Research Article

Received: 15 March 2010, Revised: 10 January 2011, Accepted: 14 February 2011, Published online in Wiley Online Library: 4 April 2011

(wileyonlinelibrary.com) DOI: 10.1002/nbm.1705

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MRS characterization of central neurocytomasusing glycineTariq Shaha*, Rama Jayasundara, Virendera Paul Singhb and Chitra Sarkarc

This study reports in vivo MRS findings in 11 patien

NMR Biom

ts with histologically diagnosed central neurocytomas, whichare rare intraventricular tumors of neuronal origin. Single‐voxel 1H MRS was carried out prior to surgery using apoint‐resolved spectroscopy sequence with TR= 6 s, TE= 135ms and 128 scans. In vitro high‐resolution 1Hspectroscopy was also carried out on two surgically excised samples. The striking features of the spectra from thecentral neurocytomas were the presence of high glycine, decreased N‐acetylaspartate, increased choline andalanine. Retrospective, blind analysis of the spectra by two independent observers correctly identified all but onecentral neurocytoma based on the presence of glycine. The presence of glycine and prominent choline in the 1H MRspectrum is a characteristic feature of the central neurocytomas, and could be used to characterize and differentiatethem from other brain tumors. Copyright © 2011 John Wiley & Sons, Ltd.

Keywords: 1H MRS; central neurocytomas; glycine; N‐acetylaspartate; intraventricular tumor; alanine; high‐resolution NMRspectroscopy; choline

* Correspondence to: T. Shah, 217 Traylor, 720 Rutland Ave., Department ofRadiology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.E‐mail: tariq196@yahoo.com

a T. Shah, R. JayasundarDepartment of NMR, All India Institute of Medical Sciences, New Delhi, India

b V. P. SinghDepartment of Neurosurgery, All India Institute of Medical Sciences, New Delhi,India

c C. SarkarDepartment of Pathology, All India Institute of Medical Sciences, New Delhi,India

Abbreviations used: Ala, alanine; Cho, choline; CNC, central neurocytoma;Cr/PCr, creatine/phosphocreatine; Gly, glycine; Glx, glutamate/glutamine; Lac,lactate; LLV, left lateral ventricle; mI, myo‐inositol; NAA, N‐acetylaspartate; PC,phosphocholine; TEM, transmission electron microscopy.

INTRODUCTION

Central neurocytomas (CNCs) are rare intraventricular tumors ofneuronal origin occurring frequently in young adults in theforamen of Monroe in the lateral ventricles (1,2). The majorpresurgical diagnostic criteria for these tumors, generallyassociated with a benign clinical behavior, are the patient’s ageand the location of the tumor within the ventricles, the latterbeing provided by radiological imaging. The final diagnosis ofthese tumors is always by postsurgery histology. Histologically,however, CNCs are known tomimic oligodendroglioma, primitiveneuroectodermal tumor and ependymoma (3–6). The postoper-ative final diagnosis, therefore, is made by additional studies, suchas immunohistochemistry and transmission electron microscopy(TEM), which show characteristic features.

CNCs are generally considered to have a good prognosis andhence surgical excision is not generally followed by adjuvantradiotherapy or chemotherapy. However, the increasing incidence/report of atypical CNCs (atypical with respect to location, age of thepatient, histological features, proliferation index and clinicalbehavior) has called for a rethink of not only the classification ofthese tumors, but also patient management, in particular the roleof the extent of tumor resection and postoperative radiotherapy(7–10). This also necessitates a closer look at the question ofunambiguous and preferably preoperative diagnosis of thesetumors, which, at present, is not always possible with radiologicalimaging (1,2,5), but may be possible with MRS. This article, inaddition to discussing the role of MRS in providing additionalinformation to aid in the diagnosis of these rare tumors, providesthe largest series reported so far of 1H MRS studies of CNCs.

