- Email: [email protected]
Endoscopic Histologic Mapping of a Mixed Germ Pineal Tumor
Accepted Manuscript Endoscopic histological mapping of a mixed germ pineal tumor. Case report Carlos Velásquez, M.D, Mónica Rivero-Garvía, M.D. PhD., Eloy Rivas, M.D, María de los Angeles Cañizares, M.D, María José Mayorga-Buiza, M.D., Ph.D., Javier Márquez-Rivas, M.D., Ph.D. PII:
S1878-8750(16)30709-4
DOI:
10.1016/j.wneu.2016.08.043
Reference:
WNEU 4453
To appear in:
World Neurosurgery
Received Date: 6 July 2016 Revised Date:
9 August 2016
Accepted Date: 10 August 2016
Please cite this article as: Velásquez C, Rivero-Garvía M, Rivas E, Cañizares MdlA, Mayorga-Buiza MJ, Márquez-Rivas J, Endoscopic histological mapping of a mixed germ pineal tumor. Case report, World Neurosurgery (2016), doi: 10.1016/j.wneu.2016.08.043. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Velásquez - 1 -
ACCEPTED MANUSCRIPT
Endoscopic histological mapping of a mixed germ pineal tumor. Case report Carlos Velásqueza, M.D., Mónica Rivero-Garvíab, M.D. PhD., Eloy Rivasc, M.D., María de los Angeles Cañizaresd, M.D., María José Mayorga-Buizae, M.D., Ph.D. and Javier Márquez-
a
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Rivas, M.D., Ph.D.b Department of Neurological Surgery and Spine Unit, Hospital Universitario Marqués de
Valdecilla and Fundación Instituto de Investigación Marqués de Valdecilla (IDIVAL). Avda.
b
Department of Neurosurgery,
c
SC
Valdecilla s/n, 39008. Santander, Spain.
Department of Pathology,
e
Department of Pediatric
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Anestesiology, Hospitales Universitarios Virgen del Rocio. Av. Manuel Siurot, s/n, 41013. Seville, Spain. d
Department of Neurosurgery, Complejo Hospitalario de Toledo. Av. de Barber, 30, 45071.
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Toledo, Spain.
Corresponding author: Javier Márquez, M.D., Ph.D. Department of Neurosurgery, Hospitales Universitarios Virgen del Rocio. Av. Manuel Siurot,
EP
s/n, 41013. Sevilla, Spain. Phone: 942202701; Fax: 942203478; Email: [email protected]
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Key words: biopsy, disgerminoma, endoscopy, pineal tumor, ventriculostomy, yolk sac.
Abbreviations:
AFP=alpha-fetoprotein,
βhCG=β-human
chorionic
gonadotropin,
CSF=cerebrospinal fluid, CT=computed tomography, GCT=germ cell tumor, FLAIR=fluidattenuated
inversion
recovery,
MRI=magnetic
resonance
imaging,
germinomatous germ cell tumor, PLAP=Placental alkaline phosphatase.
NGGCT=non-
Velásquez - 2 -
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Abstract Backround: The accurate histological diagnosis of germ cell tumors in the pineal region is a keystone for determining the best treatment strategy and their prognosis. This poses a
RI PT
challenge for the neuropathologist, considering the lack of a standarized procedure to obtain the biopsy samples which results in few and small specimens which are not suitable for diagnosis.
SC
Case Description: The authors report a case in which a pineal region mixed germ cell tumor was accurately diagnosed by performing a histologic mapping through a dual burr-hole
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endoscopic approach. The technical pitfalls and other considerations necessary for obtaining an accurate diagnosis in this tumor subgroup are specified. In addition, the histological analysis regarding the sampling technique employed is described.
Conclusions: The supraorbital frontal endoscopic approach enables the surgeon to perform a
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histological mapping of pineal region tumors, allowing to standarize the procedure used to obtain the specimens. This could result in a more accurate diagnosis, especially in mixed
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germ cell neoplasms.
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Introduction
Pineal region tumors account for 2.5-5% of intracranial tumors in children, and 50-70% of them are germ cell tumors (GCT).
1
Their accurate diagnosis is extremely important for
determining the treatment strategy and prognosis,
2, 3
especially in the mixed GCT subgroup,
in which the identification of all the tumoral histologic components represents a real challenge for the neuropathologist. 4
Velásquez - 3 -
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Despite the technical advances in neuroimaging techniques, radiological findings are not specific enough for differential diagnosis. 5, 6 Current neuroendoscopic approaches allow for a tumoral biopsy to be performed, although several technical questions remain about the procedure and different negative biopsy rates have been described,
7, 8
the majority being
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those with a low number of samples and limited to a small tumoral area.
We describe a pineal mixed GCT histological mapping procedure through an endoscopic
SC
supraorbital approach and outline the technical pitfalls which need to be overcome in order to
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obtain an accurate diagnosis.
Case Report History and examination
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A 13-year-old male with no previous medical history was admitted to the emergency department with headache and seizures. In the previous month he presented three generalized, self-limited, tonic episodes with consciousness impairment, the last one just before admission.
EP
On admission he had mild consciousness impairment without any motor or sensory focal signs. CT scan (Fig. 1 A) showed a large pineal tumor with secondary supratentorial
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hydrocephalus. Based on his clinical and radiological features the patient underwent an urgent endoscopic ventriculostomy and biopsy.
