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BACKGROUND: Percutaneous tibial nerve stimulation is a third-line treatment for overactive bladder and urgency urinary incontinence. During the procedure, a needle is inserted cephalad to the medial malleolus and posterior to the tibia. In recent years, permanent implants and leads have been developed for insertion into the medial ankle via a small incision. There are many important structures present in the medial compartment of the ankle, including the great saphenous vein, saphenous nerve, tibial nerve, posterior tibial vessels, and tendons of the posterior compartment leg muscles. OBJECTIVE: The primary objective of this study was to identify the proximity of the percutaneous tibial nerve stimulation needle placed per Food and Drug Administration-approved device instructions to nearby important anatomic structures. The secondary objectives were to identify the proximity of the tibial nerve to the needle site, identify clinically relevant ankle anatomic structures, and confirm the tibial nerve and posterior tibial vasculature by histologic analysis. STUDY DESIGN: Detailed medial ankle dissections were performed bilaterally on 10 female lightly embalmed anatomic donors (cadavers) obtained from the Willed Body Program at the University of Louisville. A pin was inserted at the percutaneous tibial nerve stimulation needle site, and the medial ankle was minimally dissected so the surrounding anatomic structures were visible but not disrupted. The shortest distance from the pin to the selected structures of the medial ankle region was measured. On completion of each dissection and set of measurements, tissue was harvested for histologic examination. The distances between the pin and each structure were assessed using means and standard deviations. A paired t test was used to assess the difference in the locations between the left and right ankles. Statistical analysis was performed on left-sided, right-sided, and combined measurements. An 80% prediction interval was found to represent the expected range of values for the measurement of a new cadaver or patient, and the 95% confidence interval of the mean was computed to characterize the average distance across all cadavers or patients. RESULTS: The medial ankle of 10 adult female lightly embalmed cadavers were examined bilaterally. Dissections were completed from October 2021 to July 2022. Of note, 80% prediction intervals for the tibial nerve, the posterior tibial artery or vein, and the flexor digitorum longus tendon had a lower range of 0.0 mm from the pin and extending to 12.1, 9.5, and 13.9 mm, respectively. Moreover, 2 of the structures were found to be asymmetrical between the right and left ankles. The great saphenous vein was further from the pin on the left (20.5 mm [standard deviation of 6.4 mm] on the left vs 18.1 mm [standard deviation of 5.3 mm] on the right; P=.04). The calcaneal (Achilles) tendon was further from the pin on the right side (13.2 mm [standard deviation of 6.8 mm] vs 7.9 mm [standard deviation of 6.7 mm]; P=.04). Tibial neurovascular structures were confirmed with microscopic analysis. CONCLUSION: The anatomic structures within the medial ankle lie unexpectedly close to the percutaneous tibial nerve stimulation needle site as noted per Food and Drug Administration-approved device instructions. There is a possibility that some medial ankle structures are not symmetrical. It is crucial that practitioners understand medial ankle anatomy when performing percutaneous tibial nerve stimulation or permanent device insertion.
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Articulação do Tornozelo , Tornozelo , Estados Unidos , Adulto , Humanos , Feminino , Tornozelo/inervação , Tornozelo/cirurgia , Articulação do Tornozelo/patologia , Articulação do Tornozelo/cirurgia , Pé/anatomia & histologia , Pé/cirurgia , Nervo Tibial/anatomia & histologia , Nervo Tibial/cirurgia , CadáverRESUMO
Zika virus (ZIKV) can infect and cause microcephaly and Zika-associated neurological complications in the developing fetal and adult brains. In terms of pathogenesis, a critical question is how ZIKV overcomes the barriers separating the brain from the circulation and gains access to the central nervous system (CNS). Despite the importance of ZIKV pathogenesis, the route ZIKV utilizes to cross CNS barriers remains unclear. Here we show that in mouse models, ZIKV-infected cells initially appeared in the periventricular regions of the brain, including the choroid plexus and the meninges, prior to infection of the cortex. The appearance of ZIKV in cerebrospinal fluid (CSF) preceded infection of the brain parenchyma. Further the brain infection was significantly attenuated by neutralization of the virus in the CSF, indicating that ZIKV in the CSF at the early stage of infection might be responsible for establishing a lethal infection of the brain. We show that cells infected by ZIKV in the choroid plexus were pericytes. Using in vitro systems, we highlight the possibility that ZIKV crosses the blood-CSF barrier by disrupting the choroid plexus epithelial layer. Taken together, our results suggest that ZIKV might exploit the blood-CSF barrier rather than the blood-brain barrier to invade the CNS.
