MAPK pathway alterations in polymorphous low-grade neuroepithelial tumor of the young: diagnostic considerations.

Polymorphous low-grade neuroepithelial tumor of the young (PLNTY) is a recently recognised tumor type with indolent behaviour with characteristic imaging and histomolecular features. We describe the clinical, imaging, histo-molecular features of 15 cases diagnosed as low-grade glioma suggestive of PLNTY, over a period of 3 years. Immunohistochemistry (IHC) and fluorescence in situ hybridisation were used to assess molecular alterations. The tumors were seen predominantly in children (range 5-65 years). Most of the patients presented with history of seizures. Imaging revealed cortical-subcortical well demarcated solid-cystic tumor with intratumoral calcification. Histopathology revealed a low-grade tumor with oligodendroglia-Iike cells admixed with astrocytic cells immunopositive for CD34. BRAF p.V600E mutations and FGFR2 breakapart were observed in six cases each, while three showed FGFR3 breakapart. FGFR2 breakapart positive PLNTY were seen in children exclusively. The majority of cases were seizure free post-surgery, except two patients who succumbed to the illness. PLNTY, needs to be considered as a prime differential diagnosis in a solid-cystic tumor in a young patient with history of seizures. Characteristic clinical features, radiology, histomorphology with an IHC panel of OLIG2, GFAP and CD34 correlates with one of the MAPK alterations in PLNTY (BRAF p.V600E, FGFR2/3 gene rearrangement). In a resource limited setting, this limited panel may be sufficient for a correlative diagnosis.

Polymorphous Low-Grade Neuroepithelial Tumor of the Young (PLNTY): Scoping Review of Case Reports and Case Series.

Polymorphous low-grade neuroepithelial tumor of the young (PLNTY) is considered one of the low-grade neuroepithelial tumors, as per the World Health Organization 2021 classification of brain tumors. First described in 2016, these morphologically variable tumors are characterized by oligodendroglioma-like cellular components, infiltrative growth patterns, and cluster of differentiation 34 immunopositivity. A literature search of the PubMed/MEDLINE, SCOPUS, ScienceDirect, and COCHRANE databases (from inception to 20th June 2022) was carried out to identify relevant studies. To identify additional studies, we performed a recursive search of the bibliographies of the selected articles and published systematic reviews on this topic. The search yielded a total of 64 results. After removing duplicates, 26 articles were eligible for the review. The diagnostic criteria for these glioneuronal variants, representing a broad neuropathological spectrum, are not distinct and hence impede proper diagnosis and prognosis. Frequent genetic abnormalities involving mitogen-activated protein kinase pathway constituents, such as B-Raf proto-oncogene or fibroblast growth receptor 2/3, are harbored by PLNTYs. Recent advances in molecular diagnostics have resulted in more accurate tumor classification systems, based on gene expression profiles and DNA methylation patterns. Gross total resection seems curative, with a low recurrence rate. Malignant transformation is rare; however, adjuvant radiation therapy and chemotherapy may be beneficial in selected cases.

Pediatric-type diffuse low-grade gliomas.

The World Health Organization's 5th edition classification of Central Nervous System (CNS) tumors differentiates diffuse gliomas into adult and pediatric variants. Pediatric-type diffuse low-grade gliomas (pDLGGs) are distinct from adult gliomas in their molecular characteristics, biological behavior, clinical progression, and prognosis. Various molecular alterations identified in pDLGGs are crucial for treatment. There are four distinct entities of pDLGGs. All four of these tumor subtypes exhibit diffuse growth and share overlapping histopathological and imaging characteristics. Molecular analysis is essential for differentiating these lesions.

Diffuse Gliomas with FGFR3::TACC3 Fusion: Morphological and Molecular Features and Classification Challenges.

