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BACKGROUND: Transnasal endoscopy (TNE) does not require general anesthesia, an attractive characteristic for monitoring eosinophilic esophagitis (EoE). We evaluated the adequacy of TNE-obtained esophageal biopsies using the EoE Histology Scoring System (EoEHSS). METHODS: The Cincinnati Center for Eosinophilic Disorders database was searched for esophageal biopsies obtained by the same endoscopist, using either TNE or conventional endoscopy (CE). Whole-slide biopsy images were evaluated. The Mann-Whitney test was used for median (interquartile range) values and Fisher exact test for categorical variables. P ≤ .05 was considered significant. RESULTS: Median age (P = .82) or height (P = .83) did not differ between TNE (n = 17) and CE (n = 17) groups. Although median largest piece size (mm2) differed between the groups (TNE: 0.59 (0.45, 0.86), CE: 2.24 (1.09, 2.82), P < .001), all 8 EoEHSS features were evaluated in each group; only 1 feature (lamina propria fibrosis) was missing in both groups (TNE: 19/34, CE: 11/34, P = .09). The median peak eosinophil count/high-power field differed (TNE: 3 (0, 29), CE: 16 (1, 66), P = .03), but overall grade (TNE: 0.17 (0.10, 0.29), CE: 0.22 (0.14, 0.46), P = .12), stage (TNE: 0.14 (0.10, 0.24), CE: 0.20 (0.10, 0.43), P = .15), and non-eosinophil-related individual EoEHSS scores did not differ. CONCLUSIONS: TNE- and CE-obtained esophageal biopsies are similarly sufficient for evaluation of key pathological features in EoE.
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Esofagite Eosinofílica , Esôfago , Humanos , Esofagite Eosinofílica/patologia , Esofagite Eosinofílica/diagnóstico , Feminino , Masculino , Biópsia , Esôfago/patologia , Criança , Adolescente , Esofagoscopia , Estudos Retrospectivos , Pré-Escolar , AdultoRESUMO
Clinically significant endemic mycoses (fungal infections) in the United States (U.S.) include Blastomyces dermatitidis, Histoplasma capsulatum, and Coccidioides immitis/posadasii. While the majority of infections go clinically unnoticed, symptomatic disease can occur in immunocompromised or hospitalized patients, and occasionally in immune-competent individuals. Clinical manifestations vary widely and their diagnosis may require fungal culture, making the rapid diagnosis a challenge. Imaging can be helpful in making a clinical diagnosis prior to laboratory confirmation, as well as assist in characterizing disease extent and severity. In this review, we discuss the three major endemic fungal infections that occur in the U.S., including mycology, epidemiology, clinical presentations, and typical imaging features with an emphasis on the pediatric population.
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Blastomicose , Coccidioidomicose , Histoplasmose , Micoses , Criança , Humanos , Blastomicose/diagnóstico por imagem , Blastomicose/epidemiologia , Histoplasmose/diagnóstico por imagem , Histoplasmose/epidemiologia , Coccidioidomicose/diagnóstico por imagem , Coccidioidomicose/epidemiologia , Micoses/diagnóstico por imagem , América do Norte/epidemiologiaRESUMO
A novel group of S100- and CD34-positive spindle cell tumors with distinctive stromal and perivascular hyalinization harboring recurrent gene fusions involving kinases including RAF1, BRAF, NTRK1/2/3, and RET have been recently reported. To our knowledge, no such cases harboring ALK rearrangements have been identified. We report a previously healthy 41-year-old male with a 12-cm intramuscular shoulder mass. The tumor was composed of bland-appearing spindled to epithelioid cells, arranged in a patternless pattern in a background of loose myxoid stroma containing striking amianthoid-like stromal collagen and perivascular rings. In accordance with the previously reported tumors, the tumor cells showed diffuse immunopositivity with S100 and CD34, while lacking SOX10 expression. Targeted RNA-based next-generation sequencing identified a novel serine/threonine-protein phosphatase PP1-beta-catalytic subunit (PPP1CB)-ALK fusion gene. Although ALK break-apart was not detected by FISH, likely due to a paracentric inversion of chromosome 2, the presence of the fusion was confirmed by Sanger sequencing showing a 10-bp linker between exon 6 of PPP1CB and intron 19 of ALK while maintaining reading frame. Subsequent ALK-1 immunostain exhibited diffuse cytoplasmic staining in the tumor cells. Our case expands the molecular genetic spectrum of the distinctive group of spindle cell tumors with CD34/S100+ immunophenotype, supporting the important role of various kinases as drivers of oncogenesis. Awareness of this entity including its unique morphologic and immunophenotypic features as well as its interchangeable kinase gene fusions is crucial for correct classification and potential targeted therapy, particularly in aggressive subsets.
