- Email: [email protected]
Fluorescein sodium-guided surgery in cerebral lymphoma
Clinical Neurology and Neurosurgery 139 (2015) 125–128
Contents lists available at ScienceDirect
Clinical Neurology and Neurosurgery journal homepage: www.elsevier.com/locate/clineuro
Fluorescein sodium-guided surgery in cerebral lymphoma Karl-Michael Schebesch a,e,∗ , Julius Hoehne a,e , Christoph Hohenberger a,e , Francesco Acerbi b , Morgan Broggi b , Martin Proescholdt a,e , Christina Wendl c,e , Markus J. Riemenschneider d,e , Alexander Brawanski a,e a
Department of Neurosurgery, Regensburg University Hospital, Germany Department of Neurosurgery, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy Institute of Radiology, Neuroradiology Branch, Regensburg University Hospital, Germany d Department of Neuropathology, Regensburg University Hospital, Germany e Wilhelm-Sander Neuro-Oncology Unit, Regensburg University Hospital, Germany b c
a r t i c l e
i n f o
Article history: Received 17 June 2015 Received in revised form 20 August 2015 Accepted 22 September 2015 Available online 26 September 2015 Keywords: Primary central nervous lymphoma PCNSL Fluorescein sodium YELLOW 560 nm filter Fluorescence-guided surgery
a b s t r a c t Objectives: Growth and progress of primary central nervous lymphoma (PCNSL) severely disrupt the blood brain barrier (BBB). Such disruptions can be intraoperatively visualized by injecting fluorescein sodium (FL) and applying a YELLOW 560 nm surgical microscope filter. Here, we report a small cohort of patients with PCNSL that mimicked high grade gliomas (HGG) or cerebral metastases (CM), who had been operated on with the use of FL. Patients and methods: Retrospectively, seven patients with PCNSL were identified, who had been operated on by means of microsurgery after intravenous FL injection. The surgical reports were screened for statements on the grade of fluorescent staining in the tumor area. One representative case was chosen to show the staining under white light as well as under filtered light at different distances to the tumor area. Results: All patients had shown bright and homogenous fluorescent staining of the tumor (n = 7. 100%). No adverse effects had been observed. Conclusion: Similar to patients with HGG or CM, patients with PCNSL may benefit from use of FL and the dedicated YELLOW 560 nm filter in open surgery. © 2015 Elsevier B.V. All rights reserved.
1. Introduction Primary central nervous system lymphoma (PCNSL) is an extranodal non-Hodgkin lymphoma accounting for less than 5% of primary brain tumors [14,15,19]. Standard treatment consists of chemotherapy regimen containing high dose methotrexate sometimes combined with cytarabine or targeted anti-CD20 treatment using rituximab [19,20]. Histological confirmation of PCNSL is mandatory before initiating any further adjuvant treatment [15]. Generally, a stereotactic biopsy is taken, but an open approach – in terms of craniotomy and microsurgical dissection – may be necessary because of the possibly complicated anatomical location of the lesion for instance, close to or surrounded by principal veins and arteries. If the PCNSL causes a mass lesion with acute compression of the brain stem, a surgical resection
∗ Corresponding author at: Department of Neurosurgery, University Medical Center Regensburg, Franz-Josef-Strauss Allee 11, 93053 Regensburg, Germany. E-mail address: [email protected] (K.-M. Schebesch). http://dx.doi.org/10.1016/j.clineuro.2015.09.015 0303-8467/© 2015 Elsevier B.V. All rights reserved.
may be indicated to reduce intracranial pressure and generate a time window for adjuvant treatment. In fact, a recent study from the German PCNSL research group analyzing 551 patients has demonstrated an improved progression free and overall survival in PCNSL patients receiving subtotal or complete resection compared to biopsy only [18]. In open surgery, even neuronavigation or intraoperative ultrasound can be misleading [5,9] in the case of small or tiny lesions deeply located inside the brain, so that intraoperative fluorescence may help identify the target. Our groups have already described a fluorescein-guided technique for removal of high-grade gliomas (HGG) [1,2,17] and cerebral metastases (CM) [16] by the use of a dedicated surgical microscope filter ‘YELLOW 560 nm’ (Carl Zeiss Meditec, Germany). The retrospective analysis of our databases with regard to patients with brain tumors suspicious for HGG or CM, who had undergone surgery with FL and the YELLOW filter, identified seven patients with the histological diagnosis of PCNSL. Based on our surgical expertise with FL [16,17], we have applied FL-guided surgery almost exclusively in lesions suspicious for HGG or CM since 2012.