EXPERIMENTAL DETAILS

Patient details

The patient and study details are summarized in Table 1. Therewere six female and five male patients in the age group of

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21–35 years (average, 25 years). All patients had experiencedheadache of moderate to severe intensity for 6–8months beforethey reported to the clinic. There were no specific neurologicalsymptoms in any of the patients, except one, who hadexperienced progressive deterioration of vision in both eyesleading to complete blindness within 1month of complaint. Allpatients had tumors in the typical location. All underwent totalresection of the tumor except for three patients, two of whomdied after surgery at different time points. None of the patientswere given radiotherapy following surgery. Four of the patientswere followed up over a period ranging from 1 to 30monthsafter surgery. All patients had undergone diagnostic radiologicalimaging (either computed tomography or MRI) prior to surgery.Postsurgery, immunohistochemical studies were carried out inaddition to routine histology to confirm the diagnosis of CNC.The proliferation activity determined for all tumors using theMIB‐1 antibody labeling index was less than 1.2%, indicating thebenign nature of all the CNCs studied.

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Table 1. Clinical, radiological and surgical details of the patients with central neurocytoma (CNC)

Patient Age (years)/gender Tumor location Radiological opinion Surgery Follow‐up (months)

1 21/F BLV (FM) Glioma Complete 30 NR2 21/F RLV (FM) Glioma Partial 8 NR3 24/F BLV (FM) Epend/CNC Complete –4 18/F RLV (FM) Epend Complete 1 NR5 25/F RLV (FM) Glioma Complete 30 NR6 19/F LLV (FM) Epend Complete 15 NR7 32/M LLV (FM) Epend Complete –8 27/M RLV (FM) Glioma Complete 18 NR9 35/M BLV (FM) Epend/CNC Partial Died10 18/M RLV (FM) Epend/CNC/Oligo Partial Died11 24/M BLV (FM) Glioma/CNC Complete –

BLV, both lateral ventricles; Epend, ependymoma; F, female; FM, foramen of Monroe; LLV, left lateral ventricle; M, male; NR, norecurrence; Oligo, oligodendroglioma; RLV, right lateral ventricle; –, not followed.

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In vivo MRS studies1H MRS studies at 1.5 T were carried out prior to surgery in allpatients using a Siemens Magnetom (Siemens Medical Solution,Erlangen, Germany). T2‐weighted turbo spin‐echo images(TR = 3500ms; TE = 90ms; number of acquisitions, 1), acquiredin all three planes, formed the base images for positioning ofthe voxels, which ranged in size from 3.5 to 6mL dependingon the tumor size. The voxels were positioned well within thetumor boundary in all three orientations, thus eliminating anycontamination from nontumor tissues. Extreme care was takento exclude cysts and calcification from the voxel.Water‐suppressed 1H spectra were obtained with the point‐

resolved spectroscopy sequence using the following parameters:TR = 6 s; TE = 135ms; 2048 data points; 128 scans. The post-processing included zero filling of the free induction decay to 4 Kdata points, followed by Gaussian line broadening, and zero‐ andfirst‐order phase corrections of the Fourier‐transformed spectra.All resonances were initially referenced to water and furthercross‐checked with reference to choline (Cho) at 3.20 ppm.In vitro high‐resolution MRS studies were carried out asdescribed previously (11).

Data analysis

The 1H MR spectra from all CNCs were randomly mixed withspectra from 40 other brain tumors, including gliomas,meningiomas and other intraventricular tumors (T. Shah,unpublished results), and were evaluated in a blind manner bytwo independent observers. They were asked to classify thespectra from CNCs based on the presence of the peak at3.55 ppm. These were then correlated separately with thehistopathology reports and the radiological diagnosis. Metabo-lite ratios were also calculated from the spectra. Together withthe patient’s age and location of the tumor, the followingradiological features were considered (by radiologists) for thediagnosis of CNCs: computed tomography scans typicallydemonstrating an iso‐ or slightly hyper‐dense mass within thebody of the lateral ventricles near the foramen of Monroe, andthe presence of conspicuous calcification or cystic changes;MR images showing an iso‐intense mass in T1‐weighted andT2‐weighted images. Mild to moderate contrast enhancementwas also observed in most CNCs.

