RESUMEN
Accurate pathological diagnosis is crucial for optimal management of patients with cancer. For the approximately 100 known tumour types of the central nervous system, standardization of the diagnostic process has been shown to be particularly challenging-with substantial inter-observer variability in the histopathological diagnosis of many tumour types. Here we present a comprehensive approach for the DNA methylation-based classification of central nervous system tumours across all entities and age groups, and demonstrate its application in a routine diagnostic setting. We show that the availability of this method may have a substantial impact on diagnostic precision compared to standard methods, resulting in a change of diagnosis in up to 12% of prospective cases. For broader accessibility, we have designed a free online classifier tool, the use of which does not require any additional onsite data processing. Our results provide a blueprint for the generation of machine-learning-based tumour classifiers across other cancer entities, with the potential to fundamentally transform tumour pathology.
Asunto(s)
Neoplasias del Sistema Nervioso Central/diagnóstico , Neoplasias del Sistema Nervioso Central/genética , Metilación de ADN , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias del Sistema Nervioso Central/clasificación , Neoplasias del Sistema Nervioso Central/patología , Niño , Preescolar , Estudios de Cohortes , Femenino , Humanos , Lactante , Masculino , Persona de Mediana Edad , Reproducibilidad de los Resultados , Aprendizaje Automático no Supervisado , Adulto JovenRESUMEN
Sinonasal undifferentiated carcinoma (SNUC) is a rare and aggressive cancer of the sinonasal tract and is often characterized by intracranial invasion. However, SNUC rarely metastasizes to the spine. In this paper, we present a case of extradural metastasis and invasion of the adjacent spine by SNUC. A 42-year-old man presented to our hospital with two-month history of anosmia and nosebleeds. Imaging studies showed a neoplasm of the ethmoid sinus with extension into the anterior cranial fossa. The patient underwent resection of the carcinoma and began chemoradiotherapy. After completing chemoradiotherapy the patient complained of neck pain radiating down the right arm, and imaging showed an extradural mass at the C5 vertebral level. The patient underwent laminectomy for debulking of this tumor. One month later, the patient complained of recurrent weakness and pain in the right shoulder and arm. Imaging showed an extradural tumor wrapping around the C7 and C8 nerve roots, as well as a separate tumor at C2 adherent to the dura. The extradural tumor at C2 was surgically resected. Further imaging showed multiple new soft tissue masses at the thoracic level. We present a case of SNUC metastasis to the extradural spine representing the second case reported in the literature. Peri-dural metastasis and resulting symptoms should be included in the differential diagnosis and assessment of patients with SNUC.
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Carcinoma , Neoplasias del Seno Maxilar , Masculino , Humanos , Adulto , Carcinoma/cirugía , Carcinoma/patología , Neoplasias del Seno Maxilar/patologíaRESUMEN
AIMS: Anaplastic ganglioglioma is a rare tumour, and diagnosis has been based on histological criteria. The 5th edition of the World Health Organization Classification of Tumours of the Central Nervous System (CNS WHO) does not list anaplastic ganglioglioma as a distinct diagnosis due to lack of molecular data in previous publications. We retrospectively compiled a cohort of 54 histologically diagnosed anaplastic gangliogliomas to explore whether the molecular profiles of these tumours represent a separate type or resolve into other entities. METHODS: Samples were subjected to histological review, desoxyribonucleic acid (DNA) methylation profiling and next-generation sequencing. Morphological and molecular data were summarised to an integrated diagnosis. RESULTS: The majority of tumours designated as anaplastic gangliogliomas resolved into other CNS WHO diagnoses, most commonly pleomorphic xanthoastrocytoma (16/54), glioblastoma, isocitrate dehydrogenase protein (IDH) wild type and diffuse paediatric-type high-grade glioma, H3 wild type and IDH wild type (11 and 2/54), followed by low-grade glial or glioneuronal tumours including pilocytic astrocytoma, dysembryoplastic neuroepithelial tumour and diffuse leptomeningeal glioneuronal tumour (5/54), IDH mutant astrocytoma (4/54) and others (6/54). A subset of tumours (10/54) was not assignable to a CNS WHO diagnosis, and common molecular profiles pointing to a separate entity were not evident. CONCLUSIONS: In summary, we show that tumours histologically diagnosed as anaplastic ganglioglioma comprise a wide spectrum of CNS WHO tumour types with different prognostic and therapeutic implications. We therefore suggest assigning this designation with caution and recommend comprehensive molecular workup.