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K.-M. Schebesch et al. / Clinical Neurology and Neurosurgery 139 (2015) 125–128
Fig. 1. Case illustration (patient 1). (a) Intraoperative neuro-navigation shows a distance of approximately 10 mm to the target. (b) Intraoperative view under white light at the exact location of (a). (c) Intraoperative view through the YELLOW filter at the exact location of (a).
Here, we present our first experiences with this innovative technique of FL in patients with PCNSL. 2. Methods The neuropathological databases at Regensburg University Hospital and Fondazione IRCCS Istituto Neurologico Besta were
Fig. 2. Case illustration (patient 1). (a) Intraoperative neuro-navigation shows a close approach to the target. (b) Intraoperative view under white light at the exact location of (a). (c) Intraoperative view through the YELLOW filter at the exact location of (a).
retrospectively analyzed with regard to patients with brain tumors suspicious for HGG or CM who had presented between December 2011 and May 2015. Seven patients (four women, three men; mean age of 66.3 years) with the final diagnosis of PCNSL were identified, who had undergone open neurosurgery guided by FL and the dedicated YELLOW 560 nm filter. The regimen of FL administration
K.-M. Schebesch et al. / Clinical Neurology and Neurosurgery 139 (2015) 125–128
127
Table 1 Descriptive statistics. Pat. no.
Age
Sex
Location
Histology
Fluorescence
1 2 3 4 5 6 7
55 70 72 78 74 63 52
f m f f f m m
Right frontal Left occipital Left frontal IVth ventricle Right frontal Left temporal Left temporal
B-cell NHL (diffuse large cell) B-cell NHL (diffuse large cell) B-cell NHL (diffuse large cell) B-cell NHL (diffuse large cell) B-cell NHL (diffuse large cell) B-cell NHL (diffuse large cell) B-cell NHL (diffuse large cell)
+ + + + + + +
NHL means non-Hodgkin lymphoma, + means bright fluorescence.
has been described elsewhere [1,2,16,17]. To aid the planning of the craniotomy and the surgical approach, six patients had been examined with magnetic resonance imaging (MRI)-guided neuronavigation and one with intraoperative sonography. In all patients, preoperative contrast-enhanced MRI with gadolinium had shown a homogeneous intra-axial mass suspicious for CM or HGG. Thus, patients had received craniotomy and microsurgical dissection for removal or biopsy of the tumor. Early postoperative contrast-enhanced MRI or computed tomography (CT) had been conducted in all patients to rule out hemorrhage and to confirm the extent of resection. The surgical protocol was screened for any detailed information on the usefulness and grade of fluorescent staining of the targeted lesion (such written statements are common practice in our department). In patient 1, the entire procedure had been documented with screenshots and photographs (see case illustration, Figs. 1a–c and 2a–c). In the case of the intraoperative diagnosis of PCNSL, we had not aimed at removing the entire lesion in most cases. Therefore, we did not evaluate the extent of resection (EOR) for this report but mainly focused on the correspondence of histology (PCNSL) and the intensity of fluorescent staining. FL was used off-label, thus written informed consent had been obtained from all patients. Regarding the patients operated on at Regensburg University Hospital, the study was approved by the local Ethics Committee (14-101-0298). One of the patients from this series, operated on at Fondazione IRCCS Istituto Neurologico Besta, was initially enrolled in a phase II trial named FLUOGLIO [17,18] (approved by the local Ethics Committee and registered on the European Regulatory Authorities website, EudraCT No. 2011002527-18) but excluded for the analysis of the primary end-point of this trial (i.e. extent of resection of HGG) for the histological diagnosis of PCNSL. 3. Results The precise neuropathological diagnosis of the PCNSL of the included patients is presented in Table 1. Bright and homogenous fluorescent staining of the lesion had been documented in 100% (n = 7). Pale fluorescence or absence of fluorescent staining at the margin or inside the tumor had not been observed. In four patients, the tumor had been removed completely either due to the space-occupying effect (n = 2) or when immediate histological analysis during surgery (frozen section) did not yield the distinct diagnosis of PCNSL (n = 2). In three patients, surgery had been stopped immediately due to the clear intraoperative diagnosis of cerebral lymphoma. The case presentation (pat. 1, Figs. 1a–c and 2a–c) was chosen to show the impression of fluorescence when approaching the lesion. The screenshot of neuro-navigation (Figs. 1a and 2a), the view under white light (Figs. 1b and 2b), and the view under the YELLOW filter (Figs. 1c and 2c) had been taken at identical locations: approximately 10 mm distant to the border of the target (Fig. 1a–c) and directly at the tumor margin (Fig. 2a–c). Fig. 1c only shows very
pale fluorescent staining, but Fig. 2c depicts the bright and intensive fluorescent signal that clearly demarcates the targeted area. No adverse effects, anaphylactic reactions, or postoperative neurological deterioration had been documented for any of the patients. The intravenous administration of FL had immediately produced greenish urine in all patients for a maximum of 24 h.
