Information theory approaches to improve glioma diagnostic workflows in surgical neuropathology.

AIMS: Resource-strained healthcare ecosystems often struggle with the adoption of the World Health Organization (WHO) recommendations for the classification of central nervous system (CNS) tumors. The generation of robust clinical diagnostic aids and the advancement of simple solutions to inform investment strategies in surgical neuropathology would improve patient care in these settings. METHODS: We used simple information theory calculations on a brain cancer simulation model and real-world data sets to compare contributions of clinical, histologic, immunohistochemical, and molecular information. An image noise assay was generated to compare the efficiencies of different image segmentation methods in H&E and Olig2 stained images obtained from digital slides. An auto-adjustable image analysis workflow was generated and compared with neuropathologists for p53 positivity quantification. Finally, the density of extracted features of the nuclei, p53 positivity quantification, and combined ATRX/age feature was used to generate a predictive model for 1p/19q codeletion in IDH-mutant tumors. RESULTS: Information theory calculations can be performed on open access platforms and provide significant insight into linear and nonlinear associations between diagnostic biomarkers. Age, p53, and ATRX status have significant information for the diagnosis of IDH-mutant tumors. The predictive models may facilitate the reduction of false-positive 1p/19q codeletion by fluorescence in situ hybridization (FISH) testing. CONCLUSIONS: We posit that this approach provides an improvement on the cIMPACT-NOW workflow recommendations for IDH-mutant tumors and a framework for future resource and testing allocation.

Biomarcadores radiológicos en RM para una aproximación al diagnóstico molecular en gliomas IDH-mutados (grado II y III) / MR Imaging Biomarkers for a Diagnostic Approach of IDH-mutated Gliomas (Grades II/III)

Resumen Objetivo: Analizar características por resonancia magnética (RM) de gliomas IDH-mutados (grado II y III) en base a parámetros cualitativos, a fin de valorar el rendimiento del signo del mismatch T2-FLAIR y otras características morfológicas de los tumores, en predecir el estado del 1p/19q y su reproducibilidad interobservador. Métodos Estudio retrospectivo, descriptivo y analítico sobre una cohorte de 53 gliomas IDH-mutados (grado II y III) y molecularmente definidos respecto al 1p/19q, seleccionados a partir de la base de datos de la institución, durante el periodo 2014- 2019. Dos neuroradiólogos evaluaron características imagenológicas de forma independiente y enmascarada al diagnóstico: mismatch T2-FLAIR, localización tumoral, bordes, señal, infiltración cortical e inhomogeneidad en T2. Los casos discordantes fueron evaluados por un tercer neuroradiólogo de mayor experiencia. Resultados: Treinta de 53 (56,6%) gliomas fueron no codelecionados, y 23/53 (43,4%) codelecionados. El signo del mismatch T2-FLAIR fue positivo en 16/53 (30,18%) pacientes, 15/16 (93,75%) no codelecionados y 1/16 (6,25%) codelecionado (Exacto de Fisher p = <,0001). Los dos evaluadores demostraron una concordancia interobservador casi perfecta para ese signo, κ =,907 (95% CI, 0,781 a 1,0). La especificidad y el valor predictivo positivo del signo para predecir la ausencia de la codeleción fue de un 95,7% y un 93,8% respectivamente. Discusión: La reciente actualización en la clasificación de los gliomas los clasifica acorde a su perfil molecular. En los últimos años, varios investigadores han estudiado características morfológicas por RM de los tumores con la intención de predecir las características moleculares de los mismos. Conclusión: En nuestra población, el signo del mismatch T2-FLAIR es el único biomarcador radiológico que muestra asociación estadísticamente significativa en predecir la ausencia de codeleción en los gliomas IDH-mutados (grado II y III), con una alta especificidad y un alto valor predictivo positivo.