Asunto(s)
Astrocitoma , Neoplasias Encefálicas , Neoplasias del Sistema Nervioso Central , Ganglioglioma , Glioma , Niño , Humanos , Ganglioglioma/patología , Estudios Retrospectivos , Glioma/patología , Astrocitoma/patología , Neoplasias Encefálicas/genética , Neoplasias del Sistema Nervioso Central/patología , Isocitrato DeshidrogenasaRESUMEN
The "isomorphic subtype of diffuse astrocytoma" was identified histologically in 2004 as a supratentorial, highly differentiated glioma with low cellularity, low proliferation and focal diffuse brain infiltration. Patients typically had seizures since childhood and all were operated on as adults. To define the position of these lesions among brain tumours, we histologically, molecularly and clinically analysed 26 histologically prototypical isomorphic diffuse gliomas. Immunohistochemically, they were GFAP-positive, MAP2-, OLIG2- and CD34-negative, nuclear ATRX-expression was retained and proliferation was low. All 24 cases sequenced were IDH-wildtype. In cluster analyses of DNA methylation data, isomorphic diffuse gliomas formed a group clearly distinct from other glial/glio-neuronal brain tumours and normal hemispheric tissue, most closely related to paediatric MYB/MYBL1-altered diffuse astrocytomas and angiocentric gliomas. Half of the isomorphic diffuse gliomas had copy number alterations of MYBL1 or MYB (13/25, 52%). Gene fusions of MYBL1 or MYB with various gene partners were identified in 11/22 (50%) and were associated with an increased RNA-expression of the respective MYB-family gene. Integrating copy number alterations and available RNA sequencing data, 20/26 (77%) of isomorphic diffuse gliomas demonstrated MYBL1 (54%) or MYB (23%) alterations. Clinically, 89% of patients were seizure-free after surgery and all had a good outcome. In summary, we here define a distinct benign tumour class belonging to the family of MYB/MYBL1-altered gliomas. Isomorphic diffuse glioma occurs both in children and adults, has a concise morphology, frequent MYBL1 and MYB alterations and a specific DNA methylation profile. As an exclusively histological diagnosis may be very challenging and as paediatric MYB/MYBL1-altered diffuse astrocytomas may have the same gene fusions, we consider DNA methylation profiling very helpful for their identification.
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Neoplasias Encefálicas/genética , Glioma/genética , Proteínas Proto-Oncogénicas c-myb/genética , Proteínas Proto-Oncogénicas/genética , Transactivadores/genética , Adulto , Neoplasias Encefálicas/patología , Niño , Preescolar , Variaciones en el Número de Copia de ADN , Metilación de ADN , Femenino , Glioma/patología , Humanos , Masculino , Persona de Mediana Edad , Fusión de Oncogenes , Adulto JovenRESUMEN
INTRODUCTION: Pilocytic astrocytoma (PA) with anaplastic features (PAAF) is a rare entity associated with decreased survival. It is characterized by hypercellularity, atypia, brisk mitotic activity, variable necrosis, and association with a classic PA component or anaplastic transformation in a recurrent tumor with a previously-documented classic PA. MATERIALS AND METHODS: We present 5 PAAF cases with clinical, radiological, pathological, and molecular correlation. We interrogated ATRX, IDH, TP53, PTEN, EGFR, BRAF, 6q23, p16(Ink4a) by sequencing, FISH, and immunohistochemistry. RESULTS: Four tumors were located in the cerebellum, and 1 was supratentorial. All showed ATRX protein loss by immunohistochemistry, loss of heterozygosity for PTEN, and had no IDH/TP53/BRAF mutations, nor EGFR amplification. Two of 5 tumors showed BRAF duplication by pyrosequencing. All showed loss of PTEN nuclear expression in subsets of tumor cells, which was associated with variable cytoplasmic positivity for pS6. There was a relative correlation between loss of PTEN expression and pS6 cytoplasmic expression. p53 was expressed in ~ 50% of tumor cells in all tumors. P16 was variably lost in all cases. One tumor showed MYB/6q23 deletion. CONCLUSION: We confirm ATRX protein loss suggestive of ATRX alteration as well as dysregulation of the PI3K/AKT pathway and, less often, of the MAPK/ERK pathway in PAAF.â©.