Operation
An endoscopic echo-guided dual approach was chosen using a “two burr-hole” strategy with two different rigid endoscopes. Burr-holes were enlarged to obtain mini-craniotomies on both sides. Ventriculostomy was performed with a standard described procedure 4 through a rigth pre-coronal frontal mini-craniotomy to access the tuber cinereum in the floor of the third
Velásquez - 4 -
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ventricle with a 6mm diameter endoscope and a 0º lenses (Minop, Aesculap, USA). At this stage CSF samples for microbiology, biochemistry and tumoral markers were collected. A second, more anterior, ipsilateral supraorbital mini-craniotomy was used to reach the pineal tumor through Monro foramina in the posterior part of the third ventricle with an 8mm
RI PT
diameter endoscope with a 30º lenses (Minop InVent, Aesculap, USA).
Once the tumor was reached, several samples were taken using a multi-biopsy approach (Fig.
SC
2) to map the tumor histologically and therefore enhance the pathological diagnosis.
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Fifteen small tumor fragments were extracted, proceeding in a clockwise direction. The postoperative CT scan did not reveal intraparenchymal bleeding or any further complications other than a minor fronto-orbital epidural hematoma without any clinical impact. This was
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treated conservatively, with a favorable clinical evolution.
Laboratory and Pathological findings
Alpha-fetoprotein (AFP) and Beta-Human chorionic gonadotropin (βhCG) in serum and
EP
cerebrospinal fluid (CSF) were assessed. Serum AFP was slightly elevated (89.8 ng/ml; reference values: 0-10 ng/ml) and serum βhCG was normal. CSF AFP and βhC were also
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elevated (4.9 ng/ml and 0.414 ng/ml respectively).
Histological examination revealed a giant germ cell neoplasm (Fig. 3) with three different intermixed patterns. One fragment was diffusely infiltrated by a uniform proliferation of large germ cells with vacuolated cytoplasm and prominent nucleoli. The strong positivity for PLAP and D2-40 confirmed the diagnosis of a germinoma component. In other fragments, foci of yolk-sac tumor (YST) with a primitive tubular pattern were intermixed with a heterogeneous
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combination of immature mesenchymal matrix with chondroid differentiation and different glandular components. The immunohistochemistry (IHC) study showed a focal positivity for AFP and cytokeratins. The diagnosis of a pineal mixed germ tumor with germinoma, yolk-sac and possible immature teratoma component grade IV (WHO, 2016) was made based on these
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findings.
Postoperative course
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To complete the case assessment, cerebral and spinal MRI were performed (Fig 1 B-D). It showed a well-delimitated lobulated pineal tumor (62x21x25mm, 20ml), with a homogeneous
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low signal in T1W images and isointense in T2W and FLAIR images, as well as small cystic areas and eccentric calcifications. The tumor showed a homogeneous enhancement after intravenous contrast administration. In addition, the third ventriculostomy permeability and a
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mild reduction in the hydrocephalus were confirmed.
The patient was treated with chemotherapy (cisplatin, ifosfamide and etoposide) and radiation therapy with an excellent response (Fig 1 E-F). Finally, a posterior infratentorial
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supracerebellar approach was performed to resect the residual lesion, without complications (Fig 1 G-H). The histological examination of this residual lesion showed a complete mature
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teratoma.
Discussion
Variety in histopathological diagnosis of pineal region lesions stems from the wide range of different types of tumors. Among them, the germ cell tumors (GCT) account for 20% to 37%. 9
In the pediatric population, GCT have more than one histologic component in 2.9 to 25% of
the cases, knowed as mixed GCT. In the majority of cases, mixed GCT consists of a
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combination of a germinoma component and a non-germinomatous GCT (NGGCT) component. 2, 3
According to its prognosis, a mixed GCT could be included in the intermediate or poor
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prognostic groups. The ones with a NGGCT other than teratoma are classified in the poor prognostic group, with a 5-year survival rate of less than 50% if they have a malignant
SC
NGCGT component 10 and their prognosis is determined by the NGGCT component. 2
The accuracy of the initial histologic diagnosis is relevant in choosing treatment and 2, 3
The yolk sac component finding in the case presented here has a
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establishing prognosis.
crucial role in selecting the therapeutic approach, and more importantly, modified the prognosis significantly. In the hypothetical case that this component was not identified, and considering the serum markers, the patient would have been treated as a mixed GCT with an
dramatically.
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immature teratoma component, altering his prognosis and his projected chances of survival
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Taking into account the importance of the histologic diagnosis, the current approach for pineal region tumors, which often present with hydrocephalus, includes ventriculostomy and
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tumor biopsy. Despite the predilection for doing both procedures simultaneously, performing an endoscopic biopsy in that case, several technical questions remain. 8 The neuroendoscopic biopsy has been described as a safe procedure, with a complication rate below 13% and without significant longterm morbidity. Besides, it has the advantage that a concomitant third ventriculostomy can be performed. However, sampling errors may occur, particularly in low-grade glial tumors. 11 In contrast, the stereotactic biopsy appears to be slightly safer and more accurate than the
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single burr-hole endoscopic approach, remaining the best option for the diagnosis of pineal region tumors without hydrocephalus according to some authors.
