Analysis of 18 F-fluorodeoxyglucose positron emission tomography findings in patients with pituitary lesions

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1 ORIGINAL ARTICLE Koren J Intern Med 2013;28: Anlysis of F-fluorodeoxyglucose positron emission tomogrphy findings in ptients with pituitry lesions Hnnh Seok 1, Eun Young Lee 1, Eun Yeong Choe 1, Woo In Yng 1, Joo Young Kim 2, Dong Yeob Shin 1, Ho Jin Cho 3, Te Sung Kim 3, Mi Jin Yun 3, Jong Doo Lee 3, Eun Jig Lee 1,4, Sung-Kil Lim 1,4, nd Yumie Rhee 1,4 1 Deprtment of Internl Medicine, Yonsei University College of Medicine, Seoul; 2 Division of Endocrinology, Deprtment of Internl Medicine, Dongsuwon Generl Hospitl, Suwon; 3 Division of Nucler Medicine, Deprtment of Dignostic Rdiology, 4 Endocrine Reserch Institute, Yonsei University College of Medicine, Seoul, Kore Received: October 20, 2011 Revised : December 30, 2011 Accepted: Mrch 6, 2012 Correspondence to Yumie Rhee, M.D. Deprtment of Internl Medicine, Yonsei University College of Medicine, 50 Yonsei-ro, Seodemun-gu, Seoul , Kore Tel: Fx: E-mil: yumie@yuhs.c Bckground/Aims: Although mgnetic resonnce imging (MRI) is good visul modlity for the evlution of pituitry lesions, it hs limited vlue in the dignosis of mixed nodules nd some cystic lesions. We evluted the usefulness of F- fluorodeoxyglucose positron emission tomogrphy (FDG PET) for ptients with pituitry lesions. Methods: F-FDG PET nd MRI were performed simultneously in 32 consecutive ptients with pituitry lesions. The reltionships between FDG uptke ptterns in PET nd MRI findings were nlyzed. Results: Of 24 ptients with piuitry denoms, 19 (79.2%) showed incresed uptke of F-FDG in the pituitry glnd on PET scns. All ptients with pituitry mcrodenoms showed incresed F-FDG uptke on PET scns. Menwhile, only five (50%) of the 10 ptients with pituitry microdenoms showed positive PET scns. Interestingly, of two ptients with no bnorml MRI findings, one showed incresed F-FDG uptke on PET. For positive F-FDG uptke, mximum stndrdized uptke vlues (SUV mx ) > 2.4 hd 94.7% sensitivity nd 100% specificity. In ddition, SUV mx incresed in proportion to the size of pituitry denoms. Most cystic lesions did not show F-FDG uptke on PET scns. Consclusions: About 80% of pituitry denoms showed positivity on PET scns, nd SUV mx ws relted to the size of the denoms. PET my be used s n ncillry tool for detection nd differentition of pituitry lesions. Keywords: Pituitry; Positron-emission tomogrphy; Mgnetic resonnce imging INTRODUCTION In 99, X-ry provided the first visul documenttion of n enlrged sell turcic in ptient with cromegly [1]. In the 1970s nd 1980s, computed tomogrphy (CT) nd mgnetic resonnce imging (MRI) were introduced into clinicl prctice. These imging technologies revolutionized the dignosis nd mngement of ptients with pituitry diseses [1]. MRI, with improved resolution, hs since the 1990s been the first choice for dignosing pituitry lesions [2]. MRI cn disply surrounding structures s well s pituitry lesions [3]. Nevertheless, differentiting some cystic lesions from mss-relted chnges, such s cystic Copyright 2013 The Koren Assocition of Internl Medicine This is n Open Access rticle distributed under the terms of the Cretive Commons Attribution Non-Commercil License ( by-nc/3.0/) which permits unrestricted noncommercil use, distribution, nd reproduction in ny medium, provided the originl work is properly cited. pissn eissn

