Rosette-Forming Glioneuronal Tumor in the Pineal Region: A Series of 6 Cases and Literature Review

2021 ◽  
Author(s):  
Chun-Chieh Lin ◽  
Mahesh M Mansukhani ◽  
Jeffrey N Bruce ◽  
Peter Canoll ◽  
George Zanazzi
Keyword(s):  
New York ◽  
Medical Center ◽  
Germ Cell Tumors ◽  
Genetic Alterations ◽  
Pineal Region ◽  
Tumor Formation ◽  
Mitogen Activated Protein Kinase ◽  
Small Cells ◽  
Glioneuronal Tumor ◽  
Low Grade

Abstract Resected lesions from the pineal region are rare specimens encountered by surgical pathologists, and their heterogeneity can pose significant diagnostic challenges. Here, we reviewed 221 pineal region lesions resected at New York-Presbyterian Hospital/Columbia University Irving Medical Center from 1994 to 2019 and found the most common entities to be pineal parenchymal tumors (25.3%), glial neoplasms (18.6%), and germ cell tumors (17.6%) in this predominantly adult cohort of patients. Six cases of a rare midline entity usually found exclusively in the fourth ventricle, the rosette-forming glioneuronal tumor, were identified. These tumors exhibit biphasic morphology, with a component resembling pilocytic astrocytoma admixed with variable numbers of small cells forming compact rosettes and perivascular pseudorosettes. Targeted sequencing revealed a 100% co-occurrence of novel and previously described genetic alterations in the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) signaling pathways, suggesting a synergistic role in tumor formation. The most common recurrent mutation, PIK3CA H1047R, was identified in tumor cells forming rosettes and perivascular pseudorosettes. A review of the literature revealed 16 additional cases of rosette-forming glioneuronal tumors in the pineal region. Although rare, this distinctive low-grade tumor warrants consideration in the differential diagnosis of pineal region lesions.

scholarly journals PATH-22. COMPREHENSIVE ANALYSIS OF DIVERSE LOW-GRADE NEUROEPITHELIAL TUMORS WITH FGFR1 ALTERATIONS REVEALS A DISTINCT MOLECULAR SIGNATURE OF ROSETTE-FORMING GLIONEURONAL TUMOR

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii168-ii169
Author(s):  
Calixto-Hope G Lucas ◽  
Rohit Gupta ◽  
Pamela Doo ◽  
Matthew Wood ◽  
Marjorie Grafe ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tandem Duplication ◽  
Kinase Domain ◽  
Genetic Alterations ◽  
Glioneuronal Tumor ◽  
Tyrosine Kinase Domain ◽  
Low Grade ◽  
Missense Mutations ◽  
Ptpn11 Mutation ◽  
Pilocytic Astrocytomas

Abstract The FGFR1 gene encoding fibroblast growth factor receptor 1 has emerged as a frequently altered oncogene in the pathogenesis of multiple low-grade neuroepithelial tumor (LGNET) subtypes including pilocytic astrocytoma (PA), dysembryoplastic neuroepithelial tumor (DNT), rosette-forming glioneuronal tumor (RGNT), and extraventricular neurocytoma (EVN). These activating FGFR1 alterations in LGNET can include tandem duplication of the exons encoding the intracellular tyrosine kinase domain, in-frame gene fusions most often with TACC1 as the partner, or hotspot missense mutations within the tyrosine kinase domain (either p.N546 or p.K656). However, the specificity of these different FGFR1 events for the various LGNET subtypes and accompanying genetic alterations are not well defined, nor are the histopathologic features of pilocytic astrocytomas with FGFR1 alterations versus those harboring the more common BRAF mutations or fusions. Here we performed comprehensive genomic and epigenomic characterization on a diverse cohort of 30 LGNET with FGFR1 alterations. We identified that RGNT harbors a distinct epigenetic signature compared to other LGNET with FGFR1 alterations, and is uniquely characterized by FGFR1 kinase domain hotspot missense mutations in combination with either PIK3CA or PIK3R1 mutation, often with accompanying NF1 or PTPN11 mutation. In contrast, EVN harbors its own distinct epigenetic signature and is characterized by FGFR1-TACC1 fusion as the solitary pathogenic alteration. Additionally, DNT and PA are characterized by either kinase domain tandem duplication or hotspot missense mutations, occasionally with accompanying NF1 or PTPN11 mutation, but lacking the accompanying PIK3CA or PIK3R1 mutation that characterizes RGNT. The glial component of LGNET with FGFR1 alterations typically has a predominantly oligodendroglial morphology, and many of the pilocytic astrocytomas with FGFR1 alterations lack the biphasic pattern, piloid processes, and Rosenthal fibers that characterize pilocytic astrocytomas with BRAF mutation or fusion. Together, this analysis refines the classification and histopathologic spectrum of LGNET with FGFR1 alterations.

