Intracranial Rosai Dorfman disease - A rare differential diagnosis of multiple meningiomas: a case report.

Rosai Dorfman Destombes (RDD) disease is a non-Langerhans histiocytosis. The central nervous system is affected in < 5% of cases. We report the case of a 59-year-old man, who began 8 months before admission with headache, diminished visual acuity in the temporal hemifields, hyposmia, and seizures. Magnetic resonance imaging showed three midline skull-base lesions in anterior, media, and posterior fossae. We performed a complete resection of symptomatic lesions using a bifrontal craniotomy. The histopathological analysis determined RDD, therefore, we started steroid treatment. Our case description is due to the diagnosis and location, one of the rarest reported to date in the literature.

La enfermedad de Rosai-Dorfman-Destombes (RDD) es una histiocitosis no Langerhans. El SNC se ve afectado en menos del 5% de los casos. Presentamos el caso de un hombre de 59 años quien inició ocho meses previos al ingreso con cefalea, hemianopsia bitemporal, hiposmia y convulsiones. La resonancia magnética mostró tres lesiones de la base del cráneo en las fosas anterior, media y posterior. Realizamos una resección completa de las lesiones sintomáticas mediante una craneotomía bifrontal. El análisis histopatológico determinó RDD. Nuestro caso es debido al diagnóstico y localización, uno de los más raros reportados hasta la fecha en la literatura.

Teratoma With Malignant Ectomesenchymoma in the Pineal Region: A Case Report.

Tumors involving the pineal gland include germinomas, non-germinomatous, and parenchymal tumors. Sometimes these tumors can be differentiated into rhabdomyosarcoma, which is an aggressive and rapidly recurring sarcoma but is a rare event. We present the case of a 23-year-old male, with an eight-year-long history of a non-treated brain tumor compatible with a teratoma. Chemotherapy and radiotherapy were offered, and two years later, malignant transformation to astrocytoma, rhabdomyosarcoma, neural cell carcinoma, ganglioglioma, and low-grade chondrosarcoma was noted. Immunohistochemistry was valuable in differentiating these entities that confirmed the diagnosis. Malignant transformations may be secondary to the normal transformation of multipotent embryonic cells into more developed tissues after radiotherapy of teratoma and malignant ectomesenchymoma transformation.

The Genomic Landscape of Corticotroph Tumors: From Silent Adenomas to ACTH-Secreting Carcinomas.

Corticotroph cells give rise to aggressive and rare pituitary neoplasms comprising ACTH-producing adenomas resulting in Cushing disease (CD), clinically silent ACTH adenomas (SCA), Crooke cell adenomas (CCA) and ACTH-producing carcinomas (CA). The molecular pathogenesis of these tumors is still poorly understood. To better understand the genomic landscape of all the lesions of the corticotroph lineage, we sequenced the whole exome of three SCA, one CCA, four ACTH-secreting PA causing CD, one corticotrophinoma occurring in a CD patient who developed Nelson syndrome after adrenalectomy and one patient with an ACTH-producing CA. The ACTH-producing CA was the lesion with the highest number of single nucleotide variants (SNV) in genes such as USP8, TP53, AURKA, EGFR, HSD3B1 and CDKN1A. The USP8 variant was found only in the ACTH-CA and in the corticotrophinoma occurring in a patient with Nelson syndrome. In CCA, SNV in TP53, EGFR, HSD3B1 and CDKN1A SNV were present. HSD3B1 and CDKN1A SNVs were present in all three SCA, whereas in two of these tumors SNV in TP53, AURKA and EGFR were found. None of the analyzed tumors showed SNV in USP48, BRAF, BRG1 or CABLES1. The amplification of 17q12 was found in all tumors, except for the ACTH-producing carcinoma. The four clinically functioning ACTH adenomas and the ACTH-CA shared the amplification of 10q11.22 and showed more copy-number variation (CNV) gains and single-nucleotide variations than the nonfunctioning tumors.

The kinome, cyclins and cyclin-dependent kinases of pituitary adenomas, a look into the gene expression profile among tumors from different lineages.