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Plexo Corióideo/patologia , Pericitos/patologia , Infecção por Zika virus/patologia , Animais , Barreira Hematoencefálica/patologia , Encéfalo/patologia , Sistema Nervoso Central/patologia , Chlorocebus aethiops , Plexo Corióideo/metabolismo , Plexo Corióideo/virologia , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microcefalia/complicações , Microcefalia/virologia , Doenças do Sistema Nervoso , Pericitos/metabolismo , Pericitos/virologia , Cultura Primária de Células , Células Vero , Zika virus/fisiologia , Infecção por Zika virus/virologiaRESUMO
Intraoperative desorption electrospray ionization-mass spectrometry (DESI-MS) is used to characterize tissue smears by comparison with a library of DESI mass spectra of pathologically determined tissue types. Measurements are performed in the operating room within 3 min. These mass spectra provide direct information on tumor infiltration into white or gray brain matter based on N-acetylaspartate (NAA) and on membrane-derived complex lipids. The mass spectra also indicate the isocitrate dehydrogenase mutation status of the tumor via detection of 2-hydroxyglutarate, currently assessed postoperatively on biopsied tissue using immunohistochemistry. Intraoperative DESI-MS measurements made at surgeon-defined positions enable assessment of relevant disease state of tissue within the tumor mass and examination of the resection cavity walls for residual tumor. Results for 73 biopsies from 10 surgical resection cases show that DESI-MS allows detection of glioma and estimation of high tumor cell percentage (TCP) at surgical margins with 93% sensitivity and 83% specificity. TCP measurements from NAA are corroborated by indirect measurements based on lipid profiles. Notably, high percentages (>50%) of unresected tumor were found in one-half of the margin biopsy smears, even in cases where postoperative MRI suggested gross total tumor resection. Unresected tumor causes recurrence and malignant progression, as observed within a year in one case examined in this study. These results corroborate the utility of DESI-MS in assessing surgical margins for maximal safe tumor resection. Intraoperative DESI-MS analysis of tissue smears, ex vivo, can be inserted into the current surgical workflow with no alterations. The data underscore the complexity of glioma infiltration.
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Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/cirurgia , Glioma/patologia , Glioma/cirurgia , Monitorização Intraoperatória/métodos , Espectrometria de Massas por Ionização por Electrospray , Adulto , Idoso , Feminino , Substância Cinzenta/patologia , Substância Cinzenta/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Substância Branca/patologia , Substância Branca/cirurgiaRESUMO
Examination of tissue sections using desorption electrospray ionization (DESI)-MS revealed phospholipid-derived signals that differ between gray matter, white matter, gliomas, meningiomas, and pituitary tumors, allowing their ready discrimination by multivariate statistics. A set of lower mass signals, some corresponding to oncometabolites, including 2-hydroxyglutaric acid and N-acetyl-aspartic acid, was also observed in the DESI mass spectra, and these data further assisted in discrimination between brain parenchyma and gliomas. The combined information from the lipid and metabolite MS profiles recorded by DESI-MS and explored using multivariate statistics allowed successful differentiation of gray matter (n = 223), white matter (n = 66), gliomas (n = 158), meningiomas (n = 111), and pituitary tumors (n = 154) from 58 patients. A linear discriminant model used to distinguish brain parenchyma and gliomas yielded an overall sensitivity of 97.4% and a specificity of 98.5%. Furthermore, a discriminant model was created for tumor types (i.e., glioma, meningioma, and pituitary), which were discriminated with an overall sensitivity of 99.4% and a specificity of 99.7%. Unsupervised multivariate statistics were used to explore the chemical differences between anatomical regions of brain parenchyma and secondary infiltration. Infiltration of gliomas into normal tissue can be detected by DESI-MS. One hurdle to implementation of DESI-MS intraoperatively is the need for tissue freezing and sectioning, which we address by analyzing smeared biopsy tissue. Tissue smears are shown to give the same chemical information as tissue sections, eliminating the need for sectioning before MS analysis. These results lay the foundation for implementation of intraoperative DESI-MS evaluation of tissue smears for rapid diagnosis.