2 The Koren Journl of Internl Medicine Vol. 28, No. 1, Jnury 2013 chnges or hemorrhge, by MRI is sometimes problemtic [4]. Positron emission tomogrphy (PET) with F- fluorodeoxyglucose ( F-FDG) is vluble method for the dignosis nd stging of mlignncies s well s monitoring their therpeutic effectiveness. PET is lso helpful for some dignoses tht re difficult to obtin with MRI. However, PET hs not been frequently used for the dignosis of pituitry tumors. There re limited dt on the dignostic vlue of PET for pituitry tumors. In this regrd, we experienced one interesting cse involving Rthke s cleft cysts (RCC) (cse 27). A 59-yerold womn ws referred to the hospitl due to symptoms of pnhypopituitrism nd visul disturbnces. Becuse brin MRI reveled focl enhnced mss extending over the pituitry glnd, optic chism, nd bilterl optic trcts (Fig. 1A), she ws first dignosed with optic gliom. Her symptoms spontneously improved, nd she ws observed for 3 months. A subsequent MRI showed improvement in the lesions surrounding the optic trct, wheres cystic lesion in the pituitry foss hd expnded. A PET scn ws performed, nd it showed no uptke of F-FDG in the pituitry foss (Fig. 1B). This suggested tht it ws more likely to be cystic lesion such s RCC. She underwent trns-sphenoidl surgery for confirmtion nd ws finlly dignosed with RCC. Thus, we investigted the usefulness of F-FDG PET for the dignosis nd evlution of vrious pituitry lesions. METHODS Ptients From Jnury 2005 to August 2010, we performed PET nd MRI simultneously in 46 consecutive ptients who hd been investigted for pituitry lesions ccording to presenting symptoms, signs, lbortory dt, or other imging studies. We excluded other brin A B Figure 1. Mgnetic resonnce imging (MRI) findings nd F-fluorodeoxyglucose positron emission tomogrphy (FDG PET) imging in 58-yer-old womn with Rthke s cleft cyst (cse 27). (A) T1-weighted MRI with gdolinium contrst. Coronl (upper pnel) nd xil (lower pnel) views demonstrte n enhnced mss (white rrows) covering the pituitry glnd nd optic trcts. (B) Sgittl view of the brin on PET imging showed no bnorml F-FDG uptke in the sell turcic (blck rrow)

3 Seok H, et l. Usefulness of F-FDG PET in pituitry lesions lesions, including brin prenchyml tumors other thn pituitry tumors or metsttic brin tumors. A totl of 32 ptients were dignosed with pituitry lesions. We obtined informed consent from ll ptients, nd this study ws conducted with the pprovl of the Ethics Committee t Severnce Hospitl, Yonsei University College of Medicine. PET scnning All ptients fsted for more thn 6 hours prior to the test. Sixty minutes fter intrvenous injection of 7 to 9 mci of F-FDG, imges were obtined using GE ADVANCE PET scnner (GE, Milwukee, WI, USA). Emission scnning continued for 15 minutes (4.25 mm xil sptil resolution, 4.8 mm trnsxil sptil resolution). Trnsmission scns were performed for 8 minutes using triple Ge-68 rod sources to correct for ttenution. Gthered dt were reconstructed in mtrix with pixel size of mm by mens of filtered bck-projection lgorithm employing trnsxil 8.5-mm Hnning filter nd 8.5- mm xil rmp filter. Two experienced nucler medicine doctors evluted the F-FDG PET imges on high-resolution computer screen. The stndrdized uptke vlue (SUV) ws clculted s the concentrtion of F-FDG uptke divided by injected dose/body weight. To void prtil volume effect, the mximum SUV (SUV mx ) ws mesured within the region of interest. MRI MRI ws performed t 1.5 T (Inter Achiev, Philips Medicl Systems, Best, Netherlnds). T1- nd T2- weighted spin-echo imges were obtined in the coronl nd sgittl plnes t 3 mm sections. T1-weighted imges were then obtined fter intrvenous dministrtion of 0.1 mmol/kg of gdolinium gdolinium diethylenetrimine pentcetic cid. Sttistics All dt re shown s mens ± stndrd devitions. Fisher s exct test nd the Mnn-Whitney test were pplied for comprisons of pituitry lesion chrcteristics. The Kruskl-Wllis test ws used to compre the differences in SUV mx of pituitry cysts, microdenoms, nd mcrodenoms. The sttistics progrm used for the nlysis ws the SPSS pckge for Windows version 15.0 (SPSS Inc., Chicgo, IL, USA). RESULTS In this study, totl of 32 ptients who showed pituitry lesions were included. Femles (n = 22) comprised lrger proportion thn mles (n = 10), nd the men ge of the ptients ws 51.6 yers (rnge, 17 to 80). Twenty-four ptients hd pituitry denoms, nd eight hd cystic lesions. Of the 24 pituitry denoms, 10 were clssified s functioning tumors nd 14 s nonfunctioning tumors. There were five ptients with growth hormone-secreting denoms, two with prolctinoms, two with Cushing s disese, nd one