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Cluster of differentiation 73 (CD73), a cell surface enzyme that catalyzes adenosine monophosphate (AMP) breakdown to adenosine, is differentially expressed in cancers and has prognostic significance. We investigated its expression profile in neuroblastoma (NB), its association with NB clinical outcomes, and its influence in the regulation of cancer stem cells' (CSCs) stemness maintenance. RNA-Seq data mining (22 independent study cohorts, total n = 3836) indicated that high CD73 can predict good NB prognosis. CD73 expression (immunohistochemistry) gauged in an NB patient cohort (n = 87) showed a positive correlation with longer overall survival (OS, P = 0.0239) and relapse-free survival (RFS, P = 0.0242). Similarly, high CD73 correlated with longer OS and RFS in advanced disease stages, MYCN non-amplified (MYCN-na), and Stage-4-MYCN-na subsets. Despite no definite association in children < 2 years old (2Y), high CD73 correlated with longer OS (P = 0.0294) and RFS (P = 0.0315) in children > 2Y. Consistently, high CD73 was associated with better OS in MYCN-na, high-risk, and stage-4 subsets of children > 2Y. Multivariate analysis identified CD73 as an independent (P = 0.001) prognostic factor for NB. Silencing CD73 in patient-derived (stage 4, progressive disease) CHLA-171 and CHLA-172 cells revealed cell-line-independent activation of 58 CSC stemness maintenance molecules (QPCR profiling). Overexpressing CD73 in CHLA-20 and CHLA-90 cells with low CD73 and silencing in CHLA-171 and CHLA-172 cells with high CD73 showed that CD73 regulates epithelial to mesenchymal transition (E-Cadherin, N-Cadherin, Vimentin), stemness maintenance (Sox2, Nanog, Oct3/4), self-renewal capacity (Notch), and differentiation inhibition (leukemia inhibitory factor, LIF) proteins (confocal-immunofluorescence). These results demonstrate that high CD73 can predict good prognosis in NB, and further suggest that CD73 regulates stemness maintenance in cells that defy clinical therapy.
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Transición Epitelial-Mesenquimal , Neuroblastoma , Niño , Humanos , Preescolar , Proteína Proto-Oncogénica N-Myc/genética , Pronóstico , Neuroblastoma/genética , Regulación Neoplásica de la Expresión Génica , Línea Celular Tumoral , 5'-Nucleotidasa/genética , 5'-Nucleotidasa/metabolismo , 5'-Nucleotidasa/uso terapéutico , Proteínas Ligadas a GPI/metabolismo , Proteínas Ligadas a GPI/uso terapéuticoRESUMEN
INTRODUCTION: Chordoma is a rare, aggressive tumor that is believed to originate from notochord remnants. It can occur anywhere from the clivus to the sacrum and often recurs even after resection and radiotherapy. We present a unique case that initially suggested a different pathology based on imaging and presentation but was found to be a chordoma on gross and pathological analysis. CASE PRESENTATION: An 11-year-old girl presented outpatient for scoliosis evaluation and was found to have what appeared to be a right L4 peripheral nerve sheath tumor on MRI, causing dextroconvex scoliosis. She underwent a gross total resection via a retroperitoneal approach and was found to have what appeared to be an extraosseous, extradural, extra-spinal canal lumbar chordoma. Immunohistochemical features on surgical pathology were consistent with chordoma. The patient was referred to radiation oncology for adjuvant radiotherapy and pediatric hematology/oncology for recurrence monitoring. DISCUSSION: Our case is the first to present in such a manner, was shown to be external to the spinal canal, encasing the nerve root, and was the first such case in a pediatric patient. We reviewed the growing body of literature on spinal extraosseous chordomas and their characteristics within the pediatric patient population. We also reviewed chordoma pathogenesis theories as well as current and future treatment options.
