Faculty Bibliography

BACKGROUND:The widespread use of next-generation sequencing has allowed refinement of the classification and diagnosis of salivary gland neoplasms, leading to identification of recurrent gene fusions in a majority of salivary gland carcinoma types, and characterization of several novel entities. A small proportion of salivary gland carcinomas do not meet the diagnostic criteria for any known tumor type and are therefore classified as "salivary gland carcinoma, not otherwise specified". Given the ever-growing arsenal of tools to classify these lesions, the number of cases diagnosed as such is expected to continue decreasing. CASE PRESENTATION/METHODS:In this article we describe a novel DLG1::BRAF fusion in a high grade salivary gland carcinoma arising in the tongue of a 78 year-old woman. This tumor had solid and cribriform architectural features and was composed of a dual population of abluminal and mucinous cells. Immunohistochemically, it had variable SOX10 expression, variable and strong MUC4 reactivity and expression of p63 and p40 (delta Np63) in the abluminal cell population. The gene fusion retained the kinase domain of BRAF, without the self-inhibitory CR1 domain, which is expected to lead to upregulation of BRAF protein. The patient had a complete resection of her tumor, without evidence of local recurrence or metastasis 10 months after diagnosis. CONCLUSION/CONCLUSIONS:These findings may represent a previously undescribed type of salivary gland tumor. However, additional reports of similar lesions are necessary for definitive characterization.

BACKGROUND:Replication-repair-deficiency is associated with increased risk of developing malignant gliomas. The aim of this study was to investigate primary mismatch repair deficient gliomas (PMMRDGs), a group of IDH-wildtype and H3-wildtype gliomas that is enriched among patients with CMMRD and Lynch syndrome. METHODS:We investigated how PMMRDGs differ from other gliomas with respect to DNA methylation profile, genomic alterations, histopathology, and clinical outcomes. RESULTS:PMMRDGs occur in pediatric, adolescents and the elderly, falling in two related methylation clusters and are characterized by a high frequency of replication repair deficiency. Histology showed multinucleated giant cells, and immunohistochemistry demonstrated loss of MMR protein expression. Survival analysis revealed long-term survival in patients with high mutational burden (>50 mut/Mb) and an intact chromosome 9p region, which was validated in an independent reference cohort. CONCLUSIONS:Overall, our findings indicate that PMMRDGs represent a distinct type of IDH-wildtype gliomas with potential for long-term survival likely driven by immune activation.

BACKGROUND:Accurate molecular classification of medulloblastoma is critical for prognosis and treatment planning, but current methods rely on surgical tissue sampling and molecular profiling. This study evaluated whether in vivo proton MR spectroscopy (¹H-MRS) can provide noninvasive metabolic markers to support pre-surgical molecular group stratification. METHODS:In this single-center retrospective study, pre-treatment ¹H-MRS data were analyzed from 95 pediatric patients with medulloblastoma (median age 7.4 years; 56 male). Single-voxel PRESS spectra (TE = 35 ms, TR = 1.5-2.0 s) were acquired during routine clinical MRI, adding approximately 5 minutes of scan time. Absolute metabolite concentrations and selected ratios were quantified using automated spectral fitting. Metabolic profiles were compared across molecular groups (Group 3, n = 22; Group 4, n = 35; SHH, n = 26; WNT, n = 12) and assessed for qualitative concordance with prior ex vivo high-resolution HR-MAS NMR findings. Group differences were tested using Kruskal-Wallis with Dunn post hoc correction. RESULTS:Significant metabolic differences were observed across molecular groups, with strong group effects for taurine, creatine, choline, glutamate, and GABA (all P < .0015). Taurine was elevated in Group 3 and Group 4 relative to SHH (log₂FC = 1.77 and 1.40, adjusted P < 4 × 10⁻⁵). SHH tumors exhibited lower creatine compared with Group 3, Group 4, and WNT (adjusted P < .05). Glutamate was higher in SHH than WNT, while WNT tumors showed increased choline and GABA relative to other groups (adjusted P < .05). In vivo patterns were qualitatively concordant with ex vivo NMR findings. CONCLUSIONS:In vivo ¹H-MRS is a widely available, clinically feasible imaging biomarker that complements existing diagnostics and supports pre-surgical stratification of medulloblastoma.

