Symptomatic Remote Cyst after BCNU Wafer Implantation for Malignant Glioma

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1 Cse Report doi: /nmc.cr Neurol Med Chir (Tokyo) 58, , 2018 Symptomtic Remote Cyst fter BCNU Wfer Implnttion for Mlignnt Gliom Online My 21, 2018 Hideki MATSUMURA, 1 Eiichi ISHIKAWA, 1 Mshide MATSUDA, 1 Noriki SAKAMOTO, 1 Hiroyoshi AKUTSU, 1 Shingo TAKANO, 1 nd Akir MATSUMURA 1 1 Deprtment of Neurosurgery, University of Tsuku, Tsuku, Irki, Jpn Astrct A 43-yer-old mn ws operted on for right frontl oligostrocytom. 14 yers fter the surgery, mgnetic resonnce imging nd positron emission tomogrphy reveled new lesion ner the surgicl cvity. He underwent gross totl resection of the lesion nd implnttion of is-chloroethylnitrosoure (BCNU) wfers fter intropertive pthologicl dignosis of recurrent high-grde gliom. A few dys fter the opertion, the level of consciousness grdully worsened nd left hemipresis developed. A computed tomogrphy scn reveled cyst remote to the surgicl cvity which did not exist 3 dys prior. We performed nterior cyst wll fenestrtion nd removed ll wfers. The chrcteristic pthologicl finding t the wfer implnttion site ws severe inflmmtion within nd round smll vessels. This inflmmtory rection ws not seen on the surfce of the rin prenchym. After surgery nd rehilittion, the ptient s Krnofsky Performnce Sttus stilized to pre-incident score of 90 nd he returned to work. The exct pthophysiologicl mechnism of the cyst ws not cler, ut check-vlve nd/or osmotic grdient mechnisms relted to BCNU wfer implnttion could hve contriuted to this phenomenon. As remote cyst development hppened week fter surgery, surgeons should e wre of such rre condition when implnting wfers s consciousness impirment nd hemipresis my occur. Close rdiologicl follow-up is therefore necessry. Key words: BCNU wfers, crmustine wfers, cyst formtion, symptomtic remote cyst, mlignnt gliom Introduction is-chloroethylnitrosoure (BCNU, crmustine) wfer implnttion is common djuvnt therpy for mlignnt gliom. 1,2) After tumor removl, the wfers re plced on the wlls of the resection cvity nd BCNU is slowly relesed over period of 2 weeks. A phse III, rndomized, controlled tril demonstrted significnt improvement in the medin overll survivl time of 120 ptients y months. 1) Some complictions of BCNU wfer implnttion, such s edem formtion, hydrocephlus, nd wound site complictions, re known nd the formtion of tumor ed cysts is lso considered s compliction. 3) This is ecuse BCNU wfers sometimes form spce-occupying cyst in nd/or round the resection cvity which forms so-clled tumor ed cyst nd severl previous reports descrie this phenomenon. 4,5) However, remote cyst formtion Received Novemer 12, 2017; Accepted April 5, 2018 Copyright 2018 y The Jpn Neurosurgicl Society This work is licensed under Cretive Commons Attriution- NonCommercil-NoDerivtives Interntionl License. fter BCNU implnttion on the cvity wlls hs not een descried previously. Herein, we report first cse of remote cyst formtion cusing hemipresis nd consciousness impirment fter BCNU wfer implnttion. We lso discuss pthologicl findings of the rin prenchym round wfers nd the cyst wll. Cse Report A 43-yer-old Jpnese mn ws dignosed with right frontl rin tumor nd underwent gross totl resection. After pthologicl dignosis of oligostrocytom y the 2007 World Helth Orgniztion (WHO) Clssifiction of Tumors of the Centrl Nervous System (CNS) criteri, he susequently underwent rdition therpy (60.4 Gy) with two rounds of vincristine (2 mg) nd nimustine (140 mg). After completing the chemordiotherpy, the ptient ws dischrged nd visited regionl hospitl regulrly for follow-ups. He did not develop ny neurologicl sequele other thn occsionl episodes of epilepsy [Krnofsky Performnce Sttus (KPS) ws 90]. 270