Abstract Objective: To analyze magnetic resonance (MR) characteristics of IDH-mutated gliomas (grades II/III) utilizing qualitative parameters with the goal of assessing the performance of the T2-FLAIR mismatch sign and other morphological characteristics of tumors in predicting the 1p/19q co-deletion status as well as inter-observer reproducibility. Methods: Retrospective and descriptive study analyzing a cohort of 53 IDH-mutated lower-grade (grades II/III) gliomas with known 1p/19q co-deletion status. Patients meeting selection criteria for this study were taken from our institutional data from 2014-2019. Two neuroradiologists assessed the following imaging characteristics independently, and blinded from the diagnosis: T2-FLAIR mismatch, tumor location, borders, signal characteristics, cortical infiltration and T2* inhomogeneity. In the event of discordant interpretations, a third senior neuroradiologist also evaluated the case. Results: 23 of the 53 (43.4%) gliomas demonstrated 1p/19q co-deletion and 30 of 53 (56.6%) did not. T2-FLAIR mismatch was positive in 16 of 53 cases (30.2%) with 15 of 16 (93.8%) demonstrating no co-deletion and 1/16 (6.25%) with co-deletion (Fisher's exact p = < .0001). The two readers showed an almost perfect interreader agreement for this sign κ = 0.907 (95% CI, 0.781 to 1.0). Specificity and positive predictive value of the sign to predict the absence of co-deletion was 95.7% and 93.8% respectively. Discussion: The recent update in classification of lower-grade gliomas segregates gliomas according to molecular profile. In the recent past, many researchers have studied MR morphologic characteristics of these tumors with the intention of predicting molecular features of said tumors Conclusion: In our patient population, T2-FLAIR mismatch sign is the only radiologic biomarker that shows statistically significant association with the absence of 1p/19q co-deletion in lower-grade gliomas, with high specificity and positive predictive value.

Petroclival intravascular papillary endothelial hyperplasia with psammoma body-like structures.

Masson's tumor or intravascular papillary endothelial hyperplasia (IPEH) is considered a non-neoplastic lesion. It is probably an unusual exaggerated reorganization of a thrombus. IPEH may be present as a secondary lesion in hemangiomas. Symptomatic osseous hemangiomas are rare tumors. Few cases of clival and petrous bone hemangiomas have been described. None of them shows secondary IPEH. So far, there are only four reported cases of cranial bone IPEHs in the literature, two in the skull, one in the clivus and one in the petrous apex. The aim of this study is to report an additional case of osseous hemangioma with secondary IPEH of the petroclival region. We review the literature and describe the main clinical features of IPEHs and hemangiomas of the clivus and the petrous bone. Additionally, we report an unusual histological feature observed in our case of IPEH, the presence of psammoma body-like structures. This feature has been rarely mentioned previously in IPEH. We consider that IPEH should be included in the lesions that may present psammoma bodies to avoid misdiagnosing it as a tumor that commonly shows psammoma bodies, such as intraosseous meningioma or, less frequently, metastasis of thyroid or ovarian carcinoma.

Pituicytoma Associated with Acromegaly and Cushing Disease.

BACKGROUND: Pituicytoma is a rare neoplasm arising in the sellar region (World Health Organization grade I). Clinically, pituicytomas mimic nonfunctioning pituitary macroadenomas and are occasionally incidentally discovered at autopsy. Pituitary adenomas can occur with other sellar pathologies, and the term "collision sellar lesions" has been coined for this rare entity. There have only been a few reports of the coexistence of pituicytoma and pituitary adenoma. We present 2 cases of pituicytoma coexisting with acromegaly and Cushing disease. CASE DESCRIPTION: Case 1: A 29-year-old woman had acromegaly. The macroadenoma was partially removed in her first surgery; thus an endonasal reoperation was required for debulking and posterior radiosurgery. Pituicytoma coexisting with somatotropinoma was diagnosed on pathologic examination. Case 2: A 33-year-old woman had adrenocorticotropic hormone-dependent Cushing disease. She underwent endonasal resection. Undetectable postoperative cortisol levels provided evidence that the underlying adrenocorticotropic hormone source was successfully removed. On the basis of morphologic features and the immunohistochemical profile, pituicytoma was diagnosed on pathologic examination. Pituitary adenoma was not confirmed histologically in this patient. CONCLUSIONS: Only 117 cases of pituicytoma have been reported since it was first described in 1955. Before our report, only 5 cases of patients with pituicytoma coexisting with pituitary adenoma had been described. The coexistence of these 2 entities may not just be a mere coincidence but may be due to a yet unknown pathophysiologic link or common progenitor lineage of both lesions. Association between pituicytoma and pituitary adenoma is increasingly being reported.