4. Conclusion Similarly to HGG and CM, PCNSLs damage and disrupt the blood–brain barrier (BBB) [7,10,11,19], which can be visualized as gadolinium-uptake in the T1-weighted sequence in contrastenhanced MRI [8]. Particularly for HGG, a significant correlation has been recently reported between the intensity of fluorescent staining after the injection of FL (in combination with the use of the YELLOW 560 nm filter) and gadolinium-uptake in preoperative MRI [6]. The effectiveness of fluorescein sodium has been repeatedly proven during HGG surgery in terms of identified areas with a high tumor load [2,6]. The rates of complete and gross-total resection have been significantly increased with a sensitivity of 94% and 82.2% and a specificity of 89.5% and 90.9% [1,6]. Similarly, FL (visualized intraoperatively under the YELLOW filter) has been reported to be as effective in CM surgery [16], but sensitivity and specificity rates are not yet available for these entities. However, we hypothesized that cerebral lesions uncovered by gadolinium-uptake in the T1-weighted sequence can be intraoperatively shown by means of bright and well-defined fluorescent staining using FL and the YELLOW 560 nm filter. Our results of patients with PCNSL, operated on by means of this technique, clearly support this hypothesis. Bright and homogenous fluorescence signaling could be achieved in all patients, which helped to identify and explore the suspicious lesion. Of course we are aware that the treatment of PCNSL generally is primarily non-surgical. However, due to the large space-occupying effect with consecutive neurological deterioration, we decided to remove the tumor despite the distinct diagnose of PCNSL during frozen section. The largest retrospective analysis of biopsy versus subtotal and total resection in PCNSL has indicated an inferior outcome at least in the subtotal resection group [3]. However, the postsurgical treatment of PCNSL has now changed dramatically, therefore this study may not be appropriate anymore to estimate the benefit of surgical removal of PCNSL. In 2005, Bellinzona et al. published the outcome of 32 patients treated for PCNSL treated from 1986 to 2000 in which surgical removal of the lesion had been performed. Although a beneficial role for surgery could not have been detected, the authors outlined the need for complete resection in patients with large and space-occupying lesion in whom neurological deterioration had been documented [4]. In accordance, the G-PCNSL-SG-1 trial has demonstrated an improved PFS and OS in patients receiving surgical resection compared to biopsy only [18]. This effect was not due to differences in KPS or age, but was significantly more pronounced in patients with singular lesions.