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Neoplasias Encefálicas/metabolismo , Metabolismo dos Lipídeos , Metabolômica , Espectrometria de Massas por Ionização por Electrospray/métodos , Ácido Aspártico/análogos & derivados , Ácido Aspártico/metabolismo , Encéfalo/patologia , Diferenciação Celular , Glioma/metabolismo , Substância Cinzenta/patologia , Humanos , Análise de Componente Principal , Substância Branca/patologiaRESUMO
OBJECTIVEThe purpose of this study was to describe effects of adjuvant radiotherapy (RT) for anaplastic meningiomas (AMs) on long-term survival, and to analyze patient and RT characteristics associated with long-term survival.METHODSThe authors queried a retrospective cohort of patients with AM from the National Cancer Database (NCDB) diagnosed between 2004 and 2015 to describe treatment trends. For outcome analysis, patients with at least 10 years of follow-up were included, and they were stratified based on adjuvant RT status and propensity matched to controls for covariates. Survival curves were compared. A data-driven approach was used to find a biologically effective dose (BED) of RT with the largest difference between survival curves. Factors associated with long-term survival were quantified.RESULTSThe authors identified 2170 cases of AM in the NCDB between 2004 and 2015. They observed increased use of adjuvant RT in patients treated with higher doses. A total of 178 cases met the inclusion criteria for outcome analysis. Forty-five percent (n = 80) received adjuvant RT. Patients received a BED of 80.23 ± 16.6 Gy (mean ± IQR). The median survival time was not significantly different (32.8 months for adjuvant RT vs 38.5 months for no RT; p = 0.57, log-rank test). Dichotomizing the patients at a BED of 81 Gy showed maximal difference in survival distribution with a decrease in median survival in favor of no adjuvant RT (31.2 months for adjuvant RT vs 49.7 months for no RT; p = 0.03, log-rank test), but this difference was not significant after false discovery rate correction. Age was a significant predictor for long-term survival.CONCLUSIONSAMs are aggressive tumors that carry a poor prognosis. Conventional adjuvant RT improves local control. However, the effect of adjuvant radiation on overall survival is unclear. Further investigation into this area is warranted.
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Irradiação Craniana , Neoplasias Meníngeas/radioterapia , Meningioma/radioterapia , Radioterapia Adjuvante , Fatores Etários , Idoso , Terapia Combinada , Craniotomia , Gerenciamento Clínico , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Neoplasias Meníngeas/mortalidade , Neoplasias Meníngeas/cirurgia , Meningioma/mortalidade , Meningioma/cirurgia , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Radiocirurgia , Dosagem Radioterapêutica , Estudos Retrospectivos , Fatores Socioeconômicos , Resultado do TratamentoRESUMO
OBJECTIVE: In this phase II study, we investigate clinical outcomes and tolerability of hypofractionated radiotherapy (HRT) combined with temozolomide (TMZ) to treat elderly patients with glioblastoma (GBM). METHODS: Patients 70 years of age or older with newly diagnosed GBM received HRT to a dose of 34 Gy given in ten fractions over 2 weeks, delivered with concurrent and adjuvant TMZ. RESULTS: In this interim analysis, ten patients were enrolled on trial from 12/1/2015 to 4/5/2017. With a median follow-up of 9 months (range 3-12 months), median progression-free survival (PFS) was 6 months. The median overall survival (OS) has not been reached. Estimated 1-year OS and PFS rates were 53.3 and 44.4%, respectively. All patients completed the full course of RT, with no patients developing grade 3 or higher adverse events from treatment. CONCLUSIONS: The preliminary results of our phase II trial suggest HRT delivered over 2 weeks with concurrent and adjuvant TMZ is well tolerated in elderly patients with GBM without compromising clinical outcomes.
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Antineoplásicos Alquilantes/efeitos adversos , Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/radioterapia , Dacarbazina/análogos & derivados , Glioblastoma/tratamento farmacológico , Glioblastoma/radioterapia , Hipofracionamento da Dose de Radiação , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/mortalidade , Dacarbazina/efeitos adversos , Dacarbazina/uso terapêutico , Progressão da Doença , Intervalo Livre de Doença , Feminino , Glioblastoma/mortalidade , Humanos , Masculino , Qualidade de Vida , Inquéritos e Questionários , TemozolomidaRESUMO
BACKGROUND: Pilocytic astrocytoma is a low-grade central nervous system tumor most commonly seen in children. Dissemination from a primary intracranial tumor along the neuroaxis has been described at both presentation and disease progression. However, the development of an intradural extramedullary pilocytic astrocytoma independent of a primary intraparenchymal tumor in an adult patient with no history of pilocytic astrocytoma has rarely been reported. CASE PRESENTATION: A 69-year-old woman presented with progressive myelopathic symptoms and thoracic radicular pain. MRI imaging of the whole spine showed an enhancing intradural extramedullary lesion extending from the cervical cord to T11 causing cord compression. Laminectomies were performed for surgical decompression and histopathology was consistent with pilocytic astrocytoma. Complete staging was done that included imaging of the brain and cerebrospinal fluid cytology. No other tumor was found by these methods. Postoperatively the patient was treated with large field spinal radiation and concurrent chemotherapy followed by adjuvant chemotherapy. She has thus far been clinically and radiographically stable. CONCLUSION: This is a rare case of an adult with multiple spinal pilocytic astrocytomas in an intradural extramedullary location, typically the result of cerebrospinal fluid dissemination of neoplastic cells from a primary intracranial tumor site (i.e. drop metastasis). No conventional primary tumor was identified in this patient, suggesting these tumors may arise from heterotopic gliomas.