with thyroid-stimulting-hormone-secreting denom. Among the eight ptients with cystic lesions, seven hd RCCs, nd one hd n rchnoid cyst (Tble 1). As shown in Tble 2, of the 24 ptients with pituitry denoms, 19 (79.2%) showed incresed uptke of F- FDG on PET scns with hypermetbolic focus in the pituitry glnd. On the other hnd, uptke of F- FDG on PET ws not observed in most cses of cysts (n = 8). One exceptionl cse of cystic lesions showed suspicious F-FDG uptke in the pituitry glnd on PET, but the uptke ws very low. The totl number of pituitry mcrodenoms (men size,.6 ± 7.0 mm) ws 14, nd ll (100%) showed positive F-FDG uptke on PET scns (Tble 2, Fig. 2). The totl number of pituitry microdenoms ws 10, of which five (50.0%) showed positive F-FDG uptke on PET scns. Positive uptke of F-FDG ws shown in eight of 10 (80.0%) functioning denoms nd 11 of 14 (78.6%) nonfunctioning denoms (Tble 2). The SUV mx of F-FDG on PET scns rnged from 1.9 to The men SUV mx of mcrodenoms ws significntly higher thn tht of microdenoms or cystic lesions (6.6 ± 5.1, 2.6 ± 0.5, nd 2.3 ± 0.4; p < 0.05, respectively) (Fig. 3). There ws correltion between the size nd SUV mx of tumors (r = 0.559, p < 0.01). A > 8.5-mm-mximl dimeter of pituitry lesions hd 78.9% sensitivity nd 72.7% specificity for positive F- FDG uptke on PET scns. A SUV mx of > 2.4 hd 94.7% sensitivity nd 100% specificity for positive F-FDG uptke. Although it ws not significnt, the men SU- V mx of nonfunctioning pituitry denoms tended to

4 The Koren Journl of Internl Medicine Vol. 28, No. 1, Jnury 2013 Tble 1. Chrcteristics of ptients with pituitry lesions Cse Sex Age, yr Dignosis Size of pituitry lesion, mm F-FDG uptke 1 F 35 GH-secreting pituitry denom 29 Positive 5.56 SUV mx 2 F 57 GH-secreting pituitry denom 17 Positive M 37 GH-secreting pituitry denom 7 Negtive F 59 GH-secreting pituitry denom 10 Positive F 64 GH-secreting pituitry denom 7 Positive F 23 Prolctinom 13 Positive F 50 Prolctinom 7 Positive M 58 Cushing s disese 15 Positive F 17 Cushing s disese NA Negtive F 80 TSH-secreting pituitry denom 27 Positive F 38 Nonfunctioning pituitry denom 17 Positive F 80 Nonfunctioning pituitry denom 13 Positive F 49 Nonfunctioning pituitry denom 5 Positive F 66 Nonfunctioning pituitry denom 9 Positive 3 15 F 23 Nonfunctioning pituitry denom 10 Positive M 31 Nonfunctioning pituitry denom 6 Negtive M 58 Nonfunctioning pituitry denom 5 Negtive 2.17 M 72 Nonfunctioning pituitry denom 30 Positive M 67 Nonfunctioning pituitry denom 26 Positive F 78 Nonfunctioning pituitry denom 22 Positive F 84 Nonfunctioning pituitry denom 12 Positive F 27 Nonfunctioning pituitry denom 20 Positive M 39 Nonfunctioning pituitry denom 5 Negtive F 68 Nonfunctioning pituitry denom NA Positive F 32 Rthke s cleft cyst 8 Negtive F 31 Rthke s cleft cyst 6 Positive F 58 Rthke s cleft cyst 19 Negtive F 58 Rthke s cleft cyst 5 Negtive F 24 Rthke s cleft cyst 7 Negtive M 67 Rthke s cleft cyst 5 Negtive M 57 Rthke s cleft cyst 12 Negtive M 66 Archnoid cyst 22 Negtive 1.95 FDG, fluorodeoxyglucose; SUV mx, mximum stndrd uptke vlues; NA, not vilble. Dignosis confirmed by surgicl pthology

5 Seok H, et l. Usefulness of F-FDG PET in pituitry lesions Tble 2. F-FDG uptke positivity on positron emission tomogrphy ccording to the chrcteristics of pituitry lesions Chrcteristics of pituitry lesions Totl no. of cses % of positive F-FDG uptke p vlue Component of pituitry lesions Adenom (79.2) Cystic lesion 8 1 (12.5) Size of pituitry denoms Mcrodenom (100) Microdenom 10 5 (50.0) Function of pituitry denoms Functioning denom 10 8 (80.0) Nonfunctioning denom (78.6) FDG, fluorodeoxyglucose; NS, not significnt. Fisher s exct test for positron emission tomogrphy positivity. NS A B Figure 2. Mgnetic resonnce imging findings of nonfunctioning pituitry denom (cse 11). (A) An pproximtely 17-mm pituitry mcrodenom (blck rrow). (B) Round incresed uptke (white rrow) in the pituitry foss (mximum stndrd uptke vlues, 13.1) SUVmx Cyst Microdenom Mcrodenom Figure 3. Distribution of mximum stndrd uptke vlues (SUV mx ) of pituitry lesions (Kruskl-Wllis test). p <

