We investigated the challenging diagnostic case of a ventricular cystic glioneuronal tumor with papillary features, by RNA sequencing using the Illumina TruSight RNA Fusion panel. We did not retrieve ...the SLC44A1‐PRKCA fusion gene specific for papillary glioneuronal tumor, but an EWSR1‐PATZ1 fusion transcript. RT‐PCR followed by Sanger sequencing confirmed the EWSR1‐PATZ1 fusion. It matched with canonic EWSR1 fusion oncogene, juxtaposing the entire N‐terminal transcriptional activation domain of EWSR1 gene and the C‐terminal DNA binding domain of a transcription factor gene, PATZ1. PATZ1 protein belongs to the BTB‐ZF (broad‐complex, tramtrack and bric‐à‐brac ‐zinc finger) family. It directly regulates Pou5f1 and Nanog and is essential to maintaining stemness by inhibiting neural differentiation. EWSR1‐PATZ1 fusion is a rare event in tumors: it was only reported in six round cell sarcomas and in three gliomas of three exclusively molecular studies. The first reported glioma was a BRAFV600E negative ganglioglioma, the second a BRAFV600E negative glioneuronal tumor, not otherwise specified and the third, very recently reported, a high grade glioma, not otherwise specified. In our study, forty BRAFV600E negative gangliogliomas were screened by FISH using EWSR1 break‐apart probes. We performed methylation profiling for the index case and for seven out of the ten FISH positive cases. The index case clustered apart from other pediatric low grade glioneuronal entities, and specifically from the well‐defined ganglioglioma methylation group. An additional pediatric intraventricular ganglioglioma clustered slightly more closely with ganglioglioma, but showed differences from the main ganglioglioma group and similarities with the index case. Both cases harbored copy number variations at the PATZ1 locus. EWSR1‐PATZ1 gene fusion might define a new type of glioneuronal tumors, distinct from gangliogliomas.
Aims
We searched for recurrent pathological features and molecular alterations in a retrospective series of 72 low‐grade epilepsy‐associated neuroepithelial tumours (LEATs) with a prominent ...oligodendroglioma‐like component, in order to classify them according to the 2021 World Health Organization (WHO) classification of central nervous system (CNS) tumours.
Methods
Centralised pathological examination was performed as well as targeted molecular analysis of v‐Raf murine sarcoma viral oncogene homologue B (BRAF) and fibroblast growth factor receptor 1 (FGFR1) by multiplexed digital polymerase chain reaction (mdPCR). DNA methylation profiling was performed in cases with sufficient DNA. In cases with no genetic alteration by mdPCR and sufficient material, RNA sequencing was done.
Results
We first reclassified our cohort into three groups: ganglioglioma (GG, n = 14), dysembryoplastic neuroepithelial tumours (DNTs, n = 19) and glioneuronal tumours/paediatric‐type low‐grade glioma (LGG) not otherwise specified (GNT/PLGG NOS, n = 39). mdPCR found an alteration in 38/72 cases. Subsequent RNA sequencing revealed a fusion transcript involving BRAF, FGFR1/2/3 or neurotrophic tyrosine kinase receptor type 2 NTRK2 in 9/25 cases. DNA methylation profiling found 12/46 cases with a calibrated score ≥0.9. Unsupervised hierarchical clustering revealed two clusters: Cluster 1 was enriched with cases classified as DNT at histology, belonging to the LGG–DNT methylation class (MC), with haematopoietic progenitor cell antigen (CD34) negativity and FGRF1 alterations; Cluster 2 was enriched with cases classified at histology as GG, belonging to the LGG–GG MC MC, with BRAF V600E mutation and CD34 positivity. The tumours reclassified as GNT/PLGG NOS were equally distributed across both clusters. Interestingly, all polymorphous low‐grade neuroepithelial tumour of the young belonged to Cluster 2, whereas diffuse LGG mitogen‐activated protein kinase (MAPK) pathway‐altered were equally distributed among the two clusters. This led us to build an algorithm to classify LEATs with a prominent oligodendroglioma‐like component.
Conclusions
Integrated histomolecular diagnosis of LEATs with a prominent oligodendroglioma‐like component remains challenging. Because these tumours can be split into two major clusters of biological significance, the clinicopathological relevance of the four types recognised by the WHO CNS5 within this spectrum of tumours is questionable.
By performing centralized pathological examination as well as targeted molecular analysis by multiplexed digital PCR, DNA methylation profiling and RNA sequencing, we retrospectively studied 72 supratentorial low‐grade gliomas or glioneuronal tumours with an oligodendroglioma‐like component in order to classify them according to the 2021 WHO classification of CNS tumours. Our study highlights the challenges in the diagnosis of supratentorial tumours with an oligodendroglioma‐like component occurring in children and young adults and shows that these tumours belong to two major groups of biological relevance, although four entities are currently recognized within this spectrum of tumours by the WHO CNS5 classification.