FGFR3::TACC3 fusion is a driver, potentially targetable, genetic alteration identified in approximately 4% of high-grade diffuse gliomas and rare cases with low-grade histology. Herein, we review the genetic and epigenetic features of these tumors and highlight the challenges in their classification and grading. Diffuse gliomas with FGFR3::TACC3 fusion display unique histopathological and molecular features, including an oligodendroglioma-like appearance, calcifications, and CD34 extravascular immunoreactivity. High-grade tumors exhibit molecular alterations and a DNA methylation profile typical of glioblastoma, suggesting that they may represent a subtype clinically characterized by a slightly better prognosis. Tumors with low-grade morphology are genetically and epigenetically heterogeneous. Some, exclusive to adults, have molecular alterations typical of glioblastoma, although most do not match any methylation classes, using version 12.5 of the Heidelberg classifier. Another group, which mostly affects children or adolescents, lacks the molecular features of glioblastoma and has a DNA methylation profile similar to that of low-grade glioneuronal tumors. In conclusion, diffuse gliomas with FGFR3::TACC3 fusion do not constitute a distinct nosological entity, owing to their genetic and epigenetic diversity. Further studies are warranted to clarify the biological aggressiveness of tumors with low-grade histology to refine the grading and determine the optimal treatment strategy.

Systematic review and cumulative analysis of clinical properties of BRAF V600E mutations in PLNTY histological samples.

PURPOSE: Polymorphous low-grade neuroepithelial tumors of the young (PLNTY) represent a rare pediatric-type tumor that most commonly presents as medically refractory epilepsy. PLNTY has only recently been recognized as a distinct clinical entity, having been first described in 2016 and added to the World Health Organization classification of CNS tumors in 2021. Molecular studies have determined that PLNTY is uniformly driven by aberrant MAPK pathway activation, with most tumors carrying either a BRAF V600E mutation or activating FGFR2 or FGFR3 fusion protein. Although it is known that these driver mutations are mutually exclusive, little is known about differences in clinical presentation or treatment outcomes between PLNTY cases driven by these distinct mutations. METHODS: We performed a systematic review and cumulative analysis of PLNTY cases to assess whether or not PLNTY tumors carrying the BRAF V600E mutation exhibit different clinical behaviors. By searching the literature for all cases of PLNTY wherein BRAF V600E status was characterized, we compiled a dataset of 62 unique patient instances. Using a logistic regression-based approach, we assessed a primary outcome of what factors of a clinical presentation were associated with BRAF V600E mutations and a secondary outcome of what factors predicted total seizure freedom post-surgical resection. RESULTS: PLNTY cases carrying BRAF V600E mutations in the literature were strongly positively associated with adult patients (p = 0.0055, OR = 6.556; 95% Conf. Int. = 1.737-24.742). BRAF V600E status was also positively associated with tumor involvement of the temporal lobe (p = 0.0046, OR = 11.036; 95% Conf. Int. = 2.100-58.006). Male sex was also positively associated with BRAF V600E status, but the result did not quite achieve statistical significance (p = 0.0731). BRAF V600E status was not found to be associated with post-operative seizure freedom. CONCLUSIONS: These findings indicate that BRAF V600E-positive PLNTY exhibit characteristic clinical presentations but are not necessarily different in treatment responsiveness. Non-BRAF V600E tumors are more commonly associated with young patients.

A diffuse glioma with oligodendroglial-like cells and extensive calcifications.

The tumor showed extensive microcalcifications and cells with oval, nuclei and a clear perinuclear halo (A), positive immunostaining for OLIG-2 (B), GFAP (C), and CD34 (D), and intermingled Neu-N-positive neurons (E). FISH revealed multiple signals for the centromere of chromosome 7 (gains) (green probe) and the EGFR locus (red probe) (F, left), and a single signal for the centromere of chromosome 10 (loss) (F, right).

Polymorphous low-grade neuroepithelial tumor of the young with FGFR3-TACC3 fusion mimicking high-grade glioma: case report and series of high-grade correlates.

