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Diffuse intrinsic pontine gliomas in children: Interest of robotic frameless assisted biopsy. A technical note
Neurochirurgie 62 (2016) 327–331
Disponible en ligne sur
ScienceDirect www.sciencedirect.com
Technical note
Diffuse intrinsic pontine gliomas in children: Interest of robotic frameless assisted biopsy. A technical note H.A. Coca a,∗ , H. Cebula a , M. Benmekhbi a , M.P. Chenard b , N. Entz-Werle c , F. Proust a a b c
Service de neurochirurgie CHU Hautepierre, 67098, Strasbourg cedex, France Service de pathologie CHU Hautepierre, 67098, Strasbourg cedex, France Service de pédiatrie, unité d’hématologie-oncologie CHU Hautepierre, 67098, Strasbourg cedex, France
a r t i c l e
i n f o
Article history: Received 31 December 2015 Received in revised form 3 July 2016 Accepted 17 July 2016 Available online 27 October 2016 Keywords: Brainstem tumor Pediatric neurosurgery Robotics Biopsy Frameless
a b s t r a c t Introduction. – Diffuse intrinsic pontine gliomas (DIPG) constitute 10–15% of all brain tumors in the pediatric population; currently prognosis remains poor, with an overall survival of 7–14 months. Recently the indication of DIPG biopsy has been enlarged due to the development of molecular biology and various ongoing clinical and therapeutic trials. Classically a biopsy is performed using a stereotactic frame assisted procedure but the workflow may sometimes be heavy and more complex especially in children. In this study the authors present their experience with frameless robotic-guided biopsy of DIPG in a pediatric population. Patients and methods. – Retrospective study on a series of five consecutive pediatric patients harboring DIPG treated over a 4-year period. All patients underwent frameless robotic-guided biopsy via a transcerebellar approach. Results. – Among the 5 patients studied 3 were male and 2 female with a median age of 8.6 years [range 5 to 13 years]. Clinical presentation included ataxia, hemiparesis and cranial nerve palsy in all patients. MRI imaging of the lesion showed typical DIPG features (3 of them located in the pons) with hypo-intensity on T1 and hyper-intensity signal on T2 sequences and diffuse gadolinium enhancement. The mean procedure time was 56 minutes (range 45 to 67 minutes). No new postoperative neurological deficits were recorded. Histological diagnosis was achieved in all cases as follows: two anaplastic astrocytomas (grade III), two glioblastomas, and one diffuse astrocytoma (grade III). Conclusion. – Frameless robotic assisted biopsy of DIPG in pediatric population is an easier, effective, safe and highly accurate method to achieve diagnosis. © 2016 Elsevier Masson SAS. All rights reserved.
1. Introduction Diffuse intrinsic pontine gliomas (DIPG) constitute 10–15% of all brain tumours in the paediatric population [1]. Children in mid to late childhood are mostly affected, with a mean age of 9.6 years [2,3]. Currently prognosis in children with malignant brainstem glioma remains poor; the overall survival is estimated between 7 and 14 months with a median survival of 9 to 12 months [2,4,5]. Currently, the diagnosis of DIPG based only on imaging and clinical features is considered a suboptimal standard of care [6]. The diagnosis of DIPG is now performed with the new histological
∗ Corresponding author. 10 résidence Beau Rivage, 67460 Souffelweyersheim, France. E-mail addresses: [email protected], [email protected] (H.A. Coca). http://dx.doi.org/10.1016/j.neuchi.2016.07.005 0028-3770/© 2016 Elsevier Masson SAS. All rights reserved.
insights based on the molecular status of histone H3.3 which requires a routine biopsy to obtain tumor samples. Biopsy data on pediatric DIPG yielded a diagnosis from 96 to 100%, with no mortality and procedure related morbidity was less than 5% [7]. Despite some morbidity, a biopsy allows molecular biology analysis and in the present and near future the development of clinical trials of targeted therapies [7–11]. Despite the narrow posterior fossa in children, frame-based stereotactic biopsy is reliable, accurate and safe for the diagnosis of DIPG [7,12]. Nevertheless, the frame-based procedure may sometimes complicate surgical workflow. Frameless systems and especially robotic-guided procedure may actually simplify management. To date only few papers have reported this type of a robotic assisted procedure of a brainstem lesion [13]. The aim of our study was to report our experience regarding frameless robotic stereotactic assisted biopsy by transcerebellar approach in DIPG, focusing on its feasibility, safety and accuracy.
