudy. Theconcept sof Gal enhadpersi st edf r om thesecondcent uryrelatively uncont est edunt i l the1600s.Ga- len argued t hat t he"pituita"( f r om theGr eek pt uo[to spit]and theLatinpi t ui t a[mucus])secret edwast epr oduct sf r omthe brai nintothenasalcavities.Twoscientistsdi sprovedthiscon- cept inthe17thcent ury, Conr adSchnei derof Wi t t enber gand RichardLowerof Oxford. Usinganat omi calstudies, Schnei der and Lower pr oved t hat thepi t ui t ary was not fluid filled andt hatthebrai ndi dnot communi cat ewi t ht henasalcavities di rect l y t hr oughthepituitary.124,177,178 Despitethisevidence, significantstridesregardi ngthepi t u- i t aryr emai nedwant i ngforanot her 200years.In1886S. 200OperativeTechniquesinNeurosurgery,Vol5,No4(Month), 2002:pp200-209 Lot hri ngerandA.Dostoiewskyi ndependent l ydividedthepi- t ui t aryintochr omophobi candchromophi l i ccells. 45,~23Six yearslaterin1892,Schoenemannfurt herdifferentiatedthe chromophi l i ccellsasstainingwi t heitheraciddyes(oxyphil,acidophil,eosinophil, oralpha-cells)orbasicdyes(basophil, cyanophil, orBeta-cells). 179 Evenwi t habet t erunderst andi ng of pi t ui t ary histology,theactualrole of thepi t ui t ary in human physi ol ogywasnot fullyappreciated.Infact,someworkers cont i nuedtoregardit asa vestigial organaslateas1908.173 Evenso,experi ment al evidenceonthepossibleroleof t he pi t ui t arywasmount i ng. In1892GuilioVassaleandErcole Sacchireport edthatablationofthepi t ui t arydi st urbedfluid metabolism. 192 In1898LeComt ehadnot edthatthepi t ui t ary enlarged duri ng pregnancy.24 In1907 JacobErdhei m andEmil St umme confi rmed this finding and also observed that enlarged eosinophilicceilsof ant eri orpi t ui t ary remai nedenlargeddur- inglactation. 48 In1889Rogowitsch report edthatthepi t ui t ary enlargedandtheusualnumber of eosinophiliccellsdecreased afterexperi ment al t hyroi dect omy.166Later,asacorollary, Bernhard Aschnerreport edt hyroi d at r ophy after hypophysec- t omyof pups. 4 Crowe,Cushing,andHomansalsoperformed hypophysect omi es on dogs andreport ed at r ophy of the ovaries andut erusinthesurvivors andfailure todevelop sexualchar- acteristics in pups.Ablationof the post eri or lobe did not cause these disorders. 26 Finally, Ascoli andLegnani report ed adrenal cortical at r ophy after experi ment alhypophysect omy. 5 PituitaryasSourceof Disease.Wellbeforetherecogni t i on of asyndr ome associatedwi t hpi t ui t ary diseaseandbefore the first pi t ui t ary surgery,anatomistshadrecogni zed theabilityof thepi t ui t aryglandtoexpand. Onpost mor t emexaminations,anatomistsinthe17thand18thcenturiesnot edthatthepitu- itarycoul denlargeandcauseblindness, t8,194 Nevertheless,at theendofthe18thcent uryuncert ai nt yabout whet her the pi t ui t ary wastheseatof diseaseremained.8 However,by the end of the19th century,increasing number s of report sbegantoemergeindicatingthatthepi t ui t arycoul d growasapart ofapathologicalprocess.Before Marie' s1886 descri pt i onandcoi ni ng of thet erm acromegaly, Andrea Verga in1864 and Vincenzo Brigidi in1881had described the clinical entityandnot edanenlargedpituitary. 2~Verga'spost- mor t emanalysisdescribedthatthepi t ui t ary growt hhadcom- pressedtheopticnerves.Al t houghVergarecogni zedthatthe pat i ent harboredapi t ui t ary t umor, hebelievedthatthet umorwasrelatedtothepatient' searlylossofmenses.EvenPierre Marieremai neduncert ai nwhet her theenlargedpi t ui t aryin acromegalywaspart ofthegeneralizedorganomegal yassoci- atedwi t hthediseaseorwhet her itrepresent edat umor. He (and Marineseo)di d recognize, however, thata universalfind- ingwasanenlargedpi t ui t arythatcoul dcompresstheoptic nerves. 13o In1887,Minkowskifirst suggestedthatpi t ui t ary pat hol ogy wasnot the result but thecauseof acromegaly. 