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Cordoma , Escoliosis , Neoplasias de la Columna Vertebral , Femenino , Humanos , Niño , Cordoma/diagnóstico por imagen , Cordoma/cirugía , Cordoma/patología , Neoplasias de la Columna Vertebral/diagnóstico por imagen , Neoplasias de la Columna Vertebral/cirugía , Radioterapia Adyuvante , Imagen por Resonancia MagnéticaRESUMEN
Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a highly aggressive malignant tumor affecting predominantly young adults and adolescents with an average age of 23.9 at time of diagnosis. Up to two thirds of patients have paraneoplastic hypercalcemia. The molecular signature of these tumors is SMARCA4 mutations, with somatic and germline pathogenic variants previously described. We report a case of a previously healthy one-year-old girl who was noticed to have mild anemia and an abdominal mass during a well-child visit. Further laboratory testing revealed hypercalcemia. A computerized tomography scan showed a left-sided ovarian mass (9.3 x 7.3 x 7 cm). The resection specimen showed a large ovarian tumor with solid tan-yellow cut surfaces and small foci of necrosis. Microscopically, the tumor was composed of sheets of small, hyperchromatic epithelioid cells with focal rhabdoid large cell morphology. The tumor cells were strongly and diffusely positive for WT1 (N-terminal antibodies) with focal EMA and Pan-keratin positivity. Absent SMARCA4 (BRG1) protein expression by immunohistochemistry ultimately established the diagnosis of small cell carcinoma of the ovary, hypercalcemic type. To our knowledge, this is the youngest patient reported in the literature.
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Carcinoma de Células Pequeñas/diagnóstico , Hipercalcemia/etiología , Neoplasias Ováricas/diagnóstico , Síndromes Paraneoplásicos/etiología , Biomarcadores de Tumor/metabolismo , Carcinoma de Células Pequeñas/complicaciones , Carcinoma de Células Pequeñas/metabolismo , Carcinoma de Células Pequeñas/patología , ADN Helicasas/metabolismo , Femenino , Humanos , Hipercalcemia/diagnóstico , Lactante , Proteínas Nucleares/metabolismo , Neoplasias Ováricas/complicaciones , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Síndromes Paraneoplásicos/diagnóstico , Factores de Transcripción/metabolismoRESUMEN
AIMS: Several morphologically overlapping (myo)fibroblastic neoplasms harbour USP6 fusions, including aneurysmal bone cysts, nodular fasciitis, myositis ossificans, cranial fasciitis, fibro-osseous pseudotumour of the digits, and cellular fibroma of the tendon sheath. USP6-induced neoplasms are almost universally benign and cured by local excision. We aim to highlight the diagnostic value of USP6 fusion detection in a series of aggressive-appearing paediatric myofibroblastic tumours. METHODS AND RESULTS: Three deep-seated, radiographically aggressive, and rapidly growing childhood myofibroblastic neoplasms were morphologically and molecularly characterised by USP6 break-apart fluorescence in-situ hybridisation (FISH), transcriptome sequencing, and targeted capture analysis. Each tumour occurred in the lower-extremity deep soft tissue of a child presenting with pain, limping, or a mass. In all three patients, imaging studies showed a solid mass that infiltrated into surrounding skeletal muscle or involved/eroded underlying bone. The biopsied tumours consisted of variably cellular myofibroblastic proliferations with variable mitotic activity that lacked overt malignant cytological features. FISH showed that all tumours had USP6 rearrangements. On the basis of these results, all three patients were treated with conservative excision with positive margins. The excised tumours had foci resembling nodular fasciitis, fibromatosis, and pseudosarcomatous proliferation. Next-generation sequencing revealed COL1A1-USP6 fusions in two tumours and a COL3A1-USP6 fusion in the third tumour. One tumour had a subclonal somatic APC in-frame deletion. No recurrence was observed during follow-up (8-40 months). CONCLUSION: We present a series of benign, but aggressive-appearing, USP6-rearranged myofibroblastic tumours. These deep-seated tumours had concerning clinical and radiographic presentations and did not fit into one distinct histological category. These cases highlight the diagnostic value of USP6 fusion detection to identify benign nondescript tumours of this group, especially those with aggressive features, to avoid overtreatment.