128
K.-M. Schebesch et al. / Clinical Neurology and Neurosurgery 139 (2015) 125–128
In the other two completely resected patients, the pathologists could not reliably specify the diagnose PCNSL. Thus, it was decided to further resect all fluorescing tissue as HGG could not be excluded in these two cases. Our findings support the data provided by Okuda et al. in 2008. Patients with lesions suspicious for PCNSL received high doses of FL after opening of the dura (20 mg/kg). Some 15 min later, intensively fluorescing tissue was collected under white light conditions[12]. To the best of our knowledge, this report and our series provide the first data on the efficacy of FL in PCNSL. In the long term, users need a recommendation when to use which dye in malignant brain tumor surgery. Presently, we think that it is too early to compare the available dyes, especially 5aminolevulinic acid (5-ALA) and FL, in the setting of PCNSL surgery. There is too little data available for both technical adjuncts and large prospectively designed trials are pending. However, stereotactic needle biopsy is the most employed surgical technique to confirm PCNSL. FL has already been used in stereotactic needle biopsy in HGG successfully [13]. In this trial, the specificity of fluorescing specimen had been 100%. The similar approach should be evaluated in PCNSL biopsies as well. Although we are aware that the data presented in this short communication have only limited statistical power, we may conclude that FL under the dedicated YELLOW 560 nm filter intraoperatively visualizes PCNSL. The emerging reports of FL use in brain tumor surgery suggest that – similar to gadolinium-uptake in the MRI – intravenously administered low-dose FL in combination with the YELLOW filter visualizes all types of cerebral lesions disrupting the BBB. Funding
[3]
[4]
[5] [6]
[7] [8] [9]
[10] [11]
[12]
[13]
[14] [15] [16]
None. [17]
Conflict of interest Karl-Michael Schebesch, Francesco Acerbi and Alexander Brawanski received honoraria, travel costs, and financial support for scientific lectures from Carl Zeiss Meditec, Germany.
[18]
References [1] F. Acerbi, M. Broggi, M. Eoli, E. Anghileri, C. Cavallo, C. Boffano, R. Cordella, L. Cuppini, B. Pollo, M. Schiariti, S. Visintini, C. Orsi, E. La Corte, G. Broggi, P. Ferroli, Is fluorescein-guided technique able to help in resection of high-grade gliomas? Neurosurg. Focus 36 (2014) E5. [2] F. Acerbi, M. Broggi, M. Eoli, E. Anghileri, L. Cuppini, B. Pollo, M. Schiariti, S. Visintini, C. Orsi, A. Franzini, G. Broggi, P. Ferroli, Fluorescein-guided surgery for
[19]
[20]
grade IV gliomas with a dedicated filter on the surgical microscope: preliminary results in 12 cases, Acta Neurochir. 155 (2013) 1277–1286. B. Bataille, V. Delwail, E. Menet, P. Vandermarcq, P. Ingrand, M. Wager, G. Guy, F. Lapierre, Primary intracerebral malignant lymphoma: report of 248 cases, J. Neurosurg. 92 (2000) 261–266. M. Bellinzona, F. Roser, H. Ostertag, R.M. Gaab, M. Saini, Surgical removal of primary central nervous system lymphomas (PCNSL) presenting as space occupying lesions: a series of 33 cases, Eur. J. Surg. Oncol. 