© Masson, Paris, 2004

Neurochirurgie

, 2004,

50

, n° 2-3, 327-337

L’expérience radiochirurgicaleRésultats

HISTOPATHOLOGICAL OBSERVATIONS ON VESTIBULAR SCHWANNOMAS

AFTER GAMMA KNIFE RADIOSURGERY: THE MARSEILLE EXPERIENCE

G.T. SZEIFERT*, D. FIGARELLA-BRANGER, P.-H. ROCHE, J. RÉGIS

Centre Gamma Knife & Department of Pathology and Neuropathology, University Hospital La Timone, Marseille, France.

*

National Institute of Neurosurgery, Budapest, Hungary.

SUMMARY:

Histopathological observations on vestib-ular schwannomas after Gamma Knife radiosurgery:the Marseille experience

G. T. S

ZEIFERT

, D. F

IGARELLA

-B

RANGER

, P.-H. R

O-CHE

, J. R

ÉGIS

(Neurochirurgie,

2004,

50

, 327-337)

Background and purpose. —

Radiosurgery has becomea successful treatment modality in the management ofvestibular schwannomas (VS) during the past four de-cades. Although the number of treated cases has been in-creasing continuously we know relatively little about thepathological effect of high dose irradiation on VS fol-lowing radiosurgery. The purpose of this study was toanalyze histopathological changes in VS after LeksellGamma Knife (LGK) radiosurgery.

Methods. —

Out of a series of 1350 VS cases treatedwith LGK surgery 22 patients underwent craniotomy fortumor removal in 6-92 months interval after radiosur-gery. Surgical pathology material was available in 17cases. Routine histological and immunohistochemicalinvestigations were performed on the tissue samples.Histopathological findings were compared with clinicaland radiological follow-up data.

Results.

—

Coagulation necrosis in the central part ofthe schwannomas surrounded with a transitional zonecontaining loosened tissue structure of shrunken tumorcells covered with an outer capsule of vigorous neoplas-tic cells was the basic histopathological lesion. Granula-tion tissue proliferation with inflammatory cellinfiltration, different extent of hemorrhages and scar tis-sue development was usually present. Endothelial de-struction or wall damage of vascular channels was acommon finding. Analyzing the follow-up data it turnedout that 7 patients out of the 22 were operated on be-cause of radiological progression only without clinicaldeterioration and 4 of them was removed during the la-tency period after radiosurgery

.

RÉSUMÉ

Caractéristiques histopathologiques desschwannomes vestibulaires après radiochirurgieGamma Knife : l’expérience marseillaise

La radiochirurgie est aujourd’hui considérée comme untraitement efficace des schwannomes vestibulaires(SV). En dépit du nombre sans cesse croissant de pa-tients traités par cette technique, les effets de l’irradia-tion à haute dose unique sur le tissu tumoralschwannomateux in vivo sont peu connus. Cette étudea pour but d’étudier les modifications histopathologi-ques observées après radiochirurgie gamma knife(RGK) des SV. Sur un nombre total de 1 350 SV suc-cessivement traités par RGK à l’Hôpital de la Timone,22 patients ont nécessité une exérèse chirurgicale dansun délai compris entre 6 et 92 mois après la radiochi-rurgie. Le tissu tumoral a pu être disponible pour étudepathologique et immunohistochimique complémentairedans 17 cas. Les données de ces investigations ont étécouplées aux renseignements cliniques et radiologiquesdes patients.Les données histopathologiques régulièrement obser-vées consistaient en une plage de nécrose de coagula-tion distribuée au centre de la tumeur, entourée d’unezone transitionnelle faite d’une trame tissulaire moinsdense constituée de cellules tumorales tronquées, elle-même couverte d’une couche périphérique de cellulestumorales actives. On pouvait aussi fréquemment ob-server un infiltrat de cellules inflammatoires dans untissu de granulation, des plages hémorragiques et deszones cicatricielles. De même, des zones de lésions desparois vasculaires, en particulier endothéliales, étaientsouvent identifiables. Il faut noter que 9 tumeursavaient été réséquées sur une augmentation volumétri-que sans aggravation clinique, dont 4 pendant la phasede latence précoce après la radiochirurgie.Les résultats de cette étude suggèrent que la radiochi-rurgie Gamma Knife agit sur le schwannome par un

Reprint requests:

J. R

ÉGIS

, Department of Stereotactic & Functional Neurosurgery and Centre Gamma Knife, University Hospital LaTimone, rue Saint-Pierre, F-13005 Marseille, France.