Erdheim-Chester disease: atypical presentation of a rare disease.

We report the clinical case of an adult patient referred to our hospital because of trismus due to a tumour in the right infratemporal and pterygomaxillary fossa. He referred hyporexia, weight loss and right trigeminal neuralgia. On physical examination, he had trismus and diplopia. On neuroimaging, the tumour invaded the central nervous system affecting the right temporal lobe and orbit, and the sellar region. Tumour biopsy revealed foamy histiocytes and isolated giant multinuclear cells immunoreactive to CD68 and negative to CD1a and S100. A diagnosis of Erdheim-Chester disease was made. Non-evidence of large bone involvement was found in neither plain radiographs nor Technetium 99 m bone scintigraphy. BRAFV600E mutation analysis was negative. Because of raised intracranial pressure, a debulking surgery of the intracranial histiocytic process was performed. The patient improved his symptoms and remains clinically stable after 12 months of treatment with pegylated interferon-α-2a 180 µg/weekly.

[Injury by skull osteolytic secundary syphilis]. / Lesión osteolítica de calota por sífilis secundaria.

Bone involvement of syphilis can be observed in tertiary and congenital syphilis. It is infrequent during the secondary stage. The skull is the most affected bone in secondary syphilis, and its most frequent form of presentation is proliferative osteitis. If the skull is affected, headache is usual and can be as intense as in meningitis. Osteolyitic lesions may be seen in complimentary imaging studies, with a moth eaten aspect. These lesions raise concern over a number of differential diagnoses, among which are infectious, inflammatory and neoplastic diseases. The definitive diagnosis is made by bone biopsy of the compromised bone. Molecular techniques in the affected tissues increases diagnostic performance. There is no standardized treatment protocol for syphilis since there are no guidelines available. We report a case of a 19 year old female, presenting with a unique osteolytic lesion in the skull due to secondary syphilis.

Lesión osteolítica de calota por sífilis secundaria / Injury by skull osteolytic secundary syphilis

Bone involvement of syphilis can be observed in tertiary and congenital syphilis. It is infrequent during the secondary stage. The skull is the most affected bone in secondary syphilis, and its most frequent form of presentation is proliferative osteitis. If the skull is affected, headache is usual and can be as intense as in meningitis. Osteolyitic lesions may be seen in complimentary imaging studies, with a moth eaten aspect. These lesions raise concern over a number of differential diagnoses, among which are infectious, inflammatory and neoplastic diseases. The definitive diagnosis is made by bone biopsy of the compromised bone. Molecular techniques in the affected tissues increases diagnostic performance. There is no standardized treatment protocol for syphilis since there are no guidelines available. We report a case of a 19 year old female, presenting with a unique osteolytic lesion in the skull due to secondary syphilis.

El compromiso óseo de la sífilis se observa predominantemente en la sífilis terciaria y en la sífilis congénita, siendo infrecuente durante el estadio secundario. El hueso más afectado durante la sífilis secundaria es el cráneo, siendo la osteítis proliferativa la forma más frecuente de presentación. Cuando afecta la calota, la cefalea es habitual y puede ser tan intensa que se confunde con un proceso meníngeo. En las imágenes se observan lesiones líticas de aspecto apolillado, planteando el diagnóstico diferencial con otras patologías infecciosas, inflamatorias y neoplásicas. El diagnóstico definitivo se realiza por estudio histológico del hueso comprometido. Las técnicas de biología molecular en los tejidos afectados aumentan el rendimiento diagnóstico. No existen protocolos estandarizados para el tratamiento de la sífilis con compromiso óseo. Presentamos el caso clínico de una mujer de 19 años de edad, con una lesión osteolítica única de calota debida a una sífilis secundaria.

Specific Preferences in Lineage Choice and Phenotypic Plasticity of Glioma Stem Cells Under BMP4 and Noggin Influence.