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Quinase do Linfoma Anaplásico/genética , Proteínas de Fusão Oncogênica/genética , Neoplasias de Células Epitelioides Perivasculares/genética , Proteína Fosfatase 1/genética , Adulto , Antígenos CD34/genética , Antígenos CD34/metabolismo , Vasos Sanguíneos/patologia , Humanos , Masculino , Neoplasias de Células Epitelioides Perivasculares/patologia , Proteínas S100/genética , Proteínas S100/metabolismo , Ombro/patologia , Células Estromais/patologiaRESUMO
Inflammatory myofibroblastic tumors arising in infants are rare, poorly investigated and mostly reported as isolated cases or as a part of larger series thus, their clinicopathological and molecular features are essentially unknown. Archival files from two large pediatric institutions and a tumor registry were queried for pediatric inflammatory myofibroblastic tumors. Available material from patients ≤12 months of age was reviewed. Additional immunostains (ALK-1, D240, WT1) and ALK-FISH studies were performed as needed. Targeted anchored multiplex PCR with next-generation sequencing was done in all cases. A total of 12 of 131 infantile cases (mean 5.5 months) were identified (M:F of 2:1). Anatomic locations included intestinal/mesenteric (n = 6), head/neck (n = 3), and viscera (n = 3). Half of tumors showed a hypocellular myxoid pattern, perivascular condensation, and prominent vasculature with vague glomeruloid structures present in four of them. The remaining cases exhibited a more cellular pattern with minimal myxoid component. ALK-1 immunohistochemistry was positive in most cases (11/12) with cytoplasmic-diffuse (n = 6), cytoplasmic-granular (n = 2), and dot-like (n = 3) staining patterns. ALK fusion partners identified in five cases included EML4, TPM4, RANBP2, and a novel KLC1. Three inflammatory myofibroblastic tumors showed fusions with other kinases including TFG-ROS1 and novel FN1-ROS1 and RBPMS-NTRK3 rearrangements. Favorable outcome was documented in most cases (10/11) with available follow-up (median 17 months) while three patients were successfully treated with crizotinib. In summary, infantile inflammatory myofibroblastic tumors are rare and can exhibit paucicellular, extensively myxoid/vascular morphology with peculiar immunophenotype mimicking other mesenchymal or vascular lesions. All tumors harbored kinase fusions involving ALK, ROS1, and NTRK3 including three novel fusion partners (KLC1, FN1, and RBPMS, respectively). A favorable response to crizotinib seen in three cases supports its potential use in infants as seen in older patients. Awareness of these unusual morphologic, immunophenotypic, and molecular features is critical for appropriate diagnosis and optimized targeted therapy.
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Biomarcadores Tumorais/genética , Miofibroblastos/patologia , Neoplasias de Tecido Muscular/genética , Neoplasias de Tecido Muscular/patologia , Neoplasias de Tecidos Moles/genética , Neoplasias de Tecidos Moles/patologia , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/análise , Crizotinibe/uso terapêutico , Feminino , Fusão Gênica , Rearranjo Gênico , Predisposição Genética para Doença , Humanos , Lactente , Recém-Nascido , Itália , Cinesinas , Masculino , Miofibroblastos/efeitos dos fármacos , Miofibroblastos/enzimologia , Neoplasias de Tecido Muscular/tratamento farmacológico , Neoplasias de Tecido Muscular/enzimologia , Fenótipo , Philadelphia , Inibidores de Proteínas Quinases/uso terapêutico , Sistema de Registros , Neoplasias de Tecidos Moles/tratamento farmacológico , Neoplasias de Tecidos Moles/enzimologiaRESUMO
BACKGROUND: Ricin is a protein toxin derived from the castor bean plant Ricinus communis. Several cases secondary to its consumption have been published and, more recently, its use as a potential bioterrorism agent has also been reported. Oral absorption of ricin is highly erratic, leading to a wide spectrum of symptoms. In addition, conventional urine drug screening tests will not be able to detect this compound, posing a diagnostic challenge. CASE REPORT: A male teenager intended to die by ingesting 200 castor beans after mixing and blending them with juice. Eight hours later, he presented with weakness, light-headedness, nausea, and vomiting and sought medical treatment. The patient was admitted and treated conservatively. An immune-based standard urine toxicology drug screen panel was reported as negative. A comprehensive untargeted urine drug screen test showed the presence of ricinine, a surrogate marker of ricin intoxication. He was transferred to the psychiatric service 3 days after admission. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: This case highlights the importance of knowing the peculiar pharmacokinetic properties of ricin after oral ingestion of castor beans and toxin release through mastication. Emergency physicians should be aware that oral absorption of ricin is dependent on several factors, such type and size of seeds and the geographic harvesting region, making it extremely difficult to estimate its lethality based solely on the number of ingested beans. Finally, comprehensive untargeted urine drug screening testing is highly valuable as a diagnostic tool in this context.