14~ After Massa- longo proposed that pi t ui t ary hyper f unct i on causes acromegaly in1892,in1900 Benda suggestedthattheeosinophilic cells he observedinpost mor t emexami nat i onswerethes our c e . 13A32 Cushing' s1909observationsthatpatientsi mprovedclinically after partial hypophysect omy furt her suppor t ed the pi t ui t ary as thesourceof acromegaly. 34 Atthet urnofthe20t hcentury, increasingreport sshowed thatacromegalywasnot theonl ysyndr omeassociatedwi t h pi t ui t ary tumors.Joseph Babinski in1900 and Alfred Froehl i ch in1901report edsellar regiont umors, likely crani opharyngi o- mas,thatcausedwhat waslatert ermeddyst rophi aadiposo- genitalis. 7,57 By1906Cushi nghadreport edhisinitialexperi- ence wi t hthisnewl y described syndrome.35 Thus, bythebegi nni ngofthe20thcent ury, thefieldof endocri nol ogyhadbeenestablished.Morewasknownaboutot herglandsandtheirrelatedpat hol ogyt hanthepituitary. Al t houghsomestillregardedthepi t ui t ary asa vestigial organ, evidence related the pituitary,in a yetundet er mi ned manner, to growth, sexualdevel opment , t hyroi dfunct i on, lactation,and the adrenals.Pi t ui t ary enl argementwas knownto compress the optic nerve, and at least twoclinical syndromes associated wi t h pi t ui t arydiseasewererecognized:acromegaly(growt hhor- mone adenoma)anddyst rophi a adiposo-genitalis(crani ophar- yngiomas).St at usofRadi ol ogy Duri ngthistime,significant advances werealso being madein thefieldofradiology.Wi l hel mRoentgenfirstreport edthe existenceofX-raysin1895.165Theapplicabilityofthisnew mode of investigation was qui ckl y appreciated by Harvey Cush- ing, who in1897 report ed the useof X-ray t echnol ogy to image a bul l et fragment wi t hi nthespinalcord of amanwi t h Brown- Sequards yndr ome? ~In1899,atthemeet i ngoftheBerlin SocietyofPsychiatryandNervousDiseases,theneurol ogi stHer mannOppenhei mdemonst rat edthatthesellaturicawas enlarged in a pat i entwi t h acromegaly. 135 In1907 Schloffer used radi ographytoconfi rm thesellar pat hol ogy before performi ng what woul dbethefirst t ranssphenoi dal procedure.175 By1912,Art hurSchullerof Viennahadpubl i shedthefirst t ext book of skullradi ography andhadremarkedontheradio- graphicappearanceof patientswi t hsellartumors.18o Plainra- diographsallowedsurgeonstoconfi rmpreoperat i vel ywhatprevi ousl y t hey coul d onl y assume.For thefirst time, surgeons coul d see thesite of pat hol ogy before maki ngthe first incision. Thisabilityincreasedsurgicalconfidenceandembol dened theirpursui t of operative solutionsfor pi t ui t arytumors. Early equi pment , however,wasexpensive and unwieldy.Al t hough it coul d be used to bolster aclinical diagnosis,it wasnotused for intraoperative guidance. TheBirthOf PituitarySurgery By thetimeof thefirstt ranssphenoi dal operations, api t ui t ary t umor wasknowntocauseacromegaly.Nonetheless, surgical indicationsfor pi t ui t ary t umors were first visual lossandhead- ache.Despiteapubl i cat i oninthesameyear report i ngclinical i mpr ovementinanacromegalic pat i ent after subtotalhypoph-ysect omy,Cushingindicated in hisorat i on that surgery shoul d onl ybeperformedformasseffect(principallyheadacheand visualdisturbance).3s,34Healsoi mpl i edthatpi t ui t arysyn- dromesalsomi ght beduetomerehyper t r ophyorat r ophyof thegland,inwhi chcases surgery woul dnot be indicated. 