BACKGROUND AND PURPOSE/OBJECTIVE:-wt GBMs to help radiologists in differentiating them from nonmalignant mimic diagnoses (eg, encephalitis). Additionally, the histologic, genomic, and survival profiles of nonenhancing GBMs were compared with those of enhancing GBMs. MATERIALS AND METHODS/METHODS:-wt GBMs with nonmalignant mimics. Histopathologic and genomic analyses were performed on institutional cases. Overall survival between nonenhancing and enhancing GBMs was compared using Kaplan-Meier analysis. RESULTS:= .078). CONCLUSIONS:Nonenhancing GBMs demonstrate distinct MRI features that must be recognized for early diagnosis and differentiation from nonmalignant mimics. Nonenhancing GBMs demonstrated longer overall survival compared with enhancing GBMs, though they were not statistically significant.

BACKGROUND:Astroblastomas are rare brain tumors predominantly affecting children and young adults, for which molecular subtypes and clinical management remain undefined. METHODS:We analyzed tumor samples, molecular profiles, and clinical data from 200 patients, classified as "Astroblastoma, MN1-altered" under WHO criteria, using DNA methylation profiling, DNA/RNA profiling/sequencing, and survival analyses. RESULTS:DNA methylation analyses identified 3 groups: Group A (n = 143, characterized by MN1::BEND2 fusions, predominantly supratentorial location, with striking female predominance and favorable survival); Group B (n = 37, epigenetically and transcriptionally closely related to Group A, but characterized by EWSR1::BEND2 fusions, with spinal and infratentorial locations and poor prognosis); and Group C (n = 20, epigenetically and transcriptionally distinct, characterized by MN1::CXXC5 fusions, exclusively supratentorially located, with favorable survival). Progression-free and overall survival were significantly shorter in Group B (5-year PFS 14%; 10-year OS 54%) compared to A (5-year PFS 47%; 10-year OS 89%) and C (5-year PFS 75%; 10-year OS 89%). Radiotherapy improved PFS in Group B (hazard ratio 0.25), while no clear benefit was identified for Groups A and C. CONCLUSIONS:Astroblastoma, MN1-altered, comprises 3 molecularly and clinically distinct groups, characterized by different fusion genes, including those without MN1. These new insights, including the identification of potential predictive biomarkers like 14q/16q loss, provide a framework for the development of risk-stratified therapeutic approaches. Importantly, we identified a molecularly defined high-risk group that benefits from radiation therapy. Our findings redefine Astroblastoma as a molecularly diverse tumor type, propose a refined classification, support the development of risk-adapted therapeutic strategies and provide a rational standard of care.

BACKGROUND:IDH-mutant astrocytomas are classified as WHO grade 4 in the presence of conventional high-grade histologic features and/or homozygous CDKN2A/B deletion in the 5th edition of the WHO Classification of Central Nervous System Tumour guidelines. However, work over the past decade has indicated a number of other molecular alterations that warrant consideration as potential prognostic markers. METHODS:We used univariate Kaplan-Meier and multivariate Cox proportional hazards regression analysis to evaluate the prognostic effects of homozygous CDKN2A/B deletion, CDK4 amplification, CCND2 amplification, PDGFRA amplification/mutation, PIK3R1 mutation, PIK3CA mutation, MYCN amplification, EGFR amplification/mutation, TERT promoter mutation, and grade 4 histologic features in two independent cohorts of WHO grade 2-4 IDH-mutant astrocytoma (n = 840 and n = 367). RESULTS:The presence of CDK4 amplification, CCND2 amplification, PDGFRA alteration, PIK3R1 mutation, MYCN amplification, and EGFR alteration were each associated with reduced overall survival compared to WHO grade 2/3 astrocytomas without these molecular features. 17.7% (148/837) of otherwise grade 2/3 astrocytomas had one or more of these molecular criteria, with resulting intermediate clinical outcome in terms of overall survival (median survival of 67.3-82.0 months) compared to grade 2/3 astrocytomas without these molecular features (median survival of 135.0-140.7 months) and grade 4 astrocytomas (median survival of 35.3-45.0 months). CONCLUSIONS:The presence of CDK4, CCND2, PDGFRA, PIK3R1, MYCN, and EGFR alterations result in an intermediate patient survival in IDH-mutant astrocytoma. Adding these molecular alterations should be considered in future diagnostic classification systems to improve stratification of high-risk patients.

