Pineal Region Gliomas: A Single-Center Experience with 25 Cases

Accepted Manuscript Pineal region gliomas : a single center experience with 25 cases Denghui Li, Rong Wen, Yuan Gao, Yangyang Xu, Botao Xiong, Feilong Gong, Wei Wang PII:

S1878-8750(19)31846-7

DOI:

https://doi.org/10.1016/j.wneu.2019.06.189

Reference:

WNEU 12750

To appear in:

World Neurosurgery

Received Date: 12 April 2019 Revised Date:

24 June 2019

Accepted Date: 25 June 2019

Please cite this article as: Li D, Wen R, Gao Y, Xu Y, Xiong B, Gong F, Wang W, Pineal region gliomas : a single center experience with 25 cases, World Neurosurgery (2019), doi: https://doi.org/10.1016/ j.wneu.2019.06.189. 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.

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Pineal region gliomas : a single center experience with 25 cases

KEYWORDS

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Corresponding author

pineal gland ;glioma; surgery ; Chemotherapy ; radiosurgery

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Denghui Li 1,Rong Wen1, Yuan Gao1, Yangyang Xu1, Botao Xiong1,, Feilong Gong1, Wei Wang1* 1 Neurosurgery department of West China hospital affliated to Sichuan University;NO.37 Guoxue Alley,Wuhou District,Chengdu,Sichuan Province,People’s Republic of China

Abstract

Introduction Pineal region glioma is a rare systematically reported tumor in literatures ,little is known about its behavior ,development and best treatment strategies due to its complex anatomical relationship and rarity.

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Objective We review the outcomes of patients with pineal region gliomas in West China hospital in past five years and retrieve the literatures to add more information. As a result , key factors related to prognosis are identified.

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Methods 25 patients with pineal region gliomas are selected, information are collected about detailed medical history ,imaging data ,treatment methods , pathological results and latest neurosurgical, radiological progress during follow up.

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Results Pilocytic astrocytomas (20%) and glioblastoma (24%) were the most common pathological subtypes. 23 patients went through open surgery, 3 GKRS and 4 WBRT . CHT was applied to 3 patients . Low grade gliomas tended to have a better prognosis than high grade. Karnofsky Performance Status score at admission( 60) was intimately associated with prognosis for low grade gliomas. As for high grade gliomas , age at admission( 30) had better prognosis than older( 30). However ,whatever the grade was, there was no overall survival difference as to gender , GTR vs nGTR , preoperative maximal tumor diameter (≤4 cm VS 4cm), and time since first symptoms ≤30 days VS 30 days , and RT VS not. Conclusion Open surgery is the first line strategy for pineal region gliomas with tolerable mortality and disability rate . Radiosurgery and CHT can be applied as

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contraindicated.

Introduction

Material and methods

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Pineal region is a special area in brain with complicated anatomy relationship with surrounding structures where more than 17 tumor types occur, the majority of which is germinoma, followed by astrocytoma, teratoma and pineoblastoma. Each kind of tumor can be in further divided into subgroups according to the pathology or immunohistochemistry . Glioma is most often reported to be located supratentorially, whereas less than 10% infratentorial & spinal cord glial tumors are reported ,and pineal region glioma is even rare.1, 2 Taking the anatomy and pathology into consideration ,the most suitable therapy method is obviously different from experience accumulated in supratentorial region or germinomas of pineal region .Here we report our cases of comprehensive treatment of pineal region gliomas, meanwhile ,we review the current limited literatures about gliomas in this special zone.

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A retrospective analysis is conducted with pineal regional gliomas patients from neurosurgery department in West China hospital from 2011 to 2015. By retrieval of electronic medical records , cases not pathologically confirmed or not supported with radiographic evidence were excluded from analysis.

Surgery procedures

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On accommodation, patients routinely had a serum or CSF(if EVD performed) screening for tumor markers of AFP, β-HCG .If both markers were negative and pre -operation 3D enhanced MRI was in favor of glioma diagnosis ,such as, a peripheral origin , homogenous signal or heterogeneously ring-enhanced ,no hemorrhagic lesions ,with or without calcification. Then a microsurgery was conducted , an EVD tube was kept or replaced with a new one on the other hemisphere until 7 to 10 days or drawn if subsequent CT indicated no ventriculomegaly after EVD was closed . Both supratentorial and infratentorial approaches were performed by a skilled professor in our department .However , supratentorial approach was preferred because we were more familiar and comfort with this approach .When larger tumor extended supratentorially or laterally to the trigone of the lateral ventricle , transcortical transventricular approaches were used. For TCIH(Figure-1A) ,a supine position was preferred , and craniotomy was centered over the coronal suture . Bridging veins sacrificed were avoided as much as possible . Corpus callosotomy was centered

ACCEPTED MANUSCRIPT over the maximal bulge of the tumor .Opening of the splenium was avoided unless exposure of the tumor was unsatisfactory . Tentorium and falx could be opened to provide additional exposure .Deep venous system and venous collaterals were preserved .Small vessels from the ependymal surface and septum pellucidum were meticulously dissected and coagulated .