Background: Polymorphous low-grade neuroepithelial tumor of the young (PLNTY) is a recently described entity that can mimic high-grade glioma (HGG) in histologic and molecular features; however, factors predicting aggressive behavior in these tumors are unclear. Methods: We present an indolent neuroepithelial neoplasm in a 59-year-old female with imaging initially suggestive of HGG, and a series of adult patients with HGG harboring FGFR3-TACC3 fusions are also presented for comparison. Results: Pathology in the case patient revealed low-grade cytomorphology, microcalcifications, unusual neovascularization, and a low proliferation index. The lesion was diffusely CD34+ and harbored an FGFR3-TACC3 fusion and TERT promoter mutation. A diagnosis of PLNTY was therefore favored and the patient was observed with no progression at 15-month follow-up. In patients with HGG with FGFR3-TACC3 fusions, molecular findings included IDH-wildtype status, absence of 1p19q codeletion, CDKN2A loss, TERT promoter mutations and lack of MGMT promoter methylation. These patients demonstrated a median 15-month overall survival and a 6-month progression-free survival. Conclusion: PLNTY is a rare low-grade entity that can display characteristics of HGG, particularly in adults. Presence of FGFR3-TACC3 fusions and other high-grade features should raise concern for a more malignant precursor lesion when a diagnosis of PLNTY is considered.

Clinical significance of molecular subgroups of polymorphous low-grade neuroepithelial tumor of the young (PLNTY): A small single institutional case series and integrated analysis.

INTRODUCTION: Polymorphous low-grade neuroepithelial tumor of the young (PLNTY) is a recently described entity. The clinicopathological features and prognosis of the molecular subgroups of these rare tumors is poorly understood. In this study, we presented a small case series of three new cases and integrated the data with published cases in the literature to characterize the similarities and differences of molecular subgroups of PLNTY. METHODS: We searched our institutional archive for PLNTY cases and searched PubMed and Web of Science for relevant data. Demographic, clinical, radiologic, histopathological, molecular, and follow-up data of our four cases with published cases were integrated for final analyses. RESULTS: We identified three institutional cases of PLNTY. The median age of our patients was 17 years (range: 13-42). All patients had a prior history of chronic seizures and all had tumors affecting the temporal lobes. Histopathologically, all cases showed oligodendroglial-like morphology with intratumoral calcifications and at least partially infiltrative growth patterns. Tumor cells were immunoreactive with CD34 and GFAP. Genetically, all cases harbored BRAF V600E mutations. Integrated analyses, including a total of 67 cases, demonstrated that PLNTYs with FGFR2 mutation were significantly younger (median age 11.0 years) than those with BRAF V600E or FGFR3 fusions (median age 41.0 and 16.0 years, respectively). All BRAF V600E-positive PLNTYs were free of tumor recurrence, while four of PLNTYs in other molecular subgroups developed tumor recurrence by imaging. CONCLUSION: Our study suggests that PLNTYs have distinct clinicopathological features and are driven by genetic alterations in the MAPK pathway. The molecular subgroups of PLNTYs share similar findings, but also demonstrate distinct patient demographics.

A "masked" pleomorphic xanthoastrocytoma.

The latest WHO Classification of tumours of the Central Nervous System (CNS) emphasizes the necessity of an integrated diagnostic approach during the workup of a CNS neoplasm. In addition to the mutational status, assessment of methylation profile of a tumour emerged as a helpful (often necessary) tool to make a correct and unequivocal diagnosis. Here we present a case of a Pleomorphic Xanthoastrocytoma with clinical, radiological and histopathological findings remarkably overlapping with a recently described paediatric-type glioma namly Polymorphic Low-grade Neuroepithelial Tumour of the Young (PLNTY). The differential diagnosis here discussed represents a methodological paradigm in the modern neuropathology. In fact, the presentation of this case is a demonstration that in day-to-day practice, clinical, radiological, and histopathological data can all be misleading, and the correct diagnosis can only be reached by integration with molecular analysis. In the modern neuro-oncology, it is by far mandatory for all the specialists dealing with cerebral tumours to "contaminate" their own cultural heritage with other ones, to optimally manage a patient with CNS tumour.