Pineal tumors: analysis of treatment results in 20 patients

2005 ◽  
Vol 102 ◽  
pp. 175-179 ◽  
Author(s):  
Beatriz E. Amendola ◽  
Aizik Wolf ◽  
Sammie R. Coy ◽  
Marco A. Amendola ◽  
Daryl Eber
Keyword(s):  
Systemic Chemotherapy ◽  
Germ Cell Tumors ◽  
Pineal Region ◽  
Tumor Control ◽  
Low Grade ◽  
Primary Tumors ◽  
Pineal Tumors ◽  
Content Type ◽  
Conventional Radiation ◽  
Fine Print

Object. The authors evaluate their results when using gamma knife surgery (GKS) in the management of patients with tumors in the pineal region. Methods. This is a retrospective clinical evaluation of 20 patients with primary tumors of the pineal region treated with GKS from November 1994 through August 2003. There were 13 germ cell tumors, two pineoblastomas, two low-grade gliomas, one primitive neuroectodermal tumor, one teratoma, and one pineocytoma. There were 10 male and 10 female patients. Their median age was 15.5 years (range 5–71 years). The median margin dose was 11 Gy (range 8–20 Gy). The median target volume was 3.1 cm3 (range 0.1–49.9 cm3). Five patients received sequential systemic chemotherapy and four underwent adjuvant conventional radiation therapy. Seventeen (85%) of 20 patients are alive with a median survival of 30.4 months (range 0–-85.7 months). Two patients required retreatment. Three patients died: one of unrelated causes, one who presented with extensive local disease, and the other of meningeal carcinomatosis with local control of the primary tumor. No complications from GKS were noted. Conclusions. This initial experience suggests that GKS is a valuable treatment modality for the management of pineal region tumors. This technique offers excellent local tumor control and minimal patient morbidity, allowing for immediate use of systemic chemotherapy and/or conventional radiation if indicated.

Genetic alterations in a papillary glioneuronal tumor

2008 ◽  
Vol 1 (1) ◽  
pp. 99-102 ◽  
Author(s):  
Claudia Faria ◽  
José Miguéns ◽  
João Lobo Antunes ◽  
Cândida Barroso ◽  
José Pimentel ◽  
...  
Keyword(s):  
Genetic Alterations ◽  
Point Of View ◽  
Chromosome 7 ◽  
Glioneuronal Tumor ◽  
Comparative Genomic ◽  
Low Grade ◽  
The Central Nervous System ◽  
High Level ◽  
Glioneuronal Tumors

✓Papillary glioneuronal tumors (PGNTs) are rare lesions of the central nervous system, and no information exists on the genetic alterations in these neoplasms. The authors report on such a case in a child. Genetic studies revealed that the tumor was characterized by gains and structural alterations involving only chromosome 7 with breakpoints at 7p22. By using comparative genomic hybridization, the authors observed a high-level amplification region at 7p14~q12. Fluorescence in situ hybridization with a probe for EGFR revealed that this gene was not amplified. Similar to other patients with PGNTs, the patient in the present case fared well. From a genetic point of view the data in the present case are in accordance with previous findings of EGFR amplifications as uncommon in low-grade gliomas and gangliogliomas. Recurrent rearrangements of chromosome 7 have been noted in other mixed glioneuronal tumors. The data in this case suggest that genes located at chromosome 7 can also be involved in the pathogenesis of PGNT. In clinical terms it will be especially important to corroborate, through the analysis of further cases, the involvement of the chromosome 7p22 locus, a region where glial and neuronal linked genes (RAC1 and NXPH1) are known to be located.