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FOR ITSC(Figure-1B) ,a sitting position was conducted . A median incision extend from 3 to 5cm above the external occipital protuberance and to the craniocervical level .Special attention was paid to torcular herophili during craniotomy. Dura mater was opened with a Y-shape incision. The superior cerebellar vein and draining veins coming from the surface of the cerebellum could be sacrificed to provide a wider exposure. Opened the cisterna magna to release CSF for further dissection. Deeply located veins were well preserved ,even when only subtotal resection can be achieved with remaining tumor for adjuvant therapy . Special focus was given to posterior commissure with the assistance of endoscope for resection of tumor residues and meticulous hemostasis if needed.

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For OTT , a three-quarters prone position was generally preferred. A U -shaped right occipital craniotomy was made over the sagittal sinus and just above the torcular , and extended upward for about 5 cm . Tentorium adjacent to straight sinus could be divided for exposure. Posterior callosal and dorsal mesencephalic cisterns were opened for CSF release . Insult to large veins connected with the great vein of galen should be avoided. The internal occipital vein and the posterior pericallosal vein were also well preserved.

Adjuvant therapy

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After surgery , patients with only partial remove of tumor or high grade glioma was recommended to have a RT or CHT or just observation. Patients who were reluctant to have open surgery or contraindicated had RT or CHT as primary treatment . Patients went through RT ,either as adjuvant or salvage therapy after recurrence . Radiosurgery ( Leksell gamma knife , Elekta , Sweden) was applied to residual tumors smaller than 3 cm in diameter. Prophylactic spinal irradiation dose was not applied .TMZ was used as CHT agent.

Follow-up

Follow-up data was collected by telephone or face to face interview in outpatient department office. Patients routinely had a gadolinium enhanced 3D MRI scan every 3 months in the first year and half a year in the next year, and then once a year unless the image indicated progress or the patients health situation deteriorated or lost follow up . Independent neuroradiologists evaluated the latest follow-up MRI for evidence of disease progression.

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Statistical Analysis

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Statistical analyses were performed with the statistical analysis software package SPSS (version 23.0, IBM, Armonk, New York, USA). Overall survival was analyzed by Kaplan-Meier survival curve. Statistical analyses of survival rate comparisons were performed with the Mantel-cox test. Statistical significance was defined at P < 0.05.

Results

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General Information and Symptoms

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As a result , 25 patients (12 male 13 female) were included , 23 of whose histopathological diagnosis was obtained by open surgery. The other 2 were based on clinical evidence patients ranged from 5 to 54 years old at admission (mean age 30.4 years) with the ethnic composition of Han for the majority , and only 1 Tibetan and 1 Hui nationality . Based on the WHO 2016 central nervous system classification , there were 7 WHO I tumors (5 pilocytic astrocytomas ,1 ganglioglioma,1 central neurocytoma ), 5 WHO II tumors (1 astrocytoma and 4 ependymocytomas ),2 WHO III tumors (astrocytomas) and 6 WHO IV tumors (glioblastomas) and 5 not otherwise specified Figure-2,3A-F .

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The chief complaint was one or combination of the following presentations ,headache (80%), nausea (72%) , visual impairment (16%) ataxia 8% and seizures 4% (Figure-4). Mean time interval since first symptoms neurological deficit at initial diagnosis was 44.04 days (range from 3 days to 120 days).Mean karnofsky performance score at first admission was 60.4 (range from 30 to 100); Mean maximal diameter before surgery is 3.89 cm (range 2.2–5.6) .The three-dimensional shape were irregular and 18 patients (72%) expanded into the thalamus or posteriorly over the dorsal surface of the quadrigeminal plate. Midbrain invasion was present in 10 cases (40%)

Surgery and adjuvant therapy outcome 13 (52%) of the patients developed hydrocephalus which required emergency EVD upon accommodation and subsequent with ETV (3 patients) or VP shunt (6 patients ) . 4 patients were approached by ITSC, 7 patients by TCIH ,only 1 patient by OTT, and 11 patients by TT . There was no immediate death after surgery and 3 (12 %) cases of bleeding in the resected tumor bed requiring no reoperation ,which had been handled with conservative treatment. 1 intracranial infection patient had been cured before discharge . 2 akinetic mutism,1 motor aphasia ,1 hemiplegic paralysis and 1

ACCEPTED MANUSCRIPT new onset of seizure had occurred . The degree of resection ranged from 50% to gross total resection ( 98%) .

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By the time of last follow up ,12 patients were still alive ,the majority of which were low grade gliomas . 8 (32%) patients lived without residual tumor volume progression ( 10% volume increase) . Follow up duration was from 2 to 78 months, with a median and average of 20 and 23.7 months respectively .The recurrence time interval was from 8 to 21 months . 2 had been conducted a reoperation after recurrence . 3 participates went through WBRT and 4 patients went through GKRS , either as primary 2 patients or adjuvant therapy or salvage after recurrence . Mean marginal dose of which varied from 15–25 Gy at 50–60 % isodose line. WBRT radiation dose was 40-60Gy given in 30 fractions, with 3000-4500 cGy to the ventricular system and an additional 1000-1500 cGy to the tumor bed. TMZ was applied to 1 anaplastic astrocytoma patient and 2 GBM patients . Details of the information are listed in Table 1.