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H.A. Coca et al. / Neurochirurgie 62 (2016) 327–331
Table 1 Summary of demographic, clinical and radiological features of five cases of DIPG. Case
Sex
Age (y)
Clinical presentation
Imaging location
Approach
Complications Complications during after procedure procedure
Pathology
Mutations
Overall survival (months) until death
1
F
11
Ataxia
Transcerebellar
None
None
Glioblastoma
Histone H3.3 K27M ATRX loss
8
2
M
7
Hemiparesis, oculomotor palsy
Transcerebellar
None
None
Anaplastic Grade III Astrocytoma
Histone H3.3 K27M ATRX loss
7
3
M
7
Facial palsy
Diffuse pontine lesion, mesencephalic extension Diffuse pontine lesion, middle cerebellar peduncle extension Diffuse pontine lesion
Transcerebellar
None
None
Glioblastoma
9
4
F
5
Hemiparesis
Diffuse pontine lesion
Transcerebellar
None
None
5
M
Ataxia, oculomotor palsy
Diffuse pontine lesion
Transcerebellar
Transitory bradycardia
None
Anaplastic Grade III Astrcytoma Diffuse Grade III Astrocytoma
No histone mutation ATRX loss Histone H3.1 K27M
13
Histone H3.3 K27M and PI3KCA mutations ATRX loss
11
9
M: male; F: female; y: years.
2. Patients and methods Retrospective study based on a series of five consecutive patients with DIPG treated at our institution during 4 years (from January 2012 to December 2015). MRI Imaging was consistent with DIPG (with > 50% of brainstem infiltration); all patients underwent brainstem biopsy via a frameless robotic stereotactic device (ROSA, Medtech® ). Presenting symptoms, imaging and outcome are summarized in Table 1. The reference imaging used to plan the procedure was the T1 3D Gadolinium enhanced sequences (1 m slice thickness, 320 × 260 pixels) performed 48–72 hours prior to the procedure. The biopsy needle targeting and trajectory were planned the day before surgery on a computer workstation using robot-planning software (Rosana, Medtech® ). The target zone was chosen within the most enhanced area in the MRI and trajectory passing through the middle cerebellar peduncle. The side entry point was determined using the tumor lateral predominance (Fig. 1). The stereotactic biopsy procedures were performed under general anesthesia. The patient was placed in a supine position with a
mild elevation and tilting of the ipsilateral shoulder to allow easier access to the entry point. The head was fixed and secured in a three-pin headrest attached to the robotic device; special attention was paid to ensure the previously planned trajectory. Automatic robotic frameless surface facial merge registration (without fiducial markers) was performed and accuracy of the registration was confirmed by the surgeon (Fig. 2). Sterile draping was performed and the previously planned trajectory was reached by the robotic arm (ROSA Medtech® ), which also served as an instrument holder. A 0.5-cm skin incision was performed without previous shaving. All instruments were positioned and used through an adapted holder by the robotic arm. The bone opening was performed using a 3.2-mm twist drill. Dura mater was opened using a blunt stylet. The tumor sampling was performed with a 2.5 mm side cutting biopsy needle. At least 4 samples were obtained (by a quarter technique) in all cases (Fig. 3). Needle progression was closely controlled during the procedure, and before needle removal we injected 0.5 ml of air in the target to confirm precision of the sampling on a postoperative CT scan (Fig. 4). An absorbable suture was used for skin closure.
Fig. 1. Sagittal 3D T1 weighted enhanced MRI sequences showing a hypointense pontine lesion with little enhancement in patient suffering of oculomotor palsy and ataxia. Target determination with Rosana Medtech® software, the right side of the tumor is targeted as contrast enhancement is more evident. The transcerebellar route is explored and verified. Reconstruction of 3D MRI and simulation is made to ensure the absence of conflict between the entry point and the cranial fixation during surgery.
H.A. Coca et al. / Neurochirurgie 62 (2016) 327–331
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Fig. 2. Surgical positioning. The head is fixed by a three-pin head rest to the robotic device; in this position facial scanning and surgical biopsy are performed. Entry point is clearly exposed; any possible conflict with cranial fixation is avoided. The patient is installed in supine position with a slight elevation of the ipsilateral shoulder.