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Ingestão de Alimentos/psicologia , Ricina/química , Ricinus communis/intoxicação , Adolescente , Antídotos/uso terapêutico , Ricinus communis/química , Carvão Vegetal/uso terapêutico , Depressão/complicações , Depressão/psicologia , Tontura/etiologia , Serviço Hospitalar de Emergência/organização & administração , Lavagem Gástrica/métodos , Humanos , Masculino , Debilidade Muscular/etiologia , Náusea/etiologia , Intoxicação , Ricina/efeitos adversos , Ricina/intoxicação , Suicídio , Vômito/etiologiaAssuntos
Sarcoma/genética , Adulto , Apolipoproteínas D , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Proteínas de Fusão Oncogênica , Sarcoma/classificação , Sarcoma/diagnóstico , Sarcoma/patologia , Neoplasias de Tecidos Moles , Coxa da Perna/patologia , Proteína GLI1 em Dedos de ZincoRESUMO
Microscopic examination of esophageal biopsies is essential to diagnose eosinophilic esophagitis (EoE). Eosinophil inflammation is the basis for the diagnosis, but additional abnormalities may contribute to persistent symptoms and epithelial barrier dysfunction. Both peak eosinophil count and assessments of additional features should be included in pre-therapy and post-therapy pathology reports. Pathologic abnormalities identified in esophageal biopsies of EoE are reversible in contrast to esophageal strictures.
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Enterite , Eosinofilia , Esofagite Eosinofílica , Gastrite , Humanos , Esofagite Eosinofílica/diagnóstico , Esofagite Eosinofílica/terapia , Eosinófilos , BiópsiaRESUMO
Eosinophilic gastrointestinal diseases (EGID), such as eosinophilic gastritis (EoG), eosinophilic enteritis, and eosinophilic colitis (EoC), are chronic inflammatory conditions characterized by persistent gastrointestinal symptoms and elevated levels of activated eosinophils in the gastrointestinal tract. EoG and eosinophilic duodenitis (EoD) are strongly associated with food allergen triggers and TH2 inflammation, whereas EoC shows minimal transcriptomic overlap with other EGIDs. The level of expression of certain genes associated with TH2 immune response is associated with certain histopathologic findings of EoG, EoD, and EoC. Current immune therapy for EoG depletes tissue eosinophilia with persistence of other histopathologic features of disease.
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Enterite , Eosinofilia , Esofagite Eosinofílica , Gastrite , Humanos , Esofagite Eosinofílica/diagnóstico , Esofagite Eosinofílica/terapia , Enterite/diagnóstico , Enterite/terapia , Gastrite/diagnóstico , Gastrite/terapia , InflamaçãoRESUMO
Background: Accurate identification of inflammatory cells from mucosal histopathology images is important in diagnosing ulcerative colitis. The identification of eosinophils in the colonic mucosa has been associated with disease course. Cell counting is not only time-consuming but can also be subjective to human biases. In this study we developed an automatic eosinophilic cell counting tool from mucosal histopathology images, using deep learning. Method: Four pediatric IBD pathologists from two North American pediatric hospitals annotated 530 crops from 143 standard-of-care hematoxylin and eosin (H & E) rectal mucosal biopsies. A 305/75 split was used for training/validation to develop and optimize a U-Net based deep learning model, and 150 crops were used as a test set. The U-Net model was then compared to SAU-Net, a state-of-the-art U-Net variant. We undertook post-processing steps, namely, (1) the pixel-level probability threshold, (2) the minimum number of clustered pixels to designate a cell, and (3) the connectivity. Experiments were run to optimize model parameters using AUROC and cross-entropy loss as the performance metrics. Results: The F1-score was 0.86 (95%CI:0.79-0.91) (Precision: 0.77 (95%CI:0.70-0.83), Recall: 0.96 (95%CI:0.93-0.99)) to identify eosinophils as compared to an F1-score of 0.2 (95%CI:0.13-0.26) for SAU-Net (Precision: 0.38 (95%CI:0.31-0.46), Recall: 0.13 (95%CI:0.08-0.19)). The inter-rater reliability was 0.96 (95%CI:0.93-0.97). The correlation between two pathologists and the algorithm was 0.89 (95%CI:0.82-0.94) and 0.88 (95%CI:0.80-0.94) respectively. Conclusion: Our results indicate that deep learning-based automated eosinophilic cell counting can obtain a robust level of accuracy with a high degree of concordance with manual expert annotations.
