Clinicopathological and molecular genetic heterogeneity of diffuse gliomas with the features of polymorphous low-grade neuroepithelial tumor of the young

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

Objective: To investigate the clinicopathological features and differential diagnosis of polymorphous low-grade neuroepithelial tumor of the young (PLNTY). Methods: Five cases of PLNTY diagnosed at the First Affiliated Hospital and Affiliated Brain Hospital of Nanjing Medical University, Nanjing, China from 2019 to 2021 were collected. All cases were evaluated using clinical and imaging data, histology, immunohistochemical staining and molecular genetics. The relevant literature was reviewed. Results: There were two male and three female patients, aged 10 to 39 years, with an average age of 25 years. Clinically, the tumors were in the temporal lobe (3 cases), the lateral ventricle (1 case) and the left head of caudate nucleus (1 case). The clinical manifestations included epilepsy in 3 cases, right visual disturbance in 1 case, and post-trauma incidental finding in 1 case. Microscopically, the lesions were characterized with infiltrative growth, cellular pleomorphism (oligodendroglioma-like cells were always present, with low-grade, pleomorphic nuclei) and variable calcifications. Immunohistochemically, the tumor cells were positive for GFAP and Olig2. They also showed intense and diffuse expression of CD34 while CD34 expressing ramified neural elements were present in regional cortex. Ki-67 proliferation index was less than 3%. Molecular genetics showed the BRAF V600E mutation in 2 cases, the PAK5-Q337R missense mutation in 1 case, the FGFR2-CTNNA3 fusion in 1 case, and the FGFR2-INA and FGFR2-PPRC1 concomitant fusion in 1 case. No postoperative chemoradiotherapy was given. Follow-up intervals ranged from 3 to 29 months while no recurrence or metastasis was identified. Conclusions: PLNTY is uncommon. A definite diagnosis of PLNTY relies on histopathological examination and molecular genetics. It is important to distinguish PLNTY from high grade gliomas and avoid overtreatment. The recently reported the PAK5-Q337R missense mutation and the FGFR2-PPRC1 gene fusion in PLNTY may help diagnose and understand the pathogenesis of PLNTY.

Adult diffuse gliomas with FGFR3‐TACC3 (F3T3) fusion are rare and highly heterogeneous central nervous system (CNS) tumors. Current research on the biological behavior of these tumors is limited, especially regarding whether histopathologically low‐grade tumors are indolent or represent early‐stage high‐grade tumors, thereby posing challenges for grading. In this single‐center study of 17 patients with adult F3T3 fusion diffuse gliomas (F3T3 gliomas), both low‐ and high‐grade F3T3 gliomas presented distinctive recurrent histopathological features, such as oligodendrocyte‐like cells, branched vessels and frequent calcifications. Molecularly, TERT promoter mutations and 7+/10− chromosomal alterations were common; one patient with recurrent glioma with histopathological features of polymorphous low‐grade neuroepithelial tumor of the young (PLNTY) had additional CDK4 and MDM2 amplifications. Methylation profiling of 3 samples revealed varied results. A patient whose tumor had histopathological features consistent with PLNTY and a methylation subtype classified as the mesenchymal subtype of glioblastoma (GBM) experienced tumor recurrence 8 months after surgery. After 5–62 months of follow‐up, seven patients relapsed, and six died; the primary tumors of the three patients with recurrence presented histopathological characteristics of low‐grade glioma (LGG). GBM patients had worse overall survival than LGG patients (p = 0.035) but similar progression‐free survival (p = 0.47), indicating that LGG patients may experience recurrence. For adults with tumors with histopathological features of PLNTY, further molecular and methylation analyses are needed for grading. If TERT promoter mutations are present, even with a PLNTY methylation profile, these tumors can still exhibit the biological behavior of high‐grade gliomas.

Objective: To investigate the clinicopathological features, diagnosis and prognosis of polymorphous low-grade neuroepithelial tumor of the young (PLNTY). Methods: Two cases of PLNTY diagnosed during January 2016 to December 2019 were collected from Ningbo Diagnostic Pathology Center, Zhejiang, China. The clinical features, histopathological characteristics, immunohistochemical and molecular genetic findings were analyzed and the relevant literature was reviewed. Results: The two patients were both female, at the ages of 14 and 25 years, respectively. Both patients presented with seizure attacks. The imaging study showed a mixed signal in the cerebral cortex, located in the occipital and temporal lobes, respectively. Microscopically, the tumors were characterized by the invariable presence of oligodendroglioma-like appearance, often with calcification. Immunohistochemically, the tumors were diffusely and intensely CD34 positive with ramified, CD34-expressing neural elements in regional cortex. The tumors were positive for GFAP, Olig2 and ATRX, and negative for IDH1, Neu N, nestin and EMA. The Ki-67 labeling index was less than 2%. The case number 2 harbored the BRAF V600E mutation, while the case number 1 was negative for both the BRAF V600E mutation and 1p/19q codeletion. Both patients recovered very well and were free of seizures after the following-up of 2 and 24 months, respectively. Conclusions: PLNTY is an uncommon neuroepithelial tumor. Histopathologic and immunohistochemical examinations are necessary for establishing the diagnosis and for excluding oligodendroglioma. PLNTY should be considered as a benign tumor corresponding to WHO Grade I. The prognosis is overall good after complete tumor-resection.