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Miofibroma/genética , Miofibroma/patología , Neoplasias de los Tejidos Blandos/genética , Neoplasias de los Tejidos Blandos/patología , Ubiquitina Tiolesterasa/genética , Niño , Preescolar , Fascitis/genética , Fascitis/patología , Femenino , Reordenamiento Génico , Humanos , Lactante , Masculino , Miositis Osificante/genética , Miositis Osificante/patología , Fusión de Oncogenes/genética , Proteínas de Fusión Oncogénica/genética , Periostio/patologíaRESUMEN
BACKGROUND: Disruption of tight junctions (TJs) predisposes to bacterial translocation, intestinal inflammation, and necrotizing enterocolitis (NEC). Previously, studies showed that hyaluronan (HA), a glycosaminoglycan in human milk, maintains intestinal permeability, enhances intestinal immunity, and reduces intestinal infections. In this study, we investigated the effects of HA 35 kDa on a NEC-like murine model. METHODS: Pups were divided into Sham, NEC, NEC+HA 35, and HA 35. Severity of intestinal injury was compared using a modified macroscopic gut scoring and histologic injury grading. The effect of HA 35 on intestinal permeability was determined by measuring FITC dextran and bacterial translocation. RNA and protein expression of TJ proteins (claudin-2, -3, -4, occludin, and ZO-1) were compared between the groups. RESULTS: Pups in the NEC+HA 35 group had increased survival and lower intestinal injury compared to untreated NEC. In addition, HA 35 reduced intestinal permeability, bacterial translocation, and proinflammatory cytokine release. Ileal expression of claudin-2, -3, -4, occludin, and ZO-1 was upregulated in NEC+HA 35 and HA 35 compared to untreated NEC and shams. CONCLUSION: These findings suggest that HA 35 protects against NEC partly by upregulating intestinal TJs and enhancing intestinal barrier function.
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Enterocolitis Necrotizante/prevención & control , Ácido Hialurónico/farmacología , Uniones Estrechas/efectos de los fármacos , Animales , Modelos Animales de Enfermedad , Enterocolitis Necrotizante/microbiología , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/microbiología , Klebsiella pneumoniae/aislamiento & purificación , Klebsiella pneumoniae/patogenicidad , Ratones , Uniones Estrechas/patologíaRESUMEN
Introduction: Epithelioid sarcoma is a malignant mesenchymal tumor exhibiting epithelioid cytomorphology and epithelial phenotype. Its histogenesis is unknown, but its tumorigenesis may relate to inactivation of hSNF5/SMARCB1/INI1 tumor suppressor gene. This tumor typically affects young adults and older children, but it is uncommon in infants. Case Report: We describe a unique neoplasm in a 15-month-old infant presenting with a heel mass. The tumor was remarkable for retention of SMARCB1/INI1 expression. Conventional cytogenetic analysis revealed trisomy 2 and double minutes, and SNP array analysis confirmed the trisomy 2 and identified segmental amplification of chromosome 11 containing YAP1 and BIRC3; FISH testing proved that the double minutes consisted of BIRC3 and YAP1, potent oncogenes related to tumorigenesis of several types of tumors but not described in epithelioid sarcoma. Conclusion: Our findings expand the spectrum of cytogenetic alterations in this neoplasm, help in better understanding its tumorigenesis, and suggest potential therapeutic targets.
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Proteína 3 que Contiene Repeticiones IAP de Baculovirus/genética , Regulación Neoplásica de la Expresión Génica/genética , Sarcoma/genética , Neoplasias de los Tejidos Blandos/genética , Biomarcadores de Tumor/metabolismo , Carcinogénesis/genética , Niño , Proteínas de Unión al ADN/metabolismo , Humanos , Masculino , Proteína SMARCB1/genética , Sarcoma/diagnóstico , Sarcoma/metabolismo , Neoplasias de los Tejidos Blandos/diagnóstico , Neoplasias de los Tejidos Blandos/metabolismo , Factores de Transcripción/genética , Trisomía/genética , Adulto JovenRESUMEN
BACKGROUND: MYCN amplification directly correlates with the clinical course of neuroblastoma and poor patient survival, and serves as the most critical negative prognostic marker. Although fluorescence in situ hybridization (FISH) remains the gold standard for clinical diagnosis of MYCN status in neuroblastoma, its limitations warrant the identification of rapid, reliable, less technically challenging, and inexpensive alternate approaches. METHODS: In the present study, we examined the concordance of droplet digital PCR (ddPCR, in combination with immunohistochemistry, IHC) with FISH for MYCN detection in a panel of formalin-fixed paraffin-embedded (FFPE) human neuroblastoma samples. RESULTS: In 112 neuroblastoma cases, ddPCR analysis demonstrated a 96-100% concordance with FISH. Consistently, IHC grading revealed 92-100% concordance with FISH. Comparing ddPCR with IHC, we observed a concordance of 95-98%. CONCLUSIONS: The results demonstrate that MYCN amplification status in NB cases can be assessed with ddPCR, and suggest that ddPCR could be a technically less challenging method of detecting MYCN status in FFPE specimens. More importantly, these findings illustrate the concordance between FISH and ddPCR in the detection of MYCN status. Together, the results suggest that rapid, less technically demanding, and inexpensive ddPCR in conjunction with IHC could serve as an alternate approach to detect MYCN status in NB cases, with near-identical sensitivity to that of FISH.
