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Acta Neuropathologica Feb 2020Pineoblastomas (PBs) are rare, aggressive pediatric brain tumors of the pineal gland with modest overall survival despite intensive therapy. We sought to define the...
Pineoblastomas (PBs) are rare, aggressive pediatric brain tumors of the pineal gland with modest overall survival despite intensive therapy. We sought to define the clinical and molecular spectra of PB to inform new treatment approaches for this orphan cancer. Tumor, blood, and clinical data from 91 patients with PB or supratentorial primitive neuroectodermal tumor (sPNETs/CNS-PNETs), and 2 pineal parenchymal tumors of intermediate differentiation (PPTIDs) were collected from 29 centres in the Rare Brain Tumor Consortium. We used global DNA methylation profiling to define a core group of PB from 72/93 cases, which were delineated into five molecular sub-groups. Copy number, whole exome and targeted sequencing, and miRNA expression analyses were used to evaluate the clinico-pathologic significance of each sub-group. Tumors designated as group 1 and 2 almost exclusively exhibited deleterious homozygous loss-of-function alterations in miRNA biogenesis genes (DICER1, DROSHA, and DGCR8) in 62 and 100% of group 1 and 2 tumors, respectively. Recurrent alterations of the oncogenic MYC-miR-17/92-RB1 pathway were observed in the RB and MYC sub-group, respectively, characterized by RB1 loss with gain of miR-17/92, and recurrent gain or amplification of MYC. PB sub-groups exhibited distinct clinical features: group 1-3 arose in older children (median ages 5.2-14.0 years) and had intermediate to excellent survival (5-year OS of 68.0-100%), while Group RB and MYC PB patients were much younger (median age 1.3-1.4 years) with dismal survival (5-year OS 37.5% and 28.6%, respectively). We identified age < 3 years at diagnosis, metastatic disease, omission of upfront radiation, and chr 16q loss as significant negative prognostic factors across all PBs. Our findings demonstrate that PB exhibits substantial molecular heterogeneity with sub-group-associated clinical phenotypes and survival. In addition to revealing novel biology and therapeutics, molecular sub-grouping of PB can be exploited to reduce treatment intensity for patients with favorable biology tumors.
Topics: Adolescent; Adult; Age Factors; Brain Neoplasms; Child; Child, Preschool; Cohort Studies; Female; Humans; Infant; Male; MicroRNAs; Mutation; Pineal Gland; Pinealoma; Registries; Survival Rate; Young Adult
PubMed: 31820118
DOI: 10.1007/s00401-019-02111-y -
Acta Neuropathologica Feb 2020Pineoblastoma is a rare embryonal tumor of childhood that is conventionally treated with high-dose craniospinal irradiation (CSI). Multi-dimensional molecular evaluation...
Pineoblastoma is a rare embryonal tumor of childhood that is conventionally treated with high-dose craniospinal irradiation (CSI). Multi-dimensional molecular evaluation of pineoblastoma and associated intertumoral heterogeneity is lacking. Herein, we report outcomes and molecular features of children with pineoblastoma from two multi-center, risk-adapted trials (SJMB03 for patients ≥ 3 years; SJYC07 for patients < 3 years) complemented by a non-protocol institutional cohort. The clinical cohort consisted of 58 patients with histologically diagnosed pineoblastoma (SJMB03 = 30, SJYC07 = 12, non-protocol = 16, including 12 managed with SJMB03-like therapy). The SJMB03 protocol comprised risk-adapted CSI (average-risk = 23.4 Gy, high-risk = 36 Gy) with radiation boost to the primary site and adjuvant chemotherapy. The SJYC07 protocol consisted of induction chemotherapy, consolidation with focal radiation (intermediate-risk) or chemotherapy (high-risk), and metronomic maintenance therapy. The molecular cohort comprised 43 pineal parenchymal tumors profiled by DNA methylation array (n = 43), whole-exome sequencing (n = 26), and RNA-sequencing (n = 16). Respective 5-year progression-free survival rates for patients with average-risk