4, 12, 13
This has recently
been addressed by Balossier et al case series study where they compare both approaches using two large series of pineal tumor biopsies. They found that in the stereotactic biopsy series the
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accuracy rate was higher and the perioperative morbity was less than in the single burrhole strategy endoscopic approach group. 14
Nevertheless, the differences in perioperative morbidity could be explain by the displacement
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of the fornix and other structures that sourround the foramina of Monro in the single burr-hole
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strategy used in the endoscopic group, and comparisons with the dual burr-hole approach have not been performed. Moreover, these differences are based in the diagnostic procedure only, as the stereotactic approach does not allow a simultaneous treament of the hydrocephalus and an additional procedure it is required.
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On the other hand, it has been pointed out that the differences between the MRI spectroscopy patterns of the different components of a mixed GCT could guide the stereotactic sampling. This principle could be apply in a navigated dual burr hole approach allowing a MRI
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spectroscopy-guided biopsy under direct visualisation of the tumor. 5
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Furthermore, when an endoscopic biopsy is the chosen approach, the question remains as to whether to perform a single burr-hole or a dual burr-hole strategies. Nevertheless, there is no evidence indicating which approach is more efficient in obtaining histological samples suitable for diagnosis. The recommendations to use one or the other are based on tumoral and anatomic features,
4
but the surgeon’s preferences, experience, ability, and technical support
are also important factors. In the single burr-hole approach the entry point is placed 2-3 cm anteriorly to Kocher´s point allowing to perform both procedures at once with a rigid endoscope.
4
In a large series, the
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diagnostic rate was only 85% using this procedure.7 Besides, this technique can be assisted with a neuronavigation system acchieving good results as it is described in the series of Knaus et al 15 and it can be performed with the aid of flexible endoscopes with some disadvantages,
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as the smaller working channel and the worse image definition. Regarding the two burr-holes technique, Chibbaro et al describes a 20-case series of pineal lesions approached with a dual burr-hole strategy with a 100% rate of succesful biopsies.
9
The accurate diagnosis in the case presented could be related to the two burr-hole, rigid
SC
endoscope, approach used (Fig 1 C-D). The resulting working angle and a large working
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channel endoscope that allows more efficient instrument movements, enable the surgeon to perform a histological mapping of the tumor with accurate control of the sample sites (Fig 2C). Among other advantages, it reduces the risk of fornix damage with less tissue displacement
16
Additionally, it allows a frontal visualization of the tumor whereas the angle
with a single burr-hole forces to take samples from its inferior part. Finally, endoscoped
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assited navigation over MRI spectroscopy is possible. Considering that the particular heterogeneity of mixed germ cell tumors makes it difficult to
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obtain an accurate diagnosis in small specimens, 4 the number of tissue samples taken and the strategy for obtaining them are significant technical factors. It is not clear yet if taking more
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samples results in a more accurate diagnosis without increasing complications. Besides, the number of samples is not standardized, as can be seen from several case series, in which they range from 1 to 12 specimens. Furthermore, a high variability between patients, with several patients with an undetermined number of tissue samples, can be observed. 7, 9, 11 Regarding the number of tissue samples, those series with a high and standard number, as in that reported by Chibbaro et al, reached the histological diagnosis in all cases,
9
while in a
large series reported by Ahmed et al., with a high variability in the number of tissue samples,
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the negative histological diagnosis rate was 16%. Despite the fact that comparison between these studies is impossible due to their methodological differences, to increase the number of samples, among other measures, could reduce sample error, as they themselves proposed. 7
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The histological analysis of the samples taken in this case revealed a yolk sac tumor component in just two out of fifteen specimens, less than 15% of the tissue samples, thus indicating the importance of increasing the number of samples typically taken. Furthermore, the procedure for obtaining the samples is not standardized, leading to difficulties in the
SC
consistency of the diagnosis and comparison between series. A standardized histological
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mapping of the tumor, as with the one performed in the case presented, could be an effective way of reducing the impact of these issues. Conclusions
The supraorbital frontal endoscopic approach allows the surgeon to perform a histological
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mapping of pineal region tumors. This technique enables to standarize the procedure used to obtain the specimens resulting in more representative samples. This could result in a more
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accurate diagnosis, especially in mixed germ cell neoplasms.
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Conflict of interest statment The authors report no conflict of interest concerning the materials, surgical equipment or methods used in this study or the findings specified in this paper.
Acknowledgements We want to thank Lilian Vargas and Phil Woodall for reviewing the manuscript and for their valuable comments.
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Bibliography 1. Villano JL, Propp JM, Porter KR, Stewart AK, Valyi-Nagy T, Li X, et al. Malignant
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pineal germ-cell tumors: an analysis of cases from three tumor registries. Neuro Oncol. 2008; 10(2):121-30.
2. Echevarría ME, Fangusaro J, Goldman S. Pediatric central nervous system germ cell
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tumors: a review. Oncologist. 2008; 13(6):690-9.
3. Gao Y, Jiang J, Liu Q. Clinicopathological and immunohistochemical features of
Pathol. 2014; 7(10):6965-72.
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primary central nervous system germ cell tumors: a 24-year experience. Int J Clin Exp
4. Azab WA, Nasim K, Salaheddin W. An overview of the current surgical options for pineal region tumors. Surg Neurol Int. 2014; 5:39.
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5. Deiana G, Mottolese C, Hermier M, Louis-Tisserand G, Berthezene Y. Imagery of pineal tumors. Neurochirurgie. 2015; 61(2-3):113-22. 6. Dumrongpisutikul N, Intrapiromkul J, Yousem DM. Distinguishing between
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germinomas and pineal cell tumors on MR imaging. AJNR Am J Neuroradiol. 2012; 33(3):550-5.