Although BMP4-induced differentiation of glioma stem cells (GSCs) is well recognized, details of the cellular responses triggered by this morphogen are still poorly defined. In this study, we established several GSC-enriched cell lines (GSC-ECLs) from high-grade gliomas. The expansion of these cells as adherent monolayers, and not as floating neurospheres, enabled a thorough study of the phenotypic changes that occurred during their differentiation. Herein, we evaluated GSC-ECLs' behavior toward differentiating conditions by depriving them of growth factors and/or by adding BMP4 at different concentrations. After analyzing cellular morphology, proliferation and lineage marker expression, we determined that GSC-ECLs have distinct preferences in lineage choice, where some of them showed an astrocyte fate commitment and others a neuronal one. We found that this election seems to be dictated by the expression pattern of BMP signaling components present in each GSC-ECL. Additionally, treatment of GSC-ECLs with the BMP antagonist, Noggin, also led to evident phenotypic changes. Interestingly, under certain conditions, some GSC-ECLs adopted an unexpected smooth muscle-like phenotype. As a whole, our findings illustrate the wide differentiation potential of GSCs, highlighting their molecular complexity and paving a way to facilitate personalized differentiating therapies.

Intracranial video-EEG and surgery for focal atonic seizures.

Atonic seizures are epileptic attacks characterised by a sudden loss or diminution of muscle tone. Structures corresponding to inhibitory cortical areas, such as the primary negative motor area or the supplementary negative motor area, could be responsible. We present findings observed in a patient with atonic seizures due to focal epilepsy, who underwent intracranial video-EEG monitoring and epilepsy surgery, and discuss possible underlying mechanisms. [Published with video sequences].

Supratentorial intraventricular solitary schwannoma. Case report and literature review.

OBJECTIVE: The objectives of this study were to present a case of a solitary intraventricular schwannoma with a review of the literature and to analyse the current theories of its origin. DESCRIPTION: A 16-year-old male patient, without any pathological, genetic or familial history of significance, presented with symptoms of intracranial hypertension and progressive left brachiocrural paresis. The magnetic resonance image showed a bulky intraventricular space-occupying lesion emerging from the posterior horn of the right lateral ventricle, with an irregular nodular component intimately connected to the choroid plexus, and a multiloculated cystic component extending beyond the ventricle. SURGICAL APPROACH: A right parietal craniotomy was performed, revealing a multiloculated cyst with xantochromic fluid and a soft brownish red nodule. The lesion was dissected surrounding the periphery and coagulating a vascular pedicle related to the wall of the right lateral ventricle and its choroid plexus. Total excision was achieved. The pathological exam reported an intraventricular schwannoma (WHO grade 1). The patient evolved favourably, with no recurrence at 36-month follow-up. CONCLUSION: The literature describes less than 45 cases of schwannomas not associated to cranial nerves of the following locations: intramedullary, leptomeningeal and only 12 intraventricular cases. The three theories explaining the origin of this last group describe: (1) a neoplastic transformation of peripheral nerve fibres, (2) a neoplastic transformation of autonomic neural tissue located within the intraventricular choroid plexus and (3) an abnormal embryogenesis leading to a failed migration of the neural crest cells. Complete resection is the therapeutic goal for this benign pathology to avoid recurrence.

Extranodal rosai-dorfman disease presenting as a solitary mass with human herpesvirus 6 detection in a pediatric patient.

In Rosai-Dorfman disease (RDD), exclusive extranodal involvement with lesions limited to the kidneys is very uncommon and has been described only in adult patients. Occasionally, human herpesvirus 6 (HHV-6) has also been detected in RDD tissue samples. We present the case of a 7-year-old boy referred to our center presenting a single solid mass in the right kidney measuring 3.4 cm, detected both on contrast computed tomography and magnetic resonance imaging. Surgical excision was successfully completed, and the pathology report informed characteristic histopathology and immmunohistochemistry features of RDD. Human herpesvirus 6 was detected and amplified by polymerase chain reaction, as well as by immunohistochemistry. We discuss imaging and histology-based differential diagnoses in the pediatric age group. Although RDD is a rare histiocytic disorder of unknown etiology and pathogenesis, the presence of HHV-6 observed in this case supports the possibility of an abnormal immunologic response linked to viral presence.

