MRI Radiogenomics of Pediatric Medulloblastoma: A Multicenter Study.

Background Radiogenomics of pediatric medulloblastoma (MB) offers an opportunity for MB risk stratification, which may aid therapeutic decision making, family counseling, and selection of patient groups suitable for targeted genetic analysis. Purpose To develop machine learning strategies that identify the four clinically significant MB molecular subgroups. Materials and Methods In this retrospective study, consecutive pediatric patients with newly diagnosed MB at MRI at 12 international pediatric sites between July 1997 and May 2020 were identified. There were 1800 features extracted from T2- and contrast-enhanced T1-weighted preoperative MRI scans. A two-stage sequential classifier was designed-one that first identifies non-wingless (WNT) and non-sonic hedgehog (SHH) MB and then differentiates therapeutically relevant WNT from SHH. Further, a classifier that distinguishes high-risk group 3 from group 4 MB was developed. An independent, binary subgroup analysis was conducted to uncover radiomics features unique to infantile versus childhood SHH subgroups. The best-performing models from six candidate classifiers were selected, and performance was measured on holdout test sets. CIs were obtained by bootstrapping the test sets for 2000 random samples. Model accuracy score was compared with the no-information rate using the Wald test. Results The study cohort comprised 263 patients (mean age ± SD at diagnosis, 87 months ± 60; 166 boys). A two-stage classifier outperformed a single-stage multiclass classifier. The combined, sequential classifier achieved a microaveraged F1 score of 88% and a binary F1 score of 95% specifically for WNT. A group 3 versus group 4 classifier achieved an area under the receiver operating characteristic curve of 98%. Of the Image Biomarker Standardization Initiative features, texture and first-order intensity features were most contributory across the molecular subgroups. Conclusion An MRI-based machine learning decision path allowed identification of the four clinically relevant molecular pediatric medulloblastoma subgroups. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Chaudhary and Bapuraj in this issue.

p16 Loss and E2F/cell cycle deregulation in infant posterior fossa ependymoma.

BACKGROUND: Posterior fossa (PF) ependymomas (EPNs) in infants less than 1 year of age (iEPN-PF) have a poorer clinical outcome than EPNs in older children. While radiation therapy is the standard of care for the latter, it is withheld in infants to avoid neurotoxicity to immature brain. It is unknown whether the adverse outcome in iEPN-PFs is due to treatment differences or aggressive biology. We examined this question using molecular profiling. METHODS: Six anaplastic iEPN-PFs were subjected to transcriptomic analysis and FISH for p16 loss and gains of 1q, and compared with anaplastic PF EPNs from older children. Results were validated by immunohistochemistry (IHC). RESULTS: All six iEPN-PFs were grouped within EPN PF subgroup A (PFA). E2F targets and G2M checkpoint were identified as the most enriched gene sets in iEPN-PF, which was validated in a larger independent cohort. Accordingly, MIB-1 IHC demonstrated a higher mitotic rate in iEPN-PFs than noninfant anaplastic EPN PFA. Genetic and protein analyses demonstrated that p16 loss and low p16 protein expression is a hallmark of iEPN-PF, and that none harbored 1q gains. Kaplan-Meier analysis confirmed the poorer clinical outcome of the iEPN-PF cohort. CONCLUSIONS: Biological differences, characterized by loss of p16 expression without gains of 1q in iEPN-PFs, as well as deregulated E2F target gene transcription, are indicative of deregulated p16-CDK4/6-pRB-E2F pathway activity. This may underlie the poor clinical outcome seen in this group of iEPN-PFs, rather than the withholding of radiation therapy. Results suggest a potential actionable therapy for iEPN-PF, namely cyclin-dependent kinase 4/6 (CDK4/6) inhibitors.

Predominantly periventricular necrotizing encephalitis due to toxoplasmosis: two unusual cases and review of literature.

Ventriculitis or periventriculitis as a predominant pattern of tissue involvement in cerebral toxoplasmosis was always a rare event, even at the height of the acquired immunodeficiency syndrome (AIDS) era. Ventriculitis on premortem neuroimaging or at autopsy in AIDS patients chiefly led to differential diagnoses of primary central nervous system lymphoma (PCNSL) or cytomegalovirus ventriculitis, not toxoplasmosis. Usually cerebral toxoplasmosis manifests as multifocal, necrotizing, hemorrhagic foci of cerebritis or abscesses. We report two non-AIDS patients with cerebral toxoplasmosis that presented with predominant ventriculitis/periventriculitis, with diagnosis in both cases made only at postmortem examination. A 90-year-old woman, with autoimmune hemolytic anemia and large granular lymphocytic leukemia diagnosed 2 1/2 years prior, presented with altered mental status. Neuroimaging revealed a necrotic 5.4 × 4.6 × 3.5 cm mass extending across corpus callosum and involving both periventricular frontal horn regions, diagnosed as "butterfly" glioblastoma or possible PCNSL. No consideration of infection was raised, care was withdrawn. A 44-year-old woman with systemic lupus erythematous (SLE) treated with prednisone presented with fever and generalized malaise with rapid progression to agitation and confusion. Infection was suspected, but never confirmed on extensive premortem workup. Brain autopsy in both patients revealed severe necrotizing toxoplasmosis virtually confined to periventricular regions. In the first case, necrosis extended across the corpus callosum. Large numbers of organisms were found microscopically, reflecting their immunocompromised, and untreated, status. Cerebral toxoplasmosis should be included in the differential diagnosis when encountering patients with necrotizing ventriculitis, even in the non-AIDS immunosuppressed population.