Survival analysis

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We used Mantel-cox test to analyzed different factors that may affect survival rate as follows. At the end of follow-up ,the survival rate of low grade patients was higher than that of high grade patients (48.70 % vs 15.63%, P=0.0069); the survival rate of patients with age 30 years old was higher than that with age 30 years for high grade gliomas (33.33% vs 0, P=0.0320) but not for low grade gliomas (44.44% vs 100%, p=0.4429); the survival rate of KPS 60 patients was higher than that of KPS 60 patients for low grade gliomas ( 100% vs 0, p=0.0195) and high grade gliomas(100% VS 0,P=0.0776) ;the survival rate of GTR patients was higher than that of nGTR patients for low grade gliomas(40% vs 0 , p=0.2702) and high grade gliomas(0 vs 0,p=0.7085); the survival rate of patients with symptoms duration at admission 30 days was higher than that with duration 30 days for low grade gliomas ( 75% vs 44.44%, p=0.9258) but not for high grade gliomas (0 VS 50% ,P=0.1024) ; the survival rate of patients with preoperative maximal tumor diameter 4 cm was higher than that with diameter 4 cm patients for low grade gliomas ( 100% vs 0, p>0.9999) and high grade gliomas(37.5% VS 0,P=0.2029) the survival rate of patients with radiation was higher than that without for low grade gliomas ( 100% vs 38.89%, p=0.3009) and high grade gliomas(33.33% VS 0,P=0. 0.1938) (see Table 2 )

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Discussion General information of pineal region gliomas

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Clinical behaviors

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Gliomas in the pineal region usually affect young patients ,with a mean onset age of 26.24 years old, with a male proportion dominant over female . Gliomas accounts for 8 to 30 percents of all pineal region tumors. In a total of 349 cases, pathology distribution is as follows ,diffuse astrocytoma (24.6%) , glioblastoma (18.6%), ependymoma (15.5%) , pilocytic astrocytoma (14%), anaplastic astrocytoma (9.2%), anaplastic ependymoma (8.3%), oligodendroglioma (5.7 % , only grade II WHO included )1. Some extremely rare seen pathologies are reported in literatures like subependymal giant cell astrocytoma , pilomyxoid, astrocytoma, pleomorphic xanthoastrocytoma , ganglioglioma, papillary tumor, and ganglioneuroblastoma.3-8

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Several articles containing large-scale samples of pineal region lesions in different countries and regions have been published (see Table-3).2, 9-18However , gliomas are analyzed together with other kinds of tumors. There is neither large data nor analysis about pure pineal region gliomas .As far as we are concerned, almost all the literatures about pineal region gliomas are present as cases report due to its rarity and take it for granted without supporting evidences that they behave similarly to supratentorial counterparts . Indeed , the chief complaint of gliomas in the pineal region is not different from other common seen tumors here , namely symptoms of increased intracranial pressure from obstructive hydrocephalus, direct brainstem and cerebellar compression, or endocrine dysfunction , and the proportion of which may be different to some degree compared to other kinds of neuroectodermal original tumor.12

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Gliomas originated from astrocytes in the pineal gland tend to be encapsulated and cystic, resembling the appearance of pilocytic astrocytomas.19 Tectal gliomas derived from brainstem and ependymomas stem from ventricular system can also intrude in the pineal region , present with obstructive hydrocephalus and in rare cases, auditory deficits.15, 20-22 In our series ,there are only a few cases confined to pineal region namely the “ true ” pineal gliomas . “ True ” pineal gliomas are classically described as extremely slow growing and amenable to gross total resection and have excellent outcomes despite of some exceptions. PTPR is a relatively new addition to the WHO classification ,which appears well demarcated from the thalamus and cerebellum, grows slowly and does not transform into a higher grade tumor.8

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Surgery treatment for pineal region gliomas Surgical Management: an Overview

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The role of surgery for maximal resection is best established for benign lesions but not for aggressive malignancies, which may be more suitable to radiosurgery. However , in some cases cytoreduction is still of benefit to a degree , although these data have not reached statistical significance.12, 18 Some centers recommend “second-look” surgery if imaging abnormalities persist after initial treatment with chemotherapy or radiation. 23Tumor debulking allows for brain decompression , relief of symptoms, and pathologic diagnosis. Thus surgery remains the initial therapeutic approach for pineal region tumors. Selected patients may also benefit from reoperation at time of tumor recurrence.10, 18 With advances in technology, surgical technique, and post-operative care, pineal region gliomas can be successfully resected at tolerable levels of morbidity and mortality . In our center ,most of the patients choose to have a resection of tumor , even if not the primary choice. Surgery approaches and complications