2 Symptomtic Remote Cyst fter BCNU Wfer Implnttion yers fter the first opertion, in spite of eing symptomtic, T 2 -weighted mgnetic resonnce imging (MRI) reveled new high-intensity re round the surgicl cvity (Fig. 1) nd positron emission tomogrphy using 11 C-methionine showed high integrtion degree in tht re (Fig. 1). The lesion ws dignosed s tumor recurrence nd tumorectomy/bncu wfer implnttion on the surgicl cvity wll fter intropertive pthologicl dignosis of recurrent high-grde gliom (HGG) ws performed uneventfully s follows: The previous opertion (14 yers prior) hd fused the dur mter to the cererl surfce nd shrp dissection ws needed to detch it. The lterl ventricle ws opened during tumor resection nd we reconstructed the ventricle wll with hemosttic geltin sponge nd firin glue efore implnting 6 wfers on the resected cvity (Figs. 2 nd 2). MRI reveled no residul tumor nd no dverse events, except for smll cererl infrction (Fig. 1f, white rrow), occurred the dy fter surgery (Figs. 1c 1f). There were no new neurologicl symptoms soon fter surgery, however, the level of consciousness grdully worsened nd left hemipresis developed grdully over 4 dys fter surgery. Although no new lesions ppered on computed tomogrphy (CT) scns 4 dys post-surgery (Fig. 3), on the 7th post-surgicl dy CT scns reveled cyst with mximl dimeter of 37 mm, locted wy from the surgicl cvity, nd compressing the right primry motor re (Fig. 3). The intensity of the fluid in the cyst ws lmost the sme s the cererospinl fluid (CSF) (Figs. 3c 3f), however, fluid-ttenuted inversion recovery (FLAIR) imges showed the different intensities etween surgicl cvity nd the cyst. Though the signl intensity ws reltive vlue, the men of tumor resected cvity, contrlterl lterl ventricle, nd cyst were 194, 153, nd 497 respectively under the sme imging prmeters (Figs. 4 4c). The surgicl removl of the wfers nd fenestrtion of the nterior wll of the cyst ws then performed s follows: The exposed cyst Fig. 1 Periopertive neuroimging. A T 2 -weighted mgnetic resonnce imging (MRI) () nd 11 C-methionine positron emission tomogrphy () indicting the recurrence of the tumor next to the previous surgicl cvity in the right frontl loe. T 2 -weighted MRI on the dy fter surgery showing the postopertive cvity fter recurrent tumor resection with open nterior horn of the right lterl ventricle (c). BCNU wfers plced on the surfce of the cvity fter closing the lterl ventricle with n sorle compressed geltin sponge (d nd e). The diffusion-weighted MRI shows smll high intensity spot-like re in the right frontl loe (f, white rrow hed), the smll cererl ischemi re locted prt from the surgicl cvity.

3 272 H. Mtsumur et l. Fig. 2 Opertive findings of the tumor resection. Opertive findings showing the tumor resected cvity efore () nd fter () occlusion of the ventricle nd implnttion of 6 wfers. The upper right side indictes the frontl crnil se nd the upper left indictes the medil side. The sterisk showing the lterl ventricle reconstructed y the geltin sponge. c d e f Fig. 3 Consecutive postopertive neuroimging. Computed tomogrphy (CT) scn on 4 th dy fter the surgery shows no cyst formtion (). CT nd MRI on the 7th dy fter the surgery revels remote cyst formtion ( f). The cyst is prt from the resection cvity on sgittl T 2 -weighted MRI (d). No scess evidence on diffusionweighted imges (e). Signl intensity of liquid content of the cyst is lmost the sme s the cererospinl fluid (CSF) on T 2 -weighted MRI (f). ws visile on the rin surfce immeditely fter reopening the sutured dur mter (Figs. 5 nd 5) nd ws locted wy from the initil surgicl cvity with distnce of one to two gyri etween them. We punctured the cvity with the dissector nd trnsprent fluid resemling CSF effused with moderte pressure (Figs. 5 nd 5d). We removed the nterior wll of the cyst nd connected the cyst directly to the tumor-resected cvity. We lso removed the BCNU wfers nd opened the lterl ventricle previously occluded y the hemosttic geltin sponge (Fig. 5e). After fenestrtion, consciousness level nd left hemipresis grdully improved while susequent CT reveled decrese in cystic portion (Figs. 5c nd 5f). Pthologicl nlysis of the cyst wll reveled no inflmmtory or tumor cells (Figs. 6 nd 6) ut there ws n inflmmtory rection t the ttchment site of the BCNU wfers (Fig. 7). These inflmmtory cell infiltrtions were predominnt within nd round smll vessels which were short distnce from the BCNU wfers (Figs. 7 nd 7). After 3 months of rehilittion, the ptient returned to work with KPS of 90 s efore the opertion. The finl pthologicl dignosis ws recurrent HGG comptile with nplstic oligodendrogliom (NOS in the 2016 WHO clssifiction of CNS tumors)