31 Two conditions,one due to a pathologicalincreasedactivity of the parsant er i or . . , theotherduetoadiminishedact i vi t y. . , seem capableofclinicaldifferentiation.Theformerexpressesitself chiefly asa process of overgrowth. . . . The latter expressesitself- . . . withpersistenceof infantilesexualcharacteristics. . . . Atu- mor of the gland i t sel f . . , is naturally the lesion to which one or the other of these conditions has heretofore been attributed,though it is probablethatover-secretion fromsimplehypertrophy, orunder- secretion from atrophy, willbefoundtooccur irrespectiveof tu- AHISTORY OFPITUITARY SURGERY201 T ABL E 1.S u mma r y of t h e Ear l yTr a ns s phe noi da l Te c hni que sSubmucosalBoneremoval enroute t osphenoid Surgeon(Year) CityIncisionTransseptaldissectionsinus Schloffer(1907)17s InnsbruckLateralrhinotomyYesNoSeptum, superior andmi ddl e turbinates, Leftmedial orbital wall,maxillary and YonEiselsbergand vonFrankI-Hochwart (1907)19e Vienna Kocher (1909) 1 ~ Berne Hirsch(1909)82,8s Vienna Halstead (1910)71' 72Chicago Hirsch(1911)82.85 Vienna Cushing(1914)36Baltimore Lateralrhinotomy withmidline extension onto forehead Midline rhinotomy ? Sublabial Endonasal,hemitransfixion Sublabial ethmoi d sinuses YesNoSeptum,all turbinates, frontaland ethmoi d sinuses YesYesSeptum, vetoer NoNoLeftmi ddl e turbinate,left ethmoi d sinus YesNoSeptum,inferior turbinates YesYesSeptum YesYesSeptum mourgrowth whenexaminationof thepituitary body becomesa routinemeasureinthe postmortem examination of allcases . . . .When due to tumour, surgery is the treatment that these conditions demand. . , butcliniciansandsurgeonsmustclearlydistinguish betweenthelocalmanifestationsof theneoplasm duetoinvolve- ment of structures in its neighborhood other than the hypophysis, andthoseof a generalcharacter from disturbancesof metabolism due to alterationsof the hypophysisitself. The goals of surgery wereto decompress thetumor;gross total resectionwasassociatedwi t hahighrateof morbidity, arate thatremai nedhighunt i l theearly1950swhenhydrocort i sone andantibioticsbecameavailable. 9,2r,4a,46,6s,62 Forthisreason, most early report sdiscussthesurgeryasasubtotalorpartial hypophysectomy.3~,34.36,90,175 The FirstTranscranialSurgeries In1893 F. T. Paul of Liverpool, along wi t h Caton, publ i shed the firstreport ofasurgicali nt ervent i onforapi t ui t aryt umor.21 Al t houghhehadpl annedtoreachthet umor viaat emporalcrani ot omy inthisacromegalic patient,hesimply per f or med a t emporaldecompressi on anddid notattackthet umor. In Lon- donSir VictorHorsl ey appearstobethefirst surgeontoreach thepi t ui t ary successfully.In1906he report edhisresultsfrom 10suchoperations, thefirstofwhich, report edl y, wasper- formed in1889. 90 Severaltranscranialapproachesweredescribed.Initially Horsleyapproachedthepi t ui t arytransfrontally,but heulti- matelychangedtothesubt emporal route.9~ Ot hersurgeons,however, champi onedthesubfrontalapproach. In1912 McArt hurdescribedthefronto-orbital crani ot omy wi t hanex- traduralapproachforexposureof thepituitary. 133 Frazierde- scribedbot hani nt radural andext radural subfrontalapproach reachi ngthepituitaryt hr oughatrajectorythatbisectedthe midlineandsphenoi dwing.55, 56Thept eri onal approachwas devel oped by Heuer andreport ed by Dandy in1918. 40 Cushi ng preferred themi dl i nesubfront al route. (Cushi ng1932). EarlyTranssphenoidalSurgery AlmosttwodecadespassedafterHorsley' sfirsttranscranial operat i on before thefirst t ranssphenoi dal approacheswerede- scribed. Wi t hi n a few years of the first report ed transsphenoidal by Schloffer in1907,tr5 a flurry of technical variations emerged. Theseapproachesarediscussedfromtheperspectiveofcon- t emporaryendonasalandsublabialsubmucosal transseptal t ranssphenoi dal procedures(Table1). Transnasal Approaches.Al t houghtransitingthenose,the firstt ranssphenoi dal operation, whi chwasperformed by Her- manSchlofferofAustriain1907,wasquiteunl i kethoseof today, t75 The reci pi entof the i naugural t ranssphenoi dal proce- durewasamanwi t hheadaches, visualloss,hypopi t ui t ari sm,andanenlargedsellaturcicaonplainradiographs.Toaccess thesphenoi dsinus,Schlofferperformedalateralr hi not omy andreflected the nose laterally before proceedi ng to exent erat e most of theremai ni ngendonasalbonyst ruct uresandtoopen themaxillary andet hmoi dsinuses.Althoughsympt omat i cal l y i