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Astrocitoma/tratamento farmacológico , Astrocitoma/cirurgia , Neoplasias da Coluna Vertebral/tratamento farmacológico , Neoplasias da Coluna Vertebral/cirurgia , Idoso , Astrocitoma/líquido cefalorraquidiano , Astrocitoma/diagnóstico por imagem , Descompressão Cirúrgica , Feminino , Humanos , Laminectomia , Imageamento por Ressonância Magnética , Compressão da Medula Espinal/cirurgia , Neoplasias da Coluna Vertebral/líquido cefalorraquidiano , Neoplasias da Coluna Vertebral/diagnóstico por imagemRESUMO
PURPOSE: Ophthalmologists serve an increasing volume of a growing elderly population undergoing increasingly complex outpatient medical care, including extensive diagnostic testing and treatment. The resulting prolonged patient visit times ("patient flow times") limit quality, patient and employee satisfaction, and represent waste. Lean Six Sigma process improvement was used in a vitreoretinal practice to decrease patient flow time, demonstrating that this approach can yield significant improvement in health care. METHODS: Process flow maps were created to determine the most common care pathways within clinic. Three months' visits from the electronic medical record system, which tracks patient task times at each process step in the office were collected. Care tasks and care pathways consuming the greatest time and variation were identified and modified. Follow-up analysis from 6 weeks' visits was conducted to assess improvement. RESULTS: Nearly all patients took one of five paths through the office. Patient flow was redesigned to reduce waiting room time by having staff members immediately start patients into one of those five paths; staffing was adjusted to address high demand tasks, and scheduling was optimized around derived predictors of patient flow times. Follow-up analysis revealed a statistically significant decline in mean patient flow time by 18% and inpatient flow time SD by 4.6%. Patient and employee satisfaction scores improved. CONCLUSION: Manufacturing industry techniques, such as Lean and Six Sigma, can be used to improve patient care, minimize waste, and enhance patient and staff satisfaction in outpatient clinics.
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Instituições de Assistência Ambulatorial/normas , Eficiência Organizacional , Oftalmopatias/terapia , Oftalmologia , Satisfação do Paciente , Gestão da Qualidade Total , Fluxo de Trabalho , Humanos , UnitiolRESUMO
Touch spray mass spectrometry using medical swabs is an ambient ionization technique (ionization of unprocessed sample in the open air) that has potential intraoperative application in quickly identifying the disease state of tissue and in better characterizing the resection margin. To explore this potential, we studied 29 human brain tumor specimens and obtained evidence that this technique can provide diagnostic molecular information that is relevant to brain cancer. Touch spray using medical swabs involves the physical sampling of tissue using a medical swab on a spatial scale of a few mm2 with subsequent ionization occurring directly from the swab tip upon addition of solvent and application of a high voltage. Using a tertiary mixture of acetonitrile, N,N-dimethylformamide, and ethanol, membrane-derived phospholipids and oncometabolites are extracted from the tissue, incorporated into the sprayed microdroplets, vacuumed into the mass spectrometer, and characterized in the resulting mass spectra. The tumor cell load was assessed from the complex phospholipid pattern in the mass spectra and also separately by measurement of N-acetylaspartate. Mutation status of the isocitrate dehydrogenase gene was determined via detection of the oncometabolite 2-hydroxyglutarate. The lack of sample pretreatment makes touch spray mass spectrometry using medical swabs a feasible intraoperative strategy for rapid surgical assessment.
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Neoplasias Encefálicas/cirurgia , Glioma/cirurgia , Margens de Excisão , Espectrometria de Massas , Fosfolipídeos/análise , HumanosRESUMO
INTRODUCTION: Juxtapositional tumors of the spinal nerve roots have been noted to not only interact with the roots at various vertebral levels, but also differ among patients. Therefore, the aim of the current study was to elucidate the potential for variation among the relationships of the meningeal layers at different nerve levels. METHODS: In 20 unembalmed adult cadavers and five fetal specimens, the spinal nerve roots from the cervical, thoracic, and lumbar regions were harvested with their associated meningeal layers and subjected to microdissection, histological analysis, or radiological imaging using 9.4-T MRI. RESULTS: As the nerve rootlets passed from the cord, they received their root sheath covering from the pia. After crossing the subarachnoid space to reach the apertures in the dura, they received two additional looser sheaths, an outer from the dura and an inner from the arachnoid. The pia mater always ended proximal to the arachnoid, and the pia and arachnoid layers extended more distally along the roots with caudal descent. Although the dorsal and ventral roots generally exited through separate dural openings, a single dural opening was also observed, often in the lower spinal regions. Thin intradural septations almost always separated the dorsal and ventral rootlets. The left and right sides frequently differed within individuals. CONCLUSIONS: On the basis of our study, variations of the meninges surrounding the spinal nerve roots are common, but themes do exist. Such data support surgical observations of the different interactions between tumors in these regions with surrounding neural tissues.