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G.T. SZEIFERT et al. Neurochirurgie

Since June 1968, when the first patient wastreated in Stockholm with vestibular schwan-noma by Professor Lars Leksell [14], stereotacticradiosurgery [12] has become an effective andsuccessful treatment modality in the managementof these neoplasms. Nowadays three main stereo-tactic radiosurgical techniques are available forthis purpose: the Leksell Gamma Knife [3, 8, 16,20, 21, 24, 25], modified linear accelerators [18,19, 28] and proton or heavy-ion charged particlesgenerated in cyclotron [17]. Currently radiosur-gery may offer a sophisticated and safe alterna-tive possibility to micro-neurosurgery in selectedcases. On the other hand it can serve as a compli-mentary tool for residual or recurrent VS casesafter craniotomy related conventional surgery.Although the number of treated cases has beenincreasing continuously year to year, only sparsepublications available in the literature deal withthe pathological effect of radiosurgery on VS [6,10, 31].

The goal of the present study was to analyzemorphological changes in a series of 17 VS casesoperated on by conventional craniotomy afterLeksell Gamma Knife radiosurgery. Histopatho-logical findings in the removed tumor sampleswere compared with treatment parameters, radio-logical imaging and neurological clinical follow-updata. The first author of the paper (GTS) had theexceptional chance to review this unique surgicalpathology material in the World as an indepen-dent expert from another institution.

PATIENT, MATERIAL AND METHODS

Out of a series of 1350 VS cases treated with LGKradiosurgery since 1992 by the senior author (JR) inthe Centre Gamma Knife, Université Hôpital La Ti-mone Marseille, France, 22 patients underwent sub-sequent craniotomy for microsurgical tumor removal

in different neurosurgical units. The age of the pa-tients at the time of treatment ranged from 27 to 70years, median 51 years. As a primary interventionthey were treated with radiosurgery using the LeksellGamma Knife

®

Model-C (Elekta Instruments, Stoc-kholm, Sweden). The dose planning was based onMR and CT imaging with the Leksell Gamma Plan

tm

software. The treated volume of the 22 microsurgeryoperated cases ranged between 168 and 11405 mm

3

,median 1367mm

3

. The tumors received 9-15 Gy, me-dian 12 Gy as peripheral dose at the 50% isodoseline, the maximum dose in the center ranged from 18-30 Gy, median 24 Gy. The number of shots variedbetween 3 and 28, median 7. The irradiated neo-plasms were removed by conventional craniotomy re-lated microsurgery in a second step because of simpleradiological, or combined radiological and neurologi-cal progression after 6-92 months, median 35 monthsinterval following radiosurgery. Surgical pathologymaterial was available from 17 patients therefore the5 other cases were excluded from the histopathologi-cal study.

Microscopical investigations were carried out onthe 17 radiosurgically treated and microsurgery re-moved lesions. Five other VS operated cases withoutprevious radiosurgical intervention served as non-ir-radiated controls. The resected specimens were fixedin 10% neutral buffered formaldehyde, processedroutinely, and embedded in paraffin. Besides theconventional hematoxylin-eosin, orceine, Perls’andMasson’s trichrome stainings immunohistochemicalreactions were carried out for Ki67 antigen to scru-tinize proliferative capacity of tumor cells. FVIII-re-lated, CD31 and CD34 antigens were also studied todemonstrate endothelial activity and vascular effectsof the irradiation on tumor vessels. Biotin-streptavi-dine-peroxidase complex methods were performedaccording to standard protocols on 5

µ

m sections.The following antibodies were used in this study:anti-FVIII (Rabbit Anti-Human polyclonal, DAKOA/S, Denmark), anti-CD31 and anti-CD34 (mono-clonal Qbend/10, BioGenex, USA) to highlight theendothelial cell layer and smooth muscle wall ofchannels.

