Surgical Neurology International

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Surgicl Neurology Interntionl OPEN ACCESS For entire Editoril Bord visit : http://www.surgiclneurologyint.com Editor: Jmes I.

1 Surgicl Neurology Interntionl OPEN ACCESS For entire Editoril Bord visit : Editor: Jmes I. Ausmn, MD, PhD University of Cliforni, Los Angeles, CA, USA Cse Report Chnge in the immunophenotype of somtotroph denom resulting in gigntism Jyesh P. Thwni, Roert L. Biley, Crrie M. Burns 1, John Y. K. Lee Deprtment of Neurosurgery, Perelmn School of Medicine t the University of Pennsylvni, 3 Silverstein Building, 3400 Spruce Street, Phildelphi PA 19104, 1 Division of Endocrinology, Deprtment of Medicine, Perelmn School of Medicine t the University of Pennsylvni, 100 Centrex Building, 3400 Spruce Street, Phildelphi PA 19104, USA E mil: *Jyesh P. Thwni jyesh.thwni@uphs.upenn.edu; Roert L. Biley roert.iley@uphs.upenn.edu; Crrie M. Burns crrie.urns@uphs.upenn.edu; John Y.K. Lee john.lee3@uphs.upenn.edu *Corresponding uthor Received: 10 June 14 Accepted: 01 August 14 Pulished: 20 Octoer 14 This rticle my e cited s: Thwni JP, Biley RL, Burns CM, Lee JY. Chnge in the immunophenotype of somtotroph denom resulting in gigntism. Surg Neurol Int 2014;5:149. Aville FREE in open ccess from: Copyright: 2014 Thwni JP. This is n open ccess rticle distriuted under the terms of the Cretive Commons Attriution License, which permits unrestricted use, distriution, nd reproduction in ny medium, provided the originl uthor nd source re credited. Astrct Bckground: Exmining the pthologic progression of pituitry denom from the point of prepuescent child to n dult with gigntism ffords us n opportunity to consider why ptients my develop secretory or functioning tumors nd rises questions out whether therpeutic interventions nd surveillnce strtegies could e mde to void irreversile phenotypic chnges. Cse Description: A ptient underwent sulil trnssphenoidl resection for cliniclly non functioning mcrodenom in He underwent rdition tretment nd ws trnsiently given growth hormone (GH) supplementtion s n dolescent. His growth rpidly trversed severl percentiles nd he ws found to hve elevted GH levels. The ptient ecme symptomtic nd ws tken for second neurosurgicl procedure. Pthology nd immunohistochemicl stining demonstrted significntly higher proportion of somtotroph cells nd dense grnulrity; he ws dignosed with functionl somtotroph denom. Conclusions: While it is likely tht the descried oservtions reflect the mnifesttions of functionl somtotroph denom in development, it is possile tht puertl growth, GH supplementtion, its removl, or rdition therpy contriuted to the descried endocrine nd pthologic chnges. Access this rticle online Wesite: DOI: / Quick Response Code: Key Words: Gigntism, growth hormone, non functionl denom, pituitry denom, somtotroph denom INTRODUCTION Excessive levels of growth hormone (GH) prior to puertl closure of the epiphysel pltes, over time, cn led to errnt somtic growth nd fetures consistent with gigntism. Pituitry tumors, if lrge enough, my produce more immedite symptoms such s hedche or visul chnges from either optic nerve compression or crnil neuropthies. From nturl history dt, we know tht non functionl pituitry denoms cn present with signs of pituitry insufficiency in 44%, visul field deficits in 14%, poplexy in 14%, nd chronic hedche in 7%. [7] Chnges in hormonl secretion y pituitry denoms re recognized ut rre phenomenon. [6,17] Exmining the pthologic progression of pituitry denom from the point of prepuescent child to n dult with gigntism ffords us n opportunity to consider why ptients my develop secretory or functioning tumors nd rises questions