Left Mesial Temporooccipital PLNTY: Supracerebellar Transtentorial Approach in Epilepsy Surgery.

The supracerebellar transtentorial approach for the resection of brain lesion at the level of the mesial temporooccipital region is underused in the field of epilepsy surgery, despite the theoretical advantage of sparing normal brain structures, in particular in the dominant hemisphere for language. Hereby we present the case of a patient with a low-grade epilepsy associated tumor, presenting with weekly drug-resistant focal seizures, treated by a supracerebellar transtentorial lesionectomy. Surgery was uneventful and the histopathology revealed a pleomorphic low-grade neuroepithelial tumor of the young patient. At the 6-month follow-up, the patient did not present neurologic deficits and she never presented with seizures after surgery, so antiepileptic drug tapering started. The integration of supracerebellar transtentorial approach in the "armory" of the epilepsy neurosurgeon requires a dedicated expertise and an anesthesiologic setting used to manage the semisitting position; on the other hand, it could provide a relevant option to provide safe and complete lesionectomy in the mesial temporooccipital region, together with the more classical sublobar and transcerebral approaches (Video 1).

Neuroradiological features of the polymorphous low-grade neuroepithelial tumor of the young: five new cases with a systematic review of the literature.

PURPOSE: Polymorphous low-grade neuroepithelial tumors of the young (PLNTY) is a newly recognized brain tumor with genetic abnormalities frequently involving either BRAF or FGFR2/FGFR3. There are few publications available about the neuroradiological features of PLNTY. In this systematic review, we assessed the demographic, clinical, and neuroradiological features of PLNTY. METHODS: Literature data were extracted from database searches in MEDLINE and SCOPUS databases up to June 10, 2021. Studies reporting on pathologically proven PLNTY with neuroradiological findings were included. After reviewing 103 abstracts, 9 articles encompassing 19 cases met the inclusion criteria. We also added five patients from our hospital. The correlations between the presence of "transmantle-like sign" and the following three factors: duration of seizures; tumor size; and pathologically proven cortical dysplasia, were examined. RESULTS: The median patient age was 15.5 years (range, 5-57 years), and 15/24 (62.5%) were female. All tumors were localized supratentorialy. The main radiological features included cortical or subcortical masses (95.8%) in the temporal lobe (66.7%), calcification (83.3%), well-defined margins (72.7%), solid and cystic components (66.6%), and T2-weighted imaging (T2WI) hyperintensity (50.0%). The duration of seizure was significantly longer (positive vs. negative (median [range]), 24 months [6 - 96 months] vs. 5 months [1 - 12 months], p = 0.042), and the presence of the cortical dysplasia was significantly more frequent (3/8 vs 0/16, p = 0.042) in the patients with transmantle-like sign. CONCLUSION: PLNTY typically represents a calcified, well-defined mass in the supratentorial cortical or subcortical regions. The radiological findings defined here could facilitate the diagnosis of PLNTY.

BRAF V600E mutation mediates FDG-methionine uptake mismatch in polymorphous low-grade neuroepithelial tumor of the young.

We present a case of a 14-year old boy with tumor-associated refractory epilepsy. Positron emission tomography imaging demonstrated a region with heterogeneous high 11C-methionine uptake and a region with homogenous low 18F-fluorodeoxyglucose uptake within the tumor. Histopathological and genomic analyses confirmed the tumor as BRAF V600E-mutated polymorphous low-grade neuroepithelial tumor of the young (PLNTY). Within the high-methionine-uptake region, we observed increased protein levels of L-type amino acid transporter 1 (LAT1), a major transporter of methionine; c-Myc; and constituents of the mitogen-activated protein kinase (MAPK) pathway. We also found that LAT1 expression was linked to the BRAF V600E mutation and subsequent activation of MAPK signaling and c-Myc. Pharmacological and genetic inhibition of the MAPK pathway suppressed c-Myc and LAT1 expression in BRAF V600E-mutated PLNTY and glioblastoma cells. The BRAF inhibitor dabrafenib moderately suppressed cell viability in PLNTY. Collectively, our results indicate that BRAF V600E mutation-activated MAPK signaling and downstream c-Myc induces specific metabolic alterations in PLNTY, and may represent an attractive target in the treatment of the disease.