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7. Ahmed AI, Zaben MJ, Mathad NV, Sparrow OC. Endoscopic biopsy and third ventriculostomy for the management of pineal region tumors. World Neurosurg. 2015; 83(4):543-7.
8. Morgenstern PF, Osbun N, Schwartz TH, Greenfield JP, Tsiouris AJ, Souweidane MM. Pineal region tumors: an optimal approach for simultaneous endoscopic third ventriculostomy and biopsy. Neurosurg Focus. 2011; 30(4):E3. 9. Chibbaro S, Di Rocco F, Makiese O, Reiss A, Poczos P, Mirone G, et al. Neuroendoscopic management of posterior third ventricle and pineal region tumors:
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technique, limitation, and possible complication avoidance. Neurosurg Rev. 2012; 35(3):331-38. 10. Kamoshima Y1, Sawamura Y. Update on current standard treatments in central nervous system germ cell tumors. Curr Opin Neurol. 2010; 23(6):571-5.
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11. Constantini S, Mohanty A, Zymberg S, Cavalheiro S, Mallucci C, Hellwig D, et al. Safety and diagnostic accuracy of neuroendoscopic biopsies: an international multicenter study. J Neurosurg Pediatr. 2013; 11(6):704-9.
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12. Balossier A, Blond S, Touzet G, Lefranc M, de Saint-Denis T, Maurage CA, et al. Endoscopic versus stereotactic procedure for pineal tumour biopsies: Comparative
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review of the literature and learning from a 25-year experience. Neurochirurgie. 2015; 61(2-3):146-54.
13. Lefranc M, Touzet G, Caron S, Maurage CA, Assaker R, Blond S. Are stereotactic sample biopsies still of value in the modern management of pineal region tumours?
153(5):1111-21.
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Lessons from a single-department, retrospective series. Acta Neurochir (Wien). 2011;
14. Balossier A, Blond S, Reyns N. Endoscopic Versus Stereotactic Procedure for Pineal
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Tumor Biopsies: Focus on Overall Efficacy. World Neurosurg. 2016; 92:223-28. 15. Knaus H, Matthias S, Koch A, Thomale UW. Single burr hole endoscopic biopsy with
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third ventriculostomy-measurements and computer-assisted planning. Childs Nerv Syst. 2011. 27(8):1233-41.
16. Zhu XL, Gao R, Wong GK, Wong HT, Ng RY, Yu Y et al. Single burr hole rigid endoscopic third ventriculostomy and endoscopic tumor biopsy: What is the safe displacement range for the foramen of Monro?. Asian J Surg. 2013 36(2):74-82.
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ACCEPTED MANUSCRIPT Figures captions.
Figure 1. A: Preoperative CT scan shows a pineal region tumor (arrows) with secondary hydrocepahlus. B: Postoperative FLAIR MRI multiplanar reconstruction (MPR) in the plane of the supraorbital endoscopic trajectory to reach the pineal region tumor in order to take the
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biopsy. C: Postoperative FLAIR MRI MPR in the plane of the frontal endoscopic trajectory used to perform the third ventriculostomy. D: Postoperative sagittal turbo spin echo T2weighted MRI shows the ventriculostomy patency with flow void through third ventricle floor
SC
(arrow). E and F: Axial and sagittal gadolinium enhanced T1-weighted MRI shows the tumoral residue after chemo and radiotherapy. G and H: Axial and sagittal gadolinium
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enhanced T1-weighted MRI shows complete resection of the tumoral residue through an infratentorial supracerebellar approach. TU: Tumor, LV: Lateral ventricle, CN: Caudate nucleus, F: Fornix, MI: Massa intermedia, TV: Third ventricle, M: mesencephalon, IPC:
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Interpeduncular cistern, TC: Tuber cinereum.
Figure 2. Intraoperative photographs of the supraorbital endoscopic approach used to obtain the tumor biopsy. A: The approach angle to the foramen of Monro (dotted line) and the third
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ventricle can be observed. B: From this perspective the tumor can be reached in the posterior wall of the third ventricle and below the tela and the internal cerebral veins. C: Location of
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the samples (black dots) from the tumor (dotted line). D: The image shows the working angle to reach the tumor (black dotted line) through the foramen of Monro (white dotted line). S: Septum, TSV: Thalamo-striate vein, ACV: Anterior caudate vein, ASTV: Anterior superficial thalamic vein, ATV: Anterior thalamic vein, CP: Choroid plexus, ASV: Anterior septal vein, CF: Columns of Fornix, RF: Right fornix, LF: Left fornix, T: Tela, ICV: Internal cerebral veins, MPChA: medial posterior choroidal artery, TU: Tumor, LV: Lateral ventricle.
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Figure 3. Histological examination. A-B: Two endoscopic biopsy fragments with different germ cell tumor histological patterns (HE, x2). C and F: The germinoma component is composed of uniform large cells with clear cytoplasm (HE, x40) and strong positivity for PLAP (IHC, x20). D: YST pattern intermixed with intestinal glandular epithelium (HE, x20).
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E: primitive mesenchymal tissue from immature teratoma component (HE, x20). G: AFP focal positivity in YST areas (IHC, x10). H: cytokeratins-positive inmunolabelling (IHC,
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SC
x20).