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Biomarcadores de Tumor/genética , Neoplasias Encefálicas/patología , Recurrencia Local de Neoplasia/patología , Proteína Nuclear Ligada al Cromosoma X/genética , Adulto , Neoplasias Encefálicas/genética , Niño , ADN Helicasas/genética , Femenino , Humanos , Lactante , Masculino , Mutación/genética , Recurrencia Local de Neoplasia/genética , Fosfatidilinositol 3-Quinasas/genética , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas c-akt/genética , Transducción de SeñalRESUMEN
Rathke's cleft cysts (RCC) are sellar-suprasellar cysts that are usually discovered incidentally given their indolent clinical course. When symptoms do arise, the most common clinical presentation is headache, visual field deficits due to visual pathway compression, diplopia due to cavernous sinus compression, chemical meningitis due to spillage of the cyst contents, endocrine dysfunction, and very rarely apoplexy. We present 2 cases of RCC in sisters who developed a sudden onset of symptoms in a manner similar to pituitary apoplexy. Interestingly, one of them had a very unusual presentation with seizure. We hypothesize that acute symptoms occur due to aggressive intracystic overproduction of mucopolysaccharides (with or without hemorrhage) and a resulting compressive syndrome or local irritation of surrounding structures by spillage of the cyst contents. RCC can be encountered incidentally in family members or may have a familiar predisposition. Since both sisters presented here developed apoplexy symptoms, we propose a more frequent follow-up with sequential imaging in patients with a family history of RCC. Transsphenoidal surgery with evacuation of the cyst contents is the treatment modality of choice, with excellent outcomes.
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Quistes del Sistema Nervioso Central/diagnóstico por imagen , Hermanos , Adolescente , Femenino , Cefalea/etiología , Humanos , Imagen por Resonancia Magnética , Náusea/etiología , Enfermedades del Nervio Óptico/etiología , Convulsiones/etiología , Accidente Cerebrovascular/etiología , Trastornos de la Visión/etiologíaRESUMEN
Olfactory neuroblastoma/esthesioneuroblastoma (ONB) is an uncommon neuroectodermal neoplasm thought to arise from the olfactory epithelium. Little is known about its molecular pathogenesis. For this study, a retrospective cohort of n = 66 tumor samples with the institutional diagnosis of ONB was analyzed by immunohistochemistry, genome-wide DNA methylation profiling, copy number analysis, and in a subset, next-generation panel sequencing of 560 tumor-associated genes. DNA methylation profiles were compared to those of relevant differential diagnoses of ONB. Unsupervised hierarchical clustering analysis of DNA methylation data revealed four subgroups among institutionally diagnosed ONB. The largest group (n = 42, 64%, Core ONB) presented with classical ONB histology and no overlap with other classes upon methylation profiling-based t-distributed stochastic neighbor embedding (t-SNE) analysis. A second DNA methylation group (n = 7, 11%) with CpG island methylator phenotype (CIMP) consisted of cases with strong expression of cytokeratin, no or scarce chromogranin A expression and IDH2 hotspot mutation in all cases. T-SNE analysis clustered these cases together with sinonasal carcinoma with IDH2 mutation. Four cases (6%) formed a small group characterized by an overall high level of DNA methylation, but without CIMP. The fourth group consisted of 13 cases that had heterogeneous DNA methylation profiles and strong cytokeratin expression in most cases. In t-SNE analysis, these cases mostly grouped among sinonasal adenocarcinoma, squamous cell carcinoma, and undifferentiated carcinoma. Copy number analysis indicated highly recurrent chromosomal changes among Core ONB with a high frequency of combined loss of chromosome 1-4, 8-10, and 12. NGS sequencing did not reveal highly recurrent mutations in ONB, with the only recurrently mutated genes being TP53 and DNMT3A. In conclusion, we demonstrate that institutionally diagnosed ONB are a heterogeneous group of tumors. Expression of cytokeratin, chromogranin A, the mutational status of IDH2 as well as DNA methylation patterns may greatly aid in the precise classification of ONB.