In 2021, the World Health Organization (WHO) Classification of Tumors of the Central Nervous System (CNS) underwent significant restructuring to incorporate additional molecular diagnostics, several newly recognized tumor types, and new grading schemes for existing tumor types. The 2021 CNS WHO classification further elaborates and integrates histopathologic and molecular diagnostic criteria to improve diagnostic classification. Furthermore, it is the hope that identification of molecular alterations in pediatric and adult tumors facilitates improved prognostic information and development of novel targeted therapies for adults and children with CNS tumors. In one of the largest changes in the new WHO classification, diffuse gliomas are divided into pediatric-type and adult-type gliomas to highlight our expanding knowledge of their different molecular drivers and prognostic associations. Several new pediatric-type diffuse low-grade gliomas are defined including (I) diffuse astrocytoma, MYB- or MYBL1-altered, (II) polymorphous low-grade neuroepithelial tumor of the young (PLNTY), and (III) diffuse low-grade glioma, MAPK-pathway altered. In addition, several new pediatric-type diffuse high-grade gliomas are recognized including (I) diffuse hemispheric glioma, H3 G34R-mutant (II) diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype, and (III) infant-type hemispheric glioma. These new tumor types have associated clinical, genetic and epigenetic features that are distinct from adult-type diffuse gliomas. This review provides an overview of updates in the 2021 CNS WHO classification specific to diffuse gliomas, with a particular focus on the histopathology and molecular findings of the newly described pediatric-type low-grade and high-grade gliomas.

BackgroundThe BRAF V600E and telomerase reverse transcriptase (TERT) promoter mutations have been reported in papillary thyroid carcinoma (PTC). The aim of this retrospective cross-sectional study was to add further information regarding the prevalence of the BRAF V600E and TERT promoter mutations in Chinese PTC and their clinicopathological associations.MethodsWe detected the BRAF V600E mutation and TERT promoter mutations in 455 Chinese PTC patients and analyzed the association of these mutations with several clinicopathological features.ResultsThe BRAF V600E mutation was detected in 343 (75.4%) of 455 cases and was significantly associated with older age (p<0.001) and conventional subtype (p = 0.003). TERT promoter mutations were detected in 19 (4.4%) of 434 PTCs and were associated with older age (p<0.001), larger tumor size (p = 0.024), and advanced TNM stage(p<0.001). Of the 19 patients that were positive for TERT promoter mutations, 18 (94.7%) also harbored the BRAF V600E mutation.ConclusionWe determined the prevalence and clinicopathological associations of BRAF V600E and TERT promoter mutations in Chinese PTC patients. TERT promoter mutations but not the BRAF V600E mutation were associated with more advanced TNM stage upon diagnosis.

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. 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. 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. 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.

Simple SummaryTERT promoter mutation has recently emerged as a promising prognostic biomarker for aggressive papillary thyroid cancer (PTC), along with BRAF B600E mutation. The prevalence of the TERT promoter mutations has been reported as relatively uncommon in Asian countries. We report on a prospective study of the TERT promoter and BRAF V600E mutation in the largest number of subjects with PTC in Korea. We assume that our specific clinical settings and the favorable healthcare environment in Korea led to several distinct findings: the lowest prevalence of TERT promoter mutation ever reported, multifocal gene mutations in bilateral PTCs, and more early-stage papillary microcarcinomas included in this study. This study indicates that relevant evaluation and treatment strategies should be investigated continuously based on different circumstances.Telomerase reverse transcriptase (TERT) promoter mutation has been investigated for its clinical and prognostic significance in aggressive papillary thyroid cancer (PTC). In this study, we aimed to assess the prevalence, clinicopathologic features, and treatment outcomes of TERT mutation-positive PTCs along with the common BRAF V600E mutation. We performed mutational analyses for BRAF and the TERT promoter in thyroid cancer patients who had undergone surgery at our institution since 2019. We reviewed and analyzed 7797 patients with PTC in this study. The prevalence of BRAF V600E and TERT promoter mutations was 84.0% and 1.1%, respectively. Multifocal gene mutations in bilateral PTCs were identified. TERT promoter mutations were associated with older age, larger tumor size, tumor multifocality, tumor variants, advanced stages, more adjuvant radioactive iodine treatment (RAI), higher stimulated serum thyroglobulin level before RAI, and more uptakes in the regions outside the surgical field on a post-RAI whole-body scan. The coexistence of BRAF V600E and TERT promoter mutations exacerbated all clinicopathologic characteristics. The frequency of TERT promoter mutations was the lowest in this study, compared to previous studies. TERT promoter mutations consistently correlated with aggressive PTCs, and the synergistic effect of both mutations was evident. Specific clinical settings in our institution and in Korea may have led to these distinctive results. Prospective multicenter studies with longer follow-up periods are required to establish valuable oncologic outcomes.