or high-risk disease on SJMB03 or SJMB03-like therapy were 100% and 56.5 ± 10.3% (P = 0.007); respective 2-year progression-free survival rates for those with intermediate-risk or high-risk disease on SJYC07 were 14.3 ± 13.2% and 0% (P = 0.375). Of patients with average-risk disease treated with SJMB03/SJMB03-like therapy, 17/18 survived without progression. DNA-methylation analysis revealed four clinically relevant pineoblastoma subgroups: PB-A, PB-B, PB-B-like, and PB-FOXR2. Pineoblastoma subgroups differed in age at diagnosis, propensity for metastasis, cytogenetics, and clinical outcomes. Alterations in the miRNA-processing pathway genes DICER1, DROSHA, and DGCR8 were recurrent and mutually exclusive in PB-B and PB-B-like subgroups; PB-FOXR2 samples universally overexpressed the FOXR2 proto-oncogene. Our findings suggest superior outcome amongst older children with average-risk pineoblastoma treated with reduced-dose CSI. The identification of biologically and clinically distinct pineoblastoma subgroups warrants consideration of future molecularly-driven treatment protocols for this rare pediatric brain tumor entity.
Topics: Adolescent; Age Factors; Brain Neoplasms; Child; Child, Preschool; Cohort Studies; DNA Methylation; Female; Humans; Male; Pineal Gland; Pinealoma; Proto-Oncogene Mas; Risk Factors; Survival Rate; Young Adult
PubMed: 31802236
DOI: 10.1007/s00401-019-02106-9 -
Neurologia Medico-chirurgica Jan 2020The motion of cerebrospinal fluid (CSF) within the subarachnoid space and ventricles is greatly modulated when propagating synchronously with the cardiac pulse and...
Simple Identification of Cerebrospinal Fluid Turbulent Motion Using a Dynamic Improved Motion-sensitized Driven-equilibrium Steady-state Free Precession Method Applied to Various Types of Cerebrospinal Fluid Motion Disturbance.
The motion of cerebrospinal fluid (CSF) within the subarachnoid space and ventricles is greatly modulated when propagating synchronously with the cardiac pulse and respiratory cycle and path through the nerves, blood vessels, and arachnoid trabeculae. Water molecule movement that propagates between two spaces via a stoma, foramen, or duct presents increased acceleration when passing through a narrow area and can exhibit "turbulence." Recently, neurosurgeons have started to perform fenestration procedures using neuroendoscopy to treat hydrocephalus and cystic lesions. As part of the postoperative evaluation, a noninvasive diagnostic technique to visualize the water molecules at the fenestrated site is necessary. Because turbulence is observed at this fenestrated site, an imaging technique appropriate for observing this turbulence is essential. We therefore investigated the usefulness of a dynamic improved motion-sensitized driven-equilibrium steady-state free precession (Dynamic iMSDE SSFP) sequence of magnetic resonance imaging that is superior for ascertaining turbulent motions in healthy volunteers and patients. Images of Dynamic iMSDE SSFP from volunteers revealed that CSF motion at the ventral surface of the brainstem and the third ventricle is augmented and turbulent. Moreover, our findings confirmed that this technique is useful for evaluating treatments that utilize neuroendoscopy. As a result, Dynamic iMSDE SSFP, a simple sequence for visualizing CSF motion, entails a short imaging time, can extensively visualize CSF motion, does not require additional processes such as labeling or trigger setting, and is anticipated to have wide-ranging clinical applications in the future.
Topics: Adolescent; Adult; Cerebral Ventricles; Cerebrospinal Fluid; Child; Child, Preschool; Cysts; Female; Humans; Hydrocephalus; Magnetic Resonance Imaging; Male; Middle Aged; Motion; Pinealoma; Rheology; Subarachnoid Space; Young Adult
PubMed: 31776307
DOI: 10.2176/nmc.oa.2019-0170 -
Acta Neuropathologica Feb 2020Tumors of the pineal region comprise several different entities with distinct clinical and histopathological features. Whereas some entities predominantly affect adults,...