Whole-genomic survey of oligodendroglial tumors: correlation between allelic imbalances and gene expression profiles.

Malignant gliomas are the most common subtype of primary central nervous system (CNS) tumors. Their pathological classification, however, remains subjective, stimulating researchers to actively seek objective molecular markers to discover alternative and more reproducible tools for improved subtypification. Herein, we present a global survey of genomic alterations in oligodendroglial tumors (OT). Genetic and epigenetic alterations identified in this study are correlated with OT molecular groups we have recently reported: a neurogenic group composed of tumors with loss of heterozygosity (LOH) at 1p-19q, IDH1 mutations, and MGMT promoter methylation, showing good prognosis; an intermediate group, presenting TP53 mutations or LOH at 17p, IDH1 mutations, and GSTP1 promoter methylation; and a proliferative group, presenting major genetic alterations (LOH at 10q, EGFR amplification, and CDKN2A/ARF deletion) and poor prognosis. These results allowed us to refine our molecular characterization associated with prognosis, referring exclusively to oligodendroglial tumors.

Schwannomas vestibulares quísticos / Cystic vetibular schwannomas

Objetivo. Presentar nuestra experiencia en el tratamiento de los Schwannomas vestibulares quísticos comparándolos con lesiones sólidas. Material y método. Se evaluaron en forma retrospectiva los síntomas de presentación clínica, tasas de preservación facial, grado de resección quirúrgica, complicaciones postoperatorias y hallazgos histológicos de los Schwannomas quísticos pareados en base al tamaño tumoral con un grupo de lesiones sólidas. Resultados. Durante el período junio 1995 julio 2010, 27 pacientes con Schwannomas quísticos se operaron en nuestro Departamento. El diámetro promedio fue de 29,6 mm. Los síntomas de presentación clínica más frecuentes fueron la hipoacusia, inestabilidad en la marcha y parestesias faciales. Al año de cirugía, el 74% de los pacientes tenían función facial HB I-III sin diferencias significativas con el grupo de lesiones sólidas. La remoción completa fue 55,5% y 85% de los pacientes en las lesiones quísticas ysólidas respectivamente. Conclusión. Los Schwannomas quísticos deben ser evaluados en forma separada de las lesiones sólidas debido a que pueden crecer rápidamente, presentar mayor complejidad quirúrgica y desarrollar complicaciones postoperatorias con mayor frecuencia.

Objective. To present our experience treating this rare tumor variant.Material and Method. Retrospective evaluation of an institutional cystic vestibular schwannoma series, based on initial symptoms, rate of facial preservation, extent of surgical resection, postoperative complication rate and cystic lesion quantificationon histology in comparison to solid tumor type. Results. During the period June 1995-July 2010, 27 cysticschwannomas were operated on at the FLENI neurological Institute. Mean tumor diameter was 29,6mm. The most frequent presenting symptoms included hypoacusia, unsteadiness and facial paresthesias. One year after surgery, 74% of patients presented facial function HB I-III, showing no statistical difference in comparison to solid lesions. Complete surgical resectionwas possible in 55, 5% of the cystic and 85% of the solid tumor groups, respectively. Conclusion. Cystic vestibular schwannomas should be identified separately from vestibular schwannomas in general, particularlybecause they often undergo more rapid expansion, and may present greater surgical risk as well as higher rates ofpostoperative complications.

60-year old woman with extra-axial frontal mass.

We describe a 60 year-old woman presenting with visual loss of her left eye. No lymphadenopathies, fever, or weight loss were detected. Neuroimaging studies revealed an extra-axial mass along the posterior aspect of the left optic nerve. The mass was resected and showed xanthomatous histiocytes that were positive for CD-68, occasionally positive for S-100, and negative for CD-1. The lesion was diagnosed as Erdheim-Chester disease (ECD) affecting the CNS. The patient is under systemic evaluation in order to discover other ECD lesions. Microscopic findings and differential diagnoses are discussed.