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This study conducts a numerical comparison of the thermal performance of three distinct working fluids (pure water, TiO2, and SiO2 water-based nanofluids) within an evacuated tube solar collector using Computational Fluid Dynamics. The study evaluates thermohydraulic performance alongside global and local entropy generation rates, while considering variations in solar radiation values and inlet mass flow rates. Results indicate that nanofluids demonstrate superior performance under low solar radiation, exhibiting higher outlet temperatures, velocities, thermal efficiency, and exergy efficiency compared to pure water. However, at the higher solar radiation level, the efficiency of SiO2 water-based nanofluid diminishes due to its impact on specific heat. Furthermore, the entropy generation analysis reveals significant reductions with TiO2 water-based nanofluid in all the phenomena considered (up to 79 %). The SiO2 nanofluid performance aligns closely with pure water under high radiation value. This investigation offers valuable insights into the utilization of nanofluids in solar collectors across diverse operating conditions, emphasizing their pivotal role in enhancing overall performance.
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INTRODUCTION: Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant inherited disorder defined by the presence of two of the following endocrinopathies: primary hyperparathyroidism, anterior pituitary tumors, and duodenopancreatic neuroendocrine tumors (NETs). NETs, which can secrete hormones including insulin, gastrin, and glucagon, among others, are common in patients with MEN1 and are a major cause of morbidity and premature death. NETs are more common later in life, with very few cases described in children. Here, we describe a unique case of an adolescent with multifocal pancreatic NETs as the single presenting feature of MEN1. CASE PRESENTATION: A 13-year-old healthy male presented with severe weakness, altered mental status, and syncope in the setting of a venous blood glucose (BG) of 36 mg/dL. Workup showed an elevated insulin level (14 µIU/mL) when BG was 39 mg/dL with positive response to glucagon, concerning for hyperinsulinism. Diazoxide and chlorothiazide were started but not well tolerated secondary to emesis. Three suspected NETs were identified by magnetic resonance imaging and 68-Ga DOTATATE PET-CT imaging, including the largest, a 2.1 cm mass in the pancreatic head. A fourth mass in the pancreatic tail was identified via intraoperative ultrasound. All lesions were successfully enucleated and excised, and glucose levels normalized off diazoxide by post-op day 2. While the primary lesion stained for insulin and somatostatin by immunofluorescence (IF), consistent with his clinical presentation, the additional tumors expressed glucagon, somatostatin, pancreatic polypeptide, and chromogranin A but were negative for insulin. Genetic testing confirmed a pathogenic heterozygous mutation in MEN1 (c.969C>A, p.Tyr323). He had no other signs of MEN-associated comorbidities on screening. DISCUSSION/CONCLUSION: This case demonstrates that young patients with MEN1 can present with multifocal NETs. These NETs may have polyhormonal expression patterns despite a clinical presentation consistent with one primary hormone. Our patient had clinical symptoms and laboratory evaluation consistent with an insulinoma but was found to have four NETs, each with different IF staining patterns. Advanced preoperative and intraoperative imaging is important to identify and treat all present NETs. Moreover, serum hormone levels pre- and posttreatment could help evaluate whether NETs are actively secreting hormones into the bloodstream or simply expressing them within the pancreas. Finally, this case highlights the importance of genetic testing for MEN1 in all young patients with insulinomas.