BACKGROUND: Pituitary adenomas (PA) are the second most common intracranial tumors and are classified according to hormone they produce, and the transcription factors they express. The majority of PA occur sporadically, and their molecular pathogenesis is incompletely understood. METHODS: Here we performed transcriptome and proteome analysis of tumors derived from POU1F1 (GH-, TSH-, and PRL-tumors, N = 16), NR5A1 (gonadotropes and null cells adenomas, n = 17) and TBX19 (ACTH-tumors, n = 6) lineages as well as from silent ACTH-tumors (n = 3) to determine expression of kinases, cyclins, CDKs and CDK inhibitors. RESULTS: The expression profiles of genes encoding kinases were distinctive for each of the three PA lineage: NR5A1-derived tumors showed upregulation of ETNK2 and PIK3C2G and alterations in MAPK, ErbB and RAS signaling, POU1F1-derived adenomas showed upregulation of PIP5K1B and NEK10 and alterations in phosphatidylinositol, insulin and phospholipase D signaling pathways and TBX19-derived adenomas showed upregulation of MERTK and STK17B and alterations in VEGFA-VEGFR, EGF-EGFR and Insulin signaling pathways. In contrast, the expression of the different genes encoding cyclins, CDK and CDK inhibitors among NR5A1-, POU1F1- and TBX19-adenomas showed only subtle differences. CDK9 and CDK18 were upregulated in NR5A1-adenomas, whereas CDK4 and CDK7 were upregulated in POUF1-adenomas. CONCLUSIONS: The kinome of PA clusters these lesions into three distinct groups according to the transcription factor that drives their terminal differentiation. And these complexes could be harnessed as molecular therapy targets.

Proteomic and Transcriptomic Analysis Identify Spliceosome as a Significant Component of the Molecular Machinery in the Pituitary Tumors Derived from POU1F1- and NR5A1-Cell Lineages.

BACKGROUND: Pituitary adenomas (PA) are the second most common tumor in the central nervous system and have low counts of mutated genes. Splicing occurs in 95% of the coding RNA. There is scarce information about the spliceosome and mRNA-isoforms in PA, and therefore we carried out proteomic and transcriptomic analysis to identify spliceosome components and mRNA isoforms in PA. METHODS: Proteomic profile analysis was carried out by nano-HPLC and mass spectrometry with a quadrupole time-of-flight mass spectrometer. The mRNA isoforms and transcriptomic profiles were carried out by microarray technology. With proteins and mRNA information we carried out Gene Ontology and exon level analysis to identify splicing-related events. RESULTS: Approximately 2000 proteins were identified in pituitary tumors. Spliceosome proteins such as SRSF1, U2AF1 and RBM42 among others were found in PA. These results were validated at mRNA level, which showed up-regulation of spliceosome genes in PA. Spliceosome-related genes segregate and categorize PA tumor subtypes. The PA showed alterations in CDK18 and THY1 mRNA isoforms which could be tumor specific. CONCLUSIONS: Spliceosome components are significant constituents of the PA molecular machinery and could be used as molecular markers and therapeutic targets. Splicing-related genes and mRNA-isoforms profiles characterize tumor subtypes.

Transcriptome and methylome analysis reveals three cellular origins of pituitary tumors.

Pituitary adenomas (PA) are the second most common intracranial tumors. These neoplasms are classified according to the hormone they produce. The majority of PA occur sporadically, and their molecular pathogenesis is incompletely understood. The present transcriptomic and methylomic analysis of PA revealed that they segregate into three molecular clusters according to the transcription factor driving their terminal differentiation. First cluster, driven by NR5A1, consists of clinically non-functioning PA (CNFPA), comprising gonadotrophinomas and null cell; the second cluster consists of clinically evident ACTH adenomas and silent corticotroph adenomas, driven by TBX19; and the third, POU1F1-driven TSH-, PRL- and GH-adenomas, segregated together. Genes such as CACNA2D4, EPHA4 and SLIT1, were upregulated in each of these three clusters, respectively. Pathway enrichment analysis revealed specific alterations of these clusters: calcium signaling pathway in CNFPA; renin-angiotensin system for ACTH-adenomas and fatty acid metabolism for the TSH-, PRL-, GH-cluster. Non-tumoral pituitary scRNAseq data confirmed that this clustering also occurs in normal cytodifferentiation. Deconvolution analysis identify potential mononuclear cell infiltrate in PA consists of dendritic, NK and mast cells. Our results are consistent with a divergent origin of PA, which segregate into three clusters that depend on the specific transcription factors driving late pituitary cytodifferentiation.

Molecular alterations in non-functioning pituitary adenomas.