BRAFV600E mutation is highly prevalent in patients with papillary thyroid carcinoma (PTC), and TERT promoter (TERTp) mutation is strongly associated with cancer-related mortality. However, predictive power of the two mutations remains inconclusive. We aimed to verify the prognostic effects of both mutations to assess the value of mutation detection for risk stratification in terms of PTC prognosis and tumour invasion, to guide PTC diagnosis and treatment. We conducted a literature search in the MEDLINE (PubMed), EMBASE, Web of Science and CENTRAL (Cochrane library) databases, from inception to February 2020. Basic characteristics, prognoses and clinicopathological features were collected from the included studies for further analysis. Twelve studies involving 4184 PTC patients were enrolled in our analysis. In total, 2412 (57.6%) of the patients carried either BRAFV600E or TERTp mutation, and 290 (6.9%) patients had both mutations. TERTp mutation was more common in patients with BRAFV600E mutation (RR=1.75 [95% CI 1.44-2.13]). Patients with both mutations had a worse prognosis compared with those with a single mutation (vs BRAFV600E only: RR=5.34 [4.20-6.78] vs TERTp only: RR=2.12 [1.41-3.19]). TERTp mutation alone independently increased the risk of a poor prognosis (RR=2.90 [1.93-4.35]) in terms of mortality (RR=15.09 [7.75-29.37]), disease persistence (RR=4.00 [2.03-7.90]), recurrence (RR=4.34 [4.20-6.78]), lymph node metastasis (RR=1.57 [1.24-1.99]) and distant metastasis (RR=2.94 [1.13-7.65]). We found that PTC patients with BRAFV600E mutation were more likely to have TERTp mutation. TERTp mutation was an independent predictive factor for poor prognosis of PTC patients, but the predictive value of BRAFV600E mutation remains inconclusive. Patients with both mutations have remarkably higher risks of adverse outcomes compared with those with a single mutation. PTC patients could benefit from mutation detection for aiding risk stratification (BRAF+TERT+>BRAF-TERT+>BRAF+TERT-).

Simple SummaryAs molecular testing of thyroid nodules becomes more common, thyroid specialists must be able to interpret and understand the clinical implications of the results. A telomerase reverse transcriptase (TERT) promoter mutation can strongly predict thyroid cancer aggressiveness. However, the reason why some thyroid cancers with TERT promoter mutations are more aggressive than others remains unclear. This study aimed to examine whether TERT promoter mutations coexisting with other mutations are linked to more aggressive disease than TERT promoter mutations alone. The medical records of patients who had thyroid surgery and TERT promotor mutations were examined. Our findings showed that the likelihood of aggressive thyroid cancers was 10 times higher in patients with TERT promoter and other concurrent mutations. Thyroid specialists can use our results to accurately interpret the molecular testing of thyroid nodules, provide appropriate counseling, and discuss possible management options accordingly.This study aimed to examine whether concurrent mutations with a TERT promoter mutation are associated with a greater likelihood of more aggressive disease than a TERT promoter mutation alone. The medical records of 1477 patients who underwent thyroid surgery at two tertiary hospitals between 2017 and 2022 were reviewed. Twenty-four patients had TERT promoter mutations based on molecular profile testing. Clinicodemographic data, mutational profiles, and histopathological features were assessed. Descriptive analysis, Fisher’s exact test, and binary logistic regression were performed. Seven patients had single-gene TERT promoter mutations, and 17 had concurrent mutations, including BRAF V600E, HRAS, NRAS, PIK3CA, and EIF1AX. The overall prevalence of malignancy was 95.8%, of which 78.3% were aggressive thyroid cancers. There was a statistically significant association between concurrent mutations and disease aggressiveness. The odds of having aggressive disease were 10 times higher in patients with a TERT promoter mutation and a concurrent molecular alteration than in those with a TERT promoter mutation alone. This is an important finding for thyroid specialists to consider when counseling patients concerning risk stratification and management options.