31 (2005) 100–105. J.E. Cheon, Intraoperative neurosonography revisited: effective neuronavigation in pediatric neurosurgery, Ultrasonography 34 (2015) 79–87. R.J. Diaz, R.R. Dios, E.M. Hattab, K. Burrell, P. Rakopoulos, N. Sabha, C. Hawkins, G. Zadeh, J.T. Rutka, A.A. Cohen-Gadol, Study of the biodistribution of fluorescein in glioma-infiltrated mouse brain and histopathological correlation of intraoperative findings in high-grade gliomas resected under fluorescein fluorescence guidance, J. Neurosurg. (2015) 1–10. B.K. Hendricks, A.A. Cohen-Gadol, J.C. Miller, Novel delivery methods bypassing the blood–brain and blood–tumor barriers, Neurosurg. Focus 38 (2015) E10. J.R. Hesselink, G.A. Press, MR contrast enhancement of intracranial lesions with Gd-DTPA, Radiol. Clin. N. Am. 26 (1988) 873–887. D. Kuhnt, M.H. Bauer, C. Nimsky, Brain shift compensation and neurosurgical image fusion using intraoperative MRI: current status and future challenges, Crit. Rev. Biomed. Eng. 40 (2012) 175–185. J. Lee, A. Baird, B.P. Eliceiri, In vivo measurement of glioma-induced vascular permeability, Methods Mol. Biol. 763 (2011) 417–422. E.K. Nduom, C. Yang, M.J. Merrill, Z. Zhuang, R.R. Lonser, Characterization of the blood–brain barrier of metastatic and primary malignant neoplasms, J. Neurosurg. 119 (2013) 427–433. T. Okuda, K. Kataoka, A. Kato, Effectiveness of intraoperative fluorescence for diagnosis of malignant lymphoma, No Shinkei Geka (Neurol. Surg.) 36 (2008) 1001–1004. R. Rey-Dios, E.M. Hattab, A.A. Cohen-Gadol, Use of intraoperative fluorescein sodium fluorescence to improve the accuracy of tissue diagnosis during stereotactic needle biopsy of high-grade gliomas, Acta Neurochir. 156 (2014) 1071–1075 (discussion 1075). D. Ricard, A. Idbaih, F. Ducray, M. Lahutte, K. Hoang-Xuan, J.Y. Delattre, Primary brain tumours in adults, Lancet 379 (2012) 1984–1996. N. Schafer, M. Glas, U. Herrlinger, Primary CNS, lymphoma: a clinician’s guide, Exp. Rev. Neurother. 12 (2012) 1197–1206. K.M. Schebesch, J. Hoehne, C. Hohenberger, M. Proescholdt, M.J. Riemenschneider, C. Wendl, A. Brawanski, Fluorescein sodium-guided resection of cerebral metastases-experience with the first 30 patients, Acta Neurochir. 157 (2015) 899–904. K.M. Schebesch, M. Proescholdt, J. Hohne, C. Hohenberger, E. Hansen, M.J. Riemenschneider, W. Ullrich, C. Doenitz, J. Schlaier, M. Lange, A. Brawanski, Sodium fluorescein-guided resection under the YELLOW 560 nm surgical microscope filter in malignant brain tumor surgery – a feasibility study, Acta Neurochir. 155 (2013) 693–699. E. Thiel, A. Korfel, P. Martus, L. Kanz, F. Griesinger, M. Rauch, A. Roth, B. Hertenstein, T. von Toll, T. Hundsberger, H.G. Mergenthaler, M. Leithauser, T. Birnbaum, L. Fischer, K. Jahnke, U. Herrlinger, L. Plasswilm, T. Nagele, T. Pietsch, M. Bamberg, M. Weller, High-dose methotrexate with or without whole brain radiotherapy for primary CNS lymphoma (G-PCNSL-SG-1): a phase 3, randomised, non-inferiority trial, Lancet Oncol. 11 (2010) 1036–1047. R.M. Tyson, T. Siegal, N.D. Doolittle, C. Lacy, D.F. Kraemer, E.A. Neutwelt, Current status and future of relapsed primary central nervous system lymphoma (PCNSL), Leuk. Lymphoma 44 (2003) 627–633. J. Zacher, B. Kasenda, A. Engert, N. Skoetz, The role of additional radiotherapy for primary central nervous system lymphoma, Cochrane Database Syst. Rev. 6 (2014) CD009211.