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In Adam M. Sonabend’s summary of pineal tumors , GTR ranged from 21-88%,with mortality rates ranged from 0 to 20 % and serious morbidity from 0 to nearly 5.8 %, depending on its invasiveness and expertise of individual surgeons.1 In our center , GTR was 40% (Table-2) , there was no immediately death shortly after surgery, and limited hemorrhages in 3 patients were managed conservatively, with no hemorrhage case requiring immediate evacuation . TT was the most preferred approach in our department , whereas ITSC was the most commonly used approach reported in literatures, followed by OTT and TCIH and TT.24 Postoperative complications included but not limited to , ocular motor dysfunction , ischemic or hemorrhagic infarction, tumor dissemination, transient lethargy, seizure, and cerebellum swelling. The complication may be intimately associated with surgical approach and tumor’s histology , for example , mutism occurred in two subjects with TCIH approach ,which can be attributed to lesion of the cingulate gyrus or septum pellucidum during retraction. Overzealous brainstem manipulation and damage that causing akinetic mutism had also been reported .25-27Two patients with TT approach developed hemiparesis and motor aphasia which resolved in less than 1 months spontaneously (Table-1). Literature review of surgery for pineal region gliomas Surgery is generally curative for benign tumors, seldom with need for further adjuvant therapy. Results of large microsurgical series (one single center with more than 10 pineal region gliomas) for pineal region tumors are summarized in Table-3 . Low grade gliomas patients in reports always survived more than 2 years, and the longest reported survivor was a pilocytic astrocytomas patient still alive after 31 years

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CHT for pineal region gliomas

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follow up .9 In Juha Hernesniemi reports ,19 Low grade gliomas in the pineal region went through completely resection microscopically , and all survived beyond the last follow up time (3.5years) without any RT or CHT.18 The optimal treatment for PTPR, based on limited cases, appeared to be surgery. Most reported cases suggested that PTPR grown slowly and did not transform into a higher grade tumor .However, local recurrence was possible, and RT appeared to provide good local control for incompletely removed tumors.8 In contrast, malignant tumors even grossly resected with adjuvant therapy , died by the end of the follow-up. Consistent with Konovalov’s conclusions that the extent of tumor removal was associated with survival in almost all types of malignant tumor in this region.17 In our center the survival rate was 48.70% vs for patients who had a GTR and 15.63% for high grade gliomas which had a partial resection , although without statistical significance .

Overview of CHT for pineal region gliomas

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It is known that the pineal gland is a unique structure where the blood-brain-barrier is not present and this may be the reason why CHT agents could be effective .. CHT is an adjuvant therapy to pineal regional gliomas rather a first line strategy. CHT had been applied in 3 patients in our hospital ,with the most common used agent TMZ. Similarly, in most of the large centers, only a minority was treated with CHT (after surgery or irradiation failure) , most of which were high grade or recurrent gliomas. In a review of 349 subjects with pineal region gliomas, the use of CHT was reported for only 17 patients . In 1 case VCR and CDDP were administered in combination with RT. The use of VCR was reported in 3 cases, TMZ, CCNU, DBD, PCB, and 6 T-G in 2 cases, ACNU in 1 case .1However the review did not go details about the relationship between CHT regimens and prognosis.

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Literature review of CHT for pineal region gliomas

Low grade

Characteristically, pilocytic astrocytomas have a relatively benign clinical course, often remain quiescent for years with little or no growth , and can be cured by surgery. However in Edwards’ account , one child with neurofibromatosis and concurrent pilocytic astrocytoma died 1 year after diagnosis despite irradiation and CHT (PCB+CCNU+VCR).2 In Takeshi Ogura’ report, a 12-year-old girl with neurofibromatosis type 1 and simultaneously a pineal pilocytic astrocytomas, showed marked enlargement within 5 months after a subtotal resection of pineal pilocytic astrocytomas, remedied by a second surgery and CHT with CDDP and VCR, and stabilized during 18ms follow up.28 In extremely rarely seen Low-grade

ACCEPTED MANUSCRIPT oligodendroglioma , Subtotal resection +radiation (50.4 Gy over 28 fractions) +CHT (TMZ) was applied , and 24-months follow up demonstrated no evidence of disease.29

High grade

Neoadjuvant CHT

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S. Das et al reported 59 year old woman with an Ana-OD in pineal region went through a GTR adjuvant with fractionated external-beam RT to the tumor bed and a concurrent course of TMZ , and MRI images obtained at her 9-month follow-up visit demonstrated no evidence of recurrent disease.30 Matsuyama reported a pineal region ana-OD, who went a biopsy and 4 courses of CHT using CBP and VP-16, and progression of multiple cerebrospinal fluid dissemination was observed.31 In a review of GBM of the pineal region, characterstic of leptomeningeal and ventricular dissemination ,the mean survival duration for 12 GBM patients (mean age 40.8) was from 2 to 11 months (mean 4.9 ) ,4 patients who underwent surgery and received CHT and RT lived longer overall (4–11 months, mean survival 7 months) than those who did not . The two patients who underwent surgery and RT alone lived 4 and 6 months, respectively (mean 5 months). No patients underwent CHT and RT alone without surgical resection. Onur ozgural reported the first adult GBM reaching a survival duration of more than 2 years and also the second case that survived over 2 years according the literatures .The patient experienced VP shunt and stereotactic biopsies with adjuvant RT and CHT.32 What’s interesting was one of our GBM case went through GKRS without CHT had survived more than 42 months, longer than any ever been reported .The details of reported cases with CHT in literatures are listed in Table-4.