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Pediatric adrenocortical neoplasms (ACNs) are extremely rare tumors in contrast to their adult counterparts. Distinguishing benign from malignant is challenging based on pure morphologic grounds. Previously, 2 scoring systems were proposed in pediatric ACN, including the Wieneke criteria (WC) and its modified version (modified WC [mWC]). In adults, the reticulin algorithm (RA) has proven inexpensive, reliable, predictive, and reproducible; however, it has been validated only recently in children in a limited number of cases. This study aims to assess the RA utility compared with other scoring systems in a series of 92 pediatric ACNs. All cases were individually scored, and mitotic rate cutoffs were recorded. Reticulin alterations were classified as quantitative and qualitative. Outcome data were available in 59/92. The median age was 5 years (0.1 to 18 y) with an M:F of 0.6. Clinical presentation included virilization (39%), Cushing syndrome (21%), other symptoms (4%), and asymptomatic (36%). The reticulin framework was intact in 27% and altered in 73% of cases, showing qualitative (22%), quantitative (73%), and both (5%) alterations. In patients with favorable outcomes, 59% showed either intact reticulin or qualitative alteration compared with the unfavorable outcome group, where 90% showed quantitative alterations. All scoring systems WC ( P < 0.0001), mWC ( P = 0.0003), and the adult/pediatric RA ( P < 0.0001) had predictive value. The RA is comparable to WC and mWC, easier to apply, and is the most sensitive histopathological approach to identifying aggressive behavior in pediatric ACN. Its integration into the WC might be helpful in ACN of uncertain malignant potential and deserves further investigation.
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Neoplasias do Córtex Suprarrenal , Reticulina , Adulto , Criança , Humanos , Pré-Escolar , Neoplasias do Córtex Suprarrenal/diagnóstico , Neoplasias do Córtex Suprarrenal/patologia , Algoritmos , SíndromeRESUMO
Diagnostic advances have not kept pace with the expansion of Lyme disease caused by Borrelia burgdorferi and transmitted by ticks. Lyme disease clinical manifestations can overlap with many other diagnoses making Lyme disease a critical part of many differential diagnoses in endemic areas. Current diagnostic blood tests rely on a 2-tiered algorithm for which the second step is either a time-consuming western blot or a whole cell lysate immunoassay. Neither of these second step tests allow for rapid results of this critical rule out test. We hypothesized that using western blot confirmation information, we could create computational models to propose recombinant second-tier tests that would allow for more rapid, automated, and specific testing algorithms. We propose here a framework for assessing retrospective data to determine putative recombinant assay components. A retrospective pediatric cohort of 2755 samples submitted for Lyme disease screening was assessed using support vector machine learning algorithms to optimize tier 1 diagnostic thresholds for the Vidas IgG II assay and determine optimal tier 2 components for both a positive and negative confirmation test. In cases where the tier 1 screen was negative, but clinical suspicion was high, we found that 1 protein (L58) could be used to reduce false-negative results. For second-tier testing of screen positive cases, we found that 6 proteins could be used to reduce false-positive results (L18, L39M, L39, L41, L45, and L58) with a final machine learning classifier or 2 proteins using a final rules-based approach (L41, L18). This led to an overall accuracy of 92.36% for the proposed algorithm without a final machine learning classifier and 92.12% with integration of the machine learning classifier in the final algorithm when compared to the IgG western blot as the gold-standard. Use of this framework across multiple assays and institutions will allow for a data-driven approach to assay development to provide laboratories and patients with the improvements in turnaround time needed for this testing.
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Eosinophilic gastrointestinal disorders (EGIDs) are a collection of disorders characterized by allergy-driven inflammation of the gastrointestinal (GI) tract. Affected patients typically present with nonspecific symptoms of GI dysfunction and are frequently found to have mucosal abnormalities during endoscopy as well as increased eosinophil levels on tissue biopsy that are felt to be responsible for generating the clinical findings. Each of these findings is important in both the diagnosis and management of EGIDs. Understanding the impact of histopathologic and endoscopic changes on clinical signs and symptoms is critical to developing an understanding of the natural history of these disorders as well as to the generation of validated assessment tools and targeted therapies. We explore these relationships in this review.