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RESULTS

Table 1 summarizes the clinical, radiological and surgical detailsof the patients with CNC. Figure 1a shows an axial T2‐weightedimage of a CNC lesion from patient 4. The image shows the iso‐to hyper‐intense tumor in the lateral ventricle and the drawnsquare represents the voxel (15 × 15× 15mm3) from which thespectrum was acquired. Figure 1b and 1c show the 1H in vivo andin vitro spectra from this voxel, respectively. The in vivo spectrum(Fig. 1b) shows a prominently increased Cho and a reducedN‐acetylaspartate (NAA) and creatine/phosphocreatine (Cr/PCr)compared with normal brain cortex. In addition, glycine (Gly),alanine (Ala) and lactate (Lac) can also be seen in the in vivospectrum. Lac and Ala are seen as inverted doublets at the TEused (135ms) because of their J‐coupled induced modulation ofthe multiplet protons. Gly and Ala were identified using thein vitro spectrum from the corresponding extract and also fromour previous studies (11). All the metabolites observed in thein vivo spectrum, except NAA, are seen in the in vitro spectrum(Fig. 1c). In addition, resonances from glutamate/glutamine (Glx)and Cho‐containing compounds, such as free Cho andphosphocholine (PC), are seen.

Figure 2 shows the T2 image from patient 2 with a CNC in theright ventricle. The 1H spectra obtained from this lesion from avoxel (12 × 12× 12mm3) showed Cho and Gly. It can be seenthat, even from a small voxel size, a significant Gly peak can beobserved. Figure 3 shows the metabolite ratios from spectra ofneurocytomas, gliomas and meningiomas as histograms. It canbe seen that Cho/Cr, Gly/Cr and Cho/Ala were significantlyhigher in CNCs relative to gliomas (p< 0.01), and Cho/Cr and Gly/Cr were significantly higher in CNCs relative to meningiomas(p < 0.01). Table 2 summarizes the metabolites and theirpercentage occurrences in all CNCs. Cho was seen in all patients(100% occurrence), followed by Gly (91%), Cr and NAA (73%)and Ala (64%). The spectrum from the 10th patient (Table 1) didnot show Gly. Although the reason for this is unclear, wespeculate that it could be a result of the presence ofcalcifications and hemorrhages in the tumor observed radiolog-ically. Comparing the radiological diagnosis with that of MRS, itcan be seen from Table 1 that, radiologically, none of thepatients were identified definitively for CNC, although, in four ofthe 11 patients, CNC was a differential diagnosis together with

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Gly Cho

4.0 3.0 2.0 1.0 ppm

Figure 2. T2‐weighted axial image of a right ventricular central neurocytoma (CNC) from patient 2 showing the voxel (indicated by the box) fromwhich the 1H tumor spectrum was obtained in vivo. Cho, choline; Gly, glycine.

Lac

Ala

Cr/PCr

GPC

PC

a

b

c

InsGlxGlx

Gly

Gly

3.5 3.0 2.5 2.0 1.5 ppm

Cho

Cr

Figure 1. (a) T2‐weighted axial image of a central neurocytoma (CNC) in the bilateral ventricle from patient 4 showing the voxel (indicated by the box)from which the in vivo 1H tumor spectrum (b) was obtained. (c) In vitro 1H spectrum from the perchloric acid extract of the same tumor. Ala, alanine;Cho, choline; Cr/PCr, creatine/phosphocreatine; Gly, glycine; Glx, glutamate/glutamine; GPC, glycerophosphocholine; Lac, lactate; Ins, myo‐inositol;PC, phosphocholine.

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ependymoma and oligodendroglioma. However, retrospectiveanalysis of the MRS data carried out in a blind manner by twoindependent observers identified 91% of the CNCs correctlybased on the presence of Gly.

DISCUSSION

There is a need for noninvasive in vivo characterization to aid inthe clinical diagnosis of CNCs, which are rare intraventriculartumors of neuronal origin. However, there are only a few reportson in vivo MRS of these tumors (11–19). Table 3 summarizes theresults from all the reports. The first report on a single case ofCNC was by Warmuth‐Metz et al. (16): it showed elevated Choand the presence of NAA, Cr/PCr and Lac. The second study onfive patients by Kim et al. (14) showed increased Cho, decreased