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Neoadjuvant CHT , namely CHT administered prior to the main cancer treatment for the purpose of reducing the size of the tumor and facilitating maximum debulking . This concept has been increasing explored in central nerve system. Recent case series in patients with diffuse inoperable supratentorial LGGs demonstrated significant tumor size reduction after administration of TMZ , thereby facilitating a safe radical resection. In a case series of 17 patients undergoing resection of LGGs in eloquent brain areas, neoadjuvant TMZ significantly decreased tumor volume prior to surgery. A more than 20% reduction in tumor volume with TMZ was correlated with decreased residual tumor and permitted an increase in extent of resection from 89.5% to 93.1%. However these gilomas were located supratentorially. 33Hideo Nakamura reported a successful treatment of neoadjuvant therapy for PTPR, though radiation was applied at the same time.34Shrinkage of the giant tumor may facilitate the radical resection or the application of GKRS in pineal region ,which is worth a shot .

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RT for pineal region gliomas Traditional radiotherapy

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Pineal region tumors have either been approached surgically with the goal of GTR ,or subtotal resection adjuvant with conventional radiation . The details of RT plans were available in a limited number of cases.1 IMRT was only administered in 1 patient, up to a total dose of 5940 cGy with a GKRS boost of 12 Gy to the pineal region, but leptomeningeal and spinal metastases subsequently developed . Palliative craniospinal irradiation and CHT were initiated as salvage , and the patients died after 8 months .The location of treatment included a 1 to 3cm peritumoral margin.37 WBRT was either used alone or in combination with focal RT by Clifford .Two patients with astrocytoma lived for 45 and 2 months respectively, which may be attributed to radiation dose difference.38 Proton beam therapy might decrease the risk of radiation-related side effects in normal brain tissue but carried the risk of undertreating the margins , which had not been applied in pineal regional gliomas. Radiosurgery

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Radiosurgery has the potential to be used either as a “boost” modality in conjunction with conventional RT, or even as an alternative to RT and/or surgery altogether. Although greater patient numbers and larger follow-ups will be needed before this finding can be stated with certainty .The problem for radiosurgery was not local control ,but a distant failures. 100 % local pineocytoma , pineoblastoma control was achieved with a mean marginal dose of 15.3 Gy to the 50 % isodose line.39, 40 Germinoma also responded to radiosurgery well with marginal doses ranged from 9.9 to 25.7 Gy.41 Reported local dose for pineal gliomas was from 20- 86 Gy, and there was no agreed conclusion of proper radiation dose due to the heterogeneity of subtypes and radiological parameters (see Table 5).

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In our center , 4 patients went through GKRS , 3 went through WBRT .what’s interesting was a GBM patient treated only by GKRS survived more than 42 months beyond the longest survivor record ever reported . Patients benefited from RT compared to those without , although without statistical significance. It seemed that GKRS as first choice was only suitable for those who have surgery contraindications or unwilling taking the risks with the procedure. Methods of reducing radiation doses are being investigated to avoid the associated long-term side effects. These methods include treatment strategies that combine RT with CHT.42, 43 Should RT be carried out simultaneously with CHT or delayed until at the time of tumor progression is a question worthy of debate.

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Conclusion

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Pineal region gliomas originate from the pineal region itself or from adjacent structures like thalamus or midbrain which ultimately determines the tumor’s resectability and related complications. Microsurgery is the first line choice for patients unless contraindicated, with acceptable mortality and disability .Young age( 30 years old) and KPS 60 at admission and low grade grading are intimately associated with longer survival . RT and CHT could be applied respectively or synchronously as adjuvant or rescue method. Neoadjuvant CHT may facilitate the radical resection or the application of GKRS in pineal region. And CHT application should be based on pathological evidence . With more experience accumulated ,and with prospective large sample size, multicenter, randomized, blind, controlled trials, we will find the best treatment strategies for individuals .

Declarations of interest: none

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29.Lamis F, Paiva Neto, Stavale J and Cavalheiro S, Low-Grade Oligodendroglioma of the Pineal Region: Case Report, Journal of Neurological Surgery Reports, 2015, 76(01):e55-e58. 30.Das S., Chandler J. P, Pollack A, Biggio E. H, Diaz L, Raizer J and Batjer H, Oligodendroglioma of the pineal region. Case report, JOURNAL OF NEUROSURGERY, 2006, 105(3):461.

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31.Matsuyama J, Kaitoh T and Abe M, Oligodendroglioma Arising in the Region of the Pineal Gland: A Case Report, Neurosurgery Quarterly, 2011, 21(3):226-230.

32.Amini A, Schmidt R. H, Salzman K. L, Chin S. S. and Couldwell W. T, Glioblastoma multiforme of the pineal region, JOURNAL OF NEURO-ONCOLOGY, 2006, 79(3):307-314. 33.Blonski M, Pallud J, Gozé C, Mandonnet E, Rigau V, Bauchet L and Fabbro, M, Neoadjuvant chemotherapy may optimize the extent of resection of World Health Organization grade II gliomas: a case series of 17 patients, JOURNAL OF NEURO-ONCOLOGY, 2013, 113(2):267-275.

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34.Nakamura H, Makino K., Kochi M, Nakazato Y and Kuratsu J, Successful treatment of neoadjuvant therapy for papillary tumor of the pineal region, Brain Tumor Pathology, 2009, 26(2):73-77. 35.Oi S, Shibata M, Tominaga J, Honda Y, Shinoda M, Takei F and Tsugane, Efficacy of neuroendoscopic procedures in minimally invasive preferential management of pineal region tumors: a prospective study, JOURNAL OF NEUROSURGERY, 2000, 93(2):245-253.