Asunto(s)
Metilación de ADN , Neuroblastoma/clasificación , Neuroblastoma/genética , Trastornos del Olfato/clasificación , Trastornos del Olfato/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor , Niño , Diagnóstico Diferencial , Femenino , Humanos , Isocitrato Deshidrogenasa/genética , Masculino , Persona de Mediana Edad , Mutación , Transcriptoma , Adulto JovenRESUMEN
In the original publication, the second name of the twentieth author was incorrect. It should read as 'Miguel Sáinz-Jaspeado'. The original publication of the article has been updated to reflect the change. This correction was authored by Ulrich Schüller on behalf of all authors of the original publication.
RESUMEN
Tumors with histological features of pilocytic astrocytoma (PA), but with increased mitotic activity and additional high-grade features (particularly microvascular proliferation and palisading necrosis) have often been designated anaplastic pilocytic astrocytomas. The status of these tumors as a separate entity has not yet been conclusively demonstrated and molecular features have only been partially characterized. We performed DNA methylation profiling of 102 histologically defined anaplastic pilocytic astrocytomas. T-distributed stochastic neighbor-embedding (t-SNE) and hierarchical clustering analysis of these 102 cases against 158 reference cases from 12 glioma reference classes revealed that a subset of 83 of these tumors share a common DNA methylation profile that is distinct from the reference classes. These 83 tumors were thus denominated DNA methylation class anaplastic astrocytoma with piloid features (MC AAP). The 19 remaining tumors were distributed amongst the reference classes, with additional testing confirming the molecular diagnosis in most cases. Median age of patients with MC AAP was 41.5 years. The most frequent localization was the posterior fossa (74%). Deletions of CDKN2A/B (66/83, 80%), MAPK pathway gene alterations (49/65, 75%, most frequently affecting NF1, followed by BRAF and FGFR1) and mutations of ATRX or loss of ATRX expression (33/74, 45%) were the most common molecular alterations. All tumors were IDH1/2 wildtype. The MGMT promoter was methylated in 38/83 tumors (45%). Outcome analysis confirmed an unfavorable clinical course in comparison to PA, but better than IDH wildtype glioblastoma. In conclusion, we show that a subset of histologically defined anaplastic pilocytic astrocytomas forms a separate DNA methylation cluster, harbors recurrent alterations in MAPK pathway genes in combination with alterations of CDKN2A/B and ATRX, affects patients who are on average older than those diagnosed with PA and has an intermediate clinical outcome.
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Astrocitoma/genética , Neoplasias Encefálicas/genética , Isocitrato Deshidrogenasa/genética , Transducción de Señal/genética , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Metilación de ADN/genética , Metilasas de Modificación del ADN/metabolismo , Enzimas Reparadoras del ADN/metabolismo , Femenino , Histonas/genética , Histonas/metabolismo , Humanos , Lactante , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Quinasas de Proteína Quinasa Activadas por Mitógenos/genética , Mutación/genética , Estudios Retrospectivos , Proteínas Supresoras de Tumor/metabolismo , Proteína Nuclear Ligada al Cromosoma X/genética , Adulto JovenRESUMEN
Meningioma is the most common primary brain tumor and carries a substantial risk of local recurrence. Methylation profiles of meningioma and their clinical implications are not well understood. We hypothesized that aggressive meningiomas have unique DNA methylation patterns that could be used to better stratify patient management. Samples (n = 140) were profiled using the Illumina HumanMethylation450BeadChip. Unsupervised modeling on a training set (n = 89) identified 2 molecular methylation subgroups of meningioma (MM) with significantly different recurrence-free survival (RFS) times between the groups: a prognostically unfavorable subgroup (MM-UNFAV) and a prognostically favorable subgroup (MM-FAV). This finding was validated in the remaining 51 samples and led to a baseline meningioma methylation classifier (bMMC) defined by 283 CpG loci (283-bMMC). To further optimize a recurrence predictor, probes subsumed within the baseline classifier were subject to additional modeling using a similar training/validation approach, leading to a 64-CpG loci meningioma methylation predictor (64-MMP). After adjustment for relevant clinical variables [WHO grade, mitotic index, Simpson grade, sex, location, and copy number aberrations (CNAs)] multivariable analyses for RFS showed that the baseline methylation classifier was not significant (p = 0.0793). The methylation predictor, however, was significantly associated with tumor recurrence (p < 0.0001). CNAs were extracted from the 450k intensity profiles. Tumor samples in the MM-UNFAV subgroup showed an overall higher proportion of CNAs compared to the MM-FAV subgroup tumors and the CNAs were complex in nature. CNAs in the MM-UNFAV subgroup included recurrent losses of 1p, 6q, 14q and 18q, and gain of 1q, all of which were previously identified as indicators of poor outcome. In conclusion, our analyses demonstrate robust DNA methylation signatures in meningioma that correlate with CNAs and stratify patients by recurrence risk.