2 out whether dignosis nd therpy cn e mde prior to irreversile clinicl chnges. The following cse report uniquely demonstrtes chnge in corticotroph denom secretory ctivity sed on clinicl/growth curve dt nd histopthologic evidence, in prllel with child s growth. CASE REPORT The ptient presented t the ge of 12 with hedche nd visul chnges. Pre-opertive endocrine l vlues were within norml limits. The ptient hd n insulin like growth fctor 1 (IGF 1) level of 182 nd serum growth hormone (GH) level of 7.2 following stimultion with L 3,4 dihydroxyphenyllnine (L DOPA; upper nd lower limits 5 ng/ml nd 10 ng/ml, respectively. [14] ) Imging reveled lrge sellr enhncing lesion with lterl extension [Figure 1]. He underwent sulil trnssphenoidl opertive pproch for iopsy nd resection in 1999 t our peditric institution The Children s Hospitl of Phildelphi. Pthology demonstrted soft vsculr mss with <5% GH rectivity (Western lot nlysis; ThemoFisher Scientific, Wlthm, MA, USA). This non functioning, sprsely grnulted somtotroph denom ws treted with 6 weeks of intensity modulted rdition therpy (IMRT) directed to 3.8 cm remnnt in the left cvernous sinus, 4600 rds, 2 months fter surgery. Endocrine evlution fter tretment ws notle for hypothyroidism nd GH deficiency [Tle 1]. The ptient s tumor demonstrted decrese in size t 6 months nd 1 yer post op. At ge 14, the ptient s tumor remnnt ppered stle on mgnetic resonnce imging (MRI). He ws strted on humn growth hormone (HGH; 0.3 mg/kg/ week) in ddition to thyroid replcement therpy t tht time. Tle 1 depicts the ptient s clinicl course through development. At 16, he hd no sign of xillry or fcil hir. He ws given testosterone injections s tretment for low levels (serum testosterone 50, given 100 mcg IM 4 doses). At ge 17.3, the ptient s IGF 1 level ws 283 ng/ml [norml rnge ng/ml for Tnner V, up to ge 18]. At 17.5, the ptient self discontinued the humn GH supplementtion. His IGF 1 level ws 335 t tht time. At ge 18.5, he strted developing hedches. The IGF 1 level hd incresed to 424. MRI otined t the time showed n increse in size of the sellr mss. By ge 19, he hd full xillry nd fcil hir. His growth trjectory hd jumped severl percentiles in this rnge, oth in height nd weight (Refer to Figure 2). At this point, he remined only on thyroid replcement therpy. At ge 22.5, the ptient egn experiencing hedches nd ssocited visul chnges. Ls otined t the time were notle for n IGF 1 of 835 ng/ml (norml rnge ng/ml). He presented to Pennsylvni Hospitl with this history nd ws tken to the operting room for n endoscopic trnssphenoidl resection (2009). Figure 3 demonstrtes the ptient s pthologicl specimen. At this time, pthology nd immunohistochemicl stining demonstrted much higher proportion (70-80% sed on immunorectivity nlysis) of somtotroph cells nd wht ws deemed cliniclly functioning, densely grnulted somtotroph denom (Western lot nlysis; ThemoFisher Scientific). Microscopic nlysis demonstrted frgments of homogenous cells with uniform round to ovl nuclei nd finely stippled chromtin. Mitotic ctivity ws sprse nd necrosis ws not seen. There were no djcent frgments of norml glnd or tissue demonstrting hyperplsi. Immunohistochemicl stins to thyroid stimulting hormone (TSH), luteinizing hormone (LH), follicle stimulting hormone (FSH), prolctin, GH, nd drenocorticotropic hormone (ACTH) Tle 1: Clinicl nd developmentl chrcteristics of ptient Dte Age (yers) Age (months) Clinicl/development Endocrine Mediction 3/ IGF 1 182; GH 7.2 4/ / l DOPA stim >GH 2.9 4/ Tnner II puic; Tnner II/III genitl HGH 7/ Tnner III puic; Tnner V genitl HGH 8/ No growth of fcil/xillry hir HGH, testosterone 9/ IGF HGH (dose decresed y hlf), testosterone 3/ IGF HGH STOPPED, testosterone 11/ IGF Testosterone STOPPED 4/ Fcil/xillry hir; norml sexul function 12/ IGF / / IGF Somtosttin 10/ IGF Somtosttin 8/ IGF Somtosttin The gry cells indicte the point t which the ptient underwent trnssphenoidl surgery. Humn growth hormone (HGH) supplementtion ws initited t ge Dosing of HGH ws coincident with testosterone supplementtion. The ptient stopped tking HGH t ge IGF-1 level ws elevted leding up to the second opertion, ut ws controlled fterwrd. Note the dministrtion of somtosttin post-op

c Figure 1: MR imging. () Pre-opertive from 5/1999. () Recurrent denom, 2008. (c) MRI s/p endoscopic endonsl pproch (2nd opertion), 2009. (d) Recent MRI, 12/2012 d Figure 2: Growth chrt.

