Central nervous system dissemination in spinal cord astrocytomas: association with H3 K27M mutation.

OBJECTIVE: Patients with spinal cord astrocytomas (SCAs) are at high risk for CNS dissemination, yet comprehensive data on characteristics of dissemination are lacking. This study depicts the exact incidence and patterns of dissemination by analyzing data from a large-scale dataset of SCA. METHODS: The authors included 94 patients with SCA based on the 2021 WHO classification from 2011 to 2022, retrospectively collected their clinical and pathological characteristics, and analyzed factors influencing SCA dissemination. RESULTS: CNS dissemination, encompassing leptomeningeal spreading and/or subarachnoid seeding, was evaluated in 94 patients with and without H3 K27 alterations, with an overall dissemination rate reaching 85.0% at 5-year follow-up. Patients with altered H3 K27 had a significantly higher 5-year CNS dissemination rate than patients with H3 K27 wildtype status (95.2% vs 68.0%, p = 0.002). The median dissemination-free survival in H3 K27-altered patients was 14.37 (95% CI 2.84-25.89) months, significantly shorter than those with H3 K27 wildtype (statistics not calculated; p < 0.001). Based on univariate Cox regression analysis, H3 K27M alteration, higher histopathological grade, Ki-67 index (≥ 10%), and tumor length (≥ 4 segments) were identified as potential factors associated with CNS dissemination in SCAs. Multivariate Cox regression analysis revealed that H3 K27M alteration appeared to be a risk factor for this phenomenon (HR 2.089, 95% CI 0.940-4.642, p = 0.070). Following dissemination, H3 K27-altered patients had a median postdissemination survival of 8.83 (95% CI 7.13-10.54) months, which was significantly shorter than the 13.40 (95% CI 3.98-34.26) months in those with H3 K27 wildtype (p = 0.008). CONCLUSIONS: Factors indicative of higher SCA malignancy, such as H3 K27M alteration, higher histopathological grade, Ki-67 index (≥ 10%), and tumor length (≥ 4 segments), were similarly suggestive of higher rates of dissemination. The occurrence of dissemination is closely associated with the outcome events in patients with SCA.

Understanding spinal cord astrocytoma: Molecular mechanism, therapy, and comprehensive management.

Spinal cord astrocytoma is a rare and highly debilitating tumor, yet our knowledge of its clinical characteristics, molecular features, and pathogenesis remains limited compared to that of its counterparts in the brain. Current diagnostic and therapeutic approaches for spinal cord astrocytomas are primarily based on established guidelines for brain astrocytomas. However, recent studies have revealed unique clinical and pathological attributes that distinguish spinal cord astrocytomas from their corresponding brain counterparts. These findings underscore the inadequacy of directly applying the clinical guidelines developed for brain astrocytomas to spinal astrocytomas. In this review, we provided an up-to-date overview of the advancements in understanding spinal cord astrocytomas. We also discussed the challenges and future research prospects in this field with the aim of improving the precision of diagnosis and therapy for these tumors. Specifically, we emphasized the importance of enhancing our understanding of the molecular heterogeneity, immune characteristics, and clinical trials of spinal cord astrocytomas.

Sequencing of cerebrospinal fluid cell-free DNA facilitated early differential diagnosis of intramedullary spinal cord tumors.

Pre-surgery differential diagnosis is valuable for personalized treatment planning in intramedullary spinal cord tumors. This study assessed the performance of sequencing cell-free DNA (cfDNA) in cerebrospinal fluid (CSF) for differential diagnosis of these tumors. Prospectively enrolling 45 patients with intramedullary spinal cord lesions, including diffuse midline glioma (DMG), H3K27-altered (14/45), glioblastoma (1/45), H3-wildtype-astrocytoma (10/45), ependymoma (11/45), and other lesions (9/45), CSF samples were collected via lumbar puncture (41/45), intraoperative extraction (3/45), and Ommaya reservoir (1/45). Then, these samples underwent targeted sequencing along with paired tissue DNA. DMG, H3K27-altered patients exhibited a higher ctDNA positivity (85.7%, 12/14) compared to patients with H3-wildtype-astrocytoma (0/8, P = 0.0003), ependymoma (2/10, P = 0.003), and glioneuronal tumor (0/3, P = 0.009). The histological-grade-IV (P = 0.0027), Ki-67 index ≥10% (P = 0.014), and tumor reaching spinal cord surface (P = 0.012) are also associated with higher ctDNA positivity. Interestingly, for patients with TERT promoter mutant tumors, TERT mutation was detectable in the CSF cfDNA of one DMG case, but not other five cases with histological-grade-II tumors. Shared copy number variants were exclusively observed in DMG, H3K27-altered, and showed a strong correlation (Correlation = 0.95) between CSF and tissue. Finally, H3K27M mutations in CSF exhibited high diagnostic efficiency for DMG, H3K27-altered (Sensitivity = 85.7%, Specificity = 100.0%, AUC = 0.929). Notably, H3K27M was detectable in CSF from patients with recurrent tumors, making it easily applicable for postoperative monitoring. In conclusion, the molecular profile from ctDNA released into CSF of malignant tumors was more frequently detected compared to relatively benign ones. Sequencing of ctDNA in CSF exhibited high efficiency for the differential diagnosis of DMG, H3K27-altered.

Clinical management and prognosis of spinal myxopapillary ependymoma: a single-institution cohort of 72 patients.