Pineal tumors: analysis of treatment results in 20 patients

2005 ◽  
Vol 102 (Special_Supplement) ◽  
pp. 175-179 ◽  
Author(s):  
Beatriz E. Amendola ◽  
Aizik Wolf ◽  
Sammie R. Coy ◽  
Marco A. Amendola ◽  
Daryl Eber
Keyword(s):  
Systemic Chemotherapy ◽  
Germ Cell Tumors ◽  
Pineal Region ◽  
Tumor Control ◽  
Low Grade ◽  
Primary Tumors ◽  
Pineal Tumors ◽  
Content Type ◽  
Conventional Radiation ◽  
Fine Print

Object. The authors evaluate their results when using gamma knife surgery (GKS) in the management of patients with tumors in the pineal region. Methods. This is a retrospective clinical evaluation of 20 patients with primary tumors of the pineal region treated with GKS from November 1994 through August 2003. There were 13 germ cell tumors, two pineoblastomas, two low-grade gliomas, one primitive neuroectodermal tumor, one teratoma, and one pineocytoma. There were 10 male and 10 female patients. Their median age was 15.5 years (range 5–71 years). The median margin dose was 11 Gy (range 8–20 Gy). The median target volume was 3.1 cm3 (range 0.1–49.9 cm3). Five patients received sequential systemic chemotherapy and four underwent adjuvant conventional radiation therapy. Seventeen (85%) of 20 patients are alive with a median survival of 30.4 months (range 0–-85.7 months). Two patients required retreatment. Three patients died: one of unrelated causes, one who presented with extensive local disease, and the other of meningeal carcinomatosis with local control of the primary tumor. No complications from GKS were noted. Conclusions. This initial experience suggests that GKS is a valuable treatment modality for the management of pineal region tumors. This technique offers excellent local tumor control and minimal patient morbidity, allowing for immediate use of systemic chemotherapy and/or conventional radiation if indicated.

scholarly journals FGFR3 activating mutations induce luminal-like papillary bladder tumor formation and favor a male gender bias.

2021 ◽  
Author(s):  
Mingjun Shi ◽  
Aura Moreno-Vega ◽  
Jacqueline Fontugne ◽  
Xiang-Yu Meng ◽  
Florent Dufour ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Gender Bias ◽  
Target Genes ◽  
Genetic Alterations ◽  
Tumor Formation ◽  
Male Gender ◽  
Low Grade ◽  
Bladder Tumors ◽  
Expression Levels ◽  
Fgfr3 Mutations

