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.

Carotid Intimal Sarcoma Presenting as Large Vessel Occlusion and Diagnosed by Embolus Histopathology: Case Report.

Objective: The objective of this study was to present the clinical, histopathologic, and radiographic findings of a unique case of intimal sarcoma (IS) embolus presenting as a large vessel occlusion causing an ischemic stroke without a detectable primary tumor site. Methods: Extensive examinations, multimodal imaging, laboratory testing, and histopathologic analysis were used in evaluation. Results: We report the case of a patient who presented with acute embolic ischemic stroke and was found to have IS based on a histopathologic evaluation of his embolectomy specimen. Subsequent comprehensive imaging studies failed to detect a primary tumor site. Multidisciplinary interventions including a course of radiotherapy were performed. The patient died of recurrent multifocal strokes 92 days after diagnosis. Discussion: Meticulous histopathologic analysis should be conducted on cerebral embolectomy specimens. Histopathology may be useful in diagnosing IS.

Metastases to Meningiomas: A Comprehensive Literature Review Including Mediating Proteins.

Approximately 5-15% of solid tumors metastasizing to the central nervous system metastasize to the leptomeninges. Less common, is metastasis to leptomeningeal meningiomas. These are primarily carcinomas of the breast and lung. Awareness of this phenomenon is critical to the evaluation of meningiomas, especially since the metastases may be the first indication of an occult tumor elsewhere in the body. Lack of clear demarcation between the metastasis and meningioma parenchyma, as well as histological features similar to the meningioma, may hinder recognition. The mechanisms underlying metastases anchoring and spread along the leptomeninges are not established. However, several cell adhesion molecules are thought to contribute to this phenomenon. E cadherin is a cell adhesion molecule present in meningioma cells. Binding to endothelium by adhesion molecules such as ICAM, B1 integrin, P-selectin, PECAM-1, CXCL12 and SDF-1 have also been proposed as part of the mechanisms underlying breast carcinoma metastases. In addition, the leptomeninges and meningiomas express mesothelin that acts as an anchoring protein coupling with mucin-16. Consequently, metastatic tumor cell mucin and mesothelin may also facilitate the anchoring of metastases to meningiomas.

Brain Histopathology of Adult Decedents After Extracorporeal Membrane Oxygenation.

OBJECTIVE: To test the hypothesis that brain injury is more common and varied in patients receiving extracorporeal membrane oxygenation (ECMO) than radiographically observed, we described neuropathology findings of ECMO decedents and associated clinical factors from 3 institutions. METHODS: We conducted a retrospective multicenter observational study of brain autopsies from adult ECMO recipients. Pathology findings were examined for correlation with demographics, clinical data, ECMO characteristics, and outcomes. RESULTS: Forty-three decedents (n = 13 female, median age 47 years) received autopsies after undergoing ECMO for acute respiratory distress syndrome (n = 14), cardiogenic shock (n = 14), and cardiac arrest (n = 15). Median duration of ECMO was 140 hours, most decedents (n = 40) received anticoagulants; 60% (n = 26) underwent venoarterial ECMO, and 40% (n = 17) underwent venovenous ECMO. Neuropathology was found in 35 decedents (81%), including microhemorrhages (37%), macrohemorrhages (35%), infarctions (47%), and hypoxic-ischemic brain injury (n = 17, 40%). Most pathology occurred in frontal neocortices (n = 43 occurrences), basal ganglia (n = 33), and cerebellum (n = 26). Decedents with hemorrhage were older (median age 57 vs 38 years, p = 0.01); those with hypoxic brain injury had higher Sequential Organ Failure Assessment scores (8.0 vs 2.0, p = 0.04); and those with infarction had lower peak Paco2 (53 vs 61 mm Hg, p = 0.04). Six of 9 patients with normal neuroimaging results were found to have pathology on autopsy. The majority underwent withdrawal of life-sustaining therapy (n = 32, 74%), and 2 of 8 patients with normal brain autopsy underwent withdrawal of life-sustaining therapy for suspected neurologic injury. CONCLUSION: Neuropathological findings after ECMO are common, varied, and associated with various clinical factors. Further study on underlying mechanisms is warranted and may guide ECMO management.

Evaluation of fluid channels in the human dura and superior sagittal sinus in older patients.