Tumors of the pineal region comprise several different entities with distinct clinical and histopathological features. Whereas some entities predominantly affect adults, pineoblastoma (PB) constitutes a highly aggressive malignancy of childhood with a poor outcome. PBs mainly arise sporadically, but may also occur in the context of cancer predisposition syndromes including DICER1 and RB1 germline mutation. With this study, we investigate clinico-pathological subgroups of pineal tumors and further characterize their biological features. We performed genome-wide DNA methylation analysis in 195 tumors of the pineal region and 20 normal pineal gland controls. Copy-number profiles were obtained from DNA methylation data; gene panel sequencing was added for 93 tumors and analysis was further complemented by miRNA sequencing for 22 tumor samples. Unsupervised clustering based on DNA methylation profiling separated known subgroups, like pineocytoma, pineal parenchymal tumor of intermediate differentiation, papillary tumor of the pineal region and PB, and further distinct subtypes within these groups, including three subtypes within the core PB subgroup. The novel molecular subgroup Pin-RB includes cases of trilateral retinoblastoma as well as sporadic pineal tumors with RB1 alterations, and displays similarities with retinoblastoma. Distinct clinical associations discriminate the second novel molecular subgroup PB-MYC from other PB cases. Alterations within the miRNA processing pathway (affecting DROSHA, DGCR8 or DICER1) are found in about two thirds of cases in the three core PB subtypes. Methylation profiling revealed biologically distinct groups of pineal tumors with specific clinical and molecular features. Our findings provide a foundation for further clinical as well as molecular and functional characterization of PB and other pineal tumors, including the role of miRNA processing defects in oncogenesis.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Brain Neoplasms; Case-Control Studies; Child; DNA Methylation; Female; Humans; Male; MicroRNAs; Middle Aged; Mutation; Pineal Gland; Pinealoma; Young Adult
PubMed: 31768671
DOI: 10.1007/s00401-019-02101-0 -
AJNR. American Journal of Neuroradiology Nov 2019Supratentorial primitive neuroectodermal tumors and pineoblastomas have traditionally been grouped together for treatment purposes. Molecular profiling of these tumors...
MRI Features of Histologically Diagnosed Supratentorial Primitive Neuroectodermal Tumors and Pineoblastomas in Correlation with Molecular Diagnoses and Outcomes: A Report from the Children's Oncology Group ACNS0332 Trial.
BACKGROUND AND PURPOSE
Supratentorial primitive neuroectodermal tumors and pineoblastomas have traditionally been grouped together for treatment purposes. Molecular profiling of these tumors has revealed a number of distinct entities and has led to the term "CNS-primitive neuroectodermal tumors" being removed from the 2016 World Health Organization classification. The purpose of this study was to describe the MR imaging findings of histologically diagnosed primitive neuroectodermal tumors and pineoblastomas and correlate them with molecular diagnoses and outcomes.
MATERIALS AND METHODS
Histologically diagnosed primitive neuroectodermal tumors and pineoblastomas were enrolled in this Children's Oncology Group Phase III trial, and molecular classification was retrospectively completed using DNA methylation profiling. MR imaging features were systematically studied and correlated with molecular diagnoses and survival.
RESULTS
Of the 85 patients enrolled, 56 met the inclusion criteria, in whom 28 tumors were in pineal and 28 in nonpineal locations. Methylation profiling revealed a variety of diagnoses, including pineoblastomas ( = 27), high-grade gliomas ( = 17), embryonal tumors ( = 7), atypical teratoid/rhabdoid tumors ( = 3), and ependymomas ( = 2). Thus, 39% overall and 71% of nonpineal tumor diagnoses were discrepant with histopathology. Tumor location, size, margins, and edema were predictors of embryonal-versus-nonembryonal tumors. Larger size and ill-defined margins correlated with poor event-free survival, while metastatic disease by MR imaging did not.