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Proteína Proto-Oncogénica N-Myc/genética , Neuroblastoma/diagnóstico , Reacción en Cadena de la Polimerasa , Biomarcadores de Tumor/genética , Formaldehído , Amplificación de Genes , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Neuroblastoma/genética , Neuroblastoma/patología , Adhesión en Parafina , Sensibilidad y EspecificidadRESUMEN
Multifocal lymphangioendotheliomatosis with thrombocytopenia is a rare disease characterized by multiple cutaneous and gastrointestinal (GI) vascular lesions and thrombocytopenia refractory to platelet and blood cell transfusions. GI bleeding can become life-threatening in this condition. We report a case of multifocal lymphangioendotheliomatosis with thrombocytopenia in a male infant with isolated GI involvement, diagnosed when he was 3 months old. The patient was managed with daily aminocaproic acid, octreotide drip, and corticosteroids for 13 months after diagnosis; he had complete resolution of symptoms by 2 years of age and showed adequate height and gain by 5 years of age. This case adds to the paucity of data in the literature pertaining to the disease's phenotypic variability, long-term clinical course, and management of GI bleeding.
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Corticoesteroides/administración & dosificación , Ácido Aminocaproico/administración & dosificación , Hemorragia Gastrointestinal , Linfangioma , Octreótido/administración & dosificación , Trombocitopenia , Hemorragia Gastrointestinal/diagnóstico , Hemorragia Gastrointestinal/tratamiento farmacológico , Humanos , Lactante , Linfangioma/diagnóstico , Linfangioma/tratamiento farmacológico , Masculino , Trombocitopenia/diagnóstico , Trombocitopenia/tratamiento farmacológicoRESUMEN
A case report of a congenital, lingual, salivary gland choristoma with bifid tongue and cleft palate is presented. The patient was born with airway obstruction in supine positioning. Laryngoscopy revealed a midline tongue mass that extended into the hypopharyx and pathological examination showed a congenital ectopic salivary gland. The bifid tongue was repaired at the time of surgical excision. Literature review revealed nine additional cases of congenital lingual mass, bifid tongue, and cleft palate. The most common tongue mass reported was hamartoma (40%), but the differential diagnoses include hamartoma, teratoma, and salivary choristoma.
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Coristoma/diagnóstico , Fisura del Paladar/complicaciones , Glándulas Salivales , Enfermedades de la Lengua/diagnóstico , Lengua/anomalías , Anomalías Múltiples , Diagnóstico Diferencial , Femenino , Humanos , Recién Nacido , Laringoscopía , Lengua/cirugía , Enfermedades de la Lengua/cirugíaRESUMEN
BACKGROUND: Schimke immuno-osseous dysplasia (SIOD) is an autosomal recessive disorder caused by mutations in SMARCAL1. A frequent complication is arteriosclerosis associated with reduced elastin expression; however, the mechanism underlying the reduced elastin expression remains unknown. METHODS: Expression of transcriptional regulators of elastin (ELN) and microRNA (miRNA) regulators of ELN messenger RNA (mRNA), ELN promoter methylation, and ELN mRNA poly(A) tail length were assessed by quantitative RT-PCR, bisulfite Sanger sequencing, and the Poly(A) Tail Length Assay Kit, respectively, in unaffected developing human aortae and in an SIOD aorta. RESULTS: Comparing unaffected fetal and adult aortae, ELN precursor mRNA (pre-mRNA) levels remained nearly constant, whereas mRNA levels declined by ~10(2)-fold. This corresponded with a reduction in poly(A) tail length but not with changes in the other parameters. In contrast, compared to the unaffected fetal aortae, the SIOD aorta had 18-fold less ELN pre-mRNA and 10(4)-fold less mRNA. This corresponded with increased expression of miRNA regulators and shorter ELN mRNA poly(A) tail lengths but not with altered expression of ELN transcriptional regulators or ELN promoter methylation. CONCLUSION: Posttranscriptional mechanisms account for the reduction in ELN mRNA levels in unaffected aortae, whereas transcriptional and posttranscriptional mechanisms reduce elastin expression in SIOD aorta and predispose to arteriosclerosis.