AIM: Recent studies suggest the leptomeninges may have a lymphatic drainage system connecting the subarachnoid space with dorsal cervical lymph nodes. The distribution and histologic features of any dural "lymphatics" has not been established or extensively studied. MATERIAL AND METHODS: Duras from 113 patients were evaluated including 96 formalin-fixed dural samples (mean age 62 years) collected from 2010 to 2015. An additional 17 samples were collected from Alzheimer's disease (AD) patients (mean age 81) autopsied between 1995 and 1997. Two, 2 cm length coronal sections were taken from mid-convexity dura, parallel to the middle meningeal artery, 3-5 cm below and perpendicular to the superior sagittal sinus (SSS). Sections of twenty-two cases were also taken of the SSS and peri-SSS dura. To screen for possible lymphatics, 52 dural and 22 SSS samples from these cases were evaluated with CD31 and podoplanin (D240) immunohistochemistry. RESULTS: Numerous unlined microscopic channels were found in 101 of 113 (89 %). In non-AD duras, 86 of 92 (93 %) had numerous channels. Duras with AD had significantly less channels i.e. 15 of 21(71 %, P = 0.048). None of the channels had lymphocytes, or neutrophils in their lumena. In the superior sagittal sinus, 9 of 9 non-AD and 12/13 AD SSS duras had fluid channels. Congo red stains revealed no amyloid-like material in the AD duras. Immunohistochemically, CD31 was not found in fluid channels but was in endothelium in 36 of 36 non-AD duras and in most blood vessels including 16 of 16 AD patients. Seven of 36 (19 %) with non-AD and 1 of 16 (6%) with AD had podoplanin in thin walled vessels suggestive of lymphatics but none showed staining in fluid channels. CONCLUSIONS: Unlined fluid channels are present in the dura but not clearly lymphatic.

Basophilic invasion in the neurohypophysis is increased in patients with Alzheimer's disease.

PURPOSE: The prevalence of basophilic invasion (BI) and degenerative changes in the neurohypophysis of humans with neurodegenerative disease is not established. MATERIALS AND METHODS: We evaluated 122 pituitary glands reviewed at autopsy including 45 with Alzheimer's disease (AD) Braak and Braak stage V or VI, 18 with Lewy body disease (LBD), and 59 age-matched controls for BI. In addition, pituitary glands from 51 patients including 25 patients with AD and 18 aged-matched controls were studied with a periodic acid Schiff (PAS) stain and immunohistochemistry with a polyclonal antibody to nestin. Samples were graded as negative (0) or positive (1). RESULTS: BI was seen in 35 of 45 patients with AD (0.78 ± 0.06 mean and SE: 78%) and was significantly higher than 30 of 59 controls (0.51 ± 0.07; 51%) (p = 0.0236). BI was seen in 7 of 18 patients with LBD (0.39 ± 0.12; 39%) compared to controls (p = 0.387). BI was also significantly higher in AD compared to LBD (p = 0.0001). Nestin immunoreactivity was detected in the neurohypophysis of all patients. Definite nestin was not found in BI but was seen in Herring body-like structures, in pituicytes and axons. Phospho-τ-immunoreactive Herring bodies were seen in 65% with AD but phospho-τ-immunoreactive neurofibrillary tangles were not found. CONCLUSION: BI is increased in AD compared to controls or LBD but not associated with nestin immunoreactivity. The significance and role of BI as a marker for AD warrants additional study.

The correlation of fractional anisotropy parameters with Ki-67 index, and the clinical implication in grading of non-enhancing gliomas and neuronal-glial tumors.

PURPOSE: To investigate the correlation between the FA parameters and Ki-67 labeling index, and their diagnostic performance in grading supratentorial non-enhancing gliomas and neuronal-glial tumors (GNGT). METHODS: This institutional review board-approved, Health Insurance Portability and Accountability (HIPAA) compliant retrospective study enrolled 35 patients, including 19 with low grade GNGT and 16 with high grade GNGT. The mean FA, maximal FA and mean maximal FA values derived from diffusion tensor imaging were measured. The correlation between the FA parameters and the Ki-67 labeling index was assessed by Spearman rank test. The receiver operating characteristic curve analysis and multivariate logistic regression analysis were performed to detect the optimal imaging parameters in grading GNGT. RESULTS: The three FA parameters of low grade GNGT were significantly lower than the high grade GNGT (p < 0.001). The mean FA, maximal FA and mean maximal FA had significant positive correlation with Ki-67 labeling index (p = 0.001, p < 0.001, p < 0.001 respectively). The maximal FA showed a higher sensitivity and specificity in grading of non-enhancing GNGT with specificity of 78.9%, sensitivity of 100.0%, respectively. CONCLUSIONS: The FA parameters correlated with Ki-67 labeling index, and were useful surrogates in preoperative grading supratentorial non-enhancing GNGT.