CONCLUSIONS
In nonpineal locations, only a minority of histologically diagnosed primitive neuroectodermal tumors are embryonal tumors; therefore, high-grade glioma or ependymoma should be high on the radiographic differential. An understanding of molecularly defined tumor entities and their relative frequencies and locations will help the radiologist make more accurate predictions of the tumor types.
Topics: Adolescent; Brain Neoplasms; Child; Child, Preschool; Female; Glioma; Humans; Infant; Magnetic Resonance Imaging; Male; Neoplasms, Germ Cell and Embryonal; Neuroectodermal Tumors, Primitive; Pineal Gland; Pinealoma; Retrospective Studies; Rhabdoid Tumor; Supratentorial Neoplasms; Teratoma; Young Adult
PubMed: 31601576
DOI: 10.3174/ajnr.A6253 -
Medicine Aug 2019Tumors of the pineal region are rare, and metastatic carcinoma occurring in the pineal region is extremely rare. No previous reports have described pineal region...
INTRODUCTION
Tumors of the pineal region are rare, and metastatic carcinoma occurring in the pineal region is extremely rare. No previous reports have described pineal region metastasis with intraventricular seeding.
PATIENT CONCERNS
We report a case of a 51-year-old woman presented with a 1-week history of severe headache, nausea, and vomiting. Imaging examination revealed 2 lesions in the pineal region and the right lateral ventricle.
DIAGNOSIS
Pinealocytoma or germinoma was considered as the preoperative diagnosis. The postoperative pathological diagnosis was small cell neuroendocrine carcinoma. After bronchoscopic biopsy, small cell lung cancer was confirmed.
INTERVENTIONS
A right frontal craniotomy and a translateral ventricle approach were performed to remove 2 lesions completely. And regular radiotherapy and chemotherapy were initiated after surgery.
OUTCOMES
The patient was discharged from the hospital 2 weeks after operation and went to another cancer hospital for bronchoscopic biopsy, radiotherapy, and chemotherapy. Finally, the patient died 2 years after surgical treatment.
CONCLUSION
Metastatic tumors of the pineal region are very rare. For patients with pineal lesions, a diagnosis of a metastatic tumor should be considered. Retrograde cerebrospinal fluid circulation might be the reason for a secondary metastasis.
Topics: Diagnosis, Differential; Female; Humans; Lung Neoplasms; Middle Aged; Neoplasm Metastasis; Pinealoma; Small Cell Lung Carcinoma
PubMed: 31441839
DOI: 10.1097/MD.0000000000016652 -
World Neurosurgery Nov 2019Deep-seated cerebral lesions have fascinated and frustrated countless surgical innovators since the dawn of the microneurosurgical era. To determine the optimal...
Deep-seated cerebral lesions have fascinated and frustrated countless surgical innovators since the dawn of the microneurosurgical era. To determine the optimal approach, the microneurosurgeon must take into account the characteristics and location of the pathological lesion as well as the operator's range of technical expertise. Increasingly, microneurosurgeons must select between multiple operative corridors that can provide access to the surgical target. Innovative trajectories have emerged for many indications that provide more flexible operative angles and superior exposure but result in longer working distances and more technically demanding maneuvers. In this article, we highlight 4 innovative surgical corridors and compare their strengths and weaknesses against those of more conventional approaches. Our goal is to use these examples to illustrate the following principles of microneurosurgical innovation: (1) discover more efficient and flexible exposures with superior working angles; (2) ensure maximal early protection of critical neurovascular structures; and (3) effectively handle target pathology with minimal disruption of normal tissues.
Topics: Craniotomy; Humans; Intracranial Arteriovenous Malformations; Medical Illustration; Meningeal Neoplasms; Meningioma; Microsurgery; Neurosurgical Procedures; Pinealoma; Skull Base Neoplasms
PubMed: 31284052
DOI: 10.1016/j.wneu.2019.06.210 -
Journal of Neuropathology and... Aug 2019Pineal parenchymal tumors are rare neoplasms, ranging from WHO Grade I to IV. There are few studies characterizing the molecular profiles of these tumors. ATRX...