Conclusion. —

Results of the present histopathologicalstudy suggest that radiosurgery works with double effecton VS: it seems to destroy directly tumor cells (with ne-crosis or inducing apoptosis), and causes vascular dam-ages as well. The loss of central contrast enhancementon CT and MR images following radiosurgery might beconsequence of necrosis and vascular impairment. Fromclinical-pathological point of view we think that patientsshould not undergo craniotomy just because of radio-logical progression of the tumor without clinical deterio-ration, mainly in the latency period. This requiresconsultation and common decision-making between theradiosurgical and the microsurgical team.

Key-words:

Gamma Knife radiosurgery, vestibular schwannoma, histopatho-logy.

double mécanisme: elle paraît détruire directement lacellule tumorale (nécrose ou induction d’apoptose) etprovoquer des lésions vasculaires. La disparition du re-haussement radiologique centro-tumoral au décours dela radiochirurgie pourrait être causé par cette nécroseet les lésions vasculaires. D’un point de vue clinico-pa-thologique, nous considérons que la chirurgie d’exérèsene devrait pas être uniquement motivée par une simpleprogression radiologique de la tumeur dans la périodede latence. Une telle procédure ne devrait s’envisagerqu’après confrontation multidisciplinaire et décisioncollégiale.

Vol. 50, n° 2-3, 2004 RADIOSURGICAL PATHOLOGY OF VESTIBULAR SCHWANNOMAS

329

RESULTS

C

LINICAL

DATA

Out of the 22 patients, 7 were operated on be-cause of radiological progression only without cli-nical deterioration, and the remaining 15 casespresented with combined neurological and ima-ging progression as well. In 6 patients, the initialstate was Koos grade 2 at the time of LGK sur-gery and grade 3 at microsurgical resection. In 6patients, the clinical condition changed fromgrade 3 to grade 4, and in 3 patients from grade 2to grade 4. The remaining 7 did not change. Thevolume of the tumors varied between 866 and19709mm

3

(median: 5324mm

3

) at the time of mi-crosurgical resection. In 15 cases, total removalwas achieved; in 4 patients, a microfragment wasleft attached to the brainstem, and in the other ca-ses subtotal resection was manageable. In 10 ca-ses, the surgeon found some extra-difficultiesduring the operation; the remaining cases were re-moved routinely. In 3 cases, retrosigmoid explora-tion was selected; the others were removed via thetranslabirinther approach. Facial nerve functionwas postoperatively House-Brackman grade 1 in 6cases, grade 2 in 4 cases, grade 3 in 7 cases, grade4 in 2 cases, grade 5 in 2 cases, and follow-up datawere not available in 1 case.

M

ORPHOLOGICAL

FINDINGS

Histopathological changes affected both the pa-renchyma and the stroma of the radiosurgery trea-ted VS tissue samples. The basic histopathologicallesion was a necrotic core surrounded by a middle

transitional zone covered by an outer capsule

(figure 1a, b)

. The inner core of tumors consistedof necrotic debris containing scattered shrunkenapoptotic neoplastic cells, with narrow cytoplasmicrim and dark pycnotic basophilic nuclei without re-cognizable nucleoli. Mostly only the contour of thetumor cell nests was suspected or just a homoge-neous mass without any morphological details wasfound. There were no identifiable vascular ele-ments in this zone. This histological picture wascharacteristic of a coagulation necrosis or ischemicinfarction. This area was sharply demarcated fromthe surrounding tissues. According to a previousstudy this region gets the highest dose of irradia-tion beyond the 70% isodose line and constitutesthe so-called “cystic” part of the tumor [28]. Thesepathological findings correlated with the radiologi-cal appearance demonstrating signal changes, hy-podensity and lack of contrast enhancement in theinner part of tumor tissue on CT and MR imagesafter radiosurgery.

