Clinical utility of whole-genome DNA methylation profiling as a primary molecular diagnostic assay for central nervous system tumors-A prospective study and guidelines for clinical testing.

Background: Central nervous system (CNS) cancer is the 10th leading cause of cancer-associated deaths for adults, but the leading cause in pediatric patients and young adults. The variety and complexity of histologic subtypes can lead to diagnostic errors. DNA methylation is an epigenetic modification that provides a tumor type-specific signature that can be used for diagnosis. Methods: We performed a prospective study using DNA methylation analysis as a primary diagnostic method for 1921 brain tumors. All tumors received a pathology diagnosis and profiling by whole genome DNA methylation, followed by next-generation DNA and RNA sequencing. Results were stratified by concordance between DNA methylation and histopathology, establishing diagnostic utility. Results: Of the 1602 cases with a World Health Organization histologic diagnosis, DNA methylation identified a diagnostic mismatch in 225 cases (14%), 78 cases (5%) did not classify with any class, and in an additional 110 (7%) cases DNA methylation confirmed the diagnosis and provided prognostic information. Of 319 cases carrying 195 different descriptive histologic diagnoses, DNA methylation provided a definitive diagnosis in 273 (86%) cases, separated them into 55 methylation classes, and changed the grading in 58 (18%) cases. Conclusions: DNA methylation analysis is a robust method to diagnose primary CNS tumors, improving diagnostic accuracy, decreasing diagnostic errors and inconclusive diagnoses, and providing prognostic subclassification. This study provides a framework for inclusion of DNA methylation profiling as a primary molecular diagnostic test into professional guidelines for CNS tumors. The benefits include increased diagnostic accuracy, improved patient management, and refinements in clinical trial design.

Clinical Validation of Stimulated Raman Histology for Rapid Intraoperative Diagnosis of Central Nervous System Tumors.

Stimulated Raman histology (SRH) is an ex vivo optical imaging method that enables microscopic examination of fresh tissue intraoperatively. The conventional intraoperative method uses frozen section analysis, which is labor and time intensive, introduces artifacts that limit diagnostic accuracy, and consumes tissue. SRH imaging allows rapid microscopic imaging of fresh tissue, avoids tissue loss, and enables remote telepathology review. This improves access to expert neuropathology consultation in both low- and high-resource practices. We clinically validated SRH by performing a blinded, retrospective two-arm telepathology study to clinically validate SRH for telepathology at our institution. Using surgical specimens from 47 subjects, we generated a data set composed of 47 SRH images and 47 matched whole slide images (WSIs) of formalin-fixed, paraffin-embedded tissue stained with hematoxylin and eosin, with associated intraoperative clinicoradiologic information and structured diagnostic questions. We compared diagnostic concordance between WSI and SRH-rendered diagnoses. Also, we compared the 1-year median turnaround time (TAT) of intraoperative conventional neuropathology frozen sections with prospectively rendered SRH-telepathology TAT. All SRH images were of sufficient quality for diagnostic review. A review of SRH images showed high accuracy in distinguishing glial from nonglial tumors (96.5% SRH vs 98% WSIs) and predicting final diagnosis (85.9% SRH vs 93.1% WSIs). SRH-based diagnosis and WSI-permanent section diagnosis had high concordance (κ = 0.76). The median TAT for prospectively SRH-rendered diagnosis was 3.7 minutes, approximately 10-fold shorter than the median frozen section TAT (31 minutes). The SRH-imaging procedure did not affect ancillary studies. SRH generates diagnostic virtual histologic images with accuracy comparable to conventional hematoxylin and eosin-based methods in a rapid manner. Our study represents the largest and most rigorous clinical validation of SRH to date. It supports the feasibility of implementing SRH as a rapid method for intraoperative diagnosis complementary to conventional pathology laboratory methods.

De Novo Glioblastoma Masqueraded within a Hemispheric Dural Meningiomatosis: Rare Imaging Findings and Rationale for Two-Staged Resection.

Introduction Collision tumors present as histologically different juxtaposed neoplasms within the same anatomical region, independent of the adjacent cell population. De novo intracranial collision tumors involving metachronous primary brain neoplasms alongside dural meningiomatosis are not well documented in the literature. Clinical Presentation We present staged surgical management of a 72-year-old female with known left hemispheric stable dural-based convexity mass lesions over 10 years and new-onset expressive aphasia and headaches. MRI had revealed left supratentorial dural-based enhanced masses consistent with en plaque meningiomatosis. Embolization angiography showed an unusual tumor blush from an aberrant branch of anterior cerebral artery suggesting a deeper focal intra-axial nature; a stage 1 craniotomy for dural-based tumor resection was completed with diagnosis of a meningioma (WHO grade 1). Intraoperatively, a distinct intra-axial deep discrete lesion was verified stereotactically, concordant with the location of tumor blush. The patient made a complete neurological recovery from a transient postoperative supplemental motor area syndrome in a week. Subsequent postoperative follow-up showed worsening of right hemiparesis and MRI showed an increase in residual lesion size and perilesional edema, which prompted a stage 2 radical resection of a glioblastoma, WHO grade 4. She improved neurologically after surgery with steroids and physical therapy. At 15 months following adjuvant therapy, she remains neurologically intact throughout the postoperative course, with no recurrent tumor on MRI. Conclusion A de novo glioblastoma presented as a masquerading lesion within hemispheric convexity meningiomatosis in an elderly patient with no prior radiation/phakomatosis, inciting a non-causal juxtapositional coexistence. The authors highlight rare pathognomonic angiographic findings and the rationale for two-staged resections of these collision lesions that led to excellent clinicoradiological outcome.