Spinal tumor surgery requires rapid tissue diagnosis to guide surgical decisions and further treatment strategies, yet current intraoperative methods are time-intensive and require specialized expertise. No AI systems exist for real-time spinal tumor classification during surgery. We developed SpineXtract, the first AI-powered system for rapid intraoperative spinal tumor diagnosis using stimulated Raman histology (SRH) - a label-free Raman spectromics imaging technique without tissue processing available during surgery. We created a transformer-based classifier optimized for spinal tissue characteristics to identify common tumor types: meningioma, schwannoma, ependymoma, and metastasis. The system was tested in an international, multicenter, simulated, single-arm study using existing SRH datasets (44 patients, 142 slide-images) from three international institutions, with final pathological diagnosis as reference standard. SpineXtract achieved a 92.9% macro-average balanced accuracy (95% CI: 85.5-98.2) within 5 minutes (tumor-specific accuracy range, 84.2-98.6%), while providing quantitative microscopic feedback for granular tissue analysis. Performance remained consistent across institutions (macro balanced accuracy 91.4-92.0%) and outperformed existing brain tumor classifiers by 15.6%. Our results demonstrate clinical applicability, enabling rapid intraoperative diagnosis with performance exceeding current methods, potentially transforming intraoperative diagnostic workflows in spinal tumor surgery.

BACKGROUND:Glioblastoma intramedullary spinal cord metastasis (GISCM) is a rare sequela of high-grade astrocytoma and glioblastoma multiforme (GBM). Discrete intramedullary spinal cord metastases are less common than spinal leptomeningeal spread and may follow a more indolent course. Once identified as GISCM, palliative maximal safe resection of the tumor may be considered to alleviate neurological symptoms. Reports describing the surgical management of these rare lesions, including the use of emerging technologies that may aid in maximal safe resection, are sparse. A further understanding is also required regarding the course of disease and factors contributing to mortality in GISCM. METHODS:We reviewed the intraoperative management and clinical course of three patients treated for GISCM at our institution between 2015 and 2024. We additionally conducted a PRISMA-guided systematic literature review of PubMed Central, MEDLINE, and Bookshelf databases through May 26th, 2025, including original patient reports of GISCM from cranial astrocytoma or GBM. The disease course, management strategies, and causes of mortality in previously reported cases were analyzed. RESULTS:Our institutional cohort had a mean time to spinal metastasis of 26.2 months from diagnosis of cranial disease (range 17.5-40.5 months), with a mean survival of 9.2 months following maximal safe resection of extramedullary components (range 7-12 months). In two cases, intraoperative Stimulated Raman Histology (SRH) was employed to facilitate the rapid identification of metastatic GBM, thereby influencing surgical strategy. In one case, 5-aminolevulinic acid (5-ALA) was used to differentiate between tumor and spinal cord parenchyma, facilitating maximal safe debulking without neurological injury. Literature review identified 38 prior reported cases of GISCM, with a median time to spinal diagnosis of 11.0 months and a median survival of 3.5 months thereafter. The cause of death in the review cohort often involved multiple factors, and when analyzed for contributing factors to death, 38.7% involved cranial progression, 38.7% involved progression of spinal disease, and 29.0% involved medical complications. Gait ataxia at presentation was associated with shorter survival in review patients, potentially reflecting advanced disease with extramedullary cord compression. CONCLUSION/CONCLUSIONS:GISCM represents an entity distinct from leptomeningeal disease and may be managed in conjunction with recurrent cranial disease. Surgical debulking is a technically feasible strategy that can be safely facilitated using tools employed in the management of intracranial GBM, facilitating maximal safe resection without compromising survival.

Standard techniques for detecting genomic rearrangements in formalin-fixed paraffin-embedded (FFPE) biopsies have important limitations. We performed FFPE-compatible Hi-C on 44 clinical biopsies comprising large B cell lymphomas (n = 18), plasma cell neoplasms (n = 14), and other diverse lymphoid cancers, identifying consistent topological differences between malignant B cell and plasma cell states. Hi-C detected expected oncogene rearrangements at high concordance with fluorescence in situ hybridization (FISH) and supported enhancer hijacking in recurrent rearrangements of BCL2, CCND1, and MYC plus unanticipated variants involving homologous loci. Hi-C identified unanticipated non-coding rearrangements involving PD-1 ligand genes and other loci of potential therapeutic relevance, distinguished between functionally divergent classes of BCL6 rearrangements, and provided topological information supporting interpretation of variant MYC rearrangements. Hi-C revealed disease-selective MYC locus topological features that correlated with disease-selective MYC locus enhancers and rearrangement breakpoint distributions. FFPE-compatible Hi-C detects oncogene rearrangements and their topological consequences at genome-wide scale, finding clinically relevant drivers missed by standard approaches.