The outer capsule or mantle zone of neoplasmsusually presented densely packed tumorousSchwann cell nests with storiform pattern or nu-clear palisade arrangement. At high magnifica-tion, vigorous tumor cells with abundanteosinophilic cytoplasm, large oval nuclei with orwithout nucleoli were seen in this region. Diffe-rent degree of granulation tissue proliferationcontaining thin-walled capillaries and small ves-sels infiltrated by inflammatory cells, hemoside-rin-laden macrophages and occasionally foamycells was generally present

(figure 2)

. Scar tissueformation among and around tumor cell nests was

a bFIG. 1. — The basic histopathological lesion in vestibular schwannoma after radiosurgery: sharply demarcated necrotic areastowards surrounding tissue (Masson’s trichrome,× 100). b) Outer capsule or mantle zone, middle transitional zone and innernecrotic core in the radiolesion (H&E, × 200).FIG. 1. — a) Lésion histopathologique de base du schwannome vestibulaire après radiochirurgie. Zones de nécrose bien déli-mitée vers le tissu environnant (trichrome de Masson, × 100). b) Capsule externe ou zone de manteau, la zone médiane detransition, et la zone centrale de nécrose d’une radiolésion (HE ; × 200).

330

G.T. SZEIFERT et al. Neurochirurgie

a common finding with thick collagen bundles,hyaline degeneration, proliferating fibroblasts andfibrocytes. As the time interval had increasedfrom radiosurgery, this zone became more hypo-cellular and was replaced by bulky connective tis-sue

(figure 3)

. However, living tumor tissueremnants were demonstrated in all of the 17 trea-ted VS cases, even 92 months following radiosur-gery as well. Most of the tumor specimensexpressed dilated blood filled capillaries and veins

with patchy hemorrhages. In two cases, extensivehemorrhagic areas destroyed surrounding tumortissue. Vascular elements of tumors were injuredby degenerative processes like endothelial des-truction, vessel-wall damage and hyaline degene-ration. In an NF2 patient with the shortest timeinterval (6 months) between radiosurgery and mi-crosurgical removal foci of high proliferative acti-vity were expressed. Areas of high cell densitycontaining crowded vigorous tumor cell nests withcellular atypia, nuclear polymorphism, prominentnucleoli and frequently multinuclaeted giant cellswere recognized

(figure 4)

. The capsule area re-ceives the lowest doses of irradiation during ra-diosurgery, usually at about the 50-60% isodoseline.

The transitional zone of the tumors betweenthe outer capsule and inner necrotic core at aboutthe 60-70% isodose line demonstrated loosenedtissue structure, and the cells became shrunkenwith more compact nuclei without nucleoli. Thisregion was commonly infiltrated by granulationtissue as well.

In one case, a right sided VS was removedmicrosurgically 36 months after radiosurgery

(figure 5a)

, and a glioblastoma was resected fromthe right temporal lobe 100 months after radiosur-gery

(figure 5b)

.

I

MMUNOHISTOCHEMICAL

RESULTS

Ki67

proliferative activity was explored in 10-20cells per high power field in non-irradiated controlVS specimens

(figure 6a)

. Decreased activity wasnoticed 6 months after radiosurgery

(figure 6b)

,and it was only occasional 16 months after radio-

FIG. 2. — Granulation tissue in a Gamma Knife treatedvestibular schwannoma with hemosiderin laden macro-phages and foamy cells (H&E, ×100).FIG. 2. — Granulation tissulaire d’un schwannome vestibu-laire après Gamma Knife avec des macrophage chargésd’hémosidérine et des cellules spumeuses.

FIG. 3. — Hypocellular region replaced by massive collagenbundles containing scattered fibroblasts and fibrocytes 10months after radiosurgery (H&E, ×100).FIG. 3. — Région hypocellulaire remplacée par des faisceauxmassifs de collagène au sein duquel on trouve des fibroblasteset des fibrocytes 10 mois après la radiochirurgie (HE ; × 100)

FIG. 4. — High proliferative activity with cellular atypia, nu-clear polymorphism, prominent nucleoli and multinucleatedgiant cells 6 months after radiosurgery (H&E, ×200).FIG. 4. — Activité hautement proliférative avec des atypiescellulaires, un polymorphisme nucléaire, des nucléoles pro-éminentes, et des cellules géantes multinucléées 6 mois aprèsla radiochirurgie (HE ; × 200).