Standardized reports are essential to meeting the bone sarcoma reference center certification requirements of the French National Cancer Institute (INCa). The usual classifications of the ...Musculoskeletal Tumor Society (MSTS), the American Joint Committee on Cancer (AJCC/IUCC) TNM R classification and the American College of Pathologists, are inexact inasmuch as they fail to include chemotherapy impact on tumor cells in assessing surgical margins. This leads to inconsistent interpretation by teams managing bone sarcoma. The present literature analysis sought to assess the limitations of existing classifications for purposes of standardized reporting of the management of surgical specimens from patients with osteosarcoma or Ewing sarcoma receiving neoadjuvant chemotherapy, by addressing the following questions: 1) What is the prognostic value of margins and chemotherapy response in the classifications? 2) What are the histologic changes induced by chemotherapy, with what impact on interpretation of margins?
A PubMed literature analysis was performed, targeting the prognostic value of resection margin assessment, in September 2018. French bone pathology group (Groupe français des pathologistes osseux) and international guidelines on bone specimen management were referred to so as select items for a standardized report. Eight of the 523 articles retrieved met the study eligibility criteria.
Minimal distance between tumor and surgical margin, with a>2mm threshold, seemed to be the optimal parameter for predicting local recurrence. Good chemotherapy response and appendicular skeletal location were associated with lower risk of local recurrence. None of the available classifications take into account the microscopic changes induced by chemotherapy in interpreting resection margins.
To standardize practice, GROUPOS developed a standardized report for bone sarcoma specimens, considering the histopathologic changes in the tumor after neoadjuvant chemotherapy. The TNM R system was adapted and a threshold of>2mm was chosen as an acceptable limit to qualify surgical resection as safe (R0). R1 status (≤2mm) was subdivided into subgroups a, b and c, to include margin measurement in relation to the post-chemotherapy scar: R1a, resection within the scar; R1b, resection in healthy tissue,≤2mm from the scar and/or residual viable cells; and R1c, resection within the lesion in contact with viable cells or within coagulation necrosis areas. The GROUPOS members drew up this standardized report so as to ensure a common language, improving bone sarcoma management in specialized centers. Reliable data can thus be established for national and international multicenter studies.
IV.
Purpose Although perfusion magnetic resonance imaging (MRI) is widely used to identify pseudoprogression, this advanced technique lacks clinical reliability. Our aim was to develop a parameter ...assessing the hypervascularized fraction of glioblastomas based on volume analysis of dynamic susceptibility contrast-enhanced MRI and evaluate its performance in the diagnosis of pseudoprogression. Methods Patients with primary glioblastoma showing lesion progression on the first follow-up MRI after chemoradiotherapy were enrolled retrospectively. On both initial and first follow-up MRIs, the leakage-corrected cerebral blood volume (CBV) maps were post-processed using the conventional hot-spot method and a volume method, after manual segmentation of the contrast-enhanced delineated lesion. The maximum CBV (rCBVmax) was calculated with both methods. Secondly, the threshold of 2 was applied to the CBV values contained in the entire segmented volume, defining our new parameter: %rCBV>2. The probability of pseudoprogression based on rCBVmax and %rCBV>2 was calculated in logistic regression models and diagnostic performance assessed by receiving operator characteristic curves. Results Out of 25 patients, 11 (44%) were classified with pseudoprogression and 14 (56%) with true progression based on the Response Assessement in Neuro-Oncology criteria. rCBVmax was lower for pseudoprogression (3.4 vs. 7.6; p = 0.033) on early follow-up MRI. %rCBV>2, was lower for pseudoprogression on both initial (57.5% vs. 71.3%; p = 0.033) and early follow-up MRIs (22.1% vs. 51.8%; p = 0.0006). On early follow-up MRI, %rCBV>2 had the largest area under the curve for the diagnosis of pseudoprogression: 0.909 0.725–0.986. Conclusion The fraction of hypervascularization of glioblastomas as assessed by %rCBV>2 was lower in tumours that subsequently developed pseudoprogression both on the initial and early follow-up MRIs. This fractional parameter may help identify pseudoprogression with greater accuracy than rCBVmax.