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ACCEPTED MANUSCRIPT Highlights An accurate diagnosis of pineal region tumors is a keystone for their assesment.
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Histological mapping of pineal region tumors aided to obtain an accurate diagnosis.
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EP
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SC
A supraorbital endoscopic approach makes easier the histologic mapping.
S1878-8750(16)30709-4
DOI:
10.1016/j.wneu.2016.08.043
Reference:
WNEU 4453
To appear in:
World Neurosurgery
Received Date: 6 July 2016 Revised Date:
9 August 2016
Accepted Date: 10 August 2016
Please cite this article as: Velásquez C, Rivero-Garvía M, Rivas E, Cañizares MdlA, Mayorga-Buiza MJ, Márquez-Rivas J, Endoscopic histological mapping of a mixed germ pineal tumor. Case report, World Neurosurgery (2016), doi: 10.1016/j.wneu.2016.08.043. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Velásquez - 1 -
ACCEPTED MANUSCRIPT
Endoscopic histological mapping of a mixed germ pineal tumor. Case report Carlos Velásqueza, M.D., Mónica Rivero-Garvíab, M.D. PhD., Eloy Rivasc, M.D., María de los Angeles Cañizaresd, M.D., María José Mayorga-Buizae, M.D., Ph.D. and Javier Márquez-
a
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Rivas, M.D., Ph.D.b Department of Neurological Surgery and Spine Unit, Hospital Universitario Marqués de
Valdecilla and Fundación Instituto de Investigación Marqués de Valdecilla (IDIVAL). Avda.
b
Department of Neurosurgery,
c
SC
Valdecilla s/n, 39008. Santander, Spain.
Department of Pathology,
e
Department of Pediatric
M AN U
Anestesiology, Hospitales Universitarios Virgen del Rocio. Av. Manuel Siurot, s/n, 41013. Seville, Spain. d
Department of Neurosurgery, Complejo Hospitalario de Toledo. Av. de Barber, 30, 45071.
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Toledo, Spain.
Corresponding author: Javier Márquez, M.D., Ph.D. Department of Neurosurgery, Hospitales Universitarios Virgen del Rocio. Av. Manuel Siurot,
EP
s/n, 41013. Sevilla, Spain. Phone: 942202701; Fax: 942203478; Email: [email protected]
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Key words: biopsy, disgerminoma, endoscopy, pineal tumor, ventriculostomy, yolk sac.
Abbreviations:
AFP=alpha-fetoprotein,
βhCG=β-human
chorionic
gonadotropin,
CSF=cerebrospinal fluid, CT=computed tomography, GCT=germ cell tumor, FLAIR=fluidattenuated
inversion
recovery,
MRI=magnetic
resonance
imaging,
germinomatous germ cell tumor, PLAP=Placental alkaline phosphatase.
NGGCT=non-
Velásquez - 2 -
ACCEPTED MANUSCRIPT
Abstract Backround: The accurate histological diagnosis of germ cell tumors in the pineal region is a keystone for determining the best treatment strategy and their prognosis. This poses a
RI PT
challenge for the neuropathologist, considering the lack of a standarized procedure to obtain the biopsy samples which results in few and small specimens which are not suitable for diagnosis.
SC
Case Description: The authors report a case in which a pineal region mixed germ cell tumor was accurately diagnosed by performing a histologic mapping through a dual burr-hole
M AN U
endoscopic approach. The technical pitfalls and other considerations necessary for obtaining an accurate diagnosis in this tumor subgroup are specified. In addition, the histological analysis regarding the sampling technique employed is described.
Conclusions: The supraorbital frontal endoscopic approach enables the surgeon to perform a
TE D
histological mapping of pineal region tumors, allowing to standarize the procedure used to obtain the specimens. This could result in a more accurate diagnosis, especially in mixed
EP
germ cell neoplasms.
AC C
Introduction
Pineal region tumors account for 2.5-5% of intracranial tumors in children, and 50-70% of them are germ cell tumors (GCT).
1
Their accurate diagnosis is extremely important for
determining the treatment strategy and prognosis,
2, 3
especially in the mixed GCT subgroup,
in which the identification of all the tumoral histologic components represents a real challenge for the neuropathologist. 4
Velásquez - 3 -
ACCEPTED MANUSCRIPT
Despite the technical advances in neuroimaging techniques, radiological findings are not specific enough for differential diagnosis. 5, 6 Current neuroendoscopic approaches allow for a tumoral biopsy to be performed, although several technical questions remain about the procedure and different negative biopsy rates have been described,
7, 8
the majority being
RI PT
those with a low number of samples and limited to a small tumoral area.
We describe a pineal mixed GCT histological mapping procedure through an endoscopic
SC
supraorbital approach and outline the technical pitfalls which need to be overcome in order to
M AN U
obtain an accurate diagnosis.
Case Report History and examination
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A 13-year-old male with no previous medical history was admitted to the emergency department with headache and seizures. In the previous month he presented three generalized, self-limited, tonic episodes with consciousness impairment, the last one just before admission.
EP
On admission he had mild consciousness impairment without any motor or sensory focal signs. CT scan (Fig. 1 A) showed a large pineal tumor with secondary supratentorial
AC C
hydrocephalus. Based on his clinical and radiological features the patient underwent an urgent endoscopic ventriculostomy and biopsy.