Vol. 50, n° 2-3, 2004 RADIOSURGICAL PATHOLOGY OF VESTIBULAR SCHWANNOMAS

331

surgery

(figure 6c)

. Moderate but still existing pro-liferative capacity was seen even 48 months afterradiosurgery as well

(figure 6d)

.Vigorous

FVIII-

related antigen positivity wasexpressed in the endothelial layer of the neoplasticvessels in the non-irradiated control VS samples

(figure 7a)

. Diminished reaction was demonstratedin tumor vessels 6 months after radiosurgery

(figure 7b)

. Modest positivity was noticed 16 monthsafter radiosurgery

(figure 7c)

, and returned strongactivity was seen in the VS channels 48 months af-ter GK treatment

(figure 7d)

.Marked

CD31

positivity was revealed in endo-thelial cells of tumor vessels in non-irradiatedcontrol VS tissue specimens

(figure 8a)

. This reac-tion decreased considerably 6 months followingGK surgery

(figure 8b)

, and basically no reactioncould be identified 16 months after radiosurgery

(figure 8c)

. However recurrent reactivity was detec-ted 48 months following GK treatment

(figure 8d)

.Conspicuous

CD34

positivity was demonstra-ted in the vessels’ wall from non-irradiated VS pie-ces

(figure 9a)

. This reaction diminished 6 monthsafter radiosurgery

(figure 9b)

, and became faint 16months following GK treatment

(figure 9c)

. Stri-king CD34 reactivity was noticed again in thechannels 48 months after GK treatment

(figure 9d)

, and it still was prominent in the granu-lation tissue of a VS case even after 72 monthsfrom radiosurgery

(figure 9e)

.

DISCUSSION

Stereotactic radiosurgery has become a succes-sful and continuously developing treatment moda-

lity in the neurosurgical realm during the pastthree and half decades. Since the first patient wastreated in January 1968 at the SophiahemmetHospital in Stockholm, Sweden, with the proto-type Gamma Knife more than 200.000 patientshave been operated on worldwide with this tech-nique. Although the treatment indications and thenumber of treated patients has been increasingconsiderably, we know relatively little about thepathological background explaining radiobiologyand pathophysiological mechanisms leading tocure or undesired side effects. According to Kon-dziolka

et al

. the future of radiosurgery amongothers will be built on the better understanding ofthe biological effect of radiation, which will ena-ble treatment of new disorders [9].

In 1958, the first radiosurgical pathology land-mark paper by Larsson, Leksell

et al

. demonstra-ted in animal experiments that “with high-energyprotons a sharply delimited lesion can be made atany desired site in the central nervous system”[11]. The basic histopathological lesion created byhigh energy ionizing radiation in brain tissue is acoagulation necrosis within the target volume,which did not change in time, and the boundarybetween the necrosis and the surrounding normalstructures is distinct, according to the sharp radia-tion fall-off [1, 13, 32].

Besides the experimental results a few reportshave already been published on human pathologi-cal data concerning histological changes in cerebralarteriovenous malformations (AVM) after radio-surgery [26, 29, 30, 33, 34]. These papers have con-cluded that nidus occlusion in AVM is achievedthrough a thrombo-obliterative process in the ves-sels evoked by the ionizing energy of irradiation. In

a bFIG. 5. — a) Vestibular schwannoma remnants, 3 years after Gamma Knife treatment (H&E, ×100). b) Typical histologicalpicture of glioblastoma from the same patient, 8 years following radiosurgery (H&E, ×100).FIG. 5. — a) Restes de schwannomes vestibulaires 3 ans après un traitement par Gamma Knife HE ; × 100). b) Présentationhistologique classique d’un glioblastome chez le même patient, 8 ans après la radiochirurgie (HE ; × 100).

332

G.T. SZEIFERT et al. Neurochirurgie

a previous study from the Royal Hallamshire Hos-pital of Sheffield, England we have analyzed thehistopathological changes in AVM after LGK ra-diosurgery [29, 30]. The conclusion of the histologi-cal analysis was that proliferation of a spindle-shaped cell population with contractile capacity,generated by the gamma-irradiation in the suben-dothelial region of the vessels’ wall and stroma ofthe AVM could be relevant to the shrinking pro-cess and eventual occlusion of AVM after radiosur-gery. The immunohistochemical characteristics ofthese spindle-shaped cells were identical to myofi-broblasts, which are the activated forms of restingfibroblasts expressing contractile elements [5]. In asubsequent paper Schneider

et al

. presented similarresults in AVM after radiosurgery [26].