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36.Terushige Toyooka, Shinji Fukui, Naoki Otani, Hiroshi Nawashiro and Shima K, Central neurogenic hyperventilation in a conscious man with CSF dissemination from a pineal glioblastoma, JOURNAL OF CLINICAL NEUROSCIENCE, 2005(12):834-837.

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37.Lekovic G. P, Gonzalez L. F, Shetter A. G, Porter R. W, Smith K. A, Brachman D and Spetzler R. F, Role of Gamma Knife surgery in the management of pineal region tumors, Neurosurgical Focus, 2007, 23(6):E12.

38.Chao C. K, Lee S. T, Lin, F. J, Tang S. G and Leung W. M, A multivariate analysis of prognostic factors in management of pineal tumor, Int J Radiat Oncol Biol Phys, 1993, 27(5):1185-1191. 39.Hasegawa T, Kondziolka D, Hadjipanayis C. G, Flickinger J. C and Lunsford L. D, The role of radiosurgery for the treatment of pineal parenchymal tumors, NEUROSURGERY, 2002, 51(4):880-889. 40.Kano H, Niranjan A, Kondziolka D, Flickinger J. C and Lunsford D, Role of stereotactic radiosurgery in the management of pineal parenchymal tumors, Progress in neurological surgery, 2009, 23:44. 41.Mori Y., Stereotactic Radiosurgery for Pineal and Related Tumors, Prog Neurol Surg, 2009(23):106-118.

ACCEPTED MANUSCRIPT 42.Calaminus , Impact of Surgery, Chemotherapy and Irradiation on Long Term Outcome of Intracranial Malignant Non-Germinomatous Germ Cell Tumors: Results of the German Cooperative Trial MAKEI 89, Klinische Pädiatrie, 2004, 216(3):141-149. 43.Tseng C. K, Tsang N. M, Jaing T. H, Liau C. T, Wu C. T and Lin K. L, Outcome of central nervous system germinoma treatment by chemoradiation J Pediatr Hematol Oncol, 2011, 33(4):e138-e142. 44.Matsumoto K, Higashi H, Tomita S and Ohmoto T, Pineal region tumours treated with interstitial brachytherapy with low activity sources (192-iridium), ACTA NEUROCHIRURGICA, 1995,

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136(1-2):21-28.

45.Kreth F. W, Schätz C. R, Pagenstecher A, Faist M, Volk B and Ostertag C. B, Stereotactic

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management of lesions of the pineal region, NEUROSURGERY, 1996, 39(2):280-291.

ACCEPTED MANUSCRIPT

Table 1,patiens with pineal regional gliomas in West china hospital nt,se

ys)

Pathology

WHO

Surgical

percent

class

approach

of

x(F=

resectio

fema

n

Complication

Adjuvant

KPS

theraphy

admission

le,M =mal e) 18

gangliogliomas

I

F

18

pilocytic

I

astrocytoma F

21

pilocytic

OTT

98

hemorrhage,infection electrolytedisturbance

TCIH

30

I

limb seizures

29

pilocytic

I

astrocytoma F

5

pilocytic

TCIH

-

I

ITSC

astrocytoma M

12

pilocytic

98 I

-

astrocytoma 41

central

I

neurocytoma

100

4

70

3.5

TT

M

18

ependymoma

II

ITSC

F

18

ependymoma

II

TT

F

36

ependymoma

II

TT

F

42

astrocytoma

II

TT

M

13

astrocytoma

II

ITSC

100

Duration

symptoms(days

recurrence

of

)

interval(m

follow(mo

onths)

nths)

-

60

18

24

3

30

60

4.8

60

90

2.2

90

5.6

7 Deceased

3

78

7

GKRS 90

48

Survival -

40

60

50

Survival -

70

3.5

90

Survival

Deceased -

-

outcome

Survival -

hemiplegic paralysis

AC C

F

-

diameter(cm)