Operation
An endoscopic echo-guided dual approach was chosen using a “two burr-hole” strategy with two different rigid endoscopes. Burr-holes were enlarged to obtain mini-craniotomies on both sides. Ventriculostomy was performed with a standard described procedure 4 through a rigth pre-coronal frontal mini-craniotomy to access the tuber cinereum in the floor of the third
Velásquez - 4 -
ACCEPTED MANUSCRIPT
ventricle with a 6mm diameter endoscope and a 0º lenses (Minop, Aesculap, USA). At this stage CSF samples for microbiology, biochemistry and tumoral markers were collected. A second, more anterior, ipsilateral supraorbital mini-craniotomy was used to reach the pineal tumor through Monro foramina in the posterior part of the third ventricle with an 8mm
RI PT
diameter endoscope with a 30º lenses (Minop InVent, Aesculap, USA).
Once the tumor was reached, several samples were taken using a multi-biopsy approach (Fig.
SC
2) to map the tumor histologically and therefore enhance the pathological diagnosis.
M AN U
Fifteen small tumor fragments were extracted, proceeding in a clockwise direction. The postoperative CT scan did not reveal intraparenchymal bleeding or any further complications other than a minor fronto-orbital epidural hematoma without any clinical impact. This was
TE D
treated conservatively, with a favorable clinical evolution.
Laboratory and Pathological findings
Alpha-fetoprotein (AFP) and Beta-Human chorionic gonadotropin (βhCG) in serum and
EP
cerebrospinal fluid (CSF) were assessed. Serum AFP was slightly elevated (89.8 ng/ml; reference values: 0-10 ng/ml) and serum βhCG was normal. CSF AFP and βhC were also
AC C
elevated (4.9 ng/ml and 0.414 ng/ml respectively).
Histological examination revealed a giant germ cell neoplasm (Fig. 3) with three different intermixed patterns. One fragment was diffusely infiltrated by a uniform proliferation of large germ cells with vacuolated cytoplasm and prominent nucleoli. The strong positivity for PLAP and D2-40 confirmed the diagnosis of a germinoma component. In other fragments, foci of yolk-sac tumor (YST) with a primitive tubular pattern were intermixed with a heterogeneous
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combination of immature mesenchymal matrix with chondroid differentiation and different glandular components. The immunohistochemistry (IHC) study showed a focal positivity for AFP and cytokeratins. The diagnosis of a pineal mixed germ tumor with germinoma, yolk-sac and possible immature teratoma component grade IV (WHO, 2016) was made based on these
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findings.
Postoperative course
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To complete the case assessment, cerebral and spinal MRI were performed (Fig 1 B-D). It showed a well-delimitated lobulated pineal tumor (62x21x25mm, 20ml), with a homogeneous
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low signal in T1W images and isointense in T2W and FLAIR images, as well as small cystic areas and eccentric calcifications. The tumor showed a homogeneous enhancement after intravenous contrast administration. In addition, the third ventriculostomy permeability and a
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mild reduction in the hydrocephalus were confirmed.
The patient was treated with chemotherapy (cisplatin, ifosfamide and etoposide) and radiation therapy with an excellent response (Fig 1 E-F). Finally, a posterior infratentorial
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supracerebellar approach was performed to resect the residual lesion, without complications (Fig 1 G-H). The histological examination of this residual lesion showed a complete mature
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teratoma.
Discussion
Variety in histopathological diagnosis of pineal region lesions stems from the wide range of different types of tumors. Among them, the germ cell tumors (GCT) account for 20% to 37%. 9
In the pediatric population, GCT have more than one histologic component in 2.9 to 25% of
the cases, knowed as mixed GCT. In the majority of cases, mixed GCT consists of a
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combination of a germinoma component and a non-germinomatous GCT (NGGCT) component. 2, 3
According to its prognosis, a mixed GCT could be included in the intermediate or poor
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prognostic groups. The ones with a NGGCT other than teratoma are classified in the poor prognostic group, with a 5-year survival rate of less than 50% if they have a malignant
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NGCGT component 10 and their prognosis is determined by the NGGCT component. 2
The accuracy of the initial histologic diagnosis is relevant in choosing treatment and 2, 3
The yolk sac component finding in the case presented here has a
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establishing prognosis.
crucial role in selecting the therapeutic approach, and more importantly, modified the prognosis significantly. In the hypothetical case that this component was not identified, and considering the serum markers, the patient would have been treated as a mixed GCT with an
dramatically.
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immature teratoma component, altering his prognosis and his projected chances of survival
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Taking into account the importance of the histologic diagnosis, the current approach for pineal region tumors, which often present with hydrocephalus, includes ventriculostomy and
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tumor biopsy. Despite the predilection for doing both procedures simultaneously, performing an endoscopic biopsy in that case, several technical questions remain. 8 The neuroendoscopic biopsy has been described as a safe procedure, with a complication rate below 13% and without significant longterm morbidity. Besides, it has the advantage that a concomitant third ventriculostomy can be performed. However, sampling errors may occur, particularly in low-grade glial tumors. 11 In contrast, the stereotactic biopsy appears to be slightly safer and more accurate than the
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single burr-hole endoscopic approach, remaining the best option for the diagnosis of pineal region tumors without hydrocephalus according to some authors.