The goal of the present study was to investigatehistopathological alterations and compare themwith treatment parameters, neurodiagnostic ima-ging and clinical follow-up data in vestibularschwannomas after LGK radiosurgery. Conside-ring that the present series of 17 VS harboring pa-tients who underwent microsurgical resection afterLGK treatment expressed histopathologicallymore or less living tumor tissue remnants in theexamined specimens, we have to accept that thispatient population represents some kind of radio-surgical failure. Surviving VS islands were demons-trated in all cases mainly in the outer capsule ormantle zone, which is assumed to receive lower do-ses of irradiation at about the 50-60% isodose line[31]. If we take out from this group those 4 patients

a b

FIG. 6. — a) Ki67 proliferative activity in a control non-irradiated vestibular schwannoma (× 200); b) Decreaesed Ki67 ca-pacity 6 months after radiosurgery (× 200); c) Occasional Ki67 positivity 16 months after radiosurgery (× 200); d) Moderatelybut still existing Ki67 activity 48 months following radiosurgery (× 200).FIG. 6. — a) Activité proliférative Ki67 au sein d’un schwannome vestibulaire non-irradié (× 200). b) Diminution de l’activitéKi67 6 mois après la radiochirurgie (× 200). c) Zones Ki67 positive 16 mois après la radiochirurgie (× 200). d) Activité Ki67modérée mais présente 48 mois après la radiochirurgie. d) Activité Ki67 modérée mais présente 48 mois après la radiochirurgie.

c d

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333

who were operated on in the latency period of theirradiation, the remaining 13 failures constitute lessthan 1% of the 1350 LGK treated cases in the Cen-tre Gamma Knife, Hôpital La Timone since 1992.From the analysis of the available pathological ma-terial several pathophysiological mechanisms mightbe suspected behind the volume progression afterradiosurgery. These processes include degenerativeand proliferative changes in the tissue elements ge-nerated by the ionizing energy of focussed gamma-beams. From a morphological point of view thebiological effect of high dose irradiation on VS tu-mor tissues seems to evoke a double reaction. Oneobject is the tumor parenchyma where the radia-tion triggers cell death either via coagulation necro-

sis or induced apoptosis. Immunohistochemicalinvestigations (FVIII, CD31, CD34) revealed thatthe other target of radiosurgery is the stroma of thetumor, where it induces endothelial destructionand wall damage of the vessels with granulation tis-sue proliferation what organizes and clears up ne-crotic tumor tissue. Results of theseimmunohistochemical reactions demonstrate thatthe endothelial cell layer of the vessels is very sen-sitive and reacts early after high-dose irradiation oftumor tissue [22]. The previous observations sup-ply human pathological data and support the ex-perimental theory that microvascular endothelialcells are the primary targets of single high-doseirradiation [4, 23]. In the later stages it is suspected

a b

FIG. 7. — a) Vigorous FVIII activity in the endothelial layer of the neoplastic vessels in the non-irradiated control vestibularschwannoma (× 100); b) Decreased FVIII reaction in the tumor vessels 6 months after radiosurgery (× 100); c) Moderate FVIIIpositivity 16 months following radiosurgery (× 100); d) Returned strong FVIII activity 48 months after radiosurgery (× 100).FIG. 7. — Activité FVIII importante au sein de la couche endothéliale des vaisseaux néoplasiques d’un schwannome vestibu-laire de contrôle non irradié (× 100). b) Réactivité FVIII réduite dans les vaisseaux tumoraux 6 mois après la radiochirurgie(× 100). c) Réactivité FVIII modérée 16 mois après la radiochirurgie (× 100). d) Retour à une activité FVIII importate 48 moisaprès la radiochirurgie (× 100).

c d

334 G.T. SZEIFERT et al. Neurochirurgie

to be replaced by hypocellular connective tissuereached in collagen bundles. The process seems tofinish with hyaline degeneration and scar tissue for-mation that substitutes the destroyed parenchyma.Regarding that scar tissue prone to contraction itmight promote shrinkage of VS after LGK treat-ment in the majority of cases. However in thefailed radiosurgical tumors histological evidencewere supplied in several instances for excessive he-morrhage and extensive necrosis. These might beconsequences of vascular damages and could resultin tumor volume enlargement presenting with ra-diological progression and clinical deterioration.