Imaging and clinicopathologic features of myxoid meningiomas.

AIMS: Due to their rarity, the natural history and imaging of myxoid meningiomas are not completely characterized. We analyzed clinical, imaging, and pathologic features of myxoid meningioma seen neurosurgically or in consultation between 1999 and 2018. MATERIALS AND METHODS: Archival material was searched for meningiomas designated "myxoid meningioma" at Vanderbilt University School of Medicine (1997 - 2004) and the University of Rochester School of Medicine and Dentistry (1994 - 2018). RESULTS: Our cases were predominantly in females and presented with a slow progression of symptoms. Each tumor was in the hemispheres. Magnetic resonance imaging (MRI) found most were hyperintense on T2-weighted images. Each meningioma had foci of limited meningothelial amongst extensive myxoid histology with Alcian-blue-staining stroma and EMA-immunoreactive cells. CONCLUSION: Myxoid meningiomas present with atypical imaging and histologic characteristics but are not truly metaplastic, i.e., are not differentiated to a different cell type.

Case Report of Spinal Cord Astrocytoma Presenting with Extensive Spinal Vertebral Body Destruction.

BACKGROUND: Spinal cord astrocytomas are rare lesions in adults. CASE DESCRIPTION: In this report, we present the case of a 28-year-old female patient who presented with a 2-year history of back pain and 3-month history of leg weakness. Magnetic resonance imaging of the patient showed an intrinsic expansive spinal cord lesion with extensive vertebral body destruction. Open biopsy from the tumor with limited debulking confirmed World Health Organization grade II astrocytoma. Postoperatively, the patient had mild improvement in neurologic status. CONCLUSIONS: This case represents a rare presentation of a spinal cord astrocytoma with extensive erosion of the vertebral body.

Clinicopathologic features of incidental meningiomas: A review of the literature and the University of Rochester autopsy experience.

OBJECTIVE: Features of incidental meningiomas, found at autopsy, have not been extensively reported and may offer insight into their biology and management. DESIGN: Review of the literature on unsuspected incidental antemortem and postmortem meningiomas and those from autopsies, at the University of Rochester from 2005 to 2016. RESULTS: At autopsy, incidental meningiomas were usually found in 2 - 3% of cases. Incidental meningiomas found by neuroimaging were more commonly seen over the convexities, although our findings suggest that parasellar meningiomas are common. They are and are more commonly in males, WHO grade I, and fibrous or meningothelial, but our findings suggest psammomatous meningiomas are over-represented. CONCLUSION: Incidental meningiomas are a relatively common unrecognized tumor. They are more likely to be in males, WHO grade I, parasellar, and with calcification.
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PD-L1 expression in meningiomas.

The management of meningiomas, especially inoperable, previously irradiated recurrent and anaplastic meningiomas has been challenging due to the paucity of effective chemotherapy. Numerous studies suggest that tumor-mediated immunosuppression may facilitate progression of many malignancies. Recent identification of PD-L1 expression in some types of cancer cells has raised the possibility that its inhibition of host immunosurveillance may be part of the mechanism. Thus, tumor cell PD-L1 might be a useful new target for chemotherapy in PD-L1- bearing tumors. Several a monoclonal antibodies against PD-L1 are now in use in the management of treatment refractory or metastatic non-small cell carcinoma of the lung, metastatic renal cell carcinoma, melanoma and other malignancies. The extent of PD-L1 expression is not established in meningiomas. Depending on the degree of expression, anti-PD-L1, might be an effective treatment for meningiomas. In this study, we used a monoclonal antibody, approved by the FDA for clinical screening to evaluate PD-L1 expression in a series of 58 meningiomas including 13 with bone, brain or dural invasion. PD-L1 immunoreactivity was detected in 1 of 31 grade I, 1 of 16 grade II and 2 of 11 WHO grade III meningiomas. PD-L1 was seen in 1 grade II tumor invading brain and 1 grade III tumor invading bone but was not at sites of invasion. In each case, immunoreactivity was scored as limited. The findings suggest anti-PD-L1 therapy might be worth evaluating in a select number of positive tumors but its overall applicability may be limited.

