Neurosurg Focus 18 (6a):E4, 2005

Differentiation of tumors by advanced magnetic resonance spectroscopy

MARK D. KRIEGER, M.D., ASHOK PANIGRAHY, M.D., J. GORDON MCCOMB, M.D., MARVIN D. NELSON, M.D., XIAODONG LIU, M.D., PH.D., IGNACIO GONZALEZ-GOMEZ, M.D., FLOYD GILLES, M.D., AND STEFAN BLUML, PH.D. Departments of Neurological Surgery, Radiology, and Pathology, Childrens Hospital Los Angeles and Keck School of Medicine of the University of Southern California, Los Angeles; and Rudi Schulte Research Institute, Santa Barbara, California

Object. The management of pediatric intraventricular tumors is highly dependent on identification of the tumor type. Choroid plexus papillomas, a common intraventricular tumor in children, can be difficult to distinguish radiographi- cally from choroid plexus carcinomas and other common pediatric (CNS) tumors. In this study to overcome the limitations of current noninvasive imaging modalities, the authors use novel magnetic resonance (MR) spectroscopy techniques in vivo to elucidate the identifying biochemical features of choroid plexus tumors that may facilitate diagnosis and treatment. Methods. Based on an Internal Review Board–approved protocol, six children with newly diagnosed, untreated intraventricular brain tumors were identified. On retrospective review, this series included three choroid plexus pa- pillomas and three choroid plexus carcinomas. Single-voxel proton MR spectroscopy with a short echo time was per- formed, and absolute metabolite concentrations (in mmol/kg) were determined using fully automated quantita- tion. These results were compared with MR spectroscopy profiles obtained in 54 other untreated CNS in children. The myo-inositol (mI) level was significantly higher in choroid plexus papillomas (Ͼ 10 mmol/kg), uniquely dis- tinguishing these tumors from choroid plexus carcinomas and all other tumors. Choroid plexus carcinomas, on the other hand, had significantly elevated levels of choline when compared with choroid plexus papillomas. Conclusions. In this study the authors find that mI is a biochemical constituent that uniquely identifies choroid plexus papillomas and can be used as a noninvasive means of diagnosis and for follow-up evaluations in patients with this disease.

KEY WORDS • • • pediatric • magnetic resonance spectroscopy

Choroid plexus tumors range from the histologically and that these lesions are extremely vascular, making surgery clinically benign choroid plexus papilloma to the histolog- difficult in very young patients.12,21,23,24,26,28,30 ically and clinically malignant choroid plexus carcinoma. The management of choroid plexus tumors would be Overall, these are relatively rare CNS lesions, accounting greatly facilitated by an accurate, noninvasive, preoperative for less than 1% of all intracranial tumors.5,7,8,10,13,17,18,20,24,25, diagnosis. Traditional imaging techniques have oftentimes 29,34 Nevertheless, they are more commonly seen in chil- been inadequate in differentiating these tumors.17,34 A non- dren, accounting for up to 6% of all primary CNS neo- invasive diagnosis would aid in surgical planning; specifi- plasms in a pediatric population.25,27 Indeed, this is a disease cally, surgical approaches and adjuvant therapy, such as of the very young, with 70% of these tumors seen in chil- preoperative embolization, could be planned to address the dren less than 2 years of age.10,25,27,34 hypervascularity of choroid plexus carcinomas. Approach- Papillomas account for two thirds of choroid plexus tu- es could also be determined to address the invasiveness of mors,9,17,27,30,33 and are generally benign, even when invasion these tumors. Additionally, preoperative imaging could be requested to determine metastases in the case of choroid is seen.17 Resection is curative in these cases.10,17,22,24 In con- plexus carcinomas. For follow-up evaluations, noninvasive trast, carcinomas are malignant lesions, with overall survi- 10,17,24 diagnosis could differentiate residual or recurrent disease val rates of 40 to 50%. Surgical removal gives the best from posttreatment effects. An added benefit would be to chance of cure, and adjuvant therapy is generally recom- 3,19,24,25,28 provide a basis for stratifying patients in clinical research mended. Nevertheless, there is evidence to indicate trials.35 Abbreviations used in this paper: Cho = choline; CNS = central To aid in the preoperative evaluation of choroid plexus nervous system; Cr = creatine; Glx = glutamate ϩ glutamine; tumors, we have used novel MR spectroscopy techniques to Lac = lactate; mI = myo-inositol; MR = magnetic resonance; evaluate six such lesions in children. The goal of this study NAA = N-acetylaspartate; Tau = taurine. was to identify unique biochemical signatures that may