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Aracnoide-Máter/patologia , Dura-Máter/patologia , Feto/patologia , Neoplasias da Medula Espinal/patologia , Raízes Nervosas Espinhais/patologia , Nervos Espinhais/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeAssuntos
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , RNA Helicases DEAD-box/genética , Ribonuclease III/genética , Sarcoma/genética , Sarcoma/patologia , Criança , Feminino , Humanos , Corpos de Inclusão/patologia , Masculino , Mutação de Sentido Incorreto , Neurofibromatose 1/complicações , Adulto JovemRESUMO
Cranial fasciitis is a rare lesion of young children characterized by proliferation of fibroblastic spindle cells. Most are scalp masses and are only rarely intracranial, where an association with radiation therapy is exceptional. We report a 32-month-old toddler with a facial rhabdomyosarcoma, diagnosed at 3 months of age, and treated with surgery, chemotherapy and brachytherapy. Brain MRI at 28 months revealed a large, left parasagittal, dural-based, T2 hyperintense and T1 hypointense enhancing mass with superior sagittal sinus compression and bony hyperostosis. The mass was completely resected during an open craniotomy. Histologically, the lesion was comprised of loosely and haphazardly arranged bland spindle cells embedded in a myxoid background. Thick hyalinized collagen bundles were especially prominent. The spindle cells reacted for vimentin but not SMA, myogenin, MyoD1 or EMA. A diagnosis of cranial fasciitis was rendered. The role of radiation therapy in the pathogenesis of intracranial cranial fasciitis is discussed.
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Neoplasias Faciais/diagnóstico , Fasciite/diagnóstico , Rabdomiossarcoma/diagnóstico , Neoplasias Cranianas/diagnóstico , Pré-Escolar , Craniotomia/métodos , Neoplasias Faciais/complicações , Neoplasias Faciais/cirurgia , Fasciite/complicações , Fasciite/cirurgia , Feminino , Humanos , Rabdomiossarcoma/complicações , Rabdomiossarcoma/cirurgia , Neoplasias Cranianas/complicações , Neoplasias Cranianas/cirurgiaRESUMO
BACKGROUND: Stereotactic needle biopsy is valuable for tissue diagnosis of suspected high-grade gliomas, but limited by a sampling error that can lead to inappropriate grading of the tumor or failure to provide diagnosis. Increasing the number of biopsy attempts can increase morbidity. The authors designed a protocol to increase safety and efficiency of the procedure. METHODS: Six consecutive patients with suspected high-grade gliomas who were not candidates for cytoreductive surgery underwent fluorescein-guided stereotactic needle biopsy. All received an injection of 3 mg/kg fluorescein sodium during anesthesia induction. Samples were obtained and observed under a microscope-integrated fluorescent module. If the initial specimens were fluorescent, the procedure was complete if the pathologist confirmed diagnostic tissue. Additional specimens were obtained only at the pathologist's request. An independent neuropathologist later analyzed and graded samples for diagnostic value, tumor, and necrosis. This information was correlated to the degree of intraoperative fluorescent signal in biopsy samples. RESULTS: During six biopsy procedures, 26 specimens were obtained: 15 (58 %) fluorescent and 11 (42 %) nonfluorescent. All fluorescent specimens contained diagnostic tissue appropriate for tumor grading. Of 11 nonfluorescent specimens, four (36 %) did not contain tumor, three (27 %) contained minor hypercellularity or gliosis, and four (36 %) contained tumor with a high proportion of necrosis. All six tumors were diagnosed as glioblastoma multiforme. The sensitivity and specificity for fluorescein fluorescence was 79 % and 100 %, respectively. CONCLUSIONS: Fluorescein fluorescence may improve diagnostic accuracy and expedite stereotactic biopsy procedures.