Histological features in pediatric central nervous system tumors with FGFR alterations.

INTRODUCTION: Identification of genetic alterations in central nervous system (CNS) tumors provides diagnostic and prognostic information and allows identification of potential therapeutic targets. Next-generation sequencing (NGS) technologies currently used for molecular testing are costly and remain largely limited to major academic centers or reference labs. Identification of histologic or immunohistochemical correlates for particular molecular alterations can serve as surrogates and can help triage cases for subsequent NGS-based confirmation. Recently, adult IDH-wildtype adult glioblastomas (GBMs) with fibroblast growth factor receptor (FGFR) gene alterations were reported to show palisading monomorphic cells, delicate arcuate vasculature, and microcalcifications. We explored whether pediatric tumors with FGFR fusion also show these histologic features and whether these features could predict the presence of this gene alteration. MATERIAL AND METHODS: We reviewed pediatric CNS tumors with FGFR-fusions to retrospectively determine the presence/absence of the above-mentioned histological features in fusion-positive tumors. RESULTS: 10 pediatric tumors with FGFR fusions were identified. Pediatric tumors demonstrated histologic and tumor type diversity, with diagnoses of pilocytic/pilomyxoid astrocytoma, pediatric-type oligodendroglioma, anaplastic astrocytoma, polymorphous low-grade neuroepithelial tumor of the young, rosette-forming glioneuronal tumor, and extraventricular neurocytoma. CONCLUSIONS: Pediatric FGFR-fused CNS tumors demonstrate histologic features similar to their adult counterparts but also exhibit significant morphologic variability. As such, this histologic variability prevents the prediction of FGFR fusion and necessitates molecular testing for the identification of this alteration.

Genomic Analysis of Dysembryoplastic Neuroepithelial Tumor Spectrum Reveals a Diversity of Molecular Alterations Dysregulating the MAPK and PI3K/mTOR Pathways.

Dysembryoplastic neuroepithelial tumors (DNT) lacking key diagnostic criteria are challenging to diagnose and sometimes fall into the broader category of mixed neuronal-glial tumors (MNGT) or the recently described polymorphous low-grade neuroepithelial tumor of the young (PLNTY). We examined 41 patients with DNT, MNGT, or PLNTY for histologic features, genomic findings, and progression-free survival (PFS). Genomic analysis included sequence and copy number variants and RNA-sequencing. Classic DNT (n = 26) was compared with those with diffuse growth without cortical nodules (n = 15), 6 of which exhibited impressive CD34 staining classifying them as PLNTY. Genomic analysis was complete in 33, with sequence alterations recurrently identified in BRAF, FGFR1, NF1, and PDGFRA, as well as 7 fusion genes involving FGFR2, FGFR1, NTRK2, and BRAF. Genetic alterations did not distinguish between MNGTs, DNTs, or PLNTYs; however, FGFR1 alterations were confined to DNT, and PLNTYs contained BRAF V600E or FGFR2 fusion genes. Analysis of PFS showed no significant difference by histology or genetic alteration; however, numbers were small and follow-up time short. Further molecular characterization of a PLNTY-related gene fusion, FGFR2-CTNNA3, demonstrated oncogenic potential via MAPK/PI3K/mTOR pathway activation. Overall, DNT-MNGT spectrum tumors exhibit diverse genomic alterations, with more than half (19/33) leading to MAPK/PI3K pathway alterations.

Plenty of calcification: imaging characterization of polymorphous low-grade neuroepithelial tumor of the young.