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Enterite , Eosinofilia , Gastrite , Enterite/diagnóstico , Eosinofilia/diagnóstico , Gastrite/diagnóstico , Humanos , InflamaçãoRESUMO
BACKGROUND: Laboratory diagnosis of Lyme disease (LD) relies on a two-tier protocol. We have observed disproportionate equivocal serologies in children requiring reflex western blot (WB) using manufacturer-provided ranges based on adult studies. We aimed to determine appropriate ranges for our pediatric population. METHODS: We performed a one-year retrospective institutional review of all 2755 children with LD testing with the Vidas® Lyme IgM II/IgG II immunoassays with reflex to WB for equivocal/positive serologies. Results were assessed by frequency distributions, optimization via percent agreement analysis, and clinical adjudication. RESULTS: The proposed ranges for IgM (negative ≤0.20, equivocal ≥0.21 to <0.32, positive ≥0.32) and IgG (negative ≤0.50, positive >0.50) allowed for a decrease in the IgM equivocal rate (7% to 2%) and IgG positive rate (15% to 13%). There was a decrease in the positive percent agreement between tiers (95% to 83% and 98% to 95%) with increase in the negative (32% to 63% and 70% to 81%) and overall (65% to 73% and 85% to 88%) percent agreements for IgM and IgG, respectively. Of 15 IgM serologies reclassified as negative with a positive WB and not positive for IgG, 8 were clinically negative, 5 were clinically positive, and two had insufficient history. Of the 10 IgG serologies reclassified as negative with a positive WB 3 were clinically positive, 6 were clinically negative and one had insufficient history. CONCLUSIONS: Our modified ranges are more suitable for our pediatric population while reducing overdiagnosis, unnecessary treatment, diagnostic uncertainty, and turnaround time.
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Anticorpos Antibacterianos/sangue , Tomada de Decisão Clínica , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Doença de Lyme/sangue , Criança , Feminino , Humanos , Masculino , Estudos Retrospectivos , Testes SorológicosRESUMO
DICER1 syndrome is characterized by a unique combination of features and a growing list of associated rare tumors. Traditionally, gonadal or extra-gonadal teratomas have not been considered part of this spectrum, with only rare DICER1-related teratoid neoplasms recently reported. Besides, their methylation profiles remain elusive. We report two DICER1-associated malignancies involving the lumbar spine of a 22-year-old man (case 1) and the pelvic cavity of a 14-year-old girl (case 2). Both tumors exhibited teratoma-like features with a high-grade malignant somatic component, including rhabdomyosarcomatous elements for case 1 and a malignant neuroectodermal neoplasm with features of an embryonal tumor with multilayered rosettes (ETMR) for case 2. Both tumors showed strong SALL4 expression and H3K27me3 loss by immunohistochemistry. Next-generation sequencing studies confirmed biallelic DICER1 mutations with additional pathogenic missense mutations in KRAS (case 1) and CTNNB1 (case 2). The methylation profile of case 1 clustered with DICER1-associated sarcomas, whereas case 2 classified as an ETMR (albeit low raw and calibrated score). In conclusion, we report two DICER1-related malignancies with teratoma-like features, further expanding their morphologic spectrum and highlighting the multipotentiality of their presumed cell of origin. Notably, we describe the first ETMR identified outside the CNS with a documented DICER1 biallelic inactivation. Our findings also highlight the potential role of other molecular alterations such as KRAS and CTNNB1 mutations in defining the phenotype of embryonal and primitive DICER1-associated neoplasms, a notion that deserves further studies.
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Neoplasias Ósseas/diagnóstico , RNA Helicases DEAD-box/genética , Neoplasias Embrionárias de Células Germinativas/diagnóstico , Rabdomiossarcoma Embrionário/diagnóstico , Ribonuclease III/genética , Adolescente , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Metilação de DNA , Diagnóstico Diferencial , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Neoplasias Embrionárias de Células Germinativas/genética , Neoplasias Embrionárias de Células Germinativas/patologia , Rabdomiossarcoma Embrionário/genética , Rabdomiossarcoma Embrionário/patologia , Adulto JovemRESUMO
MNTI is a rare tumor of indeterminate histogenesis and molecular signature. We performed methylation and copy number variation (CNV) profiles in patients with MNTI (n = 7) and PAT (n = 1) compared to the methylation brain tumor classifier v11b4 (BT-C) and the medulloblastoma (MB) classifier group 3/4 v1.0 (MB3/4-C). The patients' mean age was 8 months (range: 4-48). The BT-C classified five MNTIs and one PAT (relapse) as class family MB-G3/G4, subclass group 3 (score: >0.9). The remaining two MNTIs and PAT (primary) were classified as class family plexus tumor, subclass pediatric (scores: >0.45). The MB3/4-C classified all MNTIs as high-risk MB-G3, Subtype II (score: >0.45). The primary PAT was classified as subtype III (score: 0.99) and its relapse as subtype II/III. MNTI and PAT clustered close to MB-G3. CNV analysis showed multiple rearrangements in one PAT and two MNTIs. The median follow-up was 54 months (four MNTIs in remission, one PAT died). In conclusion, we demonstrated that MNTI shares a homogenous methylation profile with MB-G3, and possibly with PAT. The role of a multipotent progenitor cell (i.e., early cranial neural crest cell) in their histogenesis and the influence of the anatomical site, tumor microenvironment, and other cytogenetic events in their divergent biologic behavior deserve further investigation.