After the procedure patients were admitted to the ICU; CT scan was performed within the first 24 hours to confirm the targeted zone (little air bubbles) and rule-out any possible hemorrhagic complication. The histological study was routinely done on the samples, which could be also partly fresh-frozen and transferred to the molecular analysis platform. First, in the histological analysis, PTEN analysis, as well as H3.3 staining was considered a loss, when no protein expression was detected in tumor cells on the slides using specific antibodies (Abcam, France and Diagenode, Belgium, respectively). EGFR status was histologically evaluated with a specific antibody (Ventana, Roche, France). ATRX nuclear expression was also detected using a specific antibody (Sigma-Aldrich, France). Genomic DNA was isolated using conventional techniques with the QIAamp DNA purification kit (Qiagen, Courtaboeuf, France). DNA quality and quantification were assessed using a Nanodrop® spectrophotometer (ThermoScientific, Wilmington, DE). The goodquality DNA was assessed by the fluorometer ratio (A260/A280) in each sample. Multiple mutation analyses were performed using a classical Sanger technique with direct sequencing of PCR-amplified
Fig. 3. Once the hole and dura piercing is done (with the help of the robotic arm), biopsy samples are performed by a 2.5-mm cutting biopsy needle.
products for H3F3A, HIST1H3B, PIK3CA, IDH1, BRAF and PDGFRA genes. 3. Results 3.1. Baseline and lesion characteristics A robotic frameless biopsy was performed in five children, three males and two females. The median age was 8.6 ± 3.29 years [range 5 to 13 years]. Clinical presentation included ataxia, hemiparesis and cranial nerve palsy as summarized in Table 1. In all cases MRI features of the lesion showed typical DIPG (involving > 50% of the pons), with hypo-intensity on T1, diffuse gadolinium enhancement and hyper-intensity on T2 sequences. In two cases (case 1, case 2) the lesion extended respectively into the mesencephalic area and cerebellar peduncle.
Fig. 4. Screenshots performed during the surgical procedure showing. A. Needle progression right after dural entry. B. Passage through the cerebellar peduncle. C. Target zone is reached and samples are performed. D. Post-operative no enhanced CT scans showing a little amount of air in the biopsy target zone.
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3.2. Procedure and complications After preoperative planning, trajectory and target were easily reached in each case, without any conflict with headrest fixation. Time of procedure was 56 ± 11 minutes, including installation, robot setting up, and skin-to-skin procedure. A case of severe perioperative bradycardia was recorded, during biopsy needle introduction, that was immediately resolved by atropine administration and the pursuit of the procedure was possible without consequences. No new postoperative neurological deficits were recorded. On the early postoperative CT scan air bubbles were located in the target area in each case and no hemorrhagic complication was detected. 3.3. Diagnostic yield and pathology Diagnosis was achieved in all cases as follows: two anaplastic astrocytoma (grade III) (cases 2 and 4), two glioblastoma (cases 1 and 3), and one diffuse astrocytoma (grade III) (case 5). In each paraffin-embedded sample, immunohistochemical analyses were done easily as described in Table 1. The estimated percentage of tumor cells was between 60 and 90%. The DNA concentrations ranged from 40 to 110 ng/l, with a fluorometric ratio between 1.6 and 2.0 for all biopsy DNAs. The amplification of mutated regions in each gene was possible with an interpretable sequencing analysis. Only histone mutation was diagnosed in 4 patients and associated in one with a PI3KCA mutation and confirmed by immunohistochemistry. ATRX loss occurred in 4 patients.