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NAA, the presence of Lac and an unidentified peak at 3.55 ppmin all five patients. The next report by Jayasundar et al. (11) ontwo patients assigned the peak seen in vivo at 3.55 ppm as Glyusing high‐resolution 1H NMR studies on the correspondingtumor extracts. There have been eight more reports on MRS inCNCs (12,13,15,17–20). This article presents the largest series ofCNCs (n=11) reported so far. The 11 cases include the tworeported previously (11).The present results are in agreement with all other reports

with regard to the observation of high Cho and reduced NAAand Cr/PCr. However, only Kim et al. (14), Bobek‐Billewicz et al.(21) and the present study observed a high occurrence of thepeak at 3.55 ppm. Lac has not been observed consistently in allstudies. For example, although Kim et al. (14) reported Lac in allof their patients, the present study observed Lac in only 9% ofpatients. Warmuth‐Metz et al. (16) also observed Lac in their

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Cho/Cr Gly/Cr Cho/Ala

met

abol

ite

rat

ios

0

1

2

3

4

5

6

7 CNC

Gliomas

Meningiomas

Figure 3. Histogram showing the metabolite ratios obtained fromspectra acquired at 135ms from neurocytomas, extraventricular gliomasand meningiomas [p<0.01 for choline/creatine (Cho/Cr), glycine/creatine(Gly/Cr) and choline/alanine (Cho/Ala) between central neurocytomas(CNCs) and gliomas; p<0.01 for Cho/Cr and Gly/Cr between CNCs andmeningiomas].

Table 2. Metabolites observed in the 1H MR spectra of thecentral neurocytomas (CNCs)

Patient Cho Cr NAA Gly Ala Lac

1 ✓ ✓ ✓ ✓ – –2 ✓ – – ✓ ✓ –3 ✓ ✓ ✓ ✓ ✓ –4 ✓ ✓ ✓ ✓ ✓ ✓

5 ✓ – – ✓ ✓ –6 ✓ ✓ ✓ ✓ – –7 ✓ – – ✓ – –8 ✓ ✓ ✓ ✓ ✓ –9 ✓ ✓ ✓ ✓ ✓ –10 ✓ ✓ ✓ – – –11 ✓ ✓ ✓ ✓ ✓ –Frequency of occurrence (%) 100 73 73 91 64 9

Ala, alanine; Cho, choline; Cr, creatine; Gly, glycine; Lac,lactate; NAA, N‐acetylaspartate.

Table 3. Literature review of the presence of glycine in the1H MR spectra of central neurocytomas (CNCs) studied to date

Reference

Tumor classification Presenceof glycine

Typical (n) Atypical (n)

Warmuth‐Metzet al. (16)

– 1 Not seen

Kim et al. (14) 5 – 5/5Kanamori et al. (13) 2 1 1/3Moller‐Hartmannet al. (20)

– 1a Not seen

Chuang et al. (12) 3 – 1/3Yeh et al. (17) 3 – 3/3Krishnamoorthyet al. (15)

3 – 3/3

Kocaoglu et al. (18) 7 – 1/7Majos et al. (19) 2 – 2/2Bobek‐Billewiczet al. (21)

2 2/2

Present study 11 – 10/11aExtraventricular.

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patient, but Krishnamoorthy et al. (15) reported the occurrenceof Lac in only one of three patients. None of the other groupsreported the presence of Lac in CNCs. The presence of Lac isgenerally attributed to anaerobic glycolysis in the tumors.Mineura et al. (22), in their positron emission tomographicstudies on blood flow, found the metabolism of CNCs, ingeneral, to be more oxidative, i.e. less anaerobic, than otherbenign tumors. Therefore, although this supports the absence ofLac in CNCs, the reason for the presence of Lac in CNCs reportedin some studies is not clear. Kim et al. (14) speculated that thepresence of Lac in the CNCs studied by them could simply be aresult of the large size of the tumors.

NAA

The presence or absence of NAA in the 1H spectra of cerebraltumors has generally been attributed to either neuronal loss/

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damage or, in the case of infiltrative tumors and tumors of non‐neuronal origin, to a contribution from normal brain tissue (23,24).In the case of CNCs, it is known that these tumors are of neuronalorigin (1,3,5,6). Considering this and the fact that no contributionfrom normal brain tissue is likely in an intraventricular tumor, thepresence of NAA in the spectrum can be taken to indicate thetumor’s neuronal origin. It is interesting to note that the finaldiagnostic tests (immunohistochemistry and TEM) for CNC alsolook for evidence of neurons in the form of synaptophysin andsynaptic vesicles (3–6).