Pineal parenchymal tumors are rare neoplasms, ranging from WHO Grade I to IV. There are few studies characterizing the molecular profiles of these tumors. ATRX alterations are strongly associated with the presence of the alternative lengthening of telomeres (ALT) phenotype, and within the central nervous system they tend to occur in subsets of gliomas, including those with IDH, NF1, or histone (H3 K27M or G34) mutations. Here, we identified ATRX frameshift mutations by next generation sequencing associated with corresponding protein loss in 2 cases of pineal parenchymal tumors of intermediate differentiation (PPTID) developing in a 21-year-old woman and a 64-year-old man. In contrast, we identified partial ATRX loss in 1 pineoblastoma, among 14 pineal parenchymal tumors of various grades (6 pineoblastomas, 4 pineocytomas, and 4 PPTID) using tissue microarrays; ALT was absent in these cases. Evaluating the cBioPortal database, an ATRX mutation was identified in one (of 3 total) PPTIDs analyzed. Thus, ATRX mutations associated with protein loss and ALT develop in a small subset of pineal parenchymal tumors and may be limited to those with intermediate differentiation. The clinical significance of these alterations requires further study.
PubMed: 31225581
DOI: 10.1093/jnen/nlz050 -
Journal of Medical Case Reports Jun 2019Cranial irradiation is one of the main treatment modalities for central nervous system tumors. It carries many complications, one being occlusive radiation vasculopathy...
BACKGROUND
Cranial irradiation is one of the main treatment modalities for central nervous system tumors. It carries many complications, one being occlusive radiation vasculopathy of large vessels. It is an underrecognized etiology for stroke, especially in the younger population. The pathophysiological process is controversial, but there is much literature supporting the theory of its being a secondary form of moyamoya disease.
CASE PRESENTATION
A 31-year-old Caucasian man with a history of pineal blastoma at the age of 3 years, which was treated with resection, radiotherapy, and chemotherapy, presented to our institution with right M1 stroke. Further assessment by computed tomographic perfusion study with acetazolamide demonstrated steal phenomenon of the right middle cerebral artery territory (type III response) with a small internal region of matched cerebral blood volume defect (that is, infarct core). Coincidentally, he was found to have multiple brain masses consistent with meningiomas. Occlusive radiation vasculopathy was the most likely culprit of the patient's stroke. The patient was treated medically with "baby" acetylsalicylic acid and clopidogrel for 3 months, then continued only on baby acetylsalicylic acid.
CONCLUSION
Late-onset occlusive radiation vasculopathy is a potentially severe iatrogenic manifestation of radiotherapy that requires a high index of suspicion as an etiology of stroke in young population, especially those with coexistent meningioma that might be a strong indicator for occlusive radiation vasculopathy as the stroke culprit. We reviewed the available literature to better understand the pathogenesis, clinical presentation, and treatment options of occlusive radiation vasculopathy. Applying perfusion studies with acetazolamide measures the cerebrovascular reserve in patients with occlusive radiation vasculopathy, which could help in determining the appropriate available treatment option.
Topics: Adult; Brain; Brain Neoplasms; Cancer Survivors; Cerebral Angiography; Cerebrovascular Disorders; Cranial Irradiation; Humans; Infarction, Middle Cerebral Artery; Magnetic Resonance Angiography; Magnetic Resonance Imaging; Male; Perfusion Imaging; Pineal Gland; Pinealoma; Platelet Aggregation Inhibitors; Radiation Injuries
PubMed: 31159883
DOI: 10.1186/s13256-019-2104-x -
Neurology India 2019
Topics: Brain Neoplasms; Humans; Pineal Gland; Pinealoma
PubMed: 31085867
DOI: 10.4103/0028-3886.258023