Rapid Deployment of Whole Slide Imaging for Primary Diagnosis in Surgical Pathology at Stanford Medicine: Responding to Challenges of the COVID-19 Pandemic.

CONTEXT.­: Stanford Pathology began stepwise subspecialty implementation of whole slide imaging (WSI) in 2018 soon after the first US Food and Drug Administration approval. In 2020, during the COVID-19 pandemic, the Centers for Medicare & Medicaid Services waived the requirement for pathologists to perform diagnostic tests in Clinical Laboratory Improvement Amendments (CLIA)-licensed facilities. This encouraged rapid implementation of WSI across all surgical pathology subspecialties. OBJECTIVE.­: To present our experience with validation and implementation of WSI at a large academic medical center encompassing a caseload of more than 50 000 cases per year. DESIGN.­: Validation was performed independently for 3 subspecialty services with a diagnostic concordance threshold above 95%. Analysis of user experience, staffing, infrastructure, and information technology was performed after department-wide expansion. RESULTS.­: Diagnostic concordance was achieved in 96% of neuropathology cases, 100% of gynecologic pathology cases, and 98% of immunohistochemistry cases. After full implementation, 8 high-capacity scanners were operational, with whole slide images generated on greater than 2000 slides per weekday, accounting for approximately 80% of histologic slides at Stanford Medicine. Multiple modifications in workflow and information technology were needed to improve performance. Within months of full implementation, most attending pathologists and trainees had adopted WSI for primary diagnosis. CONCLUSIONS.­: WSI across all surgical subspecialities is achievable at scale at an academic medical center; however, adoption required flexibility to adjust workflows and develop tailored solutions. WSI at scale supported the health and safety of medical staff while facilitating high-quality patient care and education during COVID-19 restrictions.

Machine Assist for Pediatric Posterior Fossa Tumor Diagnosis: A Multinational Study.

BACKGROUND: Clinicians and machine classifiers reliably diagnose pilocytic astrocytoma (PA) on magnetic resonance imaging (MRI) but less accurately distinguish medulloblastoma (MB) from ependymoma (EP). One strategy is to first rule out the most identifiable diagnosis. OBJECTIVE: To hypothesize a sequential machine-learning classifier could improve diagnostic performance by mimicking a clinician's strategy of excluding PA before distinguishing MB from EP. METHODS: We extracted 1800 total Image Biomarker Standardization Initiative (IBSI)-based features from T2- and gadolinium-enhanced T1-weighted images in a multinational cohort of 274 MB, 156 PA, and 97 EP. We designed a 2-step sequential classifier - first ruling out PA, and next distinguishing MB from EP. For each step, we selected the best performing model from 6-candidate classifier using a reduced feature set, and measured performance on a holdout test set with the microaveraged F1 score. RESULTS: Optimal diagnostic performance was achieved using 2 decision steps, each with its own distinct imaging features and classifier method. A 3-way logistic regression classifier first distinguished PA from non-PA, with T2 uniformity and T1 contrast as the most relevant IBSI features (F1 score 0.8809). A 2-way neural net classifier next distinguished MB from EP, with T2 sphericity and T1 flatness as most relevant (F1 score 0.9189). The combined, sequential classifier was with F1 score 0.9179. CONCLUSION: An MRI-based sequential machine-learning classifiers offer high-performance prediction of pediatric posterior fossa tumors across a large, multinational cohort. Optimization of this model with demographic, clinical, imaging, and molecular predictors could provide significant advantages for family counseling and surgical planning.

Neonatal Onset Interstitial Lung Disease as a Primary Presenting Manifestation of Mucopolysaccharidosis Type I.

We describe two cases of neonatal onset interstitial lung disease eventually diagnosed as mucopolysaccharidosis type I (MPS I). In both cases, evaluation led to lung biopsy, pathology review, and identification of glycogen deposition. Pulmonary interstitial glycogenosis (PIG) was considered as a clinical diagnosis in case one; however, further review of electron microscopy (EM) was more consistent with MPS I rather than PIG. Both cases were confirmed to have MPS I by enzyme and molecular analysis. Neonatal interstitial lung disease is an atypical presentation for MPS I which is likely under-recognized. Diagnosis through clinical guidelines and a multidisciplinary approach had a major impact on patient management. The diagnosis of MPS I prompted timely initiation of enzyme replacement therapy (ERT) and the patients ultimately underwent hematopoietic stem cell transplantation (HSCT) to improve symptomatic outcomes. In addition to treatment, immediate precautionary recommendations were made to avoid potentially catastrophic outcomes associated with cervical instability. These cases add to the clinical spectrum of MPS I in the newborn period. They further illustrate the difficulties in early recognition of the disease, and importance of a definitive diagnosis of MPS I in infants with interstitial lung disease.