Considering the neuronal origin of these tumors, one wouldhave expected to find a higher level of NAA than observed inthis study and also in the previously published reports. It isknown that NAA is produced only in mature neurons (6).Therefore, as speculated in previous reports, the reason for theobservation of low NAA in CNCs of neuronal origin could simplybe because the CNCs are formed from immature neurons(11,14,20). In the present study, NAA was observed in vivo ineight of the 11 patients. However, it was not observed in thecorresponding in vitro spectra from the extracts. This discrep-ancy between in vivo and in vitro spectra could be caused by thedifferent sampling areas of the two spectra.

However, one needs to be extremely cautious when discuss-ing the role of NAA. Although NAA is conventionally consideredto be a putative neuronal marker (25), there is increasingevidence to suggest that it can also be found in non‐neuronalcells (26). The functions of NAA have also been the subject ofconsiderable interest, and several roles have been assigned. Forexample, NAA is considered to be a donor of acetyl groups forlipid synthesis. It is also known to be involved in myelinmaturation, neuronal protein synthesis, osmoregulation and glialcell‐specific signaling (26–28). Therefore, changes in any ofthese processes in a tumor are likely to be reflected in changesin the level of NAA. Bates et al. (29) have shown that theinhibition of mitochondria results in the partial inhibition of NAAsynthesis. It has also been proposed that cytotoxic edema canresult in the redistribution of intra‐ and extracellular NAA,

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leading to an alteration of the relaxation properties which couldreduce the MR visibility of NAA (30). Therefore, caution isrequired in interpreting the changes in NAA.

Cho

The Cho resonance observed in vivo is known to containcontributions from several Cho‐containing compounds, such asfree Cho, PC and glycerophosphocholine, at high resolution,which are involved in membrane synthesis and degradation.Although the increased level of Cho in the MR spectra of tumorshas generally been associated with malignancy, it is also seen inbenign tumors, such as meningiomas (31). All the CNCs reportedin this study had a proliferation rate of less than 1.2%, indicatingtheir benign nature. It is interesting to note that Sugita et al. (32)also reported a very high level of Cho in their studies on thebiochemical analysis of neurotransmitters in CNCs. Kanamoriet al. (13) speculated on the reasons for the discrepancybetween the high Cho peak and low MIB‐1 labeling indexobserved in their CNCs. One hypothesis is that the high Chopeak observed could reflect only the elevated membranousturnover, which does not result in proliferative activity. Anotherhypothesis is that CNCs are composed of a high density of cellswithout necrosis and connective tissues, which might cause ahigh Cho peak. The second hypothesis supports the authors’own unpublished data, which show that the apparent diffusioncoefficients from some of the CNCs in the present study are verylow, indicating a high cellularity of the tumor. Recent reports onneurocytoma (18) and meningiomas, both of which are benigntumors, have correlated high Cho with the tumor’s high celldensity (determined by the Ki‐67 level) instead of acceleratedmembrane turnover. High Cho, therefore, seems to becharacteristic of CNCs, although they are benign in nature.

Gly

Jayasundar et al. (11) speculated in detail on the reasons for theobservation of Gly in the 1H MR spectra of CNCs. Gly is a provenneurotransmitter and is found in the synaptic vesicles in severalregions in the central nervous system (33). Central nervoussystem Gly is synthesized from serine and is broken down by thecytosolic enzyme complex and the Gly cleavage system (33).There are two aspects of Gly metabolism that are of particularinterest and relevance to the MRS finding of Gly in CNCs. First,glycinergic synapses are known to become functional inimmature/developing cells, where Gly has an excitatory action.Although Gly functions as an inhibitory neurotransmitter inmature neurons, it acts as an excitatory neurotransmitter inimmature neurons (33). Considering the fact that CNCs areformed from immature neurons (3), it is possible that the Glyobserved in CNCs arises from these glycinergic synapses whichbecome functional in immature neurons. Second, it is known thatthe synaptophysin–synaptobrevin complexes present in theglycinergic synaptic boutons are involved in the release of Gly(33,34). It is therefore possible that there is a direct connectionbetween the Gly observed in CNCs using MRS and thesynaptophysin observed using immunohistochemistry. Whateverthe reason for the observation of Gly in the MR spectrum, it isinteresting to note that the ultimate diagnostic tests for CNC,namely immunohistochemistry and TEM, actually look forsynaptophysin‐positive cells and synaptic vesicles, which, in turn,can be taken to reflect the presence of Gly and NAA, respectively,although indirectly.