-

EP

-

time since first

-

TE D

F

98

maximal

WBRT+reoper ation

TCIH astrocytoma

-

M AN U

F

at

RI PT

Age(

SC

Patie

38.4 Survival

50

-

-

50

5

120

-

36

Deceased

50

-

-

50

5

100

-

32.4

Deceased

80

-

WBRT

40

3

5

-

20.4

Survival

98

hemorrhage

-

60

4

7

-

2

Survival

98

-

-

80

3.2

50

-

24

Survival

ACCEPTED MANUSCRIPT

27

anaplastic

III

TT

70

-

CHT

astrocytoma M

36

astrocytoma

10 40

III

TCIH

98

mutism, ocular motility

GKRS

impairment

5

RI PT

M

12

40

Deceased 11

30

6

8

11 Deceased

54

glioblastoma

IV

TT

80

-

CHT

30

4.5

1

-

4

Deceased

M

54

glioblastoma

IV

TT

85

-

CHT

40

4.7

20

-

6

Deceased

F

15

glioblastoma

IV

-

-

-

GKRS

2

60

21

42

Survival

M

30

glioblastoma

IV

-

WBRT+reoper

12

12

TT ation

50

glioblastoma

IV

TT

50

motor aphasia

M

54

glioblastoma

IV

TT

98

hemorrhage

M

45

astrocytoma

-

TCIH

60

-

19

astrocytoma

-

ITSC

50

-

32

astrocytoma

-

TCIH

50

-

M

38

astrocytoma

-

TT

98

-

F

36

astrocytoma

-

TCIH

98

Mutism

AC C

EP

F M

60

3.8

30

-

50

3.5

20

5

5

Deceased

-

70

3

30

-

7

Survival

-

80

2.5

100

8

9

Survival

GKRS

60

3.5

60

-

20

Deceased

-

50

4

20

12

12

Survival

-

80

3

90

18

21

Deceased

-

30

5

10

-

2

Deceased

TE D

M

90

M AN U

70

SC

F

Deceased

ACCEPTED MANUSCRIPT

Table-2 different factors that may affect survival rate Number

OS (%)

low

12

48.70

high

8

15.63

≤30 years

9

44.44

＞30 years

3

100

P Value

RI PT

Variable WHO grade

3

＞30 years

5

Gender low grade male

3

female

9

33.33

SC 0.4429

0.0320

0

EP

≤30 years

AC C

high grade

TE D

low grade

M AN U

Age

0.0069

50 46.67

0.8750

ACCEPTED MANUSCRIPT

high grade 6

0

female

2

50

yes

6

40

no

4

0

yes

2

0

no

5

0.6073

RI PT

male

SC

GTR(≥98%)

≤60

6

＞60

6

high grade

EP

low grade

0.7085

0

AC C

KPS at admisson

0.2702

TE D

high grade

M AN U

low grade

0

100

0.0195

ACCEPTED MANUSCRIPT

6

0

＞60

2

100

5

75

7

44.44

≤30 days

6

0

＞30 days

2

50

0.0776

RI PT

≤60

＞30 days

8

＞4 cm

4

high grade 4

EP

≤4 cm

100

AC C

preoperative maximal tumor diameter low grade

≤4 cm

0.1024

TE D

high grade

0.9258

M AN U

≤30 days

SC

symptoms duration at admission low grade

>0.9999

0

37.5

0.2029

ACCEPTED MANUSCRIPT

＞4 cm

4

0

yes

3

100

no

9

38.89

yes

3

33.33

no

5

0

RI PT

radiation low grade

AC C

EP

SC M AN U

TE D

high grade

0.3009

0.1938

ACCEPTED MANUSCRIPT Table-3 one single center with more than 10 pineal region glioma

author

region

No.

Approac

Percent

mortality

of

h

of patients

(%)

Case

gliomas

with GTR

s* Canada

61

TCIH/I

NA

20

TSC

8

RI PT

Hoffman

9

5LG-A

3HG-A

Lapras

10

France

86

TCIH/O

65

5.8

TT

25

17A 4E

Edwards

California

36

TT/OTT

NA

/ITSC

SC

4OD

2

0

8

7A

Italy

12

Spain

Vaquero

13

29

China

Luo SQ

14

Germany

64

49

AC C

EP

Herrmann

40

15

New York

Bruce

ITSC

TCIH/I

25

NA

5

11

11 10A 1 GBM 3

TSC/OT

2A

T

1 GBM

OTT

21

TE D

Pluchino

M AN U

1GBM

11

IHTC/I

NA

10

12 9A 1 GBM 1OD 1E

8

13

TSC

1Gang 2OD 9A 1 Ana- E

160

ITSC/T

45

4

46

C/OTT

23A 6Ana-A 4 GBM 2OD 10E 1CP

Hyung-Jin Shin

16

South Korea

21

OTT

54.5

0

3 2 Ana-A 1 GBM

Konovalov

17

Russia

201

OTT ITSC

58

10

77 37LG-A 10HG-A

ACCEPTED MANUSCRIPT 5E 25Ana- E Hernesniemi

18

Finland

119

ITSC

88

0

26without detail

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ACCEPTED MANUSCRIPT Table-4 details with CHT for pineal regional gliomas in literatures author

year.

Age

Diagnosis

Treatment modalities

Duration of

Sex

Response

Clinical

Complications or Death

fU(months) Edwards

2

1988

16/M

Ana-A

Focal fra-RT+ CHT(PCB,CCNU, VCR

）

died 1year

12/F

GBM

fra-RT+ CHT(6-TG, CCNU, PCB,DBD,

died 1year

VCR) 2000

-

GBM

GTR+WBRT+CHT(ifosfamide,CDDP,

died 5 ms

VP-16) Takeshi

2004

12/F

Pil-A

Ogura28 2005

-

GBM

36

removal

+intravenous

Disseminated 9m

31

2006

59/F

Ana-OD

operation +fra-RT+ TMZ

2011

23/M

Ana-OD

Biopsy, ETV, CBP, VP16

2015

22/F

LG-OD

Present study

2019

27/M

Ana-A

none

Sub- resection,

died 11 ms

9

No recurrence

none

5

Dissemination at

Intra

5 ms

bleeding

24

No recurrence

none

12

Recurrence after

Died after 12ms

M AN U

29

SC

DAS

matsuyama

Partial

Progress within 5

ms

ACNU+2local RT

30

Lamis

23

(CDDP, VCR)

Terushige Toyooka

Sub-resection+a second surgery+ CHT

RI PT

Shizuo

35

tumoral

fra-RT, and TMZ Surgery+TMZ

10 ms

GBM

Surgery+TMZ

4

Died after 4ms

54/M

GBM

Surgery+TMZ

6

Died after 6ms

AC C

EP

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54/F

ACCEPTED MANUSCRIPT Table 5 cases with details of radiation of pineal regional gliomas author

year.