BACKGROUND: Clinically non-functioning Pituitary Adenomas (NFPA) are among the most common neoplasms of the sellar region. They usually present with compressive symptoms such as headache and visual field defects and not infrequently, are found incidentally. NFPA are classified as gonadotropinomas, null cell adenomas, according to their immunohistochemical phenotype. The molecular alterations responsible for the development of these lesions are incompletely understood, and there is scarce information regarding the molecular alterations and markers. OBJECTIVE: We carried out an in-silico analysis aimed at identifying the molecular alterations in NFPA and to discover new molecular markers. METHODS: Twenty-three microarray libraries were analyzed. Fourteen correspond to NFPA and 9 to control tissue gland. They were analyzed using Partek Genomic Suite to identify differentially expressed genes and WebGestalt and Metascape to understand the meaning behind the gene lists. RESULTS: Pituitary adenomas showed a markedly different transcriptome compared to the non-tumoral gland, regardless of their putative immunophenotype. Genes related to calcium metabolism such as CACNA2D4, immune-related CXCR4, and stem cell-related KLF8 and PITX2 were altered. CONCLUSIONS: Differentially expressed calcium metabolism and immune-related genes in NFPA represent attractive molecular markers and potential therapeutic targets.

Revisiting the Genomic and Transcriptomic Landscapes from Female Malignancies Could Provide Molecular Markers and Targets for Precision Medicine.

AIMS: Gynaecological malignancies such as breast, ovarian and cervical cancers have become an important public health problem. Detection of molecular alterations in cancer research is fundamental since it can reveal specific pathogenic patterns and genes that could serve as markers. Our aim was to characterize common genomic and transcriptomic signatures for the three gynaecologic malignancies with the highest incidence and mortality to try to identify new molecular markers, therapeutic targets and molecular signatures. METHODS: Here we analysed a total of 723 microarray libraries corresponding to equal number of breast, ovary and cervical cancer and non-cancer patient samples. Copy number variation (CNV) was carried out using 428 libraries and transcriptomic analysis using the 295 remaining samples. RESULTS: Our results showed that breast, ovary and cervical malignancies are characterized by gain of 1q chromosome. At transcriptomic level, they share 351 coding and non-coding genes, which could represent core transcriptome of gynaecological malignancies. Pathway analysis from the resulting gene lists from CNV and expression showed participation in cell cycle, metabolism, and cell adhesion molecules among others. CONCLUSIONS: Chromosome 1q characterize the gynaecological malignancies, which could harbour a richness of genetic repertoire to mine for molecular markers and targets, particular gynaecologic expression profile, containing FANCI, FH and MIR155HG among others, could represent part of the transcriptomic core for diagnostic test and attractive therapeutic targets. It may not be long before every human cancer sample is profiled for a detections test to ascertain a molecular diagnosis and prognosis and to define an optimal and precise treatment strategy.

Short-Spindled Cell Haemangioblastoma with CD34 Expression: New Histopathological Variant or Just a Stochastic Cytological Singularity?

Haemangioblastomas are neoplasms of uncertain histogenesis with cellular and reticular variants advocated in current lore. Herein we describe an intriguing cerebellar specimen with unusual traits including spindle cell morphology and CD34 positivity. A thirty-nine-year old man had an infratentorial tumour discovered incidentally and resected three times. In all the instances, histopathological diagnosis was haemangioblastoma; nonetheless, he had neither physical stigmata nor family history of von Hippel-Lindau disease. By histology, the lesion was composed of areas of conventional stromal cells admixed with territories populated by short-spindled cells packed in lobules, sometimes giving the appearance of gomitoli. Immunoperoxidase-coupled reactions confirmed the expression of inhibin A, neuron-specific enolase (NSE), PS100, and CD57 but also revealed focal immunolabeling for CD34, CD99, and FXIIIa. This case highlights the potential phenotypical diversity that can be found within these neoplasms. Rather than uncertain histogenesis, it may in fact reflect multiple lines of differentiation-histomimesis-prone to adopt unusual morpho- and immunophenotypes in a subset of haemangioblastomas.

WHO Grade IV Gliofibroma: A Grading Label Denoting Malignancy for an Otherwise Commonly Misinterpreted Neoplasm.

We report a 50-year-old woman with no relevant clinical history who presented with headache and loss of memory. Magnetic resonance imaging showed a left parieto-temporal mass with annular enhancement after contrast media administration, rendering a radiological diagnosis of high-grade astrocytic neoplasm. Tumour sampling was performed but the patient ultimately died as a result of disease. Microscopically, the lesion had areas of glioblastoma mixed with a benign mesenchymal constituent; the former showed hypercellularity, endothelial proliferation, high mitotic activity and necrosis, while the latter showed fascicles of long spindle cells surrounded by collagen and reticulin fibers. With approximately 40 previously reported cases, gliofibroma is a rare neoplasm defined as either glio-desmoplastic or glial/benign mesenchymal. As shown in our case, its prognosis is apparently determined by the degree of anaplasia of the glial component.

