WNT-activated embryonal tumors of the pineal region: ectopic medulloblastomas or a novel pineoblastoma subgroup?
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ABSTRACT:
SUBMITTER: Liu APY
PROVIDER: S-EPMC7501206 | biostudies-literature | 2020 Oct
REPOSITORIES: biostudies-literature
Publications
WNT-activated embryonal tumors of the pineal region: ectopic medulloblastomas or a novel pineoblastoma subgroup?
Liu Anthony P Y APY Priesterbach-Ackley Loudy P LP Orr Brent A BA Li Bryan K BK Gudenas Brian B Reddingius Roel E RE Suñol Mariona M Lavarino Cinzia E CE Olaciregui Nagore G NG Santa-María López Vicente V Fisher Michael J MJ Hazrati Lili-Naz LN Bouffet Eric E Huang Annie A Robinson Giles W GW Wesseling Pieter P Northcott Paul A PA Gajjar Amar A
Acta neuropathologica 20200808 4
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Project description:BackgroundRosette-forming glioneuronal tumor (RGNT) is an extremely rare entity described for the first time in the WHO classification of tumors of the central nervous system in 2007. Predominantly, single case reports of RGNT in the pineal region have been published, and specific therapy concepts are pending.MethodsThe study group comprised all patients with the RGNT (CNS WHO grade 1) in the pineal region that underwent microsurgical tumor removal in our center (August 2018-June 2021). Surgical strategy, histological findings, and clinical outcome are presented, and the results are evaluated and compared to published case reports.ResultsFour male patients aged under 50 years (range between 20 and 48 years) and one female patient, 51 years old, were included in this study. Chronic headaches and generalized epileptic seizures were the main symptoms. Supra-cerebellar infratentorial gross total tumor resection (GTR) was performed in two cases, two patients underwent subtotal tumor resection, and an endoscopic biopsy was performed in case five.ConclusionIn cases where surgical resection seems feasible with a reasonable surgical risk, we advocate GTR. Regular and long-term MRI follow-up is essential to detect a slow tumor progression. The role of additional chemotherapy or radiotherapy remains unclear.
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Project description:Background and Objective Surgical treatment for pineal tumors is technically challenging-weighing the risks and benefits of microsurgical resection for the patient with a pineal tumor versus settling for an endoscopic third ventriculostomy and biopsy is sometimes difficult. Traditional microsurgical resection for pineal region tumors has typically required large open craniotomies and involvement or retraction of neural tissue with significant mortality and morbidity. With the advancement of high-resolution fiber optics, a fully endoscopic, supracerebellar, infratentorial approach, without any cerebellar retraction or manipulation of neural tissue, is introduced for the gross total resection of pineal region tumors. Conclusion As an endoscopic modification of the open craniotomy procedure, this technique combines the advantages and benefits of both open microsurgical resection and minimally invasive endoscopic surgeries.
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Project description:BackgroundIntensive chemotherapeutic regimens with craniospinal irradiation have greatly improved survival in medulloblastoma patients. However, survival markedly differs among molecular subgroups and their biomarkers are unknown. Through unbiased screening, we found Schlafen family member 11 (SLFN11), which is known to improve response to DNA damaging agents in various cancers, to be one of the top prognostic markers in medulloblastomas. Hence, we explored the expression and functions of SLFN11 in medulloblastoma.MethodsSLFN11 expression for each subgroup was assessed by immunohistochemistry in 98 medulloblastoma patient samples and by analyzing transcriptomic databases. We genetically or epigenetically modulated SLFN11 expression in medulloblastoma cell lines and determined cytotoxic response to the DNA damaging agents cisplatin and topoisomerase I inhibitor SN-38 in vitro and in vivo.ResultsHigh SLFN11 expressing cases exhibited significantly longer survival than low expressing cases. SLFN11 was highly expressed in the WNT-activated subgroup and in a proportion of the SHH-activated subgroup. While WNT activation was not a direct cause of the high expression of SLFN11, a specific hypomethylation locus on the SLFN11 promoter was significantly correlated with high SLFN11 expression. Overexpression or deletion of SLFN11 made medulloblastoma cells sensitive and resistant to cisplatin and SN-38, respectively. Pharmacological upregulation of SLFN11 by the brain-penetrant histone deacetylase-inhibitor RG2833 markedly increased sensitivity to cisplatin and SN-38 in SLFN11-negative medulloblastoma cells. Intracranial xenograft studies also showed marked sensitivity to cisplatin by SLFN11-overexpression in medulloblastoma cells.ConclusionsHigh SLFN11 expression is one factor which renders favorable outcomes in WNT-activated and a subset of SHH-activated medulloblastoma possibly through enhancing response to cisplatin.
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Project description:Sonic Hedgehog subgroup medulloblastomas
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Project description:PurposeMedulloblastoma in children can be categorized into at least four molecular subgroups, offering the potential for targeted therapeutic approaches to reduce treatment-related morbidities. Little is known about the role of tumor microenvironment in medulloblastoma or its contribution to these molecular subgroups. Tumor microenvironment has been shown to be an important source for therapeutic targets in both adult and pediatric neoplasms. In this study, we investigated the hypothesis that expression of genes related to tumor-associated macrophages (TAM) correlates with the medulloblastoma molecular subgroups and contributes to a diagnostic signature.MethodsGene-expression profiling using human exon array (n = 168) was analyzed to identify medulloblastoma molecular subgroups and expression of inflammation-related genes. Expression of 45 tumor-related and inflammation-related genes was analyzed in 83 medulloblastoma samples to build a gene signature predictive of molecular subgroups. TAMs in medulloblastomas (n = 54) comprising the four molecular subgroups were assessed by immunohistochemistry (IHC).ResultsA 31-gene medulloblastoma subgroup classification score inclusive of TAM-related genes (CD163 and CSF1R) was developed with a misclassification rate of 2%. Tumors in the Sonic Hedgehog (SHH) subgroup had increased expression of inflammation-related genes and significantly higher infiltration of TAMs than tumors in the Group 3 or Group 4 subgroups (P < 0.0001 and P < 0.0001, respectively). IHC data revealed a strong association between location of TAMs and proliferating tumor cells.ConclusionsThese data show that SHH tumors have a unique tumor microenvironment among medulloblastoma subgroups. The interactions of TAMs and SHH medulloblastoma cells may contribute to tumor growth revealing TAMs as a potential therapeutic target.
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Project description:Tumors of the pineal region (TPRs) are rare neoplasms that are surgically challenging to resect. Conventional treatment strategies are available, but gamma knife radiosurgery (GKRS) is an alternative approach. This study presents a single-center experience with GKRS performed for TPR with and without histopathological diagnoses. The cases of 25 patients with TPRs treated with GKRS were retrospectively analyzed. Thirteen of these 25 patients had histopathological confirmation, and 13 had elevated serum alpha-fetoprotein and beta-human chorionic gonadotropin levels. The 25 patients had a mean follow-up duration of 61 months. The total response rate to GKRS was 60%, and a 53.8% decrease in the alpha-fetoprotein and beta human chorionic gonadotropin levels was observed. The findings of this study indicate that GKRS is a safe procedure for TPRs, even in the event of insufficient histopathological findings. This treatment approach provides increased Karnofsky performance scores and an extended life expectancy.
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