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Metilación de ADN/fisiología , Epigenómica/métodos , Neoplasias Meníngeas/mortalidad , Meningioma/mortalidad , Recurrencia Local de Neoplasia/mortalidad , Adulto , Anciano , Anciano de 80 o más Años , Variaciones en el Número de Copia de ADN/genética , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Antígeno Ki-67/metabolismo , Masculino , Persona de Mediana Edad , Estadísticas no Paramétricas , Adulto JovenRESUMEN
BACKGROUND: Brain metastasis from sarcoma is rare, thus limited information is available. We examined sarcoma brain metastases diagnosed at our institution over a period of 28 years. METHODS: This is a retrospective study of 112 cases. Clinical records were reviewed and clinical, pathological, and survival data were tabulated. RESULTS: Undifferentiated sarcoma was the most common source. In 50 % of cases, the primary sarcoma was in the extremities. Most patients were adults at the time of first brain metastasis, and median age was 34.8 years. Although most patients evidenced metastatic disease to other sites prior to developing brain metastasis, in almost one quarter, brain was the initial site. Most of the metastatic foci were parenchymal, nonhemorrhagic, and solitary. Forty percent of the brain metastatic deposits were located in the frontal lobes. Thirty-one percent recurred-all within 5.3 years. Seventy-six percent of patients succumbed to the disease, with a median survival time of only 0.6 years. Hemorrhagic metastatic foci were found to be associated with significantly lower recurrence-free, as well as disease-specific survivals. No difference in survival was noted between single versus multiple deposits or primary soft tissue versus bone sarcomas. No statistically significant effect on survival was found when neurosurgical resection was combined with radiotherapy. Chemotherapy, on the other hand, was found to significantly improve disease-specific survival when combined with metastasectomy. CONCLUSIONS: Undifferentiated sarcoma was the most common source of brain metastasis. Most cases showed evidence of prior metastatic disease. Surgical resection is employed to manage symptoms, but prognosis remains dismal.
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Neoplasias Óseas/patología , Neoplasias Encefálicas/secundario , Sarcoma/secundario , Neoplasias de los Tejidos Blandos/patología , Adolescente , Adulto , Anciano , Neoplasias Encefálicas/complicaciones , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/terapia , Niño , Preescolar , Supervivencia sin Enfermedad , Extremidades , Femenino , Lóbulo Frontal , Humanos , Lactante , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Sarcoma/complicaciones , Sarcoma/patología , Sarcoma/terapia , Tasa de Supervivencia , Adulto JovenRESUMEN
There is a paucity of literature reporting the outcome of intracranial sarcomas (IS) in children, adolescents, and young adults (CAYA). A multimodal therapeutic approach is commonly used, with no well-established treatment consensus. We conducted a retrospective review of CAYA with IS, treated at our institution, to determine their clinical findings, treatments, and outcomes. Immunohistochemistry (PDGFRA and EGFR) and DNA sequencing were performed on 5 tumor samples. A literature review of IS was also conducted. We reviewed 13 patients (median age, 7 years) with a primary diagnosis of IS between 1990 and 2015. Diagnoses included unclassified sarcoma (n = 9), chondrosarcoma (n = 2), and rhabdomyosarcoma (n = 2). Five patients underwent upfront gross total resection (GTR) of the tumor. The 5-drug regimen (vincristine, doxorubicin, cyclophosphamide, etoposide, and ifosfamide) was the most common treatment used. Nine patients died due to progression or recurrence (n = 8) or secondary malignancy (n = 1). The median follow-up period of the 4 surviving patients was 1.69 years (range 1.44-5.17 years). The 5-year progression-free survival and overall survival rates were 21 and 44 %, respectively. BRAF, TP53, KRAS, KIT, ERBB2, MET, RET, ATM, and EGFR mutations were detected in 4 of the 5 tissue samples. All 5 samples were immunopositive for PDGFRA, and only 2 were positive for EGFR. IS remain a therapeutic challenge due to high progression and recurrence rates. Collaborative multi-institutional studies are warranted to delineate a treatment consensus and investigate tumor biology to improve the disease outcome.