4 Symptomtic Remote Cyst fter BCNU Wfer Implnttion c d e f 273 Fig. 4 Intensity difference of tumor resected cvity, lterl ventricle, nd cyst on fluid-ttenuted inversion recovery (FLAIR) imges. FLAIR imges tken under the sme imging prmeters show the different intensities in the tumor resected cvity (), contrlterl lterl ventricle s control vlue of CSF (), nd the cyst (c). Ech column ( c) shows sme coronl FLAIR imge (upper, originl imges; lower, mgnified imges with intensity vlues of rndomly selected three points). c d e f Fig. 5 Opertive findings of the cyst fenestrtion. Opertive findings showing the cyst efore opening ( nd ) nd fter opening (d). The cyst ws esily punctured ( nd d). The posterior wll of the tumor resected cvity nd the nterior wll of the cyst re prtilly removed, nd the cyst nd the tumor resected cvity re connected to ech other (e). The left side of the imges corresponds to the frontl crnil se, nd the lower side of the imges corresponds to the medil side of the hed. CT scns the dy fter cyst fenestrtion show the disppernce of the cyst (c nd f).

5 274 H. Mtsumur et l. Fig. 6 Pthologicl exmintion of the cyst wll. No inflmmtory cell infiltrtion or tumor cells on the nterior wll of the cyst ( nd ). nd the ptient received djuvnt temozolomide. There is no evidence of recurrence t over 26 months fter the first opertion for recurrent HGG. Discussion In the present cse, the symptomtic remote cyst formtion occurred fter BCNU wfer implnttion. BCNU wfers hve een widely used for gliom djuvnt therpy fter eing pproved y the United Sttes Food nd Drug Administrtion in ) Although considered efficcious s n ntineoplstic, BCNU dverse events such s wound complictions, CSF lekge, locl edem, seizures, nd hydrocephlus hve een reported.3,7 9) Tumor ed cysts hve lso een reported previously s spce-occupying cyst in the resection cvity.4,5,10) However, to the est of our knowledge, this is the first cse of symptomtic remote cyst ssocited with BCNU wfers. Fig. 7 Pthologicl exmintion of the resected cvity wll ttched to BCNU wfers. Inflmmtory cell infiltrtion in smll vessels prt from the ttchment surfce. The inflmmtory rection is weker on the surfce thn in the distnt vessels (). Enlrged imge shows inflmmtory cells in smll vessel (). Although it ws not ovious on CT scns up to 4 dys post-surgery, we eventully detected the remote cyst on the 7th dy. Judging from such rdiologicl findings, the formtion of the cyst seems to hve occurred fter the 4th dy. Bsed on the cystic fluid exmintion nd pthologicl findings of the cyst wll, scess or hemorrhge were not oserved nd could not e relted to or cuse cyst formtion. Similrly, the tumor recurrence could not e directly relted to cyst formtion s the cyst ws chrcterized y cute formtion nd no tumor cells in the cyst wll. Therefore, the detiled pthophysiology of this remote cystic formtion remins oscure. In our cse, the lterl ventricle ws opened nd reconstructed with hemosttic geltin sponge. A previous report out tumor ed cyst identified sttisticlly negtive correltion etween tumor ed cyst enlrgement nd ventriculr opening, since the rective fluid drining into the CSF limits the enlrgement of the tumor ed cyst in cse of