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Biópsia por Agulha/métodos , Neoplasias Encefálicas/patologia , Protocolos Clínicos/normas , Meios de Contraste , Fluoresceína , Glioma/patologia , Adulto , Idoso , Biópsia por Agulha/efeitos adversos , Biópsia por Agulha/normas , Meios de Contraste/administração & dosagem , Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico , Feminino , Fluoresceína/administração & dosagem , Humanos , Imageamento Tridimensional , Masculino , Microscopia de Fluorescência/métodos , Gradação de Tumores/métodos , Gradação de Tumores/normasRESUMO
INTRODUCTION: Most sources conclude that the spinal accessory nerve (SAN) is a purely motor nerve. There are some reports that suggest a sensory component, although the exact nature of such sensory fibers has yet to be elucidated. With such discrepancies in the literature and with well-established pain syndromes of unknown etiology following SAN injury, the authors performed the present study to better clarify this anatomy. MATERIALS AND METHODS: The entire accessory nerve was harvested from 10 adult cadavers. Samples were then submitted for immunohistochemical analyses. RESULTS: Occasional microganglia cells were identified along the SAN in all specimens. These ganglia were most numerous along the intracranial segment of the SAN, but none was found along the cranial rootlets of the accessory nerve. CONCLUSIONS: Neuronal cell bodies were identified along the course of the SAN in human cadavers. Although the function is not certain, such cells have been found in other animals to be nocioceptive in nature. Pending further study, these cells may be found to be involved in enigmatic pain syndromes thought to arise in the sternocleidomastoid and trapezius muscles.
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Nervo Acessório/citologia , Corpo Celular , Neurônios/citologia , Idoso , Idoso de 80 Anos ou mais , Cadáver , Corpo Celular/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Mycosis fungoides (MF) exhibits a variety of underlying molecular defects including aberrations involving the PTEN tumor suppressor gene. Specifically, loss of heterozygosity of PTEN has been previously demonstrated. We hypothesize that abnormalities of PTEN may result in altered immunohistochemical expression of its protein product. METHODS: Thirty-six MF specimens were stained with monoclonal antibody against PTEN protein. The percentage of nuclei retaining PTEN expression and the staining intensity was recorded. RESULTS: Average percentage of lymphoma cells retaining expression of the PTEN protein was 92% within patch-stage lesions, 81.4% in plaque-stage lesions, and 81.1% in tumor-stage lesions. Average intensity of staining for patch-stage lesions was 2.90, 2.50 for plaque lesions and 2.44 for tumor lesions. Cases lacking loss of heterozygozity at PTEN (n = 6) had an average expression of 81% and an average intensity of staining of 2.42. Whereas, cases with loss of heterozygozity at PTEN (n = 6) had an average expression of 75% of cells with an average staining intensity of 2.33. CONCLUSIONS: The percentage of cells retaining PTEN and staining intensity decrease from patch- to plaque-stage lesions, whereas both parameters show mild diminution in tumor lesions compared with plaque lesions. PTEN expression in a small sample seems to correlate with previous demonstration of loss of heterozygosity at the molecular level. Although a trend for loss of PTEN expression exists with histologic progression of MF, the effect is modest and may not represent the pivotal defect in MF pathogenesis.
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Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Perda de Heterozigosidade , Micose Fungoide/enzimologia , Micose Fungoide/genética , PTEN Fosfo-Hidrolase/análise , PTEN Fosfo-Hidrolase/genética , Neoplasias Cutâneas/enzimologia , Neoplasias Cutâneas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , Biópsia , Feminino , Predisposição Genética para Doença , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Micose Fungoide/patologia , Estadiamento de Neoplasias , Fenótipo , Neoplasias Cutâneas/patologiaRESUMO
We describe a case of a 14-year-old boy who developed a cerebellar and brainstem glioblastoma 5 years after treatment for a medulloblastoma. The patient first presented in 2003 with 9 months of vomiting and a 9-kg weight loss. A head MRI showed a heterogeneously enhancing posterior fossa mass with hydrocephalus. Gross total resection was performed and the tumor was consistent with a classic medulloblastoma. Postoperative chemotherapy and craniospinal radiation was administered. The patient remained tumor-free until 2008, at which time he presented with right-sided weakness and numbness, left eye pain, vomiting and weight loss. Imaging showed abnormalities within the posterior pons, medulla, inferior cerebellar peduncles, cerebellar hemispheres and cervicomedullary junction with expansion of the medulla and cervical spinal cord. Due to the location of the lesion, biopsy was felt to be too risky and was avoided. Despite receiving chemotherapy, his symptoms continued to worsen and he died 4 months later. Post mortem examination limited to the brain and spinal cord confirmed the radiographic extent of the tumor. Microscopic examination showed a highly cellular infiltrative glial neoplasm with extensive palisading necrosis. A diagnosis of glioblastoma was rendered. The question of whether the first and second tumors were related is of potential clinical and academic interest. The first tumor was synaptophysin-positive and GFAP-negative, consistent with medulloblastoma. The second tumor was synaptophysin-negative and focally GFAP-positive, consistent with glioblastoma. The glioblastoma displayed EGF receptor amplification, and interestingly, it also displayed MYCN amplification; both tumors showed low level PTEN deletion. The medulloblastoma displayed a signal pattern consistent with an isochromosome 17q, while the glioblastoma showed some cells with an isochromosome 17q signal pattern amid a background of cells with abundant chromosomal instability. The relationship between these two tumors, particularly with regard to various molecular events, is discussed.