Massive Intradural Chondroma Masquerading as Lower Body Parkinsonism.

Intracranial chondromas of the dural convexity are exceedingly rare with less than 30 reported in the literature to date. We report a massive intradural convexity chondroma in a patient initially thought to have a frontal gait neurodegenerative disorder. This large tumor required a complex, piecemeal surgical resection due to the dense, fibrous nature of the tumor and the proximity of crucial structures. The patient had complete resolution of her preoperative symptoms after surgical excision.

Characterization of 2 Novel Ependymoma Cell Lines With Chromosome 1q Gain Derived From Posterior Fossa Tumors of Childhood.

Ependymoma (EPN) is a common brain tumor of childhood that, despite standard surgery and radiation therapy, has a relapse rate of 50%. Clinical trials have been unsuccessful in improving outcome by addition of chemotherapy, and identification of novel therapeutics has been hampered by a lack of in vitro and in vivo models. We describe 2 unique EPN cell lines (811 and 928) derived from recurrent intracranial metastases. Both cell lines harbor the high-risk chromosome 1q gain (1q+) and a derivative chromosome 6, and both are classified as molecular group A according to transcriptomic analysis. Transcriptional enrichment of extracellular matrix-related genes was a common signature of corresponding primary tumors and cell lines in both monolayer and 3D formats. EPN cell lines, when cultured in 3D format, clustered closer to the primary tumors with better fidelity of EPN-specific transcripts than when grown as a monolayer. Additionally, 3D culture revealed ependymal rosette formation and cilia-related ontologies, similar to in situ tumors. Our data confirm the validity of the 811 and 928 cell lines as representative models of intracranial, posterior fossa 1q+ EPN, which holds potential to advance translational science for patients affected by this tumor.

Histopathologic features of intracranial vascular involvement in fibromuscular dysplasia, ehlers-danlos type IV, and neurofibromatosis I.

Nonatherosclerotic cerebrovascular arteriopathies share epidemiologic and clinical features, but few studies directly compare histologic features of the intracranial vasculature. We studied 3 adult autopsy cases of fibromuscular dysplasia in patients who died of basilar artery aneurysm rupture, vertebral artery dissection, or Moyamoya syndrome. Fibromuscular dysplasia was only identified when multiple sections (optimally of the entire circle of Willis) were examined by microscopy. A fourth case of a massive subcutaneous scalp cirsoid aneurysm with classic "string-of-beads" gross appearance and microscopic medial hypertrophy was also compatible with fibromuscular dysplasia. Intracranial vascular changes were compared with those in 1 patient with Ehlers-Danlos type IV (vascular type) and in 4 patients with neurofibromatosis I. Distinct histologic features and distributions of cerebral vessel abnormalities were observed in all 3 disorders. Disordered collagen within the muscularis (identified using picrosirius red histochemistry) was confined to fibromuscular dysplasia; fibrocellular smooth muscle intimal proliferation within parenchymal cerebral arteries was confirmed using smooth muscle actin immunohistochemistry in the Moyamoya case; the patient with Ehlers-Danlos type IV showed aneurysm formation and eccentric intimal thickening of circle of Willis vessels but no obvious abnormalities of the muscularis; and neurofibromatosis I cases showed extensive leptomeningeal smaller-caliber arterial disease that particularly affected the spinal cord. Thus, cranial/intracranial artery involvement is not rare in these conditions but requires extensive sampling to identify the range of features.

Massive dissemination from spinal cord gangliogliomas negative for BRAF V600E: report of two rare adult cases.

OBJECTIVES: Metastatic leptomeningeal spread from spinal cord gangliogliomas (GGs) is exceedingly rare. METHODS: Two adult women, aged 27 and 51 years, died of massive disseminations of cervicothoracic GGs 4 and 6 years, respectively, after initial diagnoses; full autopsies were performed. BRAF status was assessed by VE1 immunohistochemistry (IHC), Sanger sequencing, and a single-nucleotide base extension assay (SNaPshot, Applied Biosystems, Princeton, NJ). RESULTS: The 27-year-old underwent two biopsies, chemotherapy, radiation, and ventriculoperitoneal shunt placement; she developed craniospinal and peritoneal dissemination. Autopsy confirmed shunt-mediated peritoneal metastases, microscopic bone marrow involvement, and profuse spinal and supratentorial leptomeningeal and parenchymal spread. The 51-year-old underwent two resections, radiation, and chemotherapy and developed pancytopenia with biopsy-proven bony metastases 15 months before death. Autopsy demonstrated leptomeningeal, subpial, and subependymal metastases. The tumors in both primary and metastatic sites were BRAF negative by VE1 IHC and two different mutational analyses. This compared with negative BRAF results for an additional four nonmetastatic adult nonsupratentorial GGs and in our study. CONCLUSIONS: We document two rare cases of massively metastatic spinal cord GGs in adult patients who were negative for BRAF V600E mutations via multiple methods.