Arms-qPCR Improves Detection Sensitivity of Earlier Diagnosis of Papillary Thyroid Cancers With Worse Prognosis Determined by Coexisting BRAF V600E and Tert Promoter Mutations

Polymorphous low-grade neuroepithelial tumor of the young (PLNTY) is a rare entity with a diffuse, infiltrative pattern, awaiting to be included in the WHO CNS tumor classification; it occurs in pediatric and young patients with seizures and harbors mutually exclusive BRAFV600E or FGFR mutations. Nonetheless, the presence of these mutations may not be obligatory for diagnosis. The conventional histology of these tumors resembles that of oligodendrogliomas. We aimed to discuss a PLNTY case in a young woman presenting with seizures due to a parietal brain tumor and to provide an analysis of the literature. Histopathologically the tumor was consistent of oligodendroglioma-like neoplastic cells showing almost diffuse CD34 and olig-2 staining, retained ATRX expression, p53-negativity, and a low Ki67 index with no necrosis or microvascular proliferation. 1p/19q statuswas analyzed with FISH; IDH1 and IDH2 mutations were analyzed with minisequence analysis. Translocations, mutations, and expression analyses were studied for 18, 19, and 21 genes via targeted new-generation deep RNA sequencing, respectively. The tumor did not carry 1p/19q codeletion, was IDH wild-type, and had radiological features compatible with the diagnosis of PLNTY. The tumor did not show BRAF or FGFR alterations but had an EGFR c.2342A>G (p.Asn781Ser) mutation which was likely a non-driver mutation due to its low allele frequency of 4%. PLNTYs are rare brain tumors, and their accurate diagnosis is important to avoid improper management. Their prognosis shall be stratified according to their mutations.

Effect of BRAFV600E and TERT Promoter Mutations on Thyroglobulin Response in Patients With Distant-Metastatic Differentiated Thyroid Cancer

Mutations in the telomerase reverse transcriptase (TERT) promoter have been reported as a convincing prognostic factor in papillary thyroid carcinomas (PTCs). We aimed to investigate the frequency of TERT promoter mutations in patients with thyroid cancer and identify the clinicopathological factors associated with them in PTCs. A total of 1086 consecutive cases of thyroid cancer composed of mostly PTCs were included in this study. TERT promoter and BRAF mutations were detected by pyrosequencing and their associations with clinicopathological features of tumour were analyzed. TERT promoter mutations were observed in 1.9% of PTCs, 6.7% of follicular thyroid carcinomas, 8.3% of Hurthle cell carcinomas and 25.0% of poorly differentiated thyroid carcinomas and in a single case of anaplastic thyroid carcinoma. In PTCs, aggressive clinicopathological features, higher stage and BRAF V600E mutation were all found to be associated with TERT promoter mutations. Distant metastasis and disease recurrence were more frequent in TERT promoter-mutated PTCs. In multivariate analysis, age ≥55 years, tall cell variant, mitoses ≥3/10 high-power fields, tumour necrosis, and gross extrathyroidal extension (ETE) were identified as independent factors associated with TERT promoter mutations in PTCs. This study revealed a relatively low frequency of TERT promoter mutations in Korean patients with PTC. Certain clinicopathological features including old age, tall cell variant, increased mitoses, tumour necrosis and gross ETE were found to be indicative of TERT promoter mutations in PTCs, suggesting that mutational analysis in a particular group of PTCs can be effective in regions with low mutation rates.

BackgroundA new type of epileptogenic tumor, the polymorphous low-grade neuroepithelial tumor of the young (PLNTY) was firstly reported by Jason T. Huse et al. at 2016. After that, only 1 case of PLNTY was reported by article. The radiological characteristics of PLNTY have not been concluded. The objective of our study was to report 3 cases of PLNTYs in details and to analyze the image characteristics and genetic alterations of PLNTYs by reviewing our cases and articles.Case presentationThere were 3 cases diagnosed as PLNTY by pathology in our hospital during the last 10 years, with the average age of 15. They were all suffered from different degrees of epilepsy. All of them underwent magnetic resonance (MR) imaging and 2 of them underwent computer tomography (CT) imaging. The PLNTYs are all appearing as a solid or solid-cystic cortical mass with little mass effect and unclear boundary with normal brain tissue. They are all shown as hyperintensity in T2WI and iso−/hypointensity in T1WI with slight or no enhancement after contract enhanced in MR imaging. The “salt and pepper sign” in T2WI and grit calcification in CT images might be specific characteristics of PLNTY. All of them recovered after excision of the tumors. The gene tests revealed fibroblast growth factor receptors 3 (FGFR3)-TACC3 fusion and FGFR3 amplification in one case, and the B-Raf proto-oncogene (BRAF) V600E mutation in another case.ConclusionIn the image, the partial ill-marginated cortical mass with “salt and pepper sign” in T2WI or grit calcification in CT imaging might be the typical imaging characteristics of PLNTY. We also prove that the BRAF V600E mutation as well as the FGFR2 and FGFR3 have a close relationship with PLNTY.