6 The Koren Journl of Internl Medicine Vol. 28, No. 1, Jnury 2013 be higher thn tht of functioning denoms (men SUV mx, 7.1 ± 5.5 vs. 3.8 ± 1.3). Tble 3 shows the PET scn nd MRI findings in 24 ptients with pituitry denoms. Of these, 22 (91.6%) showed positive findings on MRI. Of the two who did not show ny bnorml findings on MRI, one (cse 24) showed positive F-FDG uptke on PET. The remining ptient (cse 9) showed negtive FDG uptke on PET. Although this 17-yer-old femle ptient presented with prominent symptoms of hypercortisolism, neither MRI nor PET showed ny bnorml findings. She ws dignosed with Cushing s disese bsed on inferior petrosl sinus smpling nd underwent trnssphenoidl surgery. DISCUSSION MRI is n importnt method with which to investigte the ntomicl structure of pituitry lesions. Nevertheless, differentil dignosis is occsionlly difficult for cystic lesions such s cystic or hemorrhgic pituitry denoms, primry prsellr lesions with presenttion in the sellr region, nd sometimes RCC [5,6]. Interestingly, in cse 27, MRI did not llow for differentil dignosis between RCC nd optic gliom; in cse 24, n invisible lesion on MRI ws positive on the FDG PET scn. In ddition, MRI generlly provides little informtion bout the biochemicl nd functionl chrcteristics of pituitry tumors. PET emerged s functionl imging modlity in the 1970s for the first time nd hs since become n Tble 3. Comprison of positron emission tomogrphy (PET) scns with mgnetic resonnce imging (MRI) of the pituitry glnd in 24 ptients with pituitry denoms MRI Positive PET Negtive Totl Positive (81.8) 4 (.2) 22 (100) Negtive 1 (50) 1 (50) b 2 (100) Totl 19 (79.2) 5 (20.8) 24 (100) Vlues re presented s number (%). Positive predictive vlue of PET. b Negtive predictive vlue of PET. importnt dignostic technique for mny diseses. PET mesures the locl concentrtion of trcers, obtins biochemicl informtion such s glucose uptke, nd converts them into imges. The molecule most commonly used s rdiotrcer is F-FDG; however, other diverse trcer molecules hve been developed nd used in vrious fields. In tumors or metboliclly ctive cells, glycolysis is enhnced, nd thus the F- FDG uptke rte increses competitively [7,8]. Becuse the size of the norml pituitry glnd is smll nd its metbolic rte is low, it does not show F-FDG uptke on PET scns [9,10]. On the other hnd, pituitry denom nd crniophryngiom, the cells of which re more metboliclly ctive thn norml cells, induce incresed F-FDG uptke on PET scns. The F-FDG uptke rte in pituitry denom is 30% higher thn tht in the whole brin [11]. Recently, severl cses of pituitry denoms were detected incidentlly by F-FDG PET [12], s in our cse 24. One study reported n incidence of pituitry incidentlom by F-FDG PET imging combined with CT (PET-CT) of 0.073% (30 of 40,967 ptients) [13]. This rte is mrkedly lower thn tht of incidentloms by MRI or CT (3.7% to 20%) [14,15]. Severl fctors my contribute to this difference. First, wholebody PET hs lower sptil resolution thn MRI for pituitry lesions. Second, not ll pituitry tumors re FDG-vid. Third, there is still no consensus regrding pituitry uptke. F-FDG PET s modlity for dignosis of pituitry lesions hs been investigted. Most of these studies involved specified groups, such s ptients with Cushing s disese, cromegly, or other functioning nd/or nonfunctioning denoms. In our study, we investigted the usefulness of PET s n initil dignostic imging study in vrious pituitry lesions. Most cystic lesions did not show F-FDG uptke. Only one ptient with RCC (cse 26) showing heterogeneity on MRI hd suspicious uptke of F-FDG with low SUV mx on PET. Erlier studies demonstrted the usefulness of F-FDG in ptients with pituitry denoms. De Souz et l. [9] reported tht five of 12 ptients with positive PET scns showed negtive or questionble lesions on MRI nd tht there were no flse-positive cses mong ll 20 control subjects. In this study, the PET positivity rte in microdenom ws comprble with tht of MRI (60%