3 c Figure 1: MR imging. () Pre-opertive from 5/1999. () Recurrent denom, (c) MRI s/p endoscopic endonsl pproch (2nd opertion), (d) Recent MRI, 12/2012 d Figure 2: Growth chrt. () Stture with ge. () Weight with ge. The CDC growth chrt for mles (ge 2-20) is indicted y percentile. Percentiles re indicted s P where P3 represents the third percentile nd so forth were performed with dequte controls. The cells showed strong positive stining for GH immunostin only. At this point, the ptient hd known residul tumor in the left cvernous sinus tht ws deemed inoperle. He

4 c Figure 3: Non-functioning denom nd recurrent, functioning denom. () Histologicl exmintion from the first resection showed sheets of uniform popultion of neoplstic cells with loss of the norml denohypophysis rchitecture, 200. () Severl cells stined positive for GH immunohistochemistry (sprse grnultion), 200. Second resection fter 9 yers showed similr histologicl fetures HndE, 200 (c) nd more diffuse positivity for GH immunohistochemistry (dense grnultion), 200 (d) ws strted on Octreotide postopertively nd remins on this mediction. His serum IGF 1 levels hve decresed to 309 (norml rnge ng/ml) s of 4/2012. Cliniclly, he hs 6 foot 4 inch stture nd weighs pproximtely 300 ls. DISCUSSION Chnges in pituitry tumor secretory ctivity in recurrent, previously non functionl tumors hve een reported sprsely in the form of rre dult cses. These hve suggested trnsformtion from non functionl to functionl ACTH secreting (corticotroph) tumors. [5,20] One lrge series exmined 65 recurrent pituitry denoms from 1023 ptients undergoing opertions for resection of pituitry tumors. All ptients were identified within 9 yers nd ll except one underwent repet surgery. Five (7.7%) of the recurrent tumors hd different immunophenotypes. Only one of these ptients hd non functionl pituitry denom which recurred in the form of functionl corticotroph tumor. [17] Trnsformtion of enign silent or non functionl somtotroph denom to functionl vrint hs een descried in single dult ptient. The reported 41 yer old ptient ws dignosed incidentlly with sellr mss. Following surgery, he ws found to hve somtotroph denom, non functionl sed on clinicl nd lortory dt. Five yers lter, he presented with cromeglic fetures nd underwent repeted trnssphenoidl surgery. Pthologicl specimens showed strong immunorectivity for GH. However, isolted cells were lso positive for prolctin, TSH, nd α suunit. [6] d Up to one third of somtotroph denoms re considered cliniclly silent or nonfunctionl. [21] Somtotroph denoms cn e clssified into five different groups sed on secretory ctivity ccording to the presence of grnulted cells (either densely or sprsely grnulted sed on the presence of secretory grnules within the cytoplsm of cells) nd immunorectivity to hormones. [18] Although non functioning pituitry denoms hve een shown to e monoclonl in origin nd shre common cellulr linege, [1,13] the pthologicl clssifiction of somtotroph denoms does not clerly define the clinicl ehvior of tumor sutypes. The sprse GH rectivity (less thn 5%) oserved in the non functioning denom y our pthologists following the ptient s first opertion ws consistent with the ptient s lck of endocrinologic symptoms. Immunohistochemistry performed following the ptient s second opertion ws consistent with the clinicl nd lortory findings of excess GH. Incresed immunorectivity for other hormones ws not demonstrted. Although possile, it does not seem likely tht sutotl smpling resonly explins the oserved histopthologic nd clinicl findings. A comintion of epigenetic nd genetic fctors my contriute to tumorigenesis in the pituitry glnd. [12,16] While it is likely tht the descried oservtions reflect the mnifesttions of functionl somtotroph denom in development, exogenous fctors such s GH supplementtion/removl [2,10,11] or postopertive rdition therpy [9,17] my hve led to the development of phenotypic chnges. In report y Dessimoz nd collegues, [8] ptient with known microprolctinom on dopmine gonist therpy developed cromegly nd GH utonomous secretion. In this cse, the ptient developed cromegly severl yers fter eing dignosed with prolctinom y lortory nd rdiologicl dt; the ptient underwent surgery due to n increse in the size of the tumor nd negtive response to somtosttin. Although the report does not demonstrte chnge in pthology nd immunohistochemistry, the ptient s phenotype nd progression of lortory dt suggest tht de differentition nd/or itrogenic suppression of supopultion of cells could hve led to chnge in phenotype. It hs een suggested tht the sme fctors mintining the homeosttic functions served y the hypothlmus pituitry end orgn xis my impct tumorigenesis. [12,19] Exogenous medictions, utocrine, nd/or prcrine effectors could lter intrcellulr signl trnsduction impcting tumor growth nd hormonl expression. [3,4,12,16,19] Dt specificlly demonstrting growth hormone relesing hormone (GHRH) receptor expression/heterogeneity nd llosteric regultion my ccount for trnsformtionl ehviors of nonfunctionl

