Acta Neuropathologica Communications最新文献

Background: Assessing circulating cell-free DNA (cfDNA) in cerebrospinal fluid (CSF) has been proposed as a promising alternative to tissue biopsy. Advances in cfDNA sequencing have further underscored the potential of CSF liquid biopsies in the clinical setting. CSF is routinely collected for cytologic evaluation at diagnosis and at recurrence in both pediatric and adult central nervous system (CNS) tumors. Preliminary studies have shown that CSF cfDNA analysis may be more sensitive than CSF cytology for detecting the presence of tumor.

Methods: CSF specimens were prospectively collected from seven pediatric patients with primary CNS malignant tumors. When possible, CSF was collected fresh and from processed cytology specimens. Low-pass whole genome sequencing (LP-WGS) and next-generation sequencing (NGS) using a custom targeted sequencing panel were performed on the specimens to identify copy number alterations (CNAs), detect mutations, and estimate circulating tumor DNA (ctDNA) fractions. Results were compared with matched tumor tissue molecular profiles and corresponding imaging findings.

Results: Abnormalities in cfDNA were detected in four patients. Sequencing of CSF cytology supernatants demonstrated the presence of circulating tumor DNA with characteristic CNAs and mutations that matched what was seen the tumor tissue as well as the fresh CSF specimens. These studies also revealed tumor heterogeneity and genomic evolution over time.

Conclusion: This study demonstrates the feasibility of utilizing routinely discarded supernatants from CSF cytology specimens for LP-WGS and targeted NGS. Our approach optimizes the use of CSF that may be limited in pediatric patients as a source for liquid biopsy-based genomic studies. Future research will be necessary to optimize and validate the methodology to enable clinical implementation.

The 2021 World Health Organization (WHO) Classification of Central Nervous System (CNS) classification formalized routine molecular profiling, and DNA-methylation studies have since delineated PLAG-family-altered CNS entities: PLAGL1 fusion-positive supratentorial neuroepithelial tumors (NET_PLAGL1) and embryonal tumors with PLAGL1/PLAGL2 amplification. PLAG1 fusions with diverse partners have been reported in CNS embryonal tumors, but have not been described in supratentorial neuroepithelial tumors to date. We describe two pediatric supratentorial ependymal tumors with novel PLAG1 fusions that do not match any 2021 WHO-defined entity or any PLAG-family-related entity recently reported in the literature. Case 1 (4-year-old boy) had a 7.6-cm left lateral ventricular mass with edema and heterogeneous enhancement; gross total resection was performed without adjuvant therapy (alive at 8 months). Histology showed diffusely low cellularity with small- to medium-sized round nuclei, minimal atypia, and focal calcifications; no ependymal rosettes, branching vessels, or clear-cell change. Tumor cells were positive for GFAP and H3K27me3, and negative for Desmin, EMA, OLIG2, L1CAM, NF-κB and H3K27M. The MIB-1 labeling index was ~ 5%. RNA-seq identified TNC::PLAG1 fusion; FISH showed PLAG1 rearrangement. DNA methylation clustered with spinal subependymoma, despite supratentorial location. Case 2 (4-year-old girl) had a 1.4 × 1.1 cm left parahippocampal lesion; resected without adjuvant therapy (alive at 4 months). Histology showed low-to-moderate cellularity with diffuse microcystic change, focal clear/vacuolated cells, and delicate branching vessels. Tumor cells were positive for GFAP, EMA, L1CAM, H3K27me3 and ATRX, and negative for EMA, Desmin, NF-κB, OLIG2, H3K27M, and CD34 (MIB-1 ~ 2%). RNA-seq identified TXNIP::PLAG1 fusion. Methylation did not reach a class threshold. Both cases ultimately warrant a final diagnosis of ependymal tumor, not elsewhere classified. To our knowledge, TNC::PLAG1 and TXNIP::PLAG1 are first-ever fusions reported in any tumor type. They also represent the first PLAG1 fusions identified in pediatric supratentorial ependymal tumors. These cases highlight the value of integrating histology, methylation profiling, and fusion detection, and suggest a new candidate supratentorial ependymal subtype with PLAG1 fusions, pending validation in larger series.

Fibroblasts are a group of stromal cells that contribute to the scarring process in many neurological conditions in the central nervous system (CNS). Recently, single-cell sequencing efforts allowed an in-depth understanding of their cell origins and subpopulation profiles. Meanwhile, vascular leptomeningeal cells and the "type A pericytes" were also proposed as CNS fibroblast-like cells in the last decade by histological, functional and transcriptomic analysis. While these cells share overlapping features with CNS fibroblasts, the inconsistent use of nomenclature and partially overlapping cell-type markers is likely to cause confusion within the growing field of neurobiology. In this review, we will delineate the current knowledge of subtypes and functions of CNS fibroblasts, with special focus on the source of PVFs during development and the nomenclature origins of other similar cell types. We aim to provide comprehensive insights into these cells with similar functions or transcriptomic profiles.