7 Seok H, et l. Usefulness of F-FDG PET in pituitry lesions vs. 65%, respectively). PET-CT, rther thn PET lone, is now used frequently. One study investigted the dignostic vlue of fused F-FDG PET-CT in ptients with Cushing s disese [16]. They concluded tht PET- CT my be n importnt dignostic tool for dignosis of Cushing s disese becuse PET-CT might identify some Cushing s-positive ptients tht hd negtive MRI [16]. In our study, the overll denom positivity on PET ws 79.2%. All ptients with pituitry mcrodenoms showed positive PET scns (100%), wheres positive PET scns were shown only in 50% of microdenoms. SUV mx my fcilitte more ccurte dignosis, especilly in ptients with pituitry microdenoms. Our dt showed tht SUV mx of > 2.4 hd 94.7% sensitivity nd 100% specificity for positive F- FDG uptke. However, SUV mx my vry depending on mny fctors, such s the size of the mss, stndrdized mesurement times, plsm glucose levels, recovery coefficients, nd prtil volume effects. Thus, further studies of dignosis using SUV mx with greter numbers of subjects should be conducted. Men SUV mx vlues were higher in mcrodenoms thn in microdenoms or cystic lesions (Fig. 3). They lso tended to be higher in nonfunctioning denoms thn in functioning denoms, lthough there ws no difference in the sizes of these denom types (13.8 ± 8.4 mm vs ± 8.3 mm, respectively). Similrly, in previous studies it ws reported tht the F-FDG uptke levels of nonfunctionl pituitry denoms were higher thn those of functionl pituitry denoms [11,17]. The cuse of the higher F-FDG uptke by nonfunctionl pituitry denoms hs not been elucidted. A possible explntion is tht in nonfunctionl pituitry denoms, energy metbolism rtes re higher due to incomplete hormone synthesis by the tumor [11]. Second, in nonfunctionl pituitry denoms, inhibition by the finl product is inefficient; thus F-FDG uptke my be retined [11]. Finlly, becuse 50% of nonfunctionl pituitry denoms show oncocytic chnges, higher F-FDG uptke my hve occurred. In oncocytoms, which overexpress mitochondri, overrepresenttion of the hexokinse enzyme leds to incresed F-FDG uptke [17]. F-FDG PET my fcilitte differentition of recurred tumors, residul tumors, inf lmmtory rections fter surgery, nd fibrosis [9,]. After surgery, when the dignosis of residul or recurred cncer with MRI is uncler due to inflmmtion or fibrosis, PET my ssist their differentition [11]. F-FDG PET lso enbles prediction of the tretment response nd growth potentility of pituitry denoms. Bromocriptine decresed the F-FDG uptke rtes of prolctinoms by up to 20%, nd octreotide decresed the F-FDG uptke rtes in thyroid stimulting hormonend growth hormone-producing denoms by up to 53% [11]. Rdition therpy reportedly leds to 20% to 30% decresed F-FDG uptke [11,]. Therefore, the tretment outcome cn be ssessed by compring the PET findings before nd fter tretment. Becuse estimtion of the functionl tretment response, especilly in nonfunctioning pituitry denoms, is problemtic, chnges in F-FDG uptke my in such cses ssist determintion of tretment responses. In conclusion, F-FDG PET my represent n ncillry tool for detection nd differentition of pituitry lesions in certin circumstnces. Further PET studies to determine the pproprite SUV mx threshold, or conjugtion of lterntive trcer molecules, my fcilitte more ccurte dignosis of pituitry lesions. In ddition, studies of the chnge in FDG uptke rtes on PET induced by vrious tretment methods for ech pituitry disese will be informtive. KEY MESSAGE 1. In this study, bout 80% of pituitry denom showed positivity on positron emission tomogrphy (PET) scn nd mxi mum stndrdized uptke vlue (SUV mx ) ws relted to the size of denoms. 2. PET could be useful method for detecting nd differentiting vrious pituitry lesions. 3. Further PET studies determining the right threshold of SUV mx or conjugting vrious trcer molecules will be helpful. Conflict of interest No potentil conflict of interest relevnt to this rticle is reported

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