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Neoplasias do Tronco Encefálico/patologia , Neoplasias Cerebelares/patologia , Glioblastoma/patologia , Meduloblastoma/patologia , Autopsia , Biomarcadores Tumorais , Encéfalo/patologia , Neoplasias do Tronco Encefálico/genética , Neoplasias do Tronco Encefálico/psicologia , Neoplasias Cerebelares/genética , Neoplasias Cerebelares/psicologia , Criança , Metilação de DNA , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Evolução Fatal , Glioblastoma/genética , Glioblastoma/psicologia , Humanos , Hidrocefalia/etiologia , Hidrocefalia/cirurgia , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Imageamento por Ressonância Magnética , Masculino , Meduloblastoma/genética , Meduloblastoma/psicologia , Segunda Neoplasia Primária/patologia , Segunda Neoplasia Primária/radioterapia , Tomografia Computadorizada por Raios X , Proteínas Supressoras de Tumor/genética , Derivação VentriculoperitonealRESUMO
CONTEXT.: The diagnosis and clinical management of patients with diffuse gliomas (DGs) have evolved rapidly over the past decade with the emergence of molecular biomarkers that are used to classify, stratify risk, and predict treatment response for optimal clinical care. OBJECTIVE.: To develop evidence-based recommendations for informing molecular biomarker testing for pediatric and adult patients with DGs and provide guidance for appropriate laboratory test and biomarker selection for optimal diagnosis, risk stratification, and prediction. DESIGN.: The College of American Pathologists convened an expert panel to perform a systematic review of the literature and develop recommendations. A systematic review of literature was conducted to address the overarching question, "What ancillary tests are needed to classify DGs and sufficiently inform the clinical management of patients?" Recommendations were derived from quality of evidence, open comment feedback, and expert panel consensus. RESULTS.: Thirteen recommendations and 3 good practice statements were established to guide pathologists and treating physicians on the most appropriate methods and molecular biomarkers to include in laboratory testing to inform clinical management of patients with DGs. CONCLUSIONS.: Evidence-based incorporation of laboratory results from molecular biomarker testing into integrated diagnoses of DGs provides reproducible and clinically meaningful information for patient management.
Assuntos
Glioma , Patologistas , Adulto , Criança , Humanos , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Glioma/diagnóstico , Glioma/genética , Técnicas de Diagnóstico Molecular , Receptor ErbB-2/genética , Revisões Sistemáticas como AssuntoRESUMO
Astroblastomas (ABs) are rare brain tumors of unknown origin. We performed an integrative genetic and epigenetic analysis of AB-like tumors. Here, we show that tumors traceable to neural stem/progenitor cells (radial glia) that emerge during early to later brain development occur in children and young adults, respectively. Tumors with MN1-BEND2 fusion appear to present exclusively in females and exhibit overexpression of genes expressed prior to 25 post-conception weeks (pcw), including genes enriched in early ventricular zone radial glia and ependymal tumors. Other, histologically classic ABs overexpress or harbor mutations of mitogen-activated protein kinase pathway genes, outer and truncated radial glia genes, and genes expressed after 25 pcw, including neuronal and astrocyte markers. Findings support that AB-like tumors arise in the context of epigenetic and genetic changes in neural progenitors. Selective gene fusion, variable imprinting and/or chromosome X-inactivation escape resulting in biallelic overexpression may contribute to female predominance of AB molecular subtypes.