Few published series regarding robotic stereotactic frameless biopsy have shown comparable results to conventional framebased and other frame-less stereotactic procedures [13,18,21,22]. Potential advantages of these techniques are: • prior imaging acquisition away from surgical procedure; • accurate, predefined, and if necessary reprogrammable biopsy paths and trajectories; • control of possible error of manual setting that could be adjusted perioperatively; • instruments held in repetitive tasks without tremor or fatigue; • finally when applying for posterior fossa procedures (transcerebellar route) no prone position is needed (surface facial scanning) avoiding any possible trajectory conflict with a frame. In our study, we recorded a considerable surgical time reduction (about one hour) with no trajectory conflict. Target was reached in 100% of cases as well as diagnosis, allowing a good quality of histological material and DNA to perform all techniques. The extracted quantity of DNA was sufficient to completely explore those samples at the molecular level and perform complementary research molecular analyses. Transcerebellar route showed only one case of transient perioperative bradycardia with no other neurological manifestation. No complication occurred during or after surgery. Finally, it is noteworthy that no significant differences were reported when comparing transfrontal to transcerebellar route in terms of both complication and/or accuracy [23]. 5. Conclusions
3.4. Treatment and outcome The management strategy was discussed and decided during the neuro-oncology multidisciplinary meeting and consisted of fractionated radiotherapy (54 gy in 30 days, 5 days a week) coupled to targeted therapies in all patients. Mean follow-up was 18.4 months (range 7 to 43 months), overall survival was 8.75 ± 1.71 months. 4. Discussion For a number of years the diagnosis of DIPG was based on typical imaging findings on MR and clinical presentation such as, recent (less than 2 months) cranial nerve palsy, long tract signs and ataxia. These tumors were described as an infiltrating mass of the pons, hypointense on T1 and hyperintense on T2 and Flair images, at least 50% of the pons should be involved and contrast enhancement if present is usually limited or annular [14]. Differential diagnosis should be done with some form of benign pontine enlargement, such as, neurofibromatosis type I and acute demyelinating encephalomyelitis [15]. Brain stem abscesses may also mimic clinical presentation of DIPG, but MRI should clearly make the difference between the two types of lesions [16]. Stereotactic biopsy of DIPG is essential to obtain the exact diagnosis, safety and accuracy of these techniques have previously been widely established [7,17]. Most neurosurgical teams prefer frame based stereotactic devices, although some characteristics of this technique may complicate the surgical workflow. Acquisition of imaging should be routinely performed with a frame, moreover, using a transcerebellar approach the prone position is required and sometimes problems are encountered in the occipital region as there is conflict and interference with the trajectory planning [12,18]. Frameless stereotactic targeting devices are in fact comparable in diagnostic yield and clinical results to frame based devices [19,20], but lack of stabilization may limit access to deep lesions.
Pre- and per-operative procedures of DIPG biopsies on pediatric population could be simplified using stereotactic robot device. This procedure allows for a high diagnostic yield, safety and accuracy, without trajectory conflict. Disclosure of interest The authors declare that they have no competing interest. References [1] Hargrave D, Bartels U, Bouffet E. Diffuse brainstem glioma in children: critical review of clinical trials. Lancet Oncol 2006;7:241–8. [2] Donaldson SS, Laningham F, Fisher PG. Advances toward an understanding of brainstem gliomas. J Clin Oncol 2006;24:1266–72. [3] Albright AL, Packer RJ, Zimmerman R, Rorke LB, Boyett J, Hammond GD. Magnetic resonance scans should replace biopsies for the diagnosis of diffuse brain stem gliomas: a report from the children’s cancer group. Neurosurgery 1993;33(6):1026–30. [4] Leblond P, Vinchon M, Bernier-Chastagner V, Chastagner P. Diffuse intrinsic brain stem glioma in children: current treatment and future directions. Arch Pediatr 2010;17:159–65. [5] Jansen MHA, van Vuurden DG, Vandertop WP, Kaspers GJL. Diffuse intrinsic pontine gliomas: a systematic update on clinical trials and biology. Cancer Treat Rev 2012;38:27–35. [6] Hankinson TC, Campagna J, Foreman NK, Handler MH. Interpretation of magnetic resonance images in diffuse intrinsic pontine glioma: a survey of pediatric neurosurgeons. J Neurosurg Pediatrics 2011;8:97–102. [7] Puget S, Blauwblome T, Grill J. Is biopsy safe in children with newly diagnosed diffuse intrinsic pontine glioma? Am Soc Clin Oncol Educ Book 2012:629–33. [8] Khatua RM, Moore KR, Vats TS, Kestle JRW. Diffuse intrinsic pontine gliomacurrent status and future strategies. Child Nerv Syst 2011;27:1391–7. [9] Grill J, Puget S, Andreiuolo F, Philippe C, MacConaill, Kieran MW. Critical oncogenic mutations in newly diagnosed pediatric diffuse intrinsic pontine glioma. Pediatr Blood Cancer 2012;58:489–91. [10] Frazier JL, Lee J, Thomale UW, Noggle JC, Cohen KJ, Jallo G. Treatment of diffuse intrinsic brainstem gliomas: failed approaches and futures strategies. J Neurosurg Pediatrics 2009;3:259–69. [11] Walker DA, Liu JF, Kieran M, Jabado N, Picton S, Packer R, et al. A multi-disciplinary consensus statement concerning surgical approaches to low-grade, high-grade astrocytomas and diffuse intrinsic pontine gliomas