Paediatric Primary Pachymeningeal Xanthogranuloma with Scattered Foci Displaying Reticulohistiocytoma-like Features.

We report a unique case of a 4-year-old girl with an intriguing fibrohistiocytic tumour. Magnetic resonance imaging scans showed a dural mass of variegated intensity compressing the left occipital pole and apparently extending toward the superior sagittal sinus. Grossly, the cut surface of the surgical specimen was yellow, pale, and soft with reddish kernel-like crusts. Histologically, the yellow areas resembled cholesterol granulomas with widespread coagulative necrosis, cholesterol clefts, powdery calcification, foreign body-type giant cells, and foamy macrophages, while the scattered red spots contained numerous multinucleated giant cells of foreign-body and Touton types, the former with amphophilic to slightly eosinophilic cytoplasm. Immunoperoxidase reactions confirmed the expression of histiocytic markers and vimentin. As far as we know, no tumour displaying these peculiar morphological features has yet been described.

Neurocysticercosis: radiologic-pathologic correlation.

Neurocysticercosis is a neurologic parasitic disease caused by the encysted larva of the tapeworm Taenia solium and is the most important parasitic disease of the human central nervous system. It is the most common cause of acquired epilepsy in endemic settings and constitutes a public health challenge for most of the developing world. Nowadays, however, as a result of globalization, neurocysticercosis is being seen more frequently in developed countries as well. Neurocysticercosis is acquired through fecal-oral contamination, and the disease course is complex, with two intermediate hosts (ie, pigs and humans) and a definitive host (humans). Traditionally, it has been classified into active and nonactive forms according to disease location. Radiologists must be aware of its imaging appearance, which is quite variable, as is the differential diagnosis. Imaging findings depend on several factors, including the stage of the life cycle of T solium at presentation; the number and location (ie, subarachnoid, cisternal, or intraventricular) of parasites; and associated complications such as vascular involvement (ie, arteritis with or without infarction), inflammatory response (ie, edema, gliosis, or arachnoiditis), and, in ventricular forms, degree of obstruction. Thus, the diagnostic approach, management, and prognosis for neurocysticercosis differ widely depending on the type of infection.

El espectro morfológico del complejo esclerosis tuberosa: análisis de cuatro casos de autopsia / The morphological spectrum of the tuberous sclerosis complex: analysis of four necropsy cases

Se informan cuatro casos de esclerosis tuberosa. Los hallazgos post mortem más frecuentes fueron hamartomas subependimarios y angiofibromas faciales. También se encontraron astrocitomas subependimarios de células gigantes, rabdomiomas cardiacos múltiples, riñones poliquísticos, fibromas subungueales, manchas hipopigmentadas y angiomiolipomas renales. La presentación clínica y morfológica de la esclerosis tuberosa es variada y heterogénea y en esta breve serie se revisan los aspectos patológicos más importantes para su diagnóstico.

Arteritis segmentaria y focal de arterias intracraneanas: Informe de cuatro casos de autopsia / Segmental and focal arteritis of intracranial arteries: A report of four autopsy cases

El sistema nervioso central puede ser afectado por diversos tipos de vasculitis, ya sea como parte de una afección sistémica o de manera aislada. Se informan cuatro casos de arteritis segmentarias y focales de arterias intracraneanas, todos los pacientes fueron jóvenes y no presentaron datos clínicos de afección, ni lesiones en arterias extracraneanas. La afección de las arterias cerebrales fue focal y segmentaria y produjo trombosis con el consiguiente infarto isquémico en el territorio irrigado por el vaso afectado. Se revisan los conceptos sobre patogenía y clasificación de las vasculitis que afectan al sistema nervioso central, con especial atención de aquellas producidas por complejos inmunes circulantes

Histogénesis de los tumores mixtos de glándula mamaria canina / Histogenesis of canine mixed mammary tumors