Assuntos
Neoplasias Neuroepiteliomatosas , Células-Tronco Neurais , Linhagem da Célula/genética , Criança , Células Ependimogliais , Feminino , Humanos , Masculino , Neuroglia , Inativação do Cromossomo X/genética , Adulto JovemRESUMO
TP63, a member of the TP53 gene family, is a nuclear marker of myoepithelial cells. Antibody against p63 is frequently used to aid in the diagnosis of prostate carcinoma, as well as in the identification of myoepithelial cells in other tissues including the breast. p63 is also a marker for squamous cell carcinoma. Recently, it was found that all p53 family members are involved in regulating the process of muscle differentiation through the retinoblastoma (RB) protein. Ablation of these p53 family functions blocks the differentiation program and promotes malignant transformation by enabling cooperating oncogenes to transform myoblasts. We therefore studied p63 expression in a number of neoplasms with myogenic differentiation. Immunohistochemical staining for p63 was performed on paraffin sections from 38 rhabdomyosarcomas, five leiomyomas, five leiomyosarcomas, five rhabdomyomas, five rhabdomyomatous Wilms tumors, three normal cardiac muscles, one medullomyoblastoma, one pleuropulmonary blastoma with rhabdomyomatous differentiation, and one teratoma with prominent rhabdomyoblasts. Each case was also stained with desmin. Unlike the nuclear staining scored in myoepithelial cells, only cytoplasmic staining for p63 was considered positive. Of 38 cases of rhabdomyosarcoma, 36 showed cytoplasmic p63 staining; 24 of these showed highlighting of cross-striations superior to that of desmin. In addition, 5/5 rhabdomyomas, 5/5 rhabdomyomatous Wilms tumors, 1/1 pleuropulmonary blastoma with rhabdomyomatous differentiation, 1/1 teratoma with atypical rhabdoblasts, and 1/1 medullomyoblastoma exhibited cytoplasmic p63 staining. Normal cardiac muscle samples (3/3) also demonstrated positive cytoplasmic staining and distinct cross-striations. Smooth muscle tumors exhibited only very focal and faint cytoplasmic staining in 5/5 leiomyomas and 4/5 leiomyosarcomas. Immunoelectron microscopic study of skeletal muscle showed p63 localization to the Z bands of sarcomeres. We conclude that p63 immunostain is a sensitive marker for skeletal muscle differentiation and highlights the cross-striations of strap cells with exceptional definition.
Assuntos
Biomarcadores Tumorais/análise , Diferenciação Celular , Citoplasma/química , Citoplasma/patologia , Imuno-Histoquímica , Microscopia Imunoeletrônica , Músculo Esquelético/química , Músculo Esquelético/patologia , Neoplasias/química , Neoplasias/patologia , Fatores de Transcrição/análise , Proteínas Supressoras de Tumor/análise , Neoplasias Cerebelares/química , Neoplasias Cerebelares/patologia , Citoplasma/ultraestrutura , Humanos , Neoplasias Renais/química , Neoplasias Renais/patologia , Leiomioma/química , Leiomioma/patologia , Leiomiossarcoma/química , Leiomiossarcoma/patologia , Meduloblastoma/química , Meduloblastoma/patologia , Músculo Esquelético/ultraestrutura , Músculo Liso/química , Músculo Liso/patologia , Miocárdio/química , Miocárdio/patologia , Neoplasias/ultraestrutura , Blastoma Pulmonar/química , Blastoma Pulmonar/patologia , Rabdomiossarcoma/química , Rabdomiossarcoma/patologia , Teratoma/química , Teratoma/patologia , Tumor de Wilms/química , Tumor de Wilms/patologiaRESUMO
Interobserver reproducibility in the diagnosis of benign intraductal proliferative lesions has been poor. The aims of the study were to investigate the inter- and intraobserver variability and the impact of the addition of an immunostain for high- and low-molecular weight keratins on the variability. Nine pathologists reviewed 81 cases of breast proliferative lesions in three stages and assigned each of the lesions to one of the following three diagnoses: usual ductal hyperplasia, atypical ductal hyperplasia and ductal carcinoma in situ. Hematoxylin and eosin slides and corresponding slides stained with ADH-5 cocktail (cytokeratins (CK) 5, 14. 7, 18 and p63) by immunohistochemistry were evaluated. Concordance was evaluated at each stage of the study. The interobserver agreement among the nine pathologists for diagnosing the 81 proliferative breast lesions was fair (κ-value=0.34). The intraobserver κ-value ranged from 0.56 to 0.88 (moderate to strong). Complete agreement among nine pathologists was achieved in only nine (11%) cases, at least eight agreed in 20 (25%) cases and seven or more agreed in 38 (47%) cases. Following immunohistochemical stain, a significant improvement in the interobserver concordance (overall κ-value=0.50) was observed (P=0.015). There was a significant reduction in the total number of atypical ductal hyperplasia diagnosis made by nine pathologists after the use of ADH-5 immunostain. Atypical ductal hyperplasia still remains a diagnostic dilemma with wide variation in both inter- and intraobserver reproducibility among pathologists. The addition of an immunohistochemical stain led to a significant improvement in the concordance rate. More importantly, there was an 8% decrease in the number of lesions classified as atypical ductal hyperplasia in favor of usual hyperplasia; in clinical practice, this could lead to a decrease in the number of surgeries carried out for intraductal proliferative lesions.