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Unauthenticated | Downloaded 09/27/21 04:41 PM UTC M. D. Krieger, et al. facilitate diagnosis and treatment. With this study, we add Statistical Analysis to the prior work in the field by presenting a quantitative Unpaired two-tailed Student t-tests with unequal vari- analysis of the biochemical constituents of these tumors. ance were used for the following statistical comparisons: choroid plexus papillomas with choroid plexus carcinoma; choroid plexus papillomas with all other tumors; and cho- CLINICAL MATERIAL AND METHODS roid plexus carcinoma with all other tumors. Metabolite Based on an Internal Review Board–approved protocol, concentrations relative to Cho were evaluated. MR spectroscopy studies obtained in six children with newly diagnosed, untreated intraventricular brain tumors RESULTS were reviewed. Patients 5 years old and younger were anes- thetized with 100 to 200 g/min/kg propofol throughout the The MR spectroscopy images were obtained in six chil- acquisition of MR images. All tumors were resected with- dren with newly diagnosed intraventricular brain tumors. in 3 days of the MR examination, and the specimens were These images were obtained at the same time as the preop- reviewed by two independent neuropathologists. erative diagnostic MR images, and added a mean of 10 On retrospective review, this series included three cho- minutes to the procedure time. (Concentrations of metabo- roid plexus papillomas and three choroid plexus carcino- lites are displayed in square brackets.) mas. The criteria of the World Health Organization were As shown in Table 1, three patients had newly diagnosed used to classify the tumors.14 Briefly, choroid plexus papil- choroid plexus papillomas. This group included three boys lomas displayed microscopic features of normal choroid between 6 and 17 years of age (mean age 9 years). On spec- plexus, with villi lined by simple epithelium of uniform size troscopic analysis, there was a significant peak of mI in and shape. No cellular atypia or mitotic figures were seen. choroid plexus papillomas (Ͼ 15 mmol/kg), and elevated In the patients in this series, no stromal invasion was seen. [mI]/[Cho] and [Glx]/[Cho] ratios, distinguishing these tu- Choroid plexus carcinomas showed invasion of the ad- mors from choroid plexus carcinomas, all other tumors, and jacent neural tissue, with a diffuse and poorly defined pat- controls (p Ͻ 0.01) (Table 2). An MR spectroscopy study tern of growth, loss of regular papillary architecture, and obtained at a long echo time of 144 msec confirmed the evidence of cellular malignancy. assignment of mI. (Glycine coresonates with mI at 3.56 These results were also compared with MR spectroscopy ppm, and can thus be confused with mI on analysis. Gly- studies performed in 54 other children with newly di- cine is expected to have a residual signal in MR spectro- agnosed, untreated CNS lesions. This group included 14 scopy obtained with a long echo time, and this was not , five anaplastic , three as- observed.; Fig. 1) Also seen were lowered mean [Cho] trocytomas, 17 