mprovedfromtheheadaches, thepatient' svisiondidnot im- prove.Despite what wasinitially t hought to have been amaj or debulking, thepat i ent diedwi t hi nseveralmont hsof surgery fromobstructivehydrocephal usrelatedtounrecogni zedand massivei nt ravent ri cul arext ensi onof thetumor.Inthesameyear,vonEiselsbergandvonFrankl -Hochwartalsoperformedasimilartransnasalt ranssphenoi dal operat i on for a pat i entwi t h hypopi t ui t ari sm and visual loss. 196 The lateral r hi not omy wasext endedont othemi dt i neforehead.Al t hough the medial orbital wall and maxillary sinuses were notresected, vonEiselsbergdidremovethefrontalandet hmoi dsinuses. Ultimately,von Eiselsberg modified thisapproachanddiscon- t i nued openi ngthe frontal sinus. 195 Over the next5 years ot her surgeons,i ncl udi ngGods, Proust, andHochenegg, adapt ed thisapproachforpi t ui t aryprocedures.6~Infact, Hochenegg wasthe first surgeon to not e sympt omat i c i mprove- ment inanacromegalic pat i ent after transsphenoidalsurgery. In1909Kocher initiatedthenext major advancet owardthe operationsoftoday.Hewasthefirstsurgeontoper f or ma transsphenoidalsurgeryviaatransseptalsubmucosal open- ing. l~Like ot her surgeons, Kocher chose hisfirst operat i onto beperformedonanacromegalicpatient.Al t houghtransseptal and submucosal, the operat i on was still unlike those per f or med today.Thesept umwasapproachedandr emovedt hroughan external midline incision on the bridge of the nose. The frontal, ethmoidal,and maxillary sinuses,however,were not traversed. Endonasalsubmucosaltransseptal.In1910Hi rschper- formedthefirstcompl et el y endonasal t ranssphenoi dal proce- dure. s2 Inseparateproceduresher emoved theleft mi ddl etur- binateandopenedtheleftet hmoi dal sinusesbeforeent eri ng thesphenoid. Al t houghhis initialdescri pt i on wasnei t her sub- mucosal nor transseptal,Hirschultimatelyperformedthe t ranssphenoi dal approach in a single pr ocedur e using a submu- cosaldissection, s3,s5Thismet hodwasnot rei nt roducedand popul ari zedby othersunt i l t helate1980s. 65 Sublabial submucosal transseptal.InChicagoin1910,Hal- stead report ed thefirst sublabialapproachtothe sphenoid,rt,r2 Inamultistageoperation, Halsteadr emovedbot hthebony sept um and inferior turbinates.This pr ocedur e did noti ncl ude asubmucosal dissection.Halstead,however, di dpreservethe cartilaginoussept um, ret ract i ng itsuperiorly.2 0 2 JANEETAL TABLE2.SummaryofPituitaryHormoneDiscoveries Year humanami noacid HormoneYeari sol at edYear r adi oi mmunoassaysavai l abl esequenced Lut ei ni zi nghor mone1940Liet al. 1181966Mi dgl ey 139 1966Odel l etal. 1481973Shome&Par l owJ 18 Cl osse et al . 23 1974Shome&Parl ow m3 1977Shome&Par l ow ~84 1975Sai ram&Li 17~ Fol l i cl est i mul at i nghor mone Prol act i n TSHThyr oi d- st i mul at i ng hor mone Adr enocor t i cot r opi c hor mone Gr owt hhor mone 1949Lietal. 119 1933Ri ddl eet al. 162 1937Lambi e 1943Lietal. 117 1945Lietal. 113,116 1967Mi dgl ey 138 1971Hwanget al. 96 1972Hall r~ Odel l 1967147 1965Imura 971968Ber sonand Yal l ow,~5 Auber t &Fel ber, 6 Gr eenwood 64 1963Gl i cketal. 59 1972Ri ni keret al. le3 1969Lietal 1~5 Al t houghnot hisfirst reportof at ranssphenoi dal procedure,Cushingreport ed hisfirst sublabialtransseptalapproach usi ng a submucosal dissection in1914. 36 This wastheapproach used by Dot tand ultimately taught to Gui otand Hardy,the approach used whenthe t ranssphenoi dal approach had its renaissance in thelatterhalf of the20t hcentury.46,67,75 Paranasal Approaches.Various paranasal approaches to t he sellawerealsodescribed.Thesphenoi dwasalsoapproached t hr oughthepalate, 153,1s9 t hr oughtheet hmoi dal sinusesvia medialt arsorrhaphyincisions, 22,t~176andviathemaxillarysi- nuses.43,111 Reports of these approacheswere scattered intothe late1960s,but t hey didnot gain wideacceptance. 73,98,t4