Contents lists available at ScienceDirect
Clinical Neurology and Neurosurgery journal homepage: www.elsevier.com/locate/clineuro
Fluorescein sodium-guided surgery in cerebral lymphoma Karl-Michael Schebesch a,e,∗ , Julius Hoehne a,e , Christoph Hohenberger a,e , Francesco Acerbi b , Morgan Broggi b , Martin Proescholdt a,e , Christina Wendl c,e , Markus J. Riemenschneider d,e , Alexander Brawanski a,e a
Department of Neurosurgery, Regensburg University Hospital, Germany Department of Neurosurgery, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy Institute of Radiology, Neuroradiology Branch, Regensburg University Hospital, Germany d Department of Neuropathology, Regensburg University Hospital, Germany e Wilhelm-Sander Neuro-Oncology Unit, Regensburg University Hospital, Germany b c
a r t i c l e
i n f o
Article history: Received 17 June 2015 Received in revised form 20 August 2015 Accepted 22 September 2015 Available online 26 September 2015 Keywords: Primary central nervous lymphoma PCNSL Fluorescein sodium YELLOW 560 nm filter Fluorescence-guided surgery
a b s t r a c t Objectives: Growth and progress of primary central nervous lymphoma (PCNSL) severely disrupt the blood brain barrier (BBB). Such disruptions can be intraoperatively visualized by injecting fluorescein sodium (FL) and applying a YELLOW 560 nm surgical microscope filter. Here, we report a small cohort of patients with PCNSL that mimicked high grade gliomas (HGG) or cerebral metastases (CM), who had been operated on with the use of FL. Patients and methods: Retrospectively, seven patients with PCNSL were identified, who had been operated on by means of microsurgery after intravenous FL injection. The surgical reports were screened for statements on the grade of fluorescent staining in the tumor area. One representative case was chosen to show the staining under white light as well as under filtered light at different distances to the tumor area. Results: All patients had shown bright and homogenous fluorescent staining of the tumor (n = 7. 100%). No adverse effects had been observed. Conclusion: Similar to patients with HGG or CM, patients with PCNSL may benefit from use of FL and the dedicated YELLOW 560 nm filter in open surgery. © 2015 Elsevier B.V. All rights reserved.
1. Introduction Primary central nervous system lymphoma (PCNSL) is an extranodal non-Hodgkin lymphoma accounting for less than 5% of primary brain tumors [14,15,19]. Standard treatment consists of chemotherapy regimen containing high dose methotrexate sometimes combined with cytarabine or targeted anti-CD20 treatment using rituximab [19,20]. Histological confirmation of PCNSL is mandatory before initiating any further adjuvant treatment [15]. Generally, a stereotactic biopsy is taken, but an open approach – in terms of craniotomy and microsurgical dissection – may be necessary because of the possibly complicated anatomical location of the lesion for instance, close to or surrounded by principal veins and arteries. If the PCNSL causes a mass lesion with acute compression of the brain stem, a surgical resection
∗ Corresponding author at: Department of Neurosurgery, University Medical Center Regensburg, Franz-Josef-Strauss Allee 11, 93053 Regensburg, Germany. E-mail address: [email protected] (K.-M. Schebesch). http://dx.doi.org/10.1016/j.clineuro.2015.09.015 0303-8467/© 2015 Elsevier B.V. All rights reserved.
may be indicated to reduce intracranial pressure and generate a time window for adjuvant treatment. In fact, a recent study from the German PCNSL research group analyzing 551 patients has demonstrated an improved progression free and overall survival in PCNSL patients receiving subtotal or complete resection compared to biopsy only [18]. In open surgery, even neuronavigation or intraoperative ultrasound can be misleading [5,9] in the case of small or tiny lesions deeply located inside the brain, so that intraoperative fluorescence may help identify the target. Our groups have already described a fluorescein-guided technique for removal of high-grade gliomas (HGG) [1,2,17] and cerebral metastases (CM) [16] by the use of a dedicated surgical microscope filter ‘YELLOW 560 nm’ (Carl Zeiss Meditec, Germany). The retrospective analysis of our databases with regard to patients with brain tumors suspicious for HGG or CM, who had undergone surgery with FL and the YELLOW filter, identified seven patients with the histological diagnosis of PCNSL. Based on our surgical expertise with FL [16,17], we have applied FL-guided surgery almost exclusively in lesions suspicious for HGG or CM since 2012.
126
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Fig. 1. Case illustration (patient 1). (a) Intraoperative neuro-navigation shows a distance of approximately 10 mm to the target. (b) Intraoperative view under white light at the exact location of (a). (c) Intraoperative view through the YELLOW filter at the exact location of (a).
Here, we present our first experiences with this innovative technique of FL in patients with PCNSL. 2. Methods The neuropathological databases at Regensburg University Hospital and Fondazione IRCCS Istituto Neurologico Besta were
Fig. 2. Case illustration (patient 1). (a) Intraoperative neuro-navigation shows a close approach to the target. (b) Intraoperative view under white light at the exact location of (a). (c) Intraoperative view through the YELLOW filter at the exact location of (a).
retrospectively analyzed with regard to patients with brain tumors suspicious for HGG or CM who had presented between December 2011 and May 2015. Seven patients (four women, three men; mean age of 66.3 years) with the final diagnosis of PCNSL were identified, who had undergone open neurosurgery guided by FL and the dedicated YELLOW 560 nm filter. The regimen of FL administration
K.-M. Schebesch et al. / Clinical Neurology and Neurosurgery 139 (2015) 125–128
127
Table 1 Descriptive statistics. Pat. no.