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[16] [17]
in childhood (CPN Paris 2011) using the Delphi method. Neurooncology 2013;15(4):462–8. Roujeau T, Machado G, Garnett M, Miquel C, Puget S, Georger B, et al. Stereotactic biopsy of diffuse pontine lesions in children. J Neurosurg 2007;107: 1–4. Lefranc M, Capel C, Pruvot-Occean A-S, Fichten A, Desenclos C, Toussaint P, et al. Frameless robotic stereotactic biopsies: a consecutive series of 100 cases. J Neurosurg 2015;122:342–52. Puget S, Beccaria K, Blauwblomme T, Roujeau T, James S, Grill J, et al. Biopsy in a series of 130 pediatric diffuse intrinsic pontine gliomas. Childs Nerv Syst 2015;31:1773–80. Broniscer A, Gajjar A, Bhargava R, Langston JW, Heideman R, Jones D, et al. Brain stem involvement in children with neurofibromatosis type 1: role of magnetic resonance imaging and spectroscopy in the distinction from diffuse pontine glioma. Neurosurgery 1997;40(2):331–7. Fuentes S, Bouillot P, Regis J, Lena G, Choux M. Management of brainstem abscess. Br J Neurosurg 2001;15:57–62. Pérez-Gómez JL, Rodríguez-Álvarez CA, Marhx-Bracho A, Rueda-Franco F. Stereotactic biopsy for brainstem tumors in pediatric patients. Child Nerv Syst 2010;26:29–34.
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[18] Bekelis K, Rawdan TA, Desai A, Roberts DW. Frameless robotically targeted stereotactic brain biopsy: feasibility, diagnostic yield, and safety. J Neurosurg 2012;116:1002–6. [19] Cage TA, Samagh SP, Mueller S, Nicolaides T, Haas-Kogan D, Prados M, et al. Feasibility, safety, and indications for surgical biopsy of intrinsic brainstem tumors in children. Childs Nerv Syst 2013;29:1313–9. [20] Widmann G, Schullian P, Ortler M, Bale R. Frameless stereotactic targeting devices: targeting errors and clinical results. Int J Med Robot 2012;8: 1–16. [21] Haegelen C, Touzet G, Reyns N, Maurage CA, Ayachi M, Blond S. Stereotactic robot-guided biopsies of brain stem lesions: experience with 15 cases. Neurochirurgie 2010;56:363–7. [22] Lefranc M, Capel C, Pruvot AS, Fichten A, Desenclos C, Toussaint P, et al. The impact of the reference imaging modality, registration method and intraoperative flat-panel computed tomography on the accuracy of the ROSA® stereotactic robot. Stereotact Funct Neurosurg 2014;92:242–50. [23] Dellaretti M, Reyns N, Touzet G. Stereotactic biopsy for brainstem tumors: comparison of transcerebellar with transfrontal approach. Stereotact Funct Neurosurg 2012;90:79–83.
Disponible en ligne sur
ScienceDirect www.sciencedirect.com
Technical note
Diffuse intrinsic pontine gliomas in children: Interest of robotic frameless assisted biopsy. A technical note H.A. Coca a,∗ , H. Cebula a , M. Benmekhbi a , M.P. Chenard b , N. Entz-Werle c , F. Proust a a b c
Service de neurochirurgie CHU Hautepierre, 67098, Strasbourg cedex, France Service de pathologie CHU Hautepierre, 67098, Strasbourg cedex, France Service de pédiatrie, unité d’hématologie-oncologie CHU Hautepierre, 67098, Strasbourg cedex, France
a r t i c l e
i n f o
Article history: Received 31 December 2015 Received in revised form 3 July 2016 Accepted 17 July 2016 Available online 27 October 2016 Keywords: Brainstem tumor Pediatric neurosurgery Robotics Biopsy Frameless
a b s t r a c t Introduction. – Diffuse intrinsic pontine gliomas (DIPG) constitute 10–15% of all brain tumors in the pediatric population; currently prognosis remains poor, with an overall survival of 7–14 months. Recently the indication of DIPG biopsy has been enlarged due to the development of molecular biology and various ongoing clinical and therapeutic trials. Classically a biopsy is performed using a stereotactic frame assisted procedure but the workflow may sometimes be heavy and more complex especially in children. In this study the authors present their experience with frameless robotic-guided biopsy of DIPG in a pediatric population. Patients and methods. – Retrospective study on a series of five consecutive pediatric patients harboring DIPG treated over a 4-year period. All patients underwent frameless robotic-guided biopsy via a transcerebellar approach. Results. – Among the 5 patients studied 3 were male and 2 female with a median age of 8.6 years [range 5 to 13 years]. Clinical presentation included ataxia, hemiparesis and cranial nerve palsy in all patients. MRI imaging of the lesion showed typical DIPG features (3 of them located in the pons) with hypo-intensity on T1 and hyper-intensity signal on T2 sequences and diffuse gadolinium enhancement. The mean procedure time was 56 minutes (range 45 to 67 minutes). No new postoperative neurological deficits were recorded. Histological diagnosis was achieved in all cases as follows: two anaplastic astrocytomas (grade III), two glioblastomas, and one diffuse astrocytoma (grade III). Conclusion. – Frameless robotic assisted biopsy of DIPG in pediatric population is an easier, effective, safe and highly accurate method to achieve diagnosis. © 2016 Elsevier Masson SAS. All rights reserved.