Metastatic prostate cancer mimicking a subdural hematoma: A case report and literature review.

Occurrences of metastatic prostate cancer imitating a subdural hematoma are limited to a small number of case reports, even though prostate cancer spreads to the dura more than other types of cancer. Here, we present the case of a 64 year-old male whose prostate carcinoma's metastasis mimicked a subdural hematoma, and he suffered a middle cerebral artery stroke. Prostate cancer's high rate of progression to the dura is disproportionate to its relatively low rate of brain metastasis. Furthermore, we explore the potential molecular implications of prostate cancer's propensity to spread to the dura.

Ectopic brain tissue in the trigeminal nerve presenting as rapid-onset trigeminal neuralgia: case report.

The authors report the case of a 52-year-old man who presented with rapid-onset lancinating facial pain consistent with trigeminal neuralgia. Magnetic resonance imaging revealed a nonenhancing small lesion on the right trigeminal nerve concerning for an atypical schwannoma or neuroma. The patient underwent resection of the mass via a right retrosigmoid approach. His facial pain completely resolved immediately postoperatively and had not recurred at 6 months after surgery. The mass was consistent with normal brain tissue (neurons and glial cells) without evidence of mitoses. A final histopathological diagnosis of ectopic brain tissue with neural tissue demonstrating focal, chronic T-cell inflammation was made. The partial rhizotomy during resection was curative for the facial pain. To the authors' knowledge, this is the first report of neuroglial ectopia causing trigeminal neuralgia.

The preliminary radiogenomics association between MR perfusion imaging parameters and genomic biomarkers, and their predictive performance of overall survival in patients with glioblastoma.

The radiogenomics association of neovascularization is important for overall survival (OS) in glioblastoma patients and remains unclear. The purpose of this study is to assess the association between MR perfusion imaging derived parameters and genomic biomarkers of glioblastoma, and to evaluate their prognostic value. This retrospective study enrolled 41 patients with newly diagnosed glioblastoma. The mean and maximal relative cerebral blood volume (rCBV) ratio (rCBVmean and rCBVmax), derived from MR perfusion weighted imaging, of the enhancing tumor, as well as maximal rCBV ratio of peri-enhancing tumor area (rCBVperi-tumor) were measured. The ki-67 labeling index, mammalian target of rapamycin (mTOR) activation, epidermal growth factor receptor (EGFR) amplification, isocitrate dehydrogenase (IDH) mutation and TP53 were assessed. There was a significant correlation between rCBVmax and mTOR based on Pearson's correlations with Benjamini-Hochberg adjustment for controlling false discovery rate, p = 0.047. The rCBVperi-tumor showed significant correlation with mTOR (p = 0.0183) after adjustment of gender and EGFR status. The mean rCBVperi-tumor value of the patients with OS shorter than 14 months was significantly higher than patients with OS longer than 14 months, p = 0.002. The rCBVperi-tumor and age were the two strongest predictors of OS (hazard ratio = 1.29 and 1.063 respectively) by Cox regression analysis. This study showed that hemodynamic abnormalities of glioblastoma were associated with genomics activation status of mTOR-EGFR pathway, however, the radiogenomics associations are different in enhancing and peri-enhancing area of glioblastoma. The rCBVperi-tumor has better prognostic value than genomic biomarkers alone.

mTOR activation is increased in pilocytic astrocytomas from older adults compared with children.

BACKGROUND: Recent studies suggest that the behavior and biology of WHO grade I pilocytic astrocytomas (PAs) in adults is different than that associated with grade I PAs in children. METHODS: We evaluated Ki-67 labeling, BRAF abnormalities, isocitrate dehydrogenase R132 immunoreactivity phosphorylation (activation) of p44/42 mitogen activated protein kinase (MAPK), and mammalian target of rapamycin (mTOR) in formalin-fixed tissue from 21 adult (18 years or older, mean age 37 years) and 10 children (mean age 9.4 years) WHO grade I PAs. RESULTS: The mean Ki-67 labeling was 4.8% in adults and 3.8% in children. There was no significant difference between Ki-67 labeling in children and adults or either subgroups of adults. No differences were found in phospho p44/42MAPK in adult subgroups (18-33 years and 34 and older) compared to children. Activation/phosphorylation of mTOR was biphasic in adults being significantly lower than children in young adults but significantly higher than children in older adults (age 34 and older). CONCLUSIONS: Identifying mTOR phosphorylation/activation may represent a difference in biology and a new marker to guide chemotherapy with recently approved mTOR inhibitors.