Age
Sex
Location
Histology
Fluorescence
1 2 3 4 5 6 7
55 70 72 78 74 63 52
f m f f f m m
Right frontal Left occipital Left frontal IVth ventricle Right frontal Left temporal Left temporal
B-cell NHL (diffuse large cell) B-cell NHL (diffuse large cell) B-cell NHL (diffuse large cell) B-cell NHL (diffuse large cell) B-cell NHL (diffuse large cell) B-cell NHL (diffuse large cell) B-cell NHL (diffuse large cell)
+ + + + + + +
NHL means non-Hodgkin lymphoma, + means bright fluorescence.
has been described elsewhere [1,2,16,17]. To aid the planning of the craniotomy and the surgical approach, six patients had been examined with magnetic resonance imaging (MRI)-guided neuronavigation and one with intraoperative sonography. In all patients, preoperative contrast-enhanced MRI with gadolinium had shown a homogeneous intra-axial mass suspicious for CM or HGG. Thus, patients had received craniotomy and microsurgical dissection for removal or biopsy of the tumor. Early postoperative contrast-enhanced MRI or computed tomography (CT) had been conducted in all patients to rule out hemorrhage and to confirm the extent of resection. The surgical protocol was screened for any detailed information on the usefulness and grade of fluorescent staining of the targeted lesion (such written statements are common practice in our department). In patient 1, the entire procedure had been documented with screenshots and photographs (see case illustration, Figs. 1a–c and 2a–c). In the case of the intraoperative diagnosis of PCNSL, we had not aimed at removing the entire lesion in most cases. Therefore, we did not evaluate the extent of resection (EOR) for this report but mainly focused on the correspondence of histology (PCNSL) and the intensity of fluorescent staining. FL was used off-label, thus written informed consent had been obtained from all patients. Regarding the patients operated on at Regensburg University Hospital, the study was approved by the local Ethics Committee (14-101-0298). One of the patients from this series, operated on at Fondazione IRCCS Istituto Neurologico Besta, was initially enrolled in a phase II trial named FLUOGLIO [17,18] (approved by the local Ethics Committee and registered on the European Regulatory Authorities website, EudraCT No. 2011002527-18) but excluded for the analysis of the primary end-point of this trial (i.e. extent of resection of HGG) for the histological diagnosis of PCNSL. 3. Results The precise neuropathological diagnosis of the PCNSL of the included patients is presented in Table 1. Bright and homogenous fluorescent staining of the lesion had been documented in 100% (n = 7). Pale fluorescence or absence of fluorescent staining at the margin or inside the tumor had not been observed. In four patients, the tumor had been removed completely either due to the space-occupying effect (n = 2) or when immediate histological analysis during surgery (frozen section) did not yield the distinct diagnosis of PCNSL (n = 2). In three patients, surgery had been stopped immediately due to the clear intraoperative diagnosis of cerebral lymphoma. The case presentation (pat. 1, Figs. 1a–c and 2a–c) was chosen to show the impression of fluorescence when approaching the lesion. The screenshot of neuro-navigation (Figs. 1a and 2a), the view under white light (Figs. 1b and 2b), and the view under the YELLOW filter (Figs. 1c and 2c) had been taken at identical locations: approximately 10 mm distant to the border of the target (Fig. 1a–c) and directly at the tumor margin (Fig. 2a–c). Fig. 1c only shows very
pale fluorescent staining, but Fig. 2c depicts the bright and intensive fluorescent signal that clearly demarcates the targeted area. No adverse effects, anaphylactic reactions, or postoperative neurological deterioration had been documented for any of the patients. The intravenous administration of FL had immediately produced greenish urine in all patients for a maximum of 24 h.