pilocytic astrocytomas, four anaplastic ep- (p Ͻ 0.001), [Cr] (p Ͻ 0.01), [Lac] (p Ͻ 0.001), and [Glx] endymomas, five , and six pineal region ger- (p Ͻ 0.05) when compared with other tumors. Neverthe- minomas. less, these results did not reach significance when com- pared with choroid plexus carcinomas. Choroid plexus carcinomas exhibited a distinct pattern Acquisition and Analyses of MR Spectroscopy Studies that clearly distinguished them from papillomas. The most The MR imaging was performed with a 1.5-tesla clinical important distinguishing feature was the lack of mI eleva- imaging unit (General Electric Medical Systems, Milwau- tion. Despite the small number of patients studied, choroid kee, WI). Standard clinical images in three orthogonal plexus papillomas appear to be readily distinguishable from planes were acquired according to established protocols, choroid plexus carcinomas. In the latter lesions, the mean [mI] and [Glx]/[Cho] were 20 and 30%, respectively, of which included precontrast T1-weighted MR imaging, T2- weighted fast–spin echo imaging, and fluid-attenuated in- those measured in choroid plexus papillomas (Table 2). Choroid plexus carcinomas exhibited low [NAA] (p Ͻ version-recovery imaging. The T1-weighted images were obtained in at least two planes after intravenous administra- 0.001) and [Glx] (p Ͻ 0.001) when compared with other tu- tion of 0.1 mmol per kg of body weight of Gd-based con- mors. As in choroid plexus papillomas, the mean [Cr] was trast material (Magnevist; Schering, Berlin, Germany, or also reduced (p Ͻ 0.01). Although the mean [Cho] of cho- Omniscan; Nycomed, Oslo, Norway). roid plexus carcinomas was high when compared with all Single-voxel proton (1H) MR spectra of the tumors were other tumors, it did not reach significance because of the acquired using a point-resolved spectroscopy sequence small number of patients studied. Among concentration ra- with a short 35-msec TE, a 1.5-second TR, and 128 signal tios, low [NAA]/[Cho] (p Ͻ 0.001), low [Cr]/[Cho] (p Ͻ averages. Using the unsuppressed water signal of tissue as 0.0001), and low [NAA]/[Cr] (p Ͻ 0.001) were the most an internal reference, this technique allowed absolute quan- tification (in mmol/kg tissue) of NAA, Cr, Cho, mI, Lac, TABLE 1 Glx, and Tau. The regions of interest were carefully select- Clinical data in six patients with choroid plexus ed to exclude any partial volume with surrounding normal- tumors compared with 54 patients with other CNS tumors* appearing tissue. Proton spectra were processed using com- mercially available software (LCModel Version 6; Stephen No. of Age in Yrs Provencher, Inc., Oakville, Ontario, Canada). Processing of Tumor Type Patients S/I Ratio F/M Ratio (mean Ϯ SD) MR spectra was completely automated and did not require choroid plexus papilloma 3 2:1 0:3 9.2 Ϯ 6.5 user interaction. Absolute concentrations of Tau, Cr, Cho, choroid plexus carcinoma 3 3:0 1:2 1.1 Ϯ 1.4 NAA, mI, Glx, and Lac, and concentration ratios relative to other 54 26:28 24:30 7.4 Ϯ 5.1 Cho were analyzed for this report. * I = infratentorial; S = supratentorial; SD = standard deviation.