6 Symptomtic Remote Cyst fter BCNU Wfer Implnttion 275 ventriculr opening. 4) This ide ws reinforced y nother report where fluid concentrtions were clculted from the Ommy reservoir inserted into the resected tumor cvity. The verge drug concentrtion in ventriculr opening cses ws 2.05 μmol/l versus 4.49 μmol/l in non-opened cses. 11) From this previous dt, we speculte tht the check-vlve phenomenon nd/or osmotic grdient effect could e the pthophysiologicl mechnism leding to cyst formtion. Retrospective nlysis of MRI on the 1st dy fter surgery reveled smll cererl ischemic re ner the resected cvity (Fig. 1f, white rrow). As the remote cyst ws formed t the sme loction (the ischemic re), we cn hypothesize tht the smll ischemic lesion ws lso ssocited with the lrge remote cyst. As BCNU wfers cuse some inflmmtory chnge in ttched tissues nd the rchnoid memrne dmge occurred during opening the dherent dur mtter, there ws possiility of generting check-vlve mechnism through the heling process within few dys fter surgery. The ischemic, necrotic lesion could then ecome semi-isolted re due to the check-vlve mechnism of the dmged rchnoid cyst. The BCNU concentrtion oth in the resected cvity nd lesion ws elevted just fter the surgery. As the resected cvity hd connection with the lterl ventricle nd the ischemic lesion ecme semiisolted, the drug concentrtion in the ischemic lesion could ecome reltively higher thn in the resected cvity. Thus, the osmotic grdient effect ws generted, nd the ischemic lesion could pull CSF nd crete cvity which ws further enlrged from this hydrosttic pressure. The intensity difference etween the tumor resected cvity nd the cyst on FLAIR imging would support our hypothesis. We re not wre of previous reports on such cystic formtion relted to ischemic lesions. However, cogultive necrosis occurs from 3 to 37 dys s nturl course of cererl infrction 12) nd such cogultive necrosis cn e seen histopthologiclly nd mcroscopiclly t utopsy. Thus, this necrotic process could hve dmged the lood-rin rrier nd loclly compromised fluid regultion, leding to the formtion of cyst. As BCNU wfers re very unique type of locl chemotherpy nd we hve never seen formtion of sucute cysts fter neurosurgery without them, this points to n ssocition etween BCNU wfers nd remote cyst formtion. Although further reports re needed to determine the incidence of such remote cysts, their formtion fter BCNU wfer implnttion should e kept in mind, especilly if imging shows ny ischemic res ner the resection cvity. In conclusion, we experienced symptomtic remote cyst formtion fter BCNU wfer implnttion for recurrent HGG. The cyst ws formed within severl dys in the postopertive period. We hypothesized tht check-vlve or osmotic grdient effect relted to different BCNU concentrtions ws one of the mechnisms of the cyst formtion. This indictes tht ny imging nomlies, especilly those indictive of ischemi, should e monitored fter wfer implnts, even up to week fter n uneventful surgery. Acknowledgments We thnk Dr. Alexnder Zoronok of the University of Tsuku Fculty of Medicine, Deprtment of Neurosurgery, for professionl revision nd Dr. Bryn J. Mthis of the University of Tsuku Medicl English Communiction Center for ntive English revision. Conflicts of Interest Disclosure The uthors declre tht they hve no finncil or other conflicts of interest in reltion to this reserch nd its puliction. References 1) Westphl M, Hilt DC, Bortey E, et l.: A phse 3 tril of locl chemotherpy with iodegrdle crmustine (BCNU) wfers (Glidel wfers) in ptients with primry mlignnt gliom. Neuro-oncology 5: 79 88, ) Brem H, Pintdosi S, Burger PC, et l.: Plceocontrolled tril of sfety nd efficcy of intropertive controlled delivery y iodegrdle polymers of chemotherpy for recurrent glioms. The polymerrin tumor tretment group. Lncet 345: , ) Aoki T, Nishikw R, Sugiym K, et l.: A multicenter phse I/II study of the BCNU implnt (Glidel ( ) Wfer) for Jpnese ptients with mlignnt glioms. Neurol Med Chir (Tokyo) 54: , ) Hsegw Y, Iuchi T, Skid T, Yokoi S, Kwski K: The influence of crmustine wfer implnttion on tumor ed cysts nd peritumorl rin edem. J Clin Neurosci 31: 67 71, ) Dörner L, Ulmer S, Rohr A, Mehdorn HM, Nvi A: Spce-occupying cyst development in the resection cvity of mlignnt glioms following Glidel implnttion incidence, therpeutic strtegies, nd outcome. J Clin Neurosci 18: , ) Smpth P, Brem H: Implntle slow-relese chemotherpeutic polymers for the tretment of mlignnt rin tumors. Cncer Control 5: , 1998

7 276 H. Mtsumur et l. 7) Ishikw E, Ymmoto T: [Intropertive BCNU wfer implnttion for high-grde gliom questionnire trgeting Jpnese neurosurgeons]. Gn To Kgku Ryoho 43: , 2016 (Jpnese) 8) Ishikw E, Ymmoto T, Stomi K, et l.: Intropertive pthologicl dignosis in 205 gliom ptients in the pre-bcnu wfer er: retrospective nlysis with intropertive implnttion of BCNU wfers in mind. Brin Tumor Pthol 31: , ) Msud Y, Ishikw E, Ymmoto T, et l.: Erly postopertive expnsion of prenchyml highintensity res on T 2 -weighted imging predicts delyed cererl edem cused y crmustine wfer implnttion in ptients with high-grde gliom. Mgn Reson Med Sci 15: , ) Ohue S, Kohno S, Inoue A, et l.: Evlution of seril chnges on computed tomogrphy nd mgnetic resonnce imging fter implnttion of crmustine wfers in ptients with mlignnt glioms for differentil dignosis of tumor recurrence. J Neurooncol 126: , ) Ohue S: [Using BCNU Wfers in the tretment of Mlignnt Glioms]. Jpn J Neurosurg (Tokyo) 25: , 2016 (Jpnese) 12) Men H, Cdvid D, Rushing EJ: Humn cererl infrct: proposed histopthologic clssifiction sed on 137 cses. Act Neuropthol 108: , 2004 Address reprint requests to: Eiichi Ishikw, Deprtment of Neurosurgery, University of Tsuku, Tennodi, Tsuku, Irki , Jpn. e-mil: e-ishikw@md.tsuku.c.jp

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