Background FGFR3 mutations are among the most frequent genetic alterations in bladder cancer and are enriched in the luminal papillary subtype of muscle-invasive tumors (MIBC) and luminal-like classes 1 and 3 of non-MIBC. To study their oncogenic properties in vivo, we developed here a genetically engineered mouse (GEM) model expressing the most frequent FGFR3 mutation, FGFR3-S249C, in urothelial cells. Methods Bladder tumorigenesis was monitored in FGFR3-S249C mice. FGFR3 expression was assessed by RT-qPCR in the transgenic mice urothelium and in various human epithelia. Transcriptomic data were obtained from mouse bladder tumors and cross-species comparisons were performed. Sex bias in FGFR3-mutated tumors was evaluated in our GEM model and in the TCGA and UROMOL cohorts of patients including 408 MIBC and 419 NMIBC, respectively. The association of androgen receptor (AR) activity, based on the expression of its target genes, with FGFR3 mutations was examined in these two cohorts. The binding of AR to its response element and AR phosphorylation in FGFR3-dependent cell lines were evaluated. Results FGFR3-S249C expression in the urothelium of mice induced spontaneous low-grade papillary bladder tumors resembling the human counterpart at the histological and transcriptomic levels. Mutant-FGFR3 expression levels impacted tumor formation incidence in mice and mutant-FGFR3-driven human tumors were restricted to epithelia presenting high normal expression levels of FGFR3. The known bladder cancer male gender bias, also found in our model, was even higher in human FGFR3-mutated compared to wild-type tumors and associated with a higher AR regulon activity considering gender adjustment. AR phosphorylation and regulon activity were modulated by FGFR3 in FGFR3-dependent models. Conclusions Mutant-FGFR3 is an oncogene per se, inducing bladder tumorigenesis. Patients with early-stage bladder lesions could thus potentially benefit from FGFR3 targeting. Our results also reinforce the interest in elucidating the role of AR in bladder carcinogenesis, specifically in FGFR3-mutated driven tumors. Finally, our results suggest FGFR3 expression level in the epithelium as a determinant for the FGFR3-driven tumors tissue specificity.

scholarly journals Spectrum of BRAF Mutations and Gene Rearrangements in Ovarian Serous Carcinoma

2021 ◽  
pp. 1480-1492
Author(s):  
M. Herman Chui ◽  
Jason C. Chang ◽  
Yanming Zhang ◽  
Ahmet Zehir ◽  
Alison M. Schram ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Genetic Alterations ◽  
Protein Kinase Inhibitors ◽  
Mitogen Activated Protein Kinase ◽  
Serous Carcinoma ◽  
Low Grade ◽  
Gene Rearrangements ◽  
Braf Mutations ◽  
Mitogen Activated Protein ◽  
Serous Tumors

PURPOSE Low-grade serous carcinoma (LGSC) is a rare type of ovarian cancer, which commonly arises from serous borderline tumor (SBT) and is characterized by frequent activating mutations in the mitogen-activated protein kinase pathway, including BRAF. The BRAFV600E mutation is associated with improved prognosis in SBT and LGSC, and responses to BRAF inhibitor therapy have been reported. We sought to characterize the clinicopathologic and molecular features of BRAF-driven tubo-ovarian and primary peritoneal serous tumors. METHODS Retrospective analysis of our institutional cohort of SBTs (n = 22), LGSCs (n = 119) and high-grade serous carcinomas (HGSCs, n = 1,290) subjected to targeted massively parallel sequencing was performed to identify cases with BRAF genetic alterations. Putative BRAF rearrangements were confirmed using targeted RNA sequencing and/or fluorescence in situ hybridization (FISH). BRAFV600E oncoprotein expression was assessed by immunohistochemistry on selected cases. RESULTS BRAF somatic genetic alterations were identified in 29 of 1,431 (2%) serous tumors and included mutations (n = 24), gene rearrangements (n = 3), and amplification (n = 2). BRAF mutations were more frequent in SBTs (7 of 22; 32%) compared with LGSCs (11 of 119; 9%, P = .009) and HGSCs (6 of 1,290; 0.5%; P < .0001, SBT/LGSC v HGSC). The BRAFV600E hotspot mutation was most common (n = 16); however, other BRAF driver mutations were also detected (n = 8). BRAF mutations were often clonal or truncal in SBTs and LGSCs, but subclonal in most HGSCs. Pathogenic BRAF gene fusions were identified in LGSCs (n = 2) and HGSC (n = 1) and involved distinct fusion partners ( AGK, MKRN1, and AGAP3). Three patients with BRAF-mutant LGSC were treated with targeted mitogen-activated protein kinase inhibitors, one of whom was maintained on therapy for over 3 years with clinical benefit. CONCLUSION Recognition of BRAF alterations beyond V600E mutation in LGSC may have clinical implications for appropriate targeted therapy selection.

scholarly journals COVID-19 in obstetrics 2020: the experience at a New York City medical center