PURPOSE: Myxopapillary ependymoma (MPE) was classified as grade 2 tumor in the 2021 World Health Organization central nervous system classification because of its high recurrence probability. This study aimed to investigate predictive factors and management of tumor recurrence. METHODS: Seventy-two patients with spinal MPE underwent initial surgical treatment at our hospital between 2011 and 2021. Kaplan-Meier curves and Cox regression were used to analyze the correlation between clinical variables and progression-free survival (PFS). RESULTS: The median age at diagnosis was 33.5 years (range 8-60 years). Twenty-one patients (29.2%) had preoperative spinal drop metastases. Gross total resection (GTR) was performed in 37 patients (51.4%). The median follow-up was 7.2 years, and the follow-up rate was 88.9% (64 of 72 cases). Twelve of the 64 patients (18.9%) relapsed, and preoperative drop metastasis occurred in 7 patients (58.3%). The estimated 5-year and 10-year PFS rates were 82% and 77%, respectively. Univariate analysis showed that GTR was associated with improved PFS (hazard ratio [HR] 0.149, p = 0.014), while preoperative drop metastasis (HR 3.648, p = 0.027) and tumor involvement sacrococcygeal region (HR 7.563, p = 0.003) were associated with tumor recurrence. Adjuvant radiotherapy (RT) was significantly associated with improved PFS in patients with preoperative drop metastasis (p = 0.039). CONCLUSION: Complete surgical resection under the premise of protecting neurological function is an important factor in reducing spinal MPE recurrence. Adjuvant RT is recommended when the tumor invades the capsule with preoperative drop metastasis or adhesion to the nerve and cannot reach GTR.

Genomic profiling and prognostic factors of H3 K27M-mutant spinal cord diffuse glioma.

H3 K27-altered diffuse midline glioma is a highly lethal pediatric-type tumor without efficacious treatments. Recent findings have highlighted the heterogeneity among diffuse midline gliomas with different locations and ages. Compared to tumors located in the brain stem and thalamus, the molecular and clinicopathological features of H3 K27-altered spinal cord glioma are still largely elusive, thus hindering the accurate management of patients. Here we aimed to characterize the clinicopathological and molecular features of H3 K27M-mutant spinal cord glioma in 77 consecutive cases. We found that the H3 K27M-mutant spinal cord glioma, with a median age of 35 years old, had a significantly better prognosis than H3 K27M-mutant brain tumors. We noticed a molecular heterogeneity of H3 K27M-mutant spinal cord astrocytoma via targeted sequencing with 34 cases. TP53 mutation which occurred in 58.8% of cases is mutually exclusive with PPM1D (26%) and NF1 (44%) mutations. The TP53-mutant cases had a significantly higher number of copy number variants (CNV) and a marginally higher proportion of pediatric patients (age at diagnosis <18 years old, p = 0.056). Cox regression and Kaplan-Meier curve analysis showed that the higher number of CNV events (≥3), chromosome (Chr) 9p deletion, Chr 10p deletion, ATRX mutation, CDK6 amplification, and retinoblastoma protein (RB) pathway alteration are associated with worse survival. Cox regression analysis with clinicopathological features showed that glioblastoma histological type and a high Ki-67 index (>10%) are associated with a worse prognosis. Interestingly, the histological type, an independent prognostic factor in multivariate Cox regression, can also stratify molecular features of H3 K27M-mutant spinal cord glioma, including the RB pathway, KRAS/PI3K pathway, and chromosome arms CNV. In conclusion, although all H3 K27M-mutant spinal cord diffuse glioma were diagnosed as WHO Grade 4, the histological type, molecular features representing chromatin instability, and molecular alterations associated with accelerated cell proliferative activity should not be ignored in clinical management.

Spinal Cord Diffuse Midline Gliomas With H3 K27m-Mutant: Clinicopathological Features and Prognosis.

BACKGROUND: "Diffuse midline glioma, H3 K27M-mutant" (DMG) mainly arises within the pontine, thalamic, and spinal cord regions. Because of the rarity of spinal cord gliomas, the general knowledge surrounding DMGs is mainly based on pontine and thalamic gliomas, whereas tumor location tends to influence the clinicopathological features and prognosis. OBJECTIVE: To determine the clinicopathological characteristics and molecular profiles of DMGs located in the spinal cord. METHODS: The clinical and molecular pathologic features and prognosis were comprehensively analyzed in a series of 44 patients with spinal cord DMGs. RESULTS: The median age was 36 yr, and 88.7% of patients (39/44) were adults (≥18 yr). Histopathologically, malignant grades included grade II (16 cases), grade III (20 cases), and grade IV (8 cases). Compared with patients with histological grade IV, patients with lower histological grade (grade II/III) were older (37 vs 24 yr, P = .020) and were associated with longer overall survival (24.1 vs 8.6 mo, P = .007). All 30 tested tumors were isocitrate dehydrogenase (IDH) wild type, and 96% of cases (22/23) presented with unmethylated O6-methylguanine-DNA methyltransferase. Univariate and multivariate analyses showed that histological grade and presurgery McCormick Scale scores were independent prognostic factors for overall survival, whereas extensive surgical resection and chemoradiotherapy were not significantly associated with improved survival. The most frequent anatomic locations were the cervical enlargement (C4-T1, n = 16) and conus medullaris (T12-L1, n = 13), which exhibited distinctive clinical characteristics and molecular features. CONCLUSION: The findings provide guidelines for the evidence-based practice of the specialized management of spinal cord DMGs.