A partir de su descripción primaria, el origen de los distintos componente mesenquimatosos que caracterizan a los tumores mixtos de la glándula mamaria canina ha sido controvertido. La mayoría de los autores han encontrado, mediante diferentes métodos, evidencias importantes que señalan a las células mioepiteliales como responsables de lo anterior. En el presente trabajo se estudiaron 15 tumores mixtos caninos por medio de la técnica del complejo avidina-biotina-peroxidasa. Se utilizaron 7 marcadores (citoqueratinas, antígeno de membrana epitelia, antígeno carcinoembrionario, actina músculo-específica, vimetina, proteína S-100 y desmina) comerciales para humanos, previa determinación de su reacción en tejidos testigos de caninos, con el propósito de correlacionar la expresión de dichos antígenos con los cambios ultraestructurales que se presentan en los componentes tisulares en transición. La mayoría de los anticuerpos resultaron confiables en tejidos caninos, excepto la proteína S-100. Por su parte, la citoqueratina, actina múculo-específica y vimetina se expresaron de forma notable en elementos epiteliales, mioepiteliales y mesenquimatosos, respectivamente. Ultraestucturalmente se identificaron 6 tipos celulares principales, de éstos las denominadas células de transición (filamentosas, estelares y condroides) conservaban características específicas de células mioepiteliales como filamentos de actina (5 a 8 nm), demosomas y cuerpos densos. Dichos hallazgos por microscopia electrónica aunados a la expresión de antígenos de membrana y proteínas estructurales, manifiesta por inmunoperoxidasa, señalan a las células mioepiteliales o sus precursoras como responsables de la formación del componente mesenquimatoso heterólogo característico de estos tumores. Se considera también la posibilidad de que el componente epitelial se orine de células con capacidad de diferenciación divergente epimioepitelial, como aparentemente ocurre en los adenomas pleomorfos de la glándulas mamaria y salival del humano

Enfermedad de Devic (Neuromielitis óptica) Hallazgos clínico-patológicos de diez casos de autopsia / (Devic disease (optic neuromyelitis). Clinical and pathologic features in 10 autopsy cases)

Se presentan los hallazgos clínico-pathológicos de diez casos de enfermedad de Devic. La enfermedad fue más frecuente en mujeres adultas y el tiempo de evolución promedio en esta serie fue de diez meses. Las manifestaciones por lesión de la médula espinal fueron las más sobresalientes y casi todos los enfermos murieron por complicaciones pulmonares. Los hallazgos neuropatológicos más importantes fueron desmielinización, infiltrado linfocitario perivascular y cavitación del quiasma óptico y de la médula espinal. Algunos autores consideran la enfermedad de Devic como una forma de esclerosis múltiple y otros como entidad aparte, pero se sabe que es una enfermedad desmielinizante primaria confinada a nervios, quiasma y bandeletas ópticos y a la médula espina, en que el grado de destrucción es mayor aún que en las placas más antiguas de la esclerosis múltiple

Carcinoma de plexos coroides, informe de dos casos y revisión de la literatura / Carcinoma of the choroid plexus. A report of two cases and review of the literature

Se presenta el estudio clínico-patológico de dos casos de carcinoma de plexos coroides. El primero es de una niña de tres años con padecimiento final de tres meses de evolución caracterizado por convulsiones tónico-clónicas y signos meníngeos debidos a un tumor en el ventrículo lateral derecho con dilatación del sistema ventricular. En la autopsia se corroboró la presencia del tumor, algunos implantes subaracnoideos fueron más grandes que la estructura en que se asentaron, en especial el del puente y los de la médula espinal. El carcinoma de plexos coroides estaba en continuidad con un teratoma maduro. El segundo caso es un niño de ocho meses con inicio de síntomas desde el nacimiento, se le practicó derivación ventrículo-peritoneal y craneotomía fronto-parietal derecha con resección parcial de un tumor en el ventrículo lateral derecho; falleció pocos días después de la cirugía por hemorragia intraventricular y úlceras agudas gástricas con hemmoragia masiva. En la autopsia se encontró muy poco tumor residual. Se discuten los criterios de diagnóstico anatomo-patológico

Enfermedad de Moschcowitz (púrpura trombocitopénica trombótica, microangiopatía trombótica cerebral). Informe de cuatro casos / Moschcowitz disease (thrombotic thrombocytopenic purpura, thrombotic cerebral microangiopathy) A report four cases

Se informan cuatro casos de autopsia con enfermedad de Moschcowitz, una niña, un hombre y una mujer jovenes, y una de mediana edad. En todos hubo una evolución corta con somnolencia y pérdida del estado de despierto, dos enfermas presentaron crisis convulsivas, el hombre joven parestesias y alteración de funciones cerebrales superiores y otra enferma focalización con hemiplejia izquierda. En los dos primeros casos se encontraron hemorragias cerebrales pequeñas y en los otros dos casos no hubo datos macroscópicos relevantes. Los hallazgos microscópicos en todos fueron oclusión de vénulas y capilares cerebrales por trombos de fibrina y escaso infiltrado mononuclear perivascular. Esta es una entidad rara y poco entendida que médicos clínicos y patólogos deben conocer y diagnosticar