2020 ◽  
Vol 48 (9) ◽  
pp. 892-899
Author(s):  
Ashlesha K. Dayal ◽  
Armin S. Razavi ◽  
Amir K. Jaffer ◽  
Nishant Prasad ◽  
Daniel W. Skupski
Keyword(s):  
New York ◽  
Medical Center ◽  
Severe Disease ◽  
Infection Rates ◽  
Health Crisis ◽  
The Public ◽  
Public Health Crisis ◽  
Asymptomatic Carriage ◽  
Global Spread ◽  
Workforce Flexibility

AbstractThe global spread of the SARS-CoV-2 virus during the early months of 2020 was rapid and exposed vulnerabilities in health systems throughout the world. Obstetric SARS-CoV-2 disease was discovered to be largely asymptomatic carriage but included a small rate of severe disease with rapid decompensation in otherwise healthy women. Higher rates of hospitalization, Intensive Care Unit (ICU) admission and intubation, along with higher infection rates in minority and disadvantaged populations have been documented across regions. The operational gymnastics that occurred daily during the Covid-19 emergency needed to be translated to the obstetrics realm, both inpatient and ambulatory. Resources for adaptation to the public health crisis included workforce flexibility, frequent communication of operational and protocol changes for evaluation and management, and application of innovative ideas to meet the demand.

scholarly journals The COVID Army: Experiences from the Deployment of Non-Hospitalist Physician Volunteers during the 2020 COVID Pandemic

2021 ◽  
pp. 1-15
Author(s):  
Kevin Hauck ◽  
Katherine Hochman ◽  
Mark Pochapin ◽  
Sondra Zabar ◽  
Jeffrey A Wilhite ◽  
...  
Keyword(s):  
New York ◽  
New York City ◽  
Medical Center ◽  
The United States ◽  
Lessons Learned ◽  
Front Line ◽  
Clinical Leadership ◽  
Team Members ◽  
Medical Centers ◽  
Hospitalist Physician

Abstract Objective New York City was the epicenter of the outbreak of the 2020 COVID-19 pandemic in the United States. As a large, quaternary care medical center, NYU Langone Medical Center was one of many New York medical centers that experienced an unprecedented influx of patients during this time. Clinical leadership effectively identified, oriented, and rapidly deployed a “COVID Army”, consisting of non-hospitalist physicians, to meet the needs of this patient influx. We share feedback from our providers on our processes and offer specific recommendations for systems experiencing a similar influx in the current and future pandemics. Methods In order to assess the experiences and perceived readiness of these physicians (n=183), we distributed a 32-item survey between March and June of 2020. Thematic analyses and response rates were examined in order to develop results. Results Responses highlighted varying experiences and attitudes of our front-line physicians during an emerging pandemic. Thematic analyses revealed a series of lessons learned, including the need to: (1) provide orientations, (2) clarify roles/ workflow, (3) balance team workload, (4) keep teams updated on evolving policies, (5) make team members feel valued, and (6) ensure they have necessary tools available. Conclusions Lessons from our deployment and assessment are scalable at other institutions.

scholarly journals Chordoma—Current Understanding and Modern Treatment Paradigms

2021 ◽  
Vol 10 (5) ◽  
pp. 1054
Author(s):  
Sean M. Barber ◽  
Saeed S. Sadrameli ◽  
Jonathan J. Lee ◽  
Jared S. Fridley ◽  
Bin S. Teh ◽  
...  
Keyword(s):  
Growth Factor ◽  
Protein Kinase ◽  
Growth Factor Receptor ◽  
Growth Patterns ◽  
Molecular Therapy ◽  
Mitogen Activated Protein Kinase ◽  
Low Grade ◽  
Ongoing Research ◽  
Mobile Spine ◽  
Modern Treatment