4, 12, 13
This has recently
been addressed by Balossier et al case series study where they compare both approaches using two large series of pineal tumor biopsies. They found that in the stereotactic biopsy series the
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accuracy rate was higher and the perioperative morbity was less than in the single burrhole strategy endoscopic approach group. 14
Nevertheless, the differences in perioperative morbidity could be explain by the displacement
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of the fornix and other structures that sourround the foramina of Monro in the single burr-hole
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strategy used in the endoscopic group, and comparisons with the dual burr-hole approach have not been performed. Moreover, these differences are based in the diagnostic procedure only, as the stereotactic approach does not allow a simultaneous treament of the hydrocephalus and an additional procedure it is required.
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On the other hand, it has been pointed out that the differences between the MRI spectroscopy patterns of the different components of a mixed GCT could guide the stereotactic sampling. This principle could be apply in a navigated dual burr hole approach allowing a MRI
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spectroscopy-guided biopsy under direct visualisation of the tumor. 5
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Furthermore, when an endoscopic biopsy is the chosen approach, the question remains as to whether to perform a single burr-hole or a dual burr-hole strategies. Nevertheless, there is no evidence indicating which approach is more efficient in obtaining histological samples suitable for diagnosis. The recommendations to use one or the other are based on tumoral and anatomic features,
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but the surgeon’s preferences, experience, ability, and technical support
are also important factors. In the single burr-hole approach the entry point is placed 2-3 cm anteriorly to Kocher´s point allowing to perform both procedures at once with a rigid endoscope.
4
In a large series, the
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diagnostic rate was only 85% using this procedure.7 Besides, this technique can be assisted with a neuronavigation system acchieving good results as it is described in the series of Knaus et al 15 and it can be performed with the aid of flexible endoscopes with some disadvantages,
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as the smaller working channel and the worse image definition. Regarding the two burr-holes technique, Chibbaro et al describes a 20-case series of pineal lesions approached with a dual burr-hole strategy with a 100% rate of succesful biopsies.
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The accurate diagnosis in the case presented could be related to the two burr-hole, rigid
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endoscope, approach used (Fig 1 C-D). The resulting working angle and a large working
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channel endoscope that allows more efficient instrument movements, enable the surgeon to perform a histological mapping of the tumor with accurate control of the sample sites (Fig 2C). Among other advantages, it reduces the risk of fornix damage with less tissue displacement
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Additionally, it allows a frontal visualization of the tumor whereas the angle
with a single burr-hole forces to take samples from its inferior part. Finally, endoscoped
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assited navigation over MRI spectroscopy is possible. Considering that the particular heterogeneity of mixed germ cell tumors makes it difficult to
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obtain an accurate diagnosis in small specimens, 4 the number of tissue samples taken and the strategy for obtaining them are significant technical factors. It is not clear yet if taking more
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samples results in a more accurate diagnosis without increasing complications. Besides, the number of samples is not standardized, as can be seen from several case series, in which they range from 1 to 12 specimens. Furthermore, a high variability between patients, with several patients with an undetermined number of tissue samples, can be observed. 7, 9, 11 Regarding the number of tissue samples, those series with a high and standard number, as in that reported by Chibbaro et al, reached the histological diagnosis in all cases,
9
while in a
large series reported by Ahmed et al., with a high variability in the number of tissue samples,
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the negative histological diagnosis rate was 16%. Despite the fact that comparison between these studies is impossible due to their methodological differences, to increase the number of samples, among other measures, could reduce sample error, as they themselves proposed. 7
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The histological analysis of the samples taken in this case revealed a yolk sac tumor component in just two out of fifteen specimens, less than 15% of the tissue samples, thus indicating the importance of increasing the number of samples typically taken. Furthermore, the procedure for obtaining the samples is not standardized, leading to difficulties in the
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consistency of the diagnosis and comparison between series. A standardized histological
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mapping of the tumor, as with the one performed in the case presented, could be an effective way of reducing the impact of these issues. Conclusions
The supraorbital frontal endoscopic approach allows the surgeon to perform a histological
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mapping of pineal region tumors. This technique enables to standarize the procedure used to obtain the specimens resulting in more representative samples. This could result in a more
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accurate diagnosis, especially in mixed germ cell neoplasms.
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Conflict of interest statment The authors report no conflict of interest concerning the materials, surgical equipment or methods used in this study or the findings specified in this paper.
Acknowledgements We want to thank Lilian Vargas and Phil Woodall for reviewing the manuscript and for their valuable comments.
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Bibliography 1. Villano JL, Propp JM, Porter KR, Stewart AK, Valyi-Nagy T, Li X, et al. Malignant
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pineal germ-cell tumors: an analysis of cases from three tumor registries. Neuro Oncol. 2008; 10(2):121-30.
2. Echevarría ME, Fangusaro J, Goldman S. Pediatric central nervous system germ cell
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tumors: a review. Oncologist. 2008; 13(6):690-9.
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primary central nervous system germ cell tumors: a 24-year experience. Int J Clin Exp
4. Azab WA, Nasim K, Salaheddin W. An overview of the current surgical options for pineal region tumors. Surg Neurol Int. 2014; 5:39.
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5. Deiana G, Mottolese C, Hermier M, Louis-Tisserand G, Berthezene Y. Imagery of pineal tumors. Neurochirurgie. 2015; 61(2-3):113-22. 6. Dumrongpisutikul N, Intrapiromkul J, Yousem DM. Distinguishing between
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germinomas and pineal cell tumors on MR imaging. AJNR Am J Neuroradiol. 2012; 33(3):550-5.
