Faculty Bibliography

Dysembryoplastic neuroepithelial tumors (DNTs) are low-grade glioneuronal tumors with FGFR1 alterations. They show significant histologic and molecular overlap with other glioneuronal tumors, complicating diagnosis. We analyzed 44 tumors that were either classified as DNT by DNA methylation (n = 37), or were diagnosed histologically as DNT but did not classify as DNT by DNA methylation (n = 7). 13/37 (35%) DNT-classifying tumors were histologically diagnosed as DNTs. High-confidence DNTs (score >0.9, 23 cases, 62%) demonstrated variable histology, most frequently DNT (39%), oligodendroglioma, and ganglioglioma and most frequently harbored FGFR1 alterations. Lower-confidence DNTs (score < 0.9, 14 cases, 38%) showed greater heterogeneity; their histologic diagnoses included papillary glioneuronal tumor, extraventricular neurocytoma, and pilocytic astrocytoma. Tumors with low confidence score exhibited diverse molecular alterations including BRAF V600E mutations, PDGFRA amplification, or multiple gene fusions. Among 7 histologically diagnosed DNTs that did not classify as DNT by methylation, most grouped with the myxoid glioneuronal PDGFRA-mutant class despite lacking canonical PDGFRA mutations. Thus, DNTs with high confidence scores are relatively homogenous but DNTs with low methylation confidence scores are heterogenous, highlighting the importance of integrated molecular profiling. Our findings also suggest that the myxoid glioneuronal tumor methylation class may require further classification of underlying drivers.

Sellar region neurocytoma (SELN) is a rare neoplasm whose relationship to other neurocytomas within the central nervous system (CNS) has remained unclear. Prior reports have variably classified SELN as a variant of extraventricular neurocytoma (EVN), while immunohistochemical and ultrastructural studies have suggested a hypothalamic origin. Here, we performed unsupervised clustering of DNA methylation data across a large pan-cancer reference set and identified SELN (n = 20) as distinct from other neurocytomas and regional mimics, as well as clustering with neuroendocrine tumors from other organ sites. SELN exhibited a CIMP-like phenotype, TTF1 negativity (0/8), and AVP (vasopressin) promoter hypomethylation, implicating a magnocellular hypothalamic cell of origin. In evaluable cases, a neuronal/neuroendocrine immunophenotype was observed (synaptophysin 8/8, chromogranin A 5/5) with absent pituitary transcription factor expression (PIT1 and TPIT negative 0/4). DNA sequencing (n = 5) and RNA-based fusion profiling (n = 4) did not detect recurrent mutations or gene fusions, respectively. Patients often presented with visual disturbances or headaches and spanned pediatric and older age groups (median 42 years, range 12.5-75), with no sex predilection. Despite locally aggressive imaging features in some cases (cavernous sinus invasion, carotid encasement, hydrocephalus), disease-free survival (n = 13) was comparable to central neurocytoma, with no disease-related deaths during the limited follow-up. Together, these findings support SELN as a molecularly distinct hypermethylated neuroendocrine-like epitype and clinicopathologic entity.

Lung adenocarcinoma (LUAD) remains a leading cause of cancer-related mortality. While for Stage IA LUAD surgery is often curative, recurrence rates remain significant. Liquid biopsy enables monitoring residual disease and predicts recurrence, however utility in Stage IA LUAD is not well-established. Tumor-informed whole genome sequencing (WGS) represents a highly sensitive liquid biopsy method for the analysis of circulating-tumor cell-free DNA (ctDNA) without designing and maintaining patient-specific probes. We aimed to determine the prognostic value of genome-wide tumor-informed minimal residual disease (MRD) monitoring in Stage IA NSCLC using WGS of ctDNA. WGS was performed on 42 patients with Stage IA NSCLC. Tumor was sequenced at 40x and germline DNA and plasma derived ctDNA at 20x and patient specific mutational signatures were developed from the tumor-normal comparison and applied to ctDNA WGS at each time point using AI-supported pattern recognition algorithm. ctDNA results were compared with clinical recurrence. WGS ctDNA was able to predict recurrence with 0.75 sensitivity and 0.83 specificity, with median 16.7 months lead time compared to clinical or imaging recurrence. ctDNA WGS was able to distinguish between a second primary and recurrence in histologically or clinically challenging cases. Whole genome sequencing of ctDNA can predict recurrence in the earliest clinical stage of NSCLC, identifying patients who will recur, and providing information to help guide radiological follow-up and adjuvant therapy.

IMPORTANCE/UNASSIGNED:Chordoma is a rare malignant bone tumor with high local recurrence, metastatic spread in 40% to 60% of patients over the disease course, and significant morbidity. Because of its rarity, anatomical complexity, and prolonged natural history, high-quality evidence to guide management is limited. International consensus guidelines for localized chordoma were first published in 2015; however, advances in pathology, imaging, surgery, radiotherapy, and supportive care since then necessitate updated multidisciplinary recommendations. OBJECTIVE/UNASSIGNED:To update and expand the 2015 consensus recommendations on the diagnosis, treatment, and follow-up of pediatric and adult patients with primary, localized chordoma. EVIDENCE REVIEW/UNASSIGNED:In June 2025, a meeting of the Global Chordoma Consensus Group was held in Milan, Italy, that included experts from all relevant specialties as well as patient representatives. A comprehensive literature review guided structured discussions on the management of primary localized disease. Levels of evidence and grades of recommendation were assigned. FINDINGS/UNASSIGNED:A total of 305 articles were included in the literature review. Management strategies were stratified by anatomical site (skull base, mobile spine, and sacrum). The central principal of care was treatment at experienced, multidisciplinary centers, with maximally safe surgery followed by high-dose, highly conformal radiotherapy. Guidance was provided on diagnosis, surgical approaches, and radiotherapy planning for each anatomical site. Systemic therapy options; long-term, risk-adapted follow-up; and supportive, palliative, and rehabilitative care were also addressed. CONCLUSIONS AND RELEVANCE/UNASSIGNED:This global consensus statement provided updated multidisciplinary guidance for the management of primary, localized chordoma. It aimed to harmonize clinical practice, support shared decision-making, and identify priorities for future collaborative research in this rare and challenging disease.

Papillary renal neoplasm with reverse polarity (PRNRP) has been proposed as a distinct subtype of renal cell neoplasm with recurrent KRAS mutations and indolent behavior. However, its epigenetic landscape is poorly understood. In this study, 12 PRNRPs and a PRNRP initially diagnosed as "papillary adenoma" were analyzed. All 13 cases underwent targeted next-generation sequencing for driver mutations. Eleven PRNRPs were profiled using the Illumina MethylationEPIC array and compared with a reference cohort of 71 common renal cell tumors. KRAS mutations were identified in 12 of 13 (92%) cases of PRNRP. Copy-number analysis from methylation profiling showed that 9 of 11 (82%) PRNRPs lacked copy-number changes. Two cases showed a focal loss of chromosome 8 and a gain of chromosome 16, respectively. Unsupervised clustering based on methylation data showed that PRNRPs form a distinct epigenetic group, separate from papillary renal cell carcinomas (pRCCs) and other major renal tumors, but with the closest affinity to clear cell papillary renal cell tumors. In addition, DNA methylation analysis suggested PRNRP may arise from the distal nephron, in contrast to pRCC, which appears to recapitulate proximal tubules. These findings support PRNRP as a subtype of renal cell neoplasm with a distinct epigenetic signature.

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.