1. Introduction Diffuse intrinsic pontine gliomas (DIPG) constitute 10–15% of all brain tumours in the paediatric population [1]. Children in mid to late childhood are mostly affected, with a mean age of 9.6 years [2,3]. Currently prognosis in children with malignant brainstem glioma remains poor; the overall survival is estimated between 7 and 14 months with a median survival of 9 to 12 months [2,4,5]. Currently, the diagnosis of DIPG based only on imaging and clinical features is considered a suboptimal standard of care [6]. The diagnosis of DIPG is now performed with the new histological
∗ Corresponding author. 10 résidence Beau Rivage, 67460 Souffelweyersheim, France. E-mail addresses: [email protected], [email protected] (H.A. Coca). http://dx.doi.org/10.1016/j.neuchi.2016.07.005 0028-3770/© 2016 Elsevier Masson SAS. All rights reserved.
insights based on the molecular status of histone H3.3 which requires a routine biopsy to obtain tumor samples. Biopsy data on pediatric DIPG yielded a diagnosis from 96 to 100%, with no mortality and procedure related morbidity was less than 5% [7]. Despite some morbidity, a biopsy allows molecular biology analysis and in the present and near future the development of clinical trials of targeted therapies [7–11]. Despite the narrow posterior fossa in children, frame-based stereotactic biopsy is reliable, accurate and safe for the diagnosis of DIPG [7,12]. Nevertheless, the frame-based procedure may sometimes complicate surgical workflow. Frameless systems and especially robotic-guided procedure may actually simplify management. To date only few papers have reported this type of a robotic assisted procedure of a brainstem lesion [13]. The aim of our study was to report our experience regarding frameless robotic stereotactic assisted biopsy by transcerebellar approach in DIPG, focusing on its feasibility, safety and accuracy.
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Table 1 Summary of demographic, clinical and radiological features of five cases of DIPG. Case
Sex
Age (y)
Clinical presentation
Imaging location
Approach
Complications Complications during after procedure procedure
Pathology
Mutations
Overall survival (months) until death
1
F
11
Ataxia
Transcerebellar
None
None
Glioblastoma
Histone H3.3 K27M ATRX loss
8
2
M
7
Hemiparesis, oculomotor palsy
Transcerebellar
None
None
Anaplastic Grade III Astrocytoma
Histone H3.3 K27M ATRX loss
7
3
M
7
Facial palsy
Diffuse pontine lesion, mesencephalic extension Diffuse pontine lesion, middle cerebellar peduncle extension Diffuse pontine lesion
Transcerebellar
None
None
Glioblastoma
9
4
F
5
Hemiparesis
Diffuse pontine lesion
Transcerebellar
None
None
5
M
Ataxia, oculomotor palsy
Diffuse pontine lesion
Transcerebellar
Transitory bradycardia
None
Anaplastic Grade III Astrcytoma Diffuse Grade III Astrocytoma
No histone mutation ATRX loss Histone H3.1 K27M
13
Histone H3.3 K27M and PI3KCA mutations ATRX loss
11
9
M: male; F: female; y: years.