5 tumors. [15] Puertl secretion of GH my suggest role in trnsformtion from non functionl stte, ut to our knowledge, there re no existing reports tht clerly demonstrte this. Regrdless of the cuse, pre puertl effects of excessive GH relese will result in irreversile phenotypic chnges. The ove cse suggests tht ptients with cliniclly non functioning somtotroph denoms my exist in n symptomtic ut susceptile stte; djuvnt mesures nd oservtionl strtegies should e crefully considered, prticulrly in developing ptient. REFERENCES 1. Alexnder M, Biller BM, Bikkl H, Zervs NT, Arnold A, Klinski A. Cliniclly nonfunctioning pituitry tumors re monoclonl in origin. J Clin Invest 1990;86: Bllrè E, Persni L, Lni AG, Filopnti M, Gimmon E, Corett S, et l. Muttion of somtosttin receptor type 5 in n cromeglic ptient resistnt to somtosttin nlog tretment. J Clin Endocrinol Met 2001;86: Ben Shlomo A, Melmed S. Pituitry hormone receptors nd tumorigenesis. Nt Rev Cncer 2007;7 Aville from: nrc2069 c1. [Lst ccessed on 2014 July 14]. 4. Crey RM, Vrm SK, Drke CR Jr, Thorner MO, Kovcs K, Rivier J, et l. Ectopic secretion of corticotropin relesing fctor s cuse of Cushing s syndrome. A clinicl, morphologic, nd iochemicl study. N Engl J Med 1984;11: Cooper ME, Murry RM, Klnins R, Woodwrd J, Jerums G. The development of Cushing s syndrome from previously silent pituitry tumour. Aust N Z J Med 1987;17: Dems T, Verhelst J, Michotte A, Arms P, De Ridder D, As R. Modifiction of hormonl secretion in cliniclly silent pituitry denoms. Pituitry 2009;12: Dekkers OM, Neelis KJ, de Keizer RJ, Voormolen JH, Pereir AM, Romijn JA. Nonfunctioning pituitry mcrodenoms: Dignosis, tretment nd follow up. Ned Tijdschr Geneeskd 2008;152: Dessimoz C, Broweys P, Meder P, Lhermitte B, Pitteloud N, Momjin S, et l. Trnsformtion of microprolctinom into mixed growth hormone nd prolctin secreting pituitry denom. Front Endocrinol (Lusnne) 2011;2: Felix I, As SL, Kovcs K, Horvth E. Chnges in hormone production of recurrent silent corticotroph denom of the pituitry: A histologic, immunohistochemicl, ultrstructurl, nd tissue culture study. Hum Pthol 1991;22: Greenmn Y, Melmed S. Expression of three somtosttin receptor sutypes in pituitry denoms: Evidence for preferentil SSTR5 expression in the mmmosomtotroph linege. J Clin Endocrinol Met 1994;79: Hshimoto K, Kog M, Motomur T, Ksym S, Kouhr H, Ohnishi T, et l. Identifiction of lterntively spliced messenger rionucleic cid encoding truncted growth hormone relesing hormone receptor in humn pituitry denoms. J Clin Endocrinol Met 1995;80: Heney AP. Pituitry tumour pthogenesis. Br Med Bull 2005;75 76: Holm R. Null cell denoms nd oncocytoms of the pituitry glnd. Pthol Res Prct 1995;191: WHO Clssifiction of Tumors: Pthology nd Genetics: Tumors of Endocrine Orgns. I. Lyon, Frnce: IARC; Lopes MB, Gylinn BD, Thorner MO, Stoler MH. Growth hormone relesing hormone receptor mrna in cromeglic pituitry tumors. Am J Pthol 1997;150: Melmed S. Mechnisms for pituitry tumorigenesis: The plstic pituitry. J Clin Invest 2003;112: Mindermnn T, Kovcs K, Wilson CB. Chnges in the immunophenotype of recurrent pituitry denoms. Neurosurgery 1994;35: Osmur RY, Kjiy H, Tkei M, Egshir N, Toit M, Tkekoshi S, et l. Pthology of the humn pituitry denoms. Histochem Cell Biol 2008;130: Snyder PJ. Gondotroph cell denoms of the pituitry. Endocr Rev 1985;6: Vughn NJ, Lroche CM, Goodmn I, Dvies MJ, Jenkins JS. Pituitry Cushing s disese rising from previously non functionl corticotrophic chromophoe denom. Clin Endocrinol (Oxf) 1985;22: Wde AN, Bccon J, Grdy MS, Judy KD, O Rourke DM, Snyder PJ. Cliniclly silent somtotroph denoms re common. Eur J Endocrinol 2011;165:39 44.

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