Transforming Growth Factor Beta Family in the Pathogenesis of Meningiomas.

BACKGROUND: Meningiomas account for 36% of primary brain tumors. The pathogenesis of these tumors is not completely established, hindering development of effective chemotherapy. Numerous studies have identified alterations in several growth factors and receptor kinases that regulate meningioma growth. These may be targets for new therapies. One of these, sometimes overlooked, is the transforming growth factor beta (TGF-ß) family of proteins. Its receptors and signaling pathways play a critical role in development or progression of many forms of neoplasia. METHODS: Evidence suggesting a potential role for TGF-ß, bone morphogenetic protein, and their mediators is reviewed. RESULTS: TGF-ß inhibition of growth in normal leptomeninges may be lost in neoplasia. Moreover, loss of TGF-ß and bone morphogenetic protein signaling components and TGF-ß type III receptor likely contribute to the development and/or progression of higher grade meningiomas. CONCLUSIONS: Accumulating evidence suggests that derangement of TGF-ß family signaling contributes to development and progression of meningiomas. The TGF-ß family may represent new targets for chemotherapy and could include inhibitors of kinases activated by TGF-ß.

Late presentation of acromegaly in medically controlled prolactinoma patients.

Co-secretion of growth hormone (GH) and prolactin (PRL) from a single pituitary adenoma is common. In fact, up to 25% of patients with acromegaly may have PRL co-secretion. The prevalence of acromegaly among patients with a newly diagnosed prolactinoma is unknown. Given the possibility of mixed GH and PRL co-secretion, the current recommendation is to obtain an insulin-like growth factor-1 (IGF-1) in patients with prolactinoma at the initial diagnosis. Long-term follow-up of IGF-1 is not routinely done. Here, we report two cases of well-controlled prolactinoma on dopamine agonists with the development of acromegaly 10-20 years after the initial diagnoses. In both patients, a mixed PRL/GH-cosecreting adenoma was confirmed on the pathology examination after transsphenoidal surgery (TSS). Therefore, periodic routine measurements of IGF-1 should be considered regardless of the duration and biochemical control of prolactinoma. LEARNING POINTS: Acromegaly can develop in patients with well-controlled prolactinoma on dopamine agonists.The interval between prolactinoma and acromegaly diagnoses can be several decades.Periodic screening of patients with prolactinoma for growth hormone excess should be considered and can lead to an early diagnosis of acromegaly before the development of complications.

p38MAPK activation and DUSP10 expression in meningiomas.

The mitogen activated protein kinase (MAPK) p38MAPK has been implicated in regulation of cell proliferation and apoptosis. However, expression, activation and regulation has not been studied in meningiomas, to our knowledge. p38MAPK is regulated, in part, by dual specificity phosphatases (DUSP) that inactivate signaling by dephosphorylation. DUSP10 is also a likely participant in regulating meningioma proliferation. Five fetal and an adult human leptomeninges and 37 meningioma cultures (MC) were evaluated for DUSP10 as well as phosphorylation of its substrates p38MAPK and p44/42MAPK by western blot and DUSP10 expression by polymerase chain reaction. Platelet derived growth factor-BB (PDGF-BB), transforming growth factor B1 (TGFB1) and cerebrospinal fluid effects on DUSP10 and signaling were also studied in vitro. DUSP10 and phospho-p38MAPK and phospho-p44/42MAPK were detected in all six leptomeninges. DUSP10 was detected in 13 of 17 World Health Organization grade I, 11 of 14 grade II and four of six grade III meningiomas. Phospho-p38MAPK was detected in nine of 17 grade I, two of six grade II, and four of six grade III meningiomas. In the majority of meningiomas DUSP10 expression correlated inversely with phosphorylation of p38MAPK. PDGF-BB increased DUSP10 in MC2 and MC4 and weakly in MC3. TGFB1 increased phosphorylation of p38MAPK and caspase 3 activation. Thus p38MAPK and DUSP10 likely participate in the pathogenesis of meningiomas.