A notable finding of the immunohistochemicalinvestigations was (FVIII, CD31, CD34) that the

endothelial layer and the vessels’ wall were dama-ged during the irradiation latency period but thepositivity recurred again beyond the latency period.This phenomenon suggests either that the reacti-vity of the endothelial cells (FVIII, CD31, CD34)and vascular smooth muscle elements (CD34) re-cover after the latency period, or there is de novovessel genesis.

Another considerable observation was thatproliferative capacity of the tumor cells (Ki67)was detected even beyond the latency period. Thisfinding might be a consequence of a geneticallyhighly active tumorous Schwann cell populationwhat could resist to the generally used radiosurgi-cal doses in the treatment of common VS.

a b

FIG. 8. — a) Marked CD31 activity in the endothelial cells of tumor vessels in a non-irradiated control vestibular schwan-noma (× 100); b) Decreased CD31 reaction 6 months after radiosurgery (× 100); c) No CD31 positivity could be detected16 months following radiosurgery (× 100); d) Returned CD31 reactivity 48 months after radiosurgery (× 100).FIG. 8. — a) Activité CD31 marquée des cellules endothéliales des vaisseaux tumoraux au sein d’un schwannome vestibulaire decontrôle non irradié (× 100). b) Diminution de la réactivité CD31 6 mois après la radiochirurgie (× 100). c) Absence de réactivitéCD31 16 mois après la radiochirurgie (× 100). d) Réactivité CD31 de nouveau 48 mois après la radiochirurgie (× 100).

c d

Vol. 50, n° 2-3, 2004 RADIOSURGICAL PATHOLOGY OF VESTIBULAR SCHWANNOMAS 335

The analysis of this series revealed a patientpresenting with a secondary glioblastoma multi-forme in the temporal lobe on the same side 8years after LGK treatment of his VS, therefore the

issue of radiosurgery-induced brain tumors shouldbe discussed. Recently a few reports have been pu-blished on brain tumors attributed to radiosurgery.In three patients, glioblastoma multiforme develo-

a b

FIG. 9. — a) CD34 activity in the vessel wall from non-ir-radiated control vestibular schwannoma specimen (× 100);b) Decreased CD34 reaction 6 months after radiosurgery(× 100); c) Faint CD34 reactivity 16 months following ra-diosurgery (× 100); d) Returned CD34 activity 48 monthsafter radiosurgery (× 100); e) Prominent CD34 positivityin the capillaries of granulation tissue from vestibularschwannoma 72 months following radiosurgery (× 100).FIG. 9. — a) Activité CD34 au sein de la paroi vasculaired’un schwannome vestibulaire de contrôle non irradié(× 100). b) Diminution de la réactivité CD34 6 mois aprèsla radiochirurgie (× 100). c) Faible réactivité CD34 16 moisaprès la radiochirurgie (× 100). d) Réactivité CD34 de nou-veau 48 mois après la radiochirurgie (× 100). e) PositivitéCD34 importante au sein des capillaires du tissu granulaired’un schwannome vestibulaire 72 mois après la radiochi-rurgie (× 100).

c d

e

336 G.T. SZEIFERT et al. Neurochirurgie

ped after LGK treatment for a meningioma [35],for aVS [27] and for an AVM [7] as well. To deter-mine whether a tumor is induced by radiationtreatment it should fulfill all of Cahan’s criteria forradiation induced neoplasia [2]. Modified criteriaare as follows: the tumor must appear in the irra-diated field; a latent period must have elapsedbetween treatment and the appearance of the tu-mor; there must be documentation of absence ofsecondary tumor before radiation; and the histo-logy of the secondary tumor must be distinct fromthe primary tumor [35]. Our case does not meetwith the first criteria, that is the GBM did not de-veloped in the region that had been treated withthe Gamma Knife, therefore we would not regardit as radiosurgery induced tumor. Some might saythat the temporal lobe is in the “scatter field” of aVS Gamma Knife treatment, but in radiosurgerywe are thinking about sub-millimetric accuracy andsharp radiation fall-off towards the surroundingstructures. Therefore in our opinion it would beagainst the idea of radiosurgery to draw a directcausal link between a treated target and a secondtumor several cm away from the irradiated region.But as the number of treatments has been in-creasing continuously, unfortunately the theoreticalpossibility exists for potential long-term complica-tions after radiosurgery.