Despite maximally safe resection of the magnetic resonance imaging (MRI)–defined contrast-enhanced (CE) central tumor area and chemoradiotherapy, most patients with glioblastoma (GBM) relapse within ...a year in peritumoral FLAIR regions. Magnetic resonance spectroscopy imaging (MRSI) can discriminate metabolic tumor areas with higher recurrence potential as CNI+ regions (choline/
N
-acetyl-aspartate index >2) can predict relapse sites. As relapses are mainly imputed to glioblastoma stem-like cells (GSCs), CNI+ areas might be GSC enriched. In this prospective trial, 16 patients with GBM underwent MRSI/MRI before surgery/chemoradiotherapy to investigate GSC content in CNI−/+ biopsies from CE/FLAIR. Biopsy and derived-GSC characterization revealed a FLAIR/CNI+ sample enrichment in GSC and in gene signatures related to stemness, DNA repair, adhesion/migration, and mitochondrial bioenergetics. FLAIR/CNI+ samples generate GSC-enriched neurospheres faster than FLAIR/CNI−. Parameters assessing biopsy GSC content and time-to-neurosphere formation in FLAIR/CNI+ were associated with worse patient outcome. Preoperative MRI/MRSI would certainly allow better resection and targeting of FLAIR/CNI+ areas, as their GSC enrichment can predict worse outcomes.
Preoperative magnetic resonance spectroscopy imaging can detect GSC-enriched tumor areas in patients with Glioblastoma.
Histopathological diagnosis of lymphomas represents a challenge requiring either expertise or centralised review, and greatly depends on the technical process of tissue sections. Hence, we developed ...an innovative deep-learning framework, empowered with a certainty estimation level, designed for haematoxylin and eosin-stained slides analysis, with special focus on follicular lymphoma (FL) diagnosis. Whole-slide images of lymph nodes affected by FL or follicular hyperplasia were used for training, validating, and finally testing Bayesian neural networks (BNN). These BNN provide a diagnostic prediction coupled with an effective certainty estimation, and generate accurate diagnosis with an area under the curve reaching 0.99. Through its uncertainty estimation, our network is also able to detect unfamiliar data such as other small B cell lymphomas or technically heterogeneous cases from external centres. We demonstrate that machine-learning techniques are sensitive to the pre-processing of histopathology slides and require appropriate training to build universal tools to aid diagnosis.
The aim of this study was to better define the clinical and biopathological features of patients with desmoplastic/nodular medulloblastoma (DNMB) and to further characterize this subgroup. 17 ...children aged < 5 years, with initial DNMB treated according to the HIT-SKK protocol, were evaluated. A retrospective central radiological review, a pathological and immunohistochemical study, and array-CGH and sequencing of germline SUFU and PTCH1 genes were performed. 15 histologically reviewed cases were confirmed as DNMB including three cases of medulloblastoma with extensive nodularity. Median age at diagnosis was 26 months. Radiology showed five cases with a vermis location and one with T2 hyperintensity. All cases showed a SHH immunoprofile. A 9q deletion was found in 6 cases, a MYCN-MYCL amplification in 1 case, and a SUFU germline mutation in 1 case (/9). The presence of SUFU and PTCH1 germline mutations agreed with previous reports. At 3 years, progression-free survival and overallsurvival rates were 72 ± 15% and 85 ± 10%, respectively. The rate of recurrence was relatively high (4 patients). This may have been because chemotherapy was delayed in two cases. Age > 3 years, and residual tumor may also have been an explanation for recurrence.
Although understanding of T-cell exhaustion is widely based on mouse models, its analysis in patients with cancer could provide clues indicating tumor sensitivity to immune checkpoint blockade (ICB). ...Data suggest a role for costimulatory pathways, particularly CD28, in exhausted T-cell responsiveness to PD-1/PD-L1 blockade. Here, we used single-cell transcriptomic, phenotypic, and functional approaches to dissect the relation between CD8
T-cell exhaustion, CD28 costimulation, and tumor specificity in head and neck, cervical, and ovarian cancers. We found that memory tumor-specific CD8
T cells, but not bystander cells, sequentially express immune checkpoints once they infiltrate tumors, leading,
, to a functionally exhausted population. Exhausted T cells were nonetheless endowed with effector and tumor residency potential but exhibited loss of the costimulatory receptor CD28 in comparison with their circulating memory counterparts. Accordingly, PD-1 inhibition improved proliferation of circulating tumor-specific CD8
T cells and reversed functional exhaustion of specific T cells at tumor sites. In agreement with their tumor specificity, high infiltration of tumors by exhausted cells was predictive of response to therapy and survival in ICB-treated patients with head and neck cancer. Our results showed that PD-1 blockade-mediated proliferation/reinvigoration of circulating memory T cells and local reversion of exhaustion occur concurrently to control tumors.
Salivary gland-like tumours are described in the breast but remain very rare and difficult to diagnose in this location. Only 37 cases of mucoepidermoid carcinoma have been described in the ...literature. We report the challenging diagnosis of a mucoepidermoid carcinoma sampled by core biopsy in a 51-year-old woman.
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