2. Patients and methods Retrospective study based on a series of five consecutive patients with DIPG treated at our institution during 4 years (from January 2012 to December 2015). MRI Imaging was consistent with DIPG (with > 50% of brainstem infiltration); all patients underwent brainstem biopsy via a frameless robotic stereotactic device (ROSA, Medtech® ). Presenting symptoms, imaging and outcome are summarized in Table 1. The reference imaging used to plan the procedure was the T1 3D Gadolinium enhanced sequences (1 m slice thickness, 320 × 260 pixels) performed 48–72 hours prior to the procedure. The biopsy needle targeting and trajectory were planned the day before surgery on a computer workstation using robot-planning software (Rosana, Medtech® ). The target zone was chosen within the most enhanced area in the MRI and trajectory passing through the middle cerebellar peduncle. The side entry point was determined using the tumor lateral predominance (Fig. 1). The stereotactic biopsy procedures were performed under general anesthesia. The patient was placed in a supine position with a
mild elevation and tilting of the ipsilateral shoulder to allow easier access to the entry point. The head was fixed and secured in a three-pin headrest attached to the robotic device; special attention was paid to ensure the previously planned trajectory. Automatic robotic frameless surface facial merge registration (without fiducial markers) was performed and accuracy of the registration was confirmed by the surgeon (Fig. 2). Sterile draping was performed and the previously planned trajectory was reached by the robotic arm (ROSA Medtech® ), which also served as an instrument holder. A 0.5-cm skin incision was performed without previous shaving. All instruments were positioned and used through an adapted holder by the robotic arm. The bone opening was performed using a 3.2-mm twist drill. Dura mater was opened using a blunt stylet. The tumor sampling was performed with a 2.5 mm side cutting biopsy needle. At least 4 samples were obtained (by a quarter technique) in all cases (Fig. 3). Needle progression was closely controlled during the procedure, and before needle removal we injected 0.5 ml of air in the target to confirm precision of the sampling on a postoperative CT scan (Fig. 4). An absorbable suture was used for skin closure.
Fig. 1. Sagittal 3D T1 weighted enhanced MRI sequences showing a hypointense pontine lesion with little enhancement in patient suffering of oculomotor palsy and ataxia. Target determination with Rosana Medtech® software, the right side of the tumor is targeted as contrast enhancement is more evident. The transcerebellar route is explored and verified. Reconstruction of 3D MRI and simulation is made to ensure the absence of conflict between the entry point and the cranial fixation during surgery.
H.A. Coca et al. / Neurochirurgie 62 (2016) 327–331
329
Fig. 2. Surgical positioning. The head is fixed by a three-pin head rest to the robotic device; in this position facial scanning and surgical biopsy are performed. Entry point is clearly exposed; any possible conflict with cranial fixation is avoided. The patient is installed in supine position with a slight elevation of the ipsilateral shoulder.
After the procedure patients were admitted to the ICU; CT scan was performed within the first 24 hours to confirm the targeted zone (little air bubbles) and rule-out any possible hemorrhagic complication. The histological study was routinely done on the samples, which could be also partly fresh-frozen and transferred to the molecular analysis platform. First, in the histological analysis, PTEN analysis, as well as H3.3 staining was considered a loss, when no protein expression was detected in tumor cells on the slides using specific antibodies (Abcam, France and Diagenode, Belgium, respectively). EGFR status was histologically evaluated with a specific antibody (Ventana, Roche, France). ATRX nuclear expression was also detected using a specific antibody (Sigma-Aldrich, France). Genomic DNA was isolated using conventional techniques with the QIAamp DNA purification kit (Qiagen, Courtaboeuf, France). DNA quality and quantification were assessed using a Nanodrop® spectrophotometer (ThermoScientific, Wilmington, DE). The goodquality DNA was assessed by the fluorometer ratio (A260/A280) in each sample. Multiple mutation analyses were performed using a classical Sanger technique with direct sequencing of PCR-amplified
Fig. 3. Once the hole and dura piercing is done (with the help of the robotic arm), biopsy samples are performed by a 2.5-mm cutting biopsy needle.
products for H3F3A, HIST1H3B, PIK3CA, IDH1, BRAF and PDGFRA genes. 3. Results 3.1. Baseline and lesion characteristics A robotic frameless biopsy was performed in five children, three males and two females. The median age was 8.6 ± 3.29 years [range 5 to 13 years]. Clinical presentation included ataxia, hemiparesis and cranial nerve palsy as summarized in Table 1. In all cases MRI features of the lesion showed typical DIPG (involving > 50% of the pons), with hypo-intensity on T1, diffuse gadolinium enhancement and hyper-intensity on T2 sequences. In two cases (case 1, case 2) the lesion extended respectively into the mesencephalic area and cerebellar peduncle.