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Aorta/metabolismo , Arteriosclerosis/genética , Elastina/genética , Síndromes de Inmunodeficiencia/genética , Síndrome Nefrótico/genética , Osteocondrodisplasias/genética , Embolia Pulmonar/genética , Precursores del ARN/genética , Procesamiento Postranscripcional del ARN , ARN Mensajero/genética , Transcripción Genética , Adolescente , Adulto , Aorta/embriología , Aorta/patología , Arteriosclerosis/embriología , Arteriosclerosis/metabolismo , Arteriosclerosis/patología , Estudios de Casos y Controles , Células Cultivadas , Niño , Preescolar , Metilación de ADN , Regulación hacia Abajo , Elastina/metabolismo , Femenino , Edad Gestacional , Humanos , Síndromes de Inmunodeficiencia/embriología , Síndromes de Inmunodeficiencia/metabolismo , Síndromes de Inmunodeficiencia/patología , Masculino , MicroARNs/genética , MicroARNs/metabolismo , Persona de Mediana Edad , Síndrome Nefrótico/embriología , Síndrome Nefrótico/metabolismo , Síndrome Nefrótico/patología , Osteocondrodisplasias/embriología , Osteocondrodisplasias/metabolismo , Osteocondrodisplasias/patología , Enfermedades de Inmunodeficiencia Primaria , Regiones Promotoras Genéticas , Embolia Pulmonar/embriología , Embolia Pulmonar/metabolismo , Embolia Pulmonar/patología , Precursores del ARN/metabolismo , ARN Mensajero/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismoAsunto(s)
Placenta/fisiología , Recuento de Plaquetas , Embarazo/sangre , Recuento de Células Sanguíneas , Coagulación Sanguínea , Recolección de Muestras de Sangre/métodos , Capilares/fisiología , Vellosidades Coriónicas/ultraestructura , Femenino , Sangre Fetal , Hemoglobinas/análisis , Humanos , Placenta/irrigación sanguíneaRESUMEN
The aetiology of failure to thrive (FTT) in children is broad, of which some conditions are extremely rare. It is important to consider these rarer conditions, especially in the setting of other concerning signs/symptoms or when there is no improvement with conventional treatment. In this case report we highlight such a rare condition-chylomicron retention disease (CRD) as an aetiology of FTT. CRD often presents with non-specific symptoms, resulting in delayed diagnosis which is established by genetic workup and histology from small intestinal biopsies. Despite being rare, CRD needs to be considered as one of the differential diagnoses after ruling out the more common causes of FTT.
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Insuficiencia de Crecimiento , Síndromes de Malabsorción , Humanos , Insuficiencia de Crecimiento/etiología , Síndromes de Malabsorción/diagnóstico , Síndromes de Malabsorción/complicaciones , Diagnóstico Diferencial , Hipobetalipoproteinemias/genética , Hipobetalipoproteinemias/diagnóstico , Hipobetalipoproteinemias/complicaciones , Masculino , Lactante , Femenino , Intestino Delgado/patología , BiopsiaRESUMEN
Percutaneous renal biopsy is commonly used for kidney cancer diagnosis. However, the biopsy procedure remains challenging in sampling accuracy. Here we introduce a forward-viewing optical coherence tomography probe for differentiating tumor and normal tissues, aiming at precise biopsy guidance. Totally, ten human kidney samples, nine of which had malignant renal carcinoma and one had benign oncocytoma, were used for system evaluation. Based on their distinct imaging features, carcinoma could be efficiently distinguished from normal renal tissues. Additionally, oncocytoma could be differentiated from carcinoma. We developed convolutional neural networks for tissue recognition. Compared to the conventional attenuation coefficient method, convolutional neural network models provided more accurate carcinoma predictions. These models reached a tissue recognition accuracy of 99.1% on a hold-out set of four kidney samples. Furthermore, they could efficiently distinguish oncocytoma from carcinoma. In conclusion, our convolutional neural network-aided endoscopic imaging platform could enhance carcinoma diagnosis during percutaneous renal biopsy procedures.