Chordoma is a low-grade notochordal tumor of the skull base, mobile spine and sacrum which behaves malignantly and confers a poor prognosis despite indolent growth patterns. These tumors often present late in the disease course, tend to encapsulate adjacent neurovascular anatomy, seed resection cavities, recur locally and respond poorly to radiotherapy and conventional chemotherapy, all of which make chordomas challenging to treat. Extent of surgical resection and adequacy of surgical margins are the most important prognostic factors and thus patients with chordoma should be cared for by a highly experienced, multi-disciplinary surgical team in a quaternary center. Ongoing research into the molecular pathophysiology of chordoma has led to the discovery of several pathways that may serve as potential targets for molecular therapy, including a multitude of receptor tyrosine kinases (e.g., platelet-derived growth factor receptor [PDGFR], epidermal growth factor receptor [EGFR]), downstream cascades (e.g., phosphoinositide 3-kinase [PI3K]/protein kinase B [Akt]/mechanistic target of rapamycin [mTOR]), brachyury—a transcription factor expressed ubiquitously in chordoma but not in other tissues—and the fibroblast growth factor [FGF]/mitogen-activated protein kinase kinase [MEK]/extracellular signal-regulated kinase [ERK] pathway. In this review article, the pathophysiology, diagnosis and modern treatment paradigms of chordoma will be discussed with an emphasis on the ongoing research and advances in the field that may lead to improved outcomes for patients with this challenging disease.

scholarly journals GCT-25. INNOVATIVE, INTENSIVE IRRADIATION-AVOIDING/MINIMIZING CHEMOTHERAPY FOR HIGH-RISK PRIMARY CENTRAL NERVOUS SYSTEM (CNS) MIXED MALIGNANT GERM CELL TUMORS (HR-MMGCT): A PILOT STUDY AND PROPOSED MULTI-NATIONAL PROSPECTIVE TRIAL

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii333-iii333
Author(s):  
Jonathan L Finlay ◽  
Mohammad H Abu-Arja ◽  
Rolla Abu-Arja ◽  
Jeffery Auletta ◽  
Mohamed S AbdelBaki ◽  
...  
Keyword(s):  
High Risk ◽  
Induction Chemotherapy ◽  
Prospective Trial ◽  
Germ Cell Tumors ◽  
Brentuximab Vedotin ◽  
Pineal Region ◽  
Chemotherapy Drugs ◽  
Molecularly Targeted Agents ◽  
Risk Patients ◽  
Intensified Chemotherapy

Abstract BACKGROUND About one-third of children with primary CNS MMGCT experience incomplete responses to initial induction chemotherapy prior to irradiation, many of whom will subsequently relapse. Such high-risk patients are variably defined as having initial alpha-fetoprotein (AFP) elevations exceeding 1,000ng/mL, predominant histopathologies of malignant non-germinomatous GCT and incomplete responses to induction chemotherapy. Drugs targeting GCT-specific molecular markers have been identified for non-germinomatous GCT elements but have yet to be incorporated into prospective clinical trials. Four children with clearly identified HR-MMGCT characteristics have been treated on an innovative pilot regimen incorporating intensified chemotherapy and molecularly targeted agents, with avoidance or minimization of irradiation. METHODS Four children (two with pure suprasellar embryonal carcinoma (EC) - one with Down syndrome and the other with pre-diagnosis cognitive dysfunction; one with initial serum AFP exceeding 7,000ng/mL and yolk sac tumor (YST)+EC+Teratoma pathology; one with initial serum AFP exceeding 1,000ng/mL) were treated with 3 cycles of “standard” induction chemotherapy (ACNS1123), followed by 1–3 transplant cycles (thiotepa/carboplatin) each with complete radiographic and tumor marker responses. Two children with pure EC subsequently received six cycles of brentuximab-vedotin without irradiation and remain disease-free off therapy for 2–4 years. One child with YST+EC+Teratoma has subsequently received reduced dose craniospinal irradiation and pineal region boost, and will receive oral everolimus, erlotinib, palbocyclib and intravenous brentuximab-vedotin. The fourth child with YST+MT will commence everolimus, erlotinib and palbocyclib without irradiation. CONCLUSION This treatment strategy for HR-MMGCT patients provides preliminary tolerance and response data justifying extension to a multi-center trial.

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