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The group of CNS mesenchymal (non-meningothelial) and primary glial/neuronal tumors in association with EWSR1-non-ETS rearrangements comprises a growing spectrum of entities, mostly reported in isolation with incomplete molecular profiling. Archival files from three pediatric institutions were queried for unusual cases of pediatric (≤21 years) CNS EWSR1-rearranged tumors confirmed by at least one molecular technique. Extra-axial tumors and cases with a diagnosis of Ewing sarcoma (EWSR1-ETS family fusions) were excluded. Additional studies, including anchored multiplex-PCR with next-generation sequencing and DNA methylation profiling, were performed as needed to determine fusion partner status and brain tumor methylation class, respectively. Five cases (median 17 years) were identified (M:F of 3:2). Location was parenchymal (n = 3) and undetermined (n = 2) with topographic distributions including posterior fossa (n = 1), frontal (n = 1), temporal (n = 1), parietal (n = 1) and occipital (n = 1) lobes. Final designation with fusion findings included desmoplastic small round cell tumor (EWSR1-WT1; n = 1) and tumors of uncertain histogenesis (EWSR1-CREM, n = 1; EWSR1-CREB1, n = 1; EWSR1-PLAGL1, n = 1; and EWSR1-PATZ1, n = 1). Tumors showed a wide spectrum of morphology and biologic behavior. For EWSR1-CREM, EWSR1-PLAGL1 and EWSR1-PATZ1 tumors, no significant methylation scores were reached in the known brain tumor classes. Available outcome (4/5) was reported as favorable (n = 2) and unfavorable (n = 2) with a median follow-up of 30 months. In conclusion, we describe five primary EWSR1-non-ETS fused CNS tumors exhibiting morphologic and biologic heterogeneity and we highlight the clinical importance of determining specific fusion partners to improve diagnostic accuracy, treatment and monitoring. Larger prospective clinicopathological and molecular studies are needed to determine the prognostic implications of histotypes, anatomical location, fusion partners, breakpoints and methylation profiles in patients with these rare tumors.
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Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Proteína EWS de Ligação a RNA/genética , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Fusão Oncogênica , Proteínas de Fusão Oncogênica/genética , Adulto JovemRESUMO
The epithelial cell adhesion molecule (EpCAM) is involved in oncogenesis of hepatoblastomas (HBs). Prior genomic profiling studies showed higher EpCAM expression and worse prognosis in HBs containing primitive histotypes, however, this has not been fully addressed from an immunohistochemical perspective. Our goal is to characterize differential EpCAM immunohistochemistry (EpCAM-IHC) among HBs histotypes. We retrieved 62 HBs from 52 patients. EpCAM-IHC was performed (anti-MOC-31, 1:50 dilution; Cell Marque Corporation, Rocklin, CA) and graded in histotypes using the immunoreactive score. The median age of patients was 2 years (range: 0.4 to 9 y) with a M:F ratio of 1.9. Outcome information was available in 38 patients (alive=30, alive with disease=3, and deceased=5) with median follow-up of 60 months (range: 2 to 171 mo). EpCAM-IHC showed notable overexpression (immunoreactive score >4) in embryonal (89%) and crowded fetal (74%) in contrast to glandular (33%), well-differentiated fetal (32%), and small cell undifferentiated/blastemal (3%) components. Mesenchymal elements were negative. In summary, EpCAM-IHC is helpful to distinguish between epithelial components as it is progressively lost in the transition from embryonal to crowded fetal and into well-differentiated fetal histotypes. Its preferential expression among primitive HBs might have therapeutic and prognostic implications. The significance of its largely negative expression in small cell undifferentiated/blastema is interesting despite its presumed immaturity, deserving further studies.