Fig. 4. Screenshots performed during the surgical procedure showing. A. Needle progression right after dural entry. B. Passage through the cerebellar peduncle. C. Target zone is reached and samples are performed. D. Post-operative no enhanced CT scans showing a little amount of air in the biopsy target zone.
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3.2. Procedure and complications After preoperative planning, trajectory and target were easily reached in each case, without any conflict with headrest fixation. Time of procedure was 56 ± 11 minutes, including installation, robot setting up, and skin-to-skin procedure. A case of severe perioperative bradycardia was recorded, during biopsy needle introduction, that was immediately resolved by atropine administration and the pursuit of the procedure was possible without consequences. No new postoperative neurological deficits were recorded. On the early postoperative CT scan air bubbles were located in the target area in each case and no hemorrhagic complication was detected. 3.3. Diagnostic yield and pathology Diagnosis was achieved in all cases as follows: two anaplastic astrocytoma (grade III) (cases 2 and 4), two glioblastoma (cases 1 and 3), and one diffuse astrocytoma (grade III) (case 5). In each paraffin-embedded sample, immunohistochemical analyses were done easily as described in Table 1. The estimated percentage of tumor cells was between 60 and 90%. The DNA concentrations ranged from 40 to 110 ng/l, with a fluorometric ratio between 1.6 and 2.0 for all biopsy DNAs. The amplification of mutated regions in each gene was possible with an interpretable sequencing analysis. Only histone mutation was diagnosed in 4 patients and associated in one with a PI3KCA mutation and confirmed by immunohistochemistry. ATRX loss occurred in 4 patients.
Few published series regarding robotic stereotactic frameless biopsy have shown comparable results to conventional framebased and other frame-less stereotactic procedures [13,18,21,22]. Potential advantages of these techniques are: • prior imaging acquisition away from surgical procedure; • accurate, predefined, and if necessary reprogrammable biopsy paths and trajectories; • control of possible error of manual setting that could be adjusted perioperatively; • instruments held in repetitive tasks without tremor or fatigue; • finally when applying for posterior fossa procedures (transcerebellar route) no prone position is needed (surface facial scanning) avoiding any possible trajectory conflict with a frame. In our study, we recorded a considerable surgical time reduction (about one hour) with no trajectory conflict. Target was reached in 100% of cases as well as diagnosis, allowing a good quality of histological material and DNA to perform all techniques. The extracted quantity of DNA was sufficient to completely explore those samples at the molecular level and perform complementary research molecular analyses. Transcerebellar route showed only one case of transient perioperative bradycardia with no other neurological manifestation. No complication occurred during or after surgery. Finally, it is noteworthy that no significant differences were reported when comparing transfrontal to transcerebellar route in terms of both complication and/or accuracy [23]. 5. Conclusions
3.4. Treatment and outcome The management strategy was discussed and decided during the neuro-oncology multidisciplinary meeting and consisted of fractionated radiotherapy (54 gy in 30 days, 5 days a week) coupled to targeted therapies in all patients. Mean follow-up was 18.4 months (range 7 to 43 months), overall survival was 8.75 ± 1.71 months. 4. Discussion For a number of years the diagnosis of DIPG was based on typical imaging findings on MR and clinical presentation such as, recent (less than 2 months) cranial nerve palsy, long tract signs and ataxia. These tumors were described as an infiltrating mass of the pons, hypointense on T1 and hyperintense on T2 and Flair images, at least 50% of the pons should be involved and contrast enhancement if present is usually limited or annular [14]. Differential diagnosis should be done with some form of benign pontine enlargement, such as, neurofibromatosis type I and acute demyelinating encephalomyelitis [15]. Brain stem abscesses may also mimic clinical presentation of DIPG, but MRI should clearly make the difference between the two types of lesions [16]. Stereotactic biopsy of DIPG is essential to obtain the exact diagnosis, safety and accuracy of these techniques have previously been widely established [7,17]. Most neurosurgical teams prefer frame based stereotactic devices, although some characteristics of this technique may complicate the surgical workflow. Acquisition of imaging should be routinely performed with a frame, moreover, using a transcerebellar approach the prone position is required and sometimes problems are encountered in the occipital region as there is conflict and interference with the trajectory planning [12,18]. Frameless stereotactic targeting devices are in fact comparable in diagnostic yield and clinical results to frame based devices [19,20], but lack of stabilization may limit access to deep lesions.
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