4. Conclusion Similarly to HGG and CM, PCNSLs damage and disrupt the blood–brain barrier (BBB) [7,10,11,19], which can be visualized as gadolinium-uptake in the T1-weighted sequence in contrastenhanced MRI [8]. Particularly for HGG, a significant correlation has been recently reported between the intensity of fluorescent staining after the injection of FL (in combination with the use of the YELLOW 560 nm filter) and gadolinium-uptake in preoperative MRI [6]. The effectiveness of fluorescein sodium has been repeatedly proven during HGG surgery in terms of identified areas with a high tumor load [2,6]. The rates of complete and gross-total resection have been significantly increased with a sensitivity of 94% and 82.2% and a specificity of 89.5% and 90.9% [1,6]. Similarly, FL (visualized intraoperatively under the YELLOW filter) has been reported to be as effective in CM surgery [16], but sensitivity and specificity rates are not yet available for these entities. However, we hypothesized that cerebral lesions uncovered by gadolinium-uptake in the T1-weighted sequence can be intraoperatively shown by means of bright and well-defined fluorescent staining using FL and the YELLOW 560 nm filter. Our results of patients with PCNSL, operated on by means of this technique, clearly support this hypothesis. Bright and homogenous fluorescence signaling could be achieved in all patients, which helped to identify and explore the suspicious lesion. Of course we are aware that the treatment of PCNSL generally is primarily non-surgical. However, due to the large space-occupying effect with consecutive neurological deterioration, we decided to remove the tumor despite the distinct diagnose of PCNSL during frozen section. The largest retrospective analysis of biopsy versus subtotal and total resection in PCNSL has indicated an inferior outcome at least in the subtotal resection group [3]. However, the postsurgical treatment of PCNSL has now changed dramatically, therefore this study may not be appropriate anymore to estimate the benefit of surgical removal of PCNSL. In 2005, Bellinzona et al. published the outcome of 32 patients treated for PCNSL treated from 1986 to 2000 in which surgical removal of the lesion had been performed. Although a beneficial role for surgery could not have been detected, the authors outlined the need for complete resection in patients with large and space-occupying lesion in whom neurological deterioration had been documented [4]. In accordance, the G-PCNSL-SG-1 trial has demonstrated an improved PFS and OS in patients receiving surgical resection compared to biopsy only [18]. This effect was not due to differences in KPS or age, but was significantly more pronounced in patients with singular lesions.
128
K.-M. Schebesch et al. / Clinical Neurology and Neurosurgery 139 (2015) 125–128
In the other two completely resected patients, the pathologists could not reliably specify the diagnose PCNSL. Thus, it was decided to further resect all fluorescing tissue as HGG could not be excluded in these two cases. Our findings support the data provided by Okuda et al. in 2008. Patients with lesions suspicious for PCNSL received high doses of FL after opening of the dura (20 mg/kg). Some 15 min later, intensively fluorescing tissue was collected under white light conditions[12]. To the best of our knowledge, this report and our series provide the first data on the efficacy of FL in PCNSL. In the long term, users need a recommendation when to use which dye in malignant brain tumor surgery. Presently, we think that it is too early to compare the available dyes, especially 5aminolevulinic acid (5-ALA) and FL, in the setting of PCNSL surgery. There is too little data available for both technical adjuncts and large prospectively designed trials are pending. However, stereotactic needle biopsy is the most employed surgical technique to confirm PCNSL. FL has already been used in stereotactic needle biopsy in HGG successfully [13]. In this trial, the specificity of fluorescing specimen had been 100%. The similar approach should be evaluated in PCNSL biopsies as well. Although we are aware that the data presented in this short communication have only limited statistical power, we may conclude that FL under the dedicated YELLOW 560 nm filter intraoperatively visualizes PCNSL. The emerging reports of FL use in brain tumor surgery suggest that – similar to gadolinium-uptake in the MRI – intravenously administered low-dose FL in combination with the YELLOW filter visualizes all types of cerebral lesions disrupting the BBB. Funding
[3]
[4]
[5] [6]
[7] [8] [9]
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Conflict of interest Karl-Michael Schebesch, Francesco Acerbi and Alexander Brawanski received honoraria, travel costs, and financial support for scientific lectures from Carl Zeiss Meditec, Germany.
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