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7. Ahmed AI, Zaben MJ, Mathad NV, Sparrow OC. Endoscopic biopsy and third ventriculostomy for the management of pineal region tumors. World Neurosurg. 2015; 83(4):543-7.
8. Morgenstern PF, Osbun N, Schwartz TH, Greenfield JP, Tsiouris AJ, Souweidane MM. Pineal region tumors: an optimal approach for simultaneous endoscopic third ventriculostomy and biopsy. Neurosurg Focus. 2011; 30(4):E3. 9. Chibbaro S, Di Rocco F, Makiese O, Reiss A, Poczos P, Mirone G, et al. Neuroendoscopic management of posterior third ventricle and pineal region tumors:
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technique, limitation, and possible complication avoidance. Neurosurg Rev. 2012; 35(3):331-38. 10. Kamoshima Y1, Sawamura Y. Update on current standard treatments in central nervous system germ cell tumors. Curr Opin Neurol. 2010; 23(6):571-5.
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11. Constantini S, Mohanty A, Zymberg S, Cavalheiro S, Mallucci C, Hellwig D, et al. Safety and diagnostic accuracy of neuroendoscopic biopsies: an international multicenter study. J Neurosurg Pediatr. 2013; 11(6):704-9.
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12. Balossier A, Blond S, Touzet G, Lefranc M, de Saint-Denis T, Maurage CA, et al. Endoscopic versus stereotactic procedure for pineal tumour biopsies: Comparative
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review of the literature and learning from a 25-year experience. Neurochirurgie. 2015; 61(2-3):146-54.
13. Lefranc M, Touzet G, Caron S, Maurage CA, Assaker R, Blond S. Are stereotactic sample biopsies still of value in the modern management of pineal region tumours?
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Lessons from a single-department, retrospective series. Acta Neurochir (Wien). 2011;
14. Balossier A, Blond S, Reyns N. Endoscopic Versus Stereotactic Procedure for Pineal
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Tumor Biopsies: Focus on Overall Efficacy. World Neurosurg. 2016; 92:223-28. 15. Knaus H, Matthias S, Koch A, Thomale UW. Single burr hole endoscopic biopsy with
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third ventriculostomy-measurements and computer-assisted planning. Childs Nerv Syst. 2011. 27(8):1233-41.
16. Zhu XL, Gao R, Wong GK, Wong HT, Ng RY, Yu Y et al. Single burr hole rigid endoscopic third ventriculostomy and endoscopic tumor biopsy: What is the safe displacement range for the foramen of Monro?. Asian J Surg. 2013 36(2):74-82.
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Figure 1. A: Preoperative CT scan shows a pineal region tumor (arrows) with secondary hydrocepahlus. B: Postoperative FLAIR MRI multiplanar reconstruction (MPR) in the plane of the supraorbital endoscopic trajectory to reach the pineal region tumor in order to take the
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biopsy. C: Postoperative FLAIR MRI MPR in the plane of the frontal endoscopic trajectory used to perform the third ventriculostomy. D: Postoperative sagittal turbo spin echo T2weighted MRI shows the ventriculostomy patency with flow void through third ventricle floor
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(arrow). E and F: Axial and sagittal gadolinium enhanced T1-weighted MRI shows the tumoral residue after chemo and radiotherapy. G and H: Axial and sagittal gadolinium
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enhanced T1-weighted MRI shows complete resection of the tumoral residue through an infratentorial supracerebellar approach. TU: Tumor, LV: Lateral ventricle, CN: Caudate nucleus, F: Fornix, MI: Massa intermedia, TV: Third ventricle, M: mesencephalon, IPC:
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Interpeduncular cistern, TC: Tuber cinereum.
Figure 2. Intraoperative photographs of the supraorbital endoscopic approach used to obtain the tumor biopsy. A: The approach angle to the foramen of Monro (dotted line) and the third
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ventricle can be observed. B: From this perspective the tumor can be reached in the posterior wall of the third ventricle and below the tela and the internal cerebral veins. C: Location of
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the samples (black dots) from the tumor (dotted line). D: The image shows the working angle to reach the tumor (black dotted line) through the foramen of Monro (white dotted line). S: Septum, TSV: Thalamo-striate vein, ACV: Anterior caudate vein, ASTV: Anterior superficial thalamic vein, ATV: Anterior thalamic vein, CP: Choroid plexus, ASV: Anterior septal vein, CF: Columns of Fornix, RF: Right fornix, LF: Left fornix, T: Tela, ICV: Internal cerebral veins, MPChA: medial posterior choroidal artery, TU: Tumor, LV: Lateral ventricle.
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Figure 3. Histological examination. A-B: Two endoscopic biopsy fragments with different germ cell tumor histological patterns (HE, x2). C and F: The germinoma component is composed of uniform large cells with clear cytoplasm (HE, x40) and strong positivity for PLAP (IHC, x20). D: YST pattern intermixed with intestinal glandular epithelium (HE, x20).
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E: primitive mesenchymal tissue from immature teratoma component (HE, x20). G: AFP focal positivity in YST areas (IHC, x10). H: cytokeratins-positive inmunolabelling (IHC,
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x20).
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ACCEPTED MANUSCRIPT Highlights An accurate diagnosis of pineal region tumors is a keystone for their assesment.
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Histological mapping of pineal region tumors aided to obtain an accurate diagnosis.
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A supraorbital endoscopic approach makes easier the histologic mapping.