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Unauthenticated | Downloaded 09/27/21 04:41 PM UTC Differentiation of choroid plexus tumors by MR spectroscopy

TABLE 2 Choroid plexus carcinomas were distinguished by an Absolute concentrations (in mmol/kg tissue) and elevated level of Cho, which reached statistical signifi- concentration ratios of metabolites in untreated choroid plexus cance when combined in a ratio with Glx and Tau. Other tumors and other CNS lesions* research indicates that Cho is a marker of malignancy. Warren, et al.,35 and Lazareff, et al.,16 have found that a rela- Choroid Choroid Plexus Plexus All tive elevation of Cho with respect to NAA is predictive of Papilloma Carcinoma Other Tumors outcome in children with recurrent primary brain tumors. Metabolite (3 patients) (3 patients) (54 patients) Other authors have also found this change in tumors typi- cally found in adults.2,4,11 [NAA] 2.4 Ϯ 1.3 0.2 Ϯ 0.1 1.3 Ϯ 1.1† [Cr] 1.3 Ϯ 0.7 1.2 Ϯ 0.7 3.8 Ϯ 2.6‡§ The ability to distinguish between papillomas and carci- [Cho] 1.8 Ϯ 0.3 5.1 Ϯ 2.1 3.4 Ϯ 2.0|| nomas is important in the preoperative evaluation of chil- [mI] 20.4 Ϯ 3.7** 4.1 Ϯ 2.0 7.7 Ϯ 5.3†† dren with intraventricular tumors. In both types of tumors, [Glx] 6.8 Ϯ 2.0 5.4 Ϯ 0.9 12.1 Ϯ 4.5†,†† aggressive resection yields the best prognosis.7,13,15–17,19 Ne- [Tau] 0.8 Ϯ 0.9 2.5 Ϯ 0.6 2.4 Ϯ 2.6 vertheless, carcinomas can be more difficult to excise be- [Lac] 0.6 Ϯ 0.5 1.5 Ϯ 1.4 3.2 Ϯ 2.5|| cause of their invasive nature. In fact, some studies cite [NAA]/[Cho] 1.3 Ϯ 0.5 0.1 Ϯ 0.0 0.6 Ϯ 0.6† [Cr]/[Cho] 0.7 Ϯ 0.3 0.3 Ϯ 0.2 1.2 Ϯ 0.9† total excision rates of one third to two thirds for choroid 3,6,17 [mI]/[Cho] 11.9 Ϯ 3.7‡‡ 0.9 Ϯ 0.6 2.6 Ϯ 1.9‡§§ plexus carcinomas. Thus, preoperative diagnosis can [Glx]/[Cho] 3.8 Ϯ 0.5** 1.2 Ϯ 0.7 4.3 Ϯ 2.0§ help the surgeon plan an aggressive resection in these [Tau]/[Cho] 0.5 Ϯ 0.6‡‡ 0.6 Ϯ 0.3 0.7 Ϯ 0.6 cases, while being cautious to avoid damaging the invaded [Lac]/[Cho] 0.4 Ϯ 0.4 0.4. Ϯ 0.4 1.3 Ϯ 1.5††§§ substrate. * Values are given as the mean Ϯ SD. Additionally, carcinomas present more of a problem with †p Ͻ 0.001 for choroid plexus carcinoma compared with all other. vascularity, and thus blood loss, than do papillomas. This ‡p Ͻ 0.01. danger is especially important to appreciate in very young § p Ͻ 0.01. || p Ͻ 0.001 for choroid plexus papilloma compared with all other. children, in whom acute blood loss can be life threatening ** p Ͻ 0.01 for choroid plexus papilloma compared with choroid plexus in a short time. A surgeon expecting a carcinoma can thus carcinoma. tailor the approach to address tumor vascularity early and †† p Ͻ 0.05. minimize blood loss. Additionally, he or she can prepare ‡‡ p Ͻ 0.05. for a transfusion early. §§ p Ͻ 0.05. Noninvasive MR spectroscopy diagnosis can also be beneficial in following these patients postoperatively. Of- tentimes in such patients, the follow-up neuroimaging stud- significant differentiators of choroid plexus carcinomas ies demonstrate residual enhancement. The knowledge of a from other tumors. The [mI]/[Cho] (p Ͻ 0.05), and [Glx]/[Cho] (p Ͻ 0.01) were also significantly reduced.