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OBJECTIVES: Autoimmune pancreatitis (AIP) is a rare form of a chronic, immune-mediated, inflammatory pancreatic condition. There is limited data regarding presentation and outcome in the pediatric population. We described a single-center case series of 4 pediatric patients with AIP to better understand the presentation, symptoms, and outcomes of this rare condition. METHODS: Data collected included demographics, serology markers, symptoms at presentation, imaging, additional organ involvement, histology, treatment methods, and outcomes. The diagnosis of AIP was made by a combination of serology, pancreatic imaging, histology, extrapancreatic manifestations, and steroid response. RESULTS: All patients were diagnosed with type 2 AIP. Abdominal pain, emesis, and obstructive jaundice were the most common symptoms at presentation. Autoimmune markers were negative. Cross-sectional abdominal imaging showed diffuse/focal pancreatic gland enlargement and common bile duct stricture universally and main pancreatic duct irregularity in half of the patients. Biopsies showed lymphoplasmacytic infiltration with associated pancreatic fibrosis and atrophy. Treatment with an 8-week tapering course of prednisone showed prompt response with resolution of symptoms and normalization of laboratory test results. CONCLUSIONS: Our case series shows that AIP in children is a rare entity with a distinct clinical presentation, classical radiographic and histological features with good long-term prognosis.
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OBJECTIVES: Diagnosis of angiomatoid fibrous histiocytoma (AFH) can be challenging due to its variable histologic features and a lack of highly sensitive and/or specific immunohistochemical markers. The utility of TLE1 and BCOR as immunohistochemical markers for AFH is not known. METHODS: We examined the spectrum of histologic features of 36 AFHs, and studied the expression of both TLE1 and BCOR in AFH and its mimics by immunohistochemical staining. Positive nuclear expression was scored semiquantitatively. RESULTS: Both typical and unusual histologic features of AFHs were observed in this cohort. TLE1 was moderately to strongly positive in 36/36 AFHs, 4/4 synovial sarcomas, and 2/3 BCOR sarcomas; weakly positive in 4/6 inflammatory myofibroblastic tumors; negative in all dermatofibromas (n = 10), atypical fibrous histiocytomas (n = 5), myofibroma (n = 2) and juvenile xanthogranulomas (n = 5), with an overall sensitivity of 100%, and specificity of 71.4% for AFH. BCOR was moderately to strongly positive in 24/36 AFHs, 4/4 synovial sarcomas, 3/3 BCOR sarcomas, and 1/5 atypical fibrous histiocytomas; weakly positive in 10/36 AFHs; negative in the remaining tumors. The overall sensitivity and specificity of BCOR for AFH were 94.4% and 77.1%, respectively. CONCLUSIONS: TLE1 is a highly sensitive immunohistochemical marker for AFH.
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Percutaneous renal biopsy (PRB) is commonly used for kidney cancer diagnosis. However, current PRB remains challenging in sampling accuracy. This study introduces a forward-viewing optical coherence tomography (OCT) probe for differentiating tumor and normal tissues, aiming at precise PRB guidance. Five human kidneys and renal carcinoma samples were used to evaluate the performance of our probe. Based on their distinct OCT imaging features, tumor and normal renal tissues can be accurately distinguished. We examined the attenuation coefficient for tissue classification and achieved 98.19% tumor recognition accuracy, but underperformed for distinguishing normal tissues. We further developed convolutional neural networks (CNN) and evaluated two CNN architectures: ResNet50 and InceptionV3, yielding 99.51% and 99.48% accuracies for tumor recognition, and over 98.90% for normal tissues recognition. In conclusion, combining OCT and CNN significantly enhanced the PRB guidance, offering a promising guidance technology for improved kidney cancer diagnosis.