Stereotactic radiosurgery is the principal alter-native to microsurgical resection for vestibularschwannomas [8]. Changes in tumor volume andchanges in the imaging properties of neoplasms re-flect the biological response to radiosurgery. A lossof central enhancement was observed by Prasad etal. [24] in more than 50% of the treated cases. Theearliest onset of this change in their material tookplace at 4 months post-treatment and it appearedas late as 4 years as well. Spiegelmann et al. havereported that early tumor enlargement after radio-surgery was always associated with a loss of centralcontrast enhancement on MR imaging [28]. It wasthought to be the result of hyperacute tumor ische-mia with edema and proved to be transient. Ima-ging studies demonstrated volume reductions in allthese tumors later during the follow-up period. In aprevious study we have found that the loss of cen-tral contrast enhancement on MR imaging appea-red as early as 2.5 months after radiosurgery [31].Histopathological investigations revealed coagula-tion necrosis in the tumor tissue behind the ima-ging changes, which might have been theconsequence of vascular damage.

QUO VADIS?

Insomuch as pathophysiological mechanismsbehind imaging changes and radiosurgical failure

are still subjects of debate, further histopathologi-cal investigations and comparison with radiologi-cal findings would be desirable at every availablecase in the future. The role of functional examina-tions like positron emission tomography (PET)should be considered in the treatment planningand follow-up assessment of VS after radiosur-gery. This sophisticated method detects sensitivelymetabolic changes of proliferating tissues like tu-mor or granulation tissue and was found to beuseful in the dosimetry planning of radiosurgeryby Levivier et al. [15]. The combination of mor-phological and functional imaging data with histo-pathological findings probably would promotebetter understanding the radiobiology of radiationeffect on vestibular schwannomas after GammaKnife radiosurgery. In this way it would servemore sophisticated treatment planning and couldreduce the number of failed radiosurgery cases.

CONCLUSIONS

Results of the present histopathological studysuggest that radiosurgery offends a double targetduring treatment of vestibular schwannomas. Itseems to destroy directly tumor parenchyma eithervia coagulation necrosis or induced apoptosis in theneoplastic cells. Vascular channels of the connec-tive tissue stroma are also involved in the radiobio-logical response evoked by the ionizing energy ofgamma photons. Immunohistochemical investiga-tions supply human pathological support to the ex-perimental theory that vascular endothelial cellsare the principal targets of single high-dose irradia-tion. These vascular changes could be relevant inVS regression together with necrotic or apoptotictumor cell death after Gamma Knife treatment.The loss of central contrast enhancement of tumortissue and MRI signal changes might be conse-quences of the vascular damage.

Proliferative capacity of tumor cells decreased af-ter radiosurgery but still existed beyond the latencyperiod. Endothelial destruction and vascular walldamage appeared early following radiosurgery but itwas repaired after the latency period of irradiation.

Clinical pathological data do not support emer-gency craniotomy for patients with radiological pro-gression but without clinical deterioration, mainly inthe latency period. Further management of these pa-tients should be based on consultations and commondecisions by the radiosurgical and the microsurgicalteam.

ACKNOWLEDGEMENTS: Dr. Szeifert was supportedpartly by the Congress of Neurological Surgeons/Elekta International Radiosurgical Clinical Fellowshipand a grant from the Hungarian Ministry of Health &Welfare (ETT 2003-2005).

Vol. 50, n° 2-3, 2004 RADIOSURGICAL PATHOLOGY OF VESTIBULAR SCHWANNOMAS 337

Nous tenons à remercier, pour leur aide lors du recueildes données anatomo-pathologiques, les médecins desservices de Pathologie et de Neurochirurgie suivants :CHU de Poitiers, CHU de Rennes, CHU de Paris/Cré-teil, CHU de Paris/Lariboisière, CHU de Lyon et CHUde Bruxelles.

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