DISCUSSION In this study the authors examined a group of six chil- dren in whom newly diagnosed, untreated intraventricular brain tumors were investigated using MR spectroscopy. This group includes three patients with choroid plexus papillomas and three with choroid plexus carcinomas. We found a biochemical signature that uniquely distinguished the choroid plexus papillomas from the choroid plexus car- cinomas and all other tumors. This analysis was facilitated by the development of a novel method of MR spectroscopy evaluation that provides quantitative analysis of the bio- chemical constituents of these tumors. Other authors have reported the absolute quantification of metabolite concen- tration by using external standards,6 but we used the im- aged water signal of tissue as an internal standard. We have described this technique before in the analysis of untreated Fig. 1. Diagnostic MR spectra of a choroid plexus papilloma pediatric brain tumors.1 (A, left) and a choroid plexus carcinoma (B, left) acquired using a Choroid plexus papillomas were identified by a distinct short echo time, and T2-weighted (A, right) and T1-weighted MR biochemical constituent: strikingly elevated mI. This is images (B, right) acquired after addition of contrast material, indi- cating the regions of interest. Choroid plexus papillomas show a consistent with an MR spectroscopy study obtained in a prominent mI peak, whereas Cr is hardly detectable. In contrast, single patient with choroid plexus papilloma and reported the more malignant choroid plexus carcinoma shows a prominent 32 by Tzika, et al. In this series, absolute mI levels and the Cho peak, whereas mI is not elevated. The Cr is below the level of mI/Cr ratio separated these lesions from choroid plexus pa- detectability in the spectrum shown in panel B. The signal from pillomas and other tumors. The role of mI in the brain is not lipids and macromolecules resonating between 0.9 and 1.7 ppm well elucidated, and bears further study. was not analyzed in this report.

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Unauthenticated | Downloaded 09/27/21 04:41 PM UTC M. D. Krieger, et al. biochemical signature that distinguishes tumor from post- 15. Kruse B, Barker PB, van Zijl PC, et al: Multislice proton mag- operative changes can help practitioners tailor the treatment netic resonance spectroscopic imaging in X-linked adrenoleu- to the disease. kodystrophy. Ann Neurol 36:595–608, 1994 Clearly, patient numbers are an issue in this study, and 16. Lazareff JA, Gupta RK, Alger J: Variation of post-treatment H- MRSI choline intensity in pediatric . J Neurooncol 41: additional cases are needed to confirm the reproducibility 291–298, 1999 of our results. Nevertheless, we believe that the striking dif- 17. Levy ML, Goldfarb A, Hyder DJ, et al: Choroid plexus tumors in ferences seen, and the statistical significance of these dif- children: significance of stromal invasion. Neurosurgery 48: ferences, are a preliminary validation of these results. In 303–309, 2001 this series we have not provided an ex vivo analysis of the 18. Mannoji H, Becker LE: Ependymal and choroid plexus tumors. tissue to verify the presence of the biochemical constituents Cytokeratin and GFAP expression. 61:1377–1385, 1988 identified, but in other studies researchers have validated 19. Maria BL, Graham ML, Strauss LC, et al: Response of a recur- the accuracy of MR spectroscopy used in this fashion.31 We rent choroid plexus tumor to combination . J have advanced the field by using quantitative analysis to Neurooncol 3:259–262, 1985 20. Matsuda M, Uzura S, Nakasu S, et al: Primary carcinoma of the provide a noninvasive method for determining histological choroid plexus in the lateral ventricle. Surg Neurol 36:294–299, features in childhood brain tumors. We hope that future 1991 work will lead to prognostic information based on these 21. 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Warren KE, Frank JA, Black JL, et al: Proton magnetic reso- roid plexus in children. Neurosurgery 25:327–335, 1989 nance spectroscopic imaging in children with recurrent prima- 11. Fulham MJ, Bizzi A, Dietz MJ, et al: Mapping of brain tumor ry brain tumors. J Clin Oncol 18:1020–1026, 2000 metabolites with proton MR spectroscopic imaging: clinical re- levance. Radiology 185:675–686, 1992 12. Hawkins JC III: Treatment of choroid plexus papillomas in chil- Manuscript received April 22, 2005. dren: a brief analysis of twenty years’ experience. Neurosur- Accepted in final form May 18, 2005. gery 6:380–384, 1980 Funding for this study was received from the National Institutes of 13. Johnson DL: Management of choroid plexus tumors in children. Health/National Cancer Institute (Grant No. 4R33CA096032-02). Pediatr Neurosci 15:195–206, 1989 Address reprint requests to: Mark D. Krieger, M.D., Division of 14. Kleihues P, Burger PC, Scheithauer BW: The new WHO clas- Pediatric Neurosurgery, 1300 North Vermont Avenue, Suite 1006, sification of brain tumours. Brain Pathology 3:255–268, 1993 Los Angeles, California 90027. email: [email protected].

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