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This study, reporting the largest series of CNCs, consistentlyobserved in the 1H spectrum the presence of a peak at 3.56 ppm,which has been assigned to Gly using high‐resolution NMRstudies of the tumor extracts. In in vivo studies, unambiguousassignment of the Gly signal may not be possible, especially atshorter TEs, as it overlaps with the signal of myo‐inositol (mI).Although Gly has two methylene protons giving rise to a singletat 3.55 ppm, mI gives rise to coupled multiplets near the 3.55‐ppm position. These multiplets, however, are known to bereduced considerably at TEs between 100 and 170ms (35).Hattingen et al. (36), in their study on glial tumors, suggestedthat the contributions by mI and Gly to the signal at 3.56 ppm inthe 1H spectrum can be distinguished by comparing spectra atshort and long TEs. The present study was carried out at a longTE, thus minimizing the contribution from mI to the peak at3.56 ppm. Still, a minor contribution from mI cannot be ruledout. However, high‐resolution analyses of the tumor extractsfrom two of the patients helped to assign this peak to Gly.Although the in vitro results from two of the patients cannot beextrapolated to make a generalization, the theoretical possibilityof the peak at 3.55 ppm to be assigned to Gly has beendiscussed in detail by Jayasundar et al. (11). Moreover, Yeh et al.(17), in their ex vivo studies, confirmed the presence of Gly intheir CNC tumor sample.The recent study by Bobek‐Billewicz et al. (21) showed a

higher level of Gly/Cr in neurocytomas relative to gliomas,similar to our findings in Fig. 3. Majos et al. (19), in their study ofintraventricular tumors, reported a peak at 3.56 ppm not only inCNCs, but also in all four ependymomas studied. Only one of thefour ependymomas that we have studied (unpublished results)here showed a peak at 3.56 ppm, but Gly/Cr (0.7) and Cho/Cr (2.0)from the same ependymoma were lower than those from CNCsand, on this basis, it could easily be differentiated from CNC.However, further data on both CNCs and ependymomas mayprovide more information to help in their differential diagnosis.

Ala

Although high Ala is generally seen in vivo only in meningiomas(37), in the present study, Ala was observed in 64% of the CNCs.Krishnamoorthy et al. (15) also observed Ala in all three casesstudied, whereas Chuang et al. (12) observed Ala in only one oftheir three patients. The reason for the presence of Ala in 64% ofthe benign CNCs in this study is unclear.

CONCLUSION

A preoperative characterization of CNC is advantageous for thefollowing reasons: (i) an earlier diagnosis would prove useful inplanning the resection of these tumors, which generally have agood prognosis and hence can tolerate partial resection; (ii) themethod of resection is likely to be different for tumors such asCNCs, which are softer, benign and less vascular than solid andvascular tumors, such as meningiomas; thus, an a prioriknowledge of the tumor type (which, at present, is availableonly with postsurgery histopathology) may help the neuro-surgeon to plan the surgery; (iii) as CNCs have histologicalsimilarities with other tumors, such as oligodendroglioma, theirpreoperative identification would help the pathologist decide onthe confirmatory immunohistochemical and TEM studies, whichlook for the presence of neurons in the form of synaptophysinin immunohistochemistry and the ultrastructural details of

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ROLE OF GLYCINE IN CENTRAL NEUROCYTOMAS

the neurons in TEM. The present study, although showing theoccurrence of Gly in 91% of the 11 CNCs examined, alsoconfirms the findings of other reports on CNCs, where thepresence of Gly seems to be a characteristic trend. This studyadds to the spectroscopic data available for CNCs, which arerare tumors.

Acknowledgements

The authors thank the Department of Science and Technology(grant SP/SO/B‐27/94 to RJ) and Council of Scientific andIndustrial Research (grant 9/6(166)/98‐EMR‐I to TS), Governmentof India, for supporting this work.

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