PURPOSE: Polymorphous low-grade neuroepithelial tumor of the young (PLNTY) is a recently described epileptogenic neoplasm. As the name implies, PLNTYs are indolent tumors most often encountered in the pediatric or young adult population. The imaging features of PLNTY are not well characterized in the existing literature. METHODS: We performed a retrospective review, identifying nine patients with pathologically proven PLNTY and available preoperative imaging in order to identify common features which may facilitate confident imaging diagnosis of this entity. RESULTS: Patients were ages 5 to 34 years (median 16 years), and seven (78%) were female. Most tumors had a highly characteristic appearance, with temporal lobe location (6/9; 67%), calcification (8/9; 89%), cortical/subcortical origin (8/9; 89%), cystic components (8/9; 89%), and relatively infrequent contrast enhancement (3/9; 33%). CONCLUSION: PLNTYs demonstrate characteristic calcification, subcortical location, and frequent temporal lobe localization, features that may allow radiologists to prospectively suggest the diagnosis in the proper clinical setting.

Case Report of Rarely Described Polymorphous Low-Grade Neuroepithelial Tumor of the Young and Comparison with Oligodendroglioma.

BACKGROUND: Polymorphous low-grade neuroepithelial tumor of the young (PLNTY) is a central nervous system tumor that shares many qualities with oligodendroglioma but is rarely and only very recently described as a distinct entity in the literature. CASE DESCRIPTION: A previously healthy, 19-year-old man presented with new onset of seizures. Imaging showed an intracranial mass, which was treated with surgical removal. Preoperative and postoperative magnetic resonance imaging, histopathologic examination, genetic testing, and immunohistochemical staining all supported a diagnosis of PLNTY. CONCLUSIONS: Diagnostic investigation of PLNTY shows many similarities with oligodendroglioma, and thus these entities can be mistaken for one another. Certain studies are needed to distinguish PLNTY and other dysembryoplastic neuroepithelial tumors, such as oligodendroglioma.

Low-grade neuroepithelial tumor: Unusual presentation in an adult without history of seizures.

Low-grade neuroepithelial tumors (LGNT) show a broad histopathological spectrum and may be difficult to classify using current World Health Organization (WHO) criteria. A 57-year-old man came to medical attention because of headaches. The patient medical history was otherwise unremarkable. Magnetic resonance imaging (MRI) revealed a 2.5 cm lesion, partially cystic, with an increased signal on T2-weighted imaging, located in the right frontal lobe. The patient underwent right frontal craniotomy and the surgical specimen was entirely evaluated. Microscopic examination showed a tumor arranged predominantly in sheets and nests, with an infiltrative growth pattern and oligodendroglioma-like appearance. Tumor cells were round to oval with cytoplasmic clearing, hyperchromatic nuclei and inconspicuous nucleoli. Only one mitosis was identified. Necrosis was absent. Differential diagnostic considerations included oligodendroglioma, clear cell ependymoma, polymorphous low-grade neuroepithelial tumor of the young (PLNTY) and long-term epilepsy-associated tumor with clear cell morphology. Neoplastic cells showed positivity for glial fibrillary acidic protein (GFAP), oligodendrocyte transcription factor 2 (OLIG2), α-thalasemia X-linked mental retardation syndrome (ATRX) (retained nuclear expression) and CD34. Epithelial membrane antigen (EMA), neuronal nuclear antigen, microtubule-associated protein-2e, cyclo-oxygenase-2, chromogranin A and isocitrate dehydrogenase 1 (IDH1) (R132H) were negative. Ki-67 labeling index was 2-3%. Molecular analysis identified neither IDH1/IDH2 mutations nor 1p19q codeletion. Rapidly accelerated fibrosarcoma homolog B1 (BRAF) V600E mutation was also absent by both molecular and immunohistochemical testing. Polymerase chain reaction analysis revealed the presence of fibroblast growth factor receptor 3 (FGFR3)-transforming acidic coiled-coil (TACC) fusion. Taken together, the morphological, immunohistochemical and molecular findings supported the final diagnosis of PLNTY.