Age

Diagnosis

Treatment modalities

Duration

Sex 2

1988

Edwards

of

Response

Clinical fU 6Ana-A

＜18

fra-focal-RT（6500 to 5500 rads）+

6ms-3ys

Complications or Death

5alive,1 dead

CHT（1）

1992

Snipes

fra-RT(7200rads)+CHT

Tumor progression 1.5years

Pil-A

fra-RT+ CHT

died 12 ms

Ple-gra

VP shunt+Surgery+ GKRS(56Gy)

cell A

Surgery+ GKRS(45Gy)

27/M

NOS-A

Sub-resection+WBRT (20Gy)

41/F

grade

Sub-resection;WBRT (40Gy)+Local

II-A

boost(20Gy);

grade

Biopsy+RT(50Gy)+ interstitial

Disseminated

III-A

brachytherapy(36Gy)

After 16ms

25/F

kreth

45

1995

1996

27/M

-

9 Pil-A

5

Wait

and

died 45ms

See,3Interstitial

38ms

RS(60Gy),1resection, 11 grade II gliomas 5

Grade

9Interstitial RS,2resection,

2005

40/M

36

GBM

40ms

1Progress

no

1 died 12 ms

after 1y

died with in

Treatment

1, 5, 9, and 27 ms,

Partial

removal+CHT+local

RT(60Gy)+ additional local

Toyooka

1Progress after 2ys

gliomas

Terushige

died 18 ms

3RT(60Gy),2multimodality

TE D

III

1 recurrence

died 2ms

SC

44

M AN U

Matsumoto

1993

8ys,18ms

at 4 ms

38/M Clifford38

RI PT

5

GBM

Disseminated

died 12 ms

After 9ms

RT(20GY)

37

2007

27/F

LG-A

EP

Lekovic

AC C

29/M

masaya

Nagaishi Lamis

29

2011

36/m

Ana-A

Endoscopic

biopsy+

resection

21 ms

CR at 21 ms

none

8m s

distant

died

GKRS(24Gy)+ 5940 cGy

progr at

ms after

IMRT +craniospinal

5 ms

GKRS

No

none

+GKRS(28Gy)

Open

biopsy+

RT(3600cGy)+ CHT Pil-A

Biopsy+RT(31WBRT+20 local Gy)

7

2015

22/F

Recurrence at 6ms

LG-OD

Sub-resection,

24ms

fra-RT(50.4 Gy), and TML Present

2019

18/F

8

Pil-A

Surgery+WBRT(40Gy )+reoperation

recurrence 24ms

study

Recurrence

Survived

After 18ms 16/M

Pil-A

GKRS(15Gy)

60ms

No

Survived

36/M

E

Surgery+WBRT(50Gy)

20.4ms

No

Survived

36/M

grade

Surgery+ GKRS(25Gy)

11ms

Recurrence

died

8

ACCEPTED MANUSCRIPT III-A 15/F

GBM

GKRS(25Gy)

42 ms

After 11ms

ms

Recurrence

Survived

21ms 30/M

GBM

12 ms

Surgery+ WBRT(60Gy)+reoperation

12ms

died

12

ms 19/F

NOS-A

20ms

Surgery+GKRS(18Gy)

-

died

AC C

EP

TE D

M AN U

SC

RI PT

ms

20

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

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ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT

AC C

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Declarations of interest: none

AC C

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A=astrocytomas ACNU=nimustine AFP=alpha fetoprotein Ana=Anaplastic CBP=carboplatin CCNU=lomustine CDDP=cisplatin CHT=chemotherapy CSF=cerebrospinal fluid CP=choroid plexus papilloma CR=complete response DBD=dibromodulcitol E=Ependymoma ETV=endoscopic third ventriculostomy EVD=external ventricular drainage Fra=fractionated Fu=follow up Gang=Gangliocytom GBM=glioblastoma GKRS=Gamma knife radiosurgery GTR=gross total resection HCG = human chorionic gonadotropin HG=high grade IMRT=intensity modulated radiotherapy ITSC=infratentorial supracerebellar KPS =Karnofsky Performance Status LG=low grade LGGs=Low grade gliomas ms=months NOS=not otherwise specified NA= not available nGTR= not gross total resection OD= Oligodendrogliomas OS=Overall survival OTT=occipital transtentorial approach PCB=procarbazine Pil=pilocytic Ple-gra =Pleomorphic granular PTPR=Papillary tumor of the pineal region RT=radiationtherapy TCIH=transcallosal interhemispheric approach TMZ=temozolomide TT=transcortical transventricular approach VCR=vincristine

RI PT

ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT

AC C

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VP=ventriculo-peritoneal VP-16=etoposide WBRT=whole brain radiation therapy ys=years 6T-G=6-thioguanine