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Biomarcadores de Tumor/metabolismo , Neoplasias Encefálicas/patología , Recurrencia Local de Neoplasia/patología , Neoplasias de los Tejidos Blandos/patología , Adolescente , Adulto , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/terapia , Niño , Preescolar , Terapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Técnicas para Inmunoenzimas , Lactante , Recién Nacido , Masculino , Recurrencia Local de Neoplasia/metabolismo , Recurrencia Local de Neoplasia/terapia , Estadificación de Neoplasias , Pronóstico , Neoplasias de los Tejidos Blandos/metabolismo , Neoplasias de los Tejidos Blandos/terapia , Tasa de Supervivencia , Adulto JovenRESUMEN
Myeloid sarcoma (MS) is an extramedullary malignancy of myeloid origin. It can occur in any organ. Common sites are skin, bone, lymph nodes, and soft tissue. Central nervous system (CNS) involvement is very uncommon. We report 12 new pathology-confirmed cases of CNS MS with literature review. Median age was 42.5 years (range: 0 - 84 years). Bone marrow involvement by hematologic neoplasia was co-incidental (n = 8) or occurred 8 - 51 months prior to CNS MS (n = 3). Abnormal radiological findings detected in all patients, included hemorrhagic (n = 5) or enhancing (n = 2) lesions, with multiple ring-enhancing dura-based masses in 1 patient. Seven tumors had abnormal cytogenetics including: t(11; 19) (q23; p13.3), +8, inv (16), t(9; 22), t(8; 21), del(5q), and +21. One had a complex karyotype and 2 were cytogenetically normal. One MS had the JAK2V617F mutation. Treatment modalities included surgery for decompression (n = 2), radiotherapy (n = 2), chemotherapy (n = 6), and stem cell transplant (n = 2). Nine patients died days to 12 months post CNS MS diagnosis (median = 4 months). Two patients were alive without evidence of disease at 16 and 50 months following MS diagnosis and one was lost to follow-up. The clinical and imaging features for CMS MS overlap with those of intracranial hemorrhage and primary CNS tumors. It is therefore important to maintain a high index of suspicion and perform a biopsy whenever clinically appropriate. A meticulous workup is necessary to avoid misdiagnosis of other hematopoietic or nonhematopoietic neoplasms. Since CNS MS is potentially curable, timely recognition is paramount.
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Neoplasias del Sistema Nervioso Central/patología , Sarcoma Mieloide/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Preescolar , Femenino , Humanos , Lactante , Masculino , Persona de Mediana EdadRESUMEN
Diffuse gliomas are up till now graded based upon morphology. Recent findings indicate that isocitrate dehydrogenase (IDH) mutation status defines biologically distinct groups of tumors. The role of tumor grade and mitotic index in patient outcome has not been evaluated following stratification by IDH mutation status. To address this, we interrogated 558 WHO grade II-III diffuse gliomas for IDH1/2 mutations and investigated the prognostic impact of WHO grade within IDH-mutant and IDH-wild type tumor subsets independently. The prognostic impact of grade was modest in IDH-mutant [hazard ratio (HR) = 1.21, 95 % confidence interval (CI) = 0.91-1.61] compared to IDH-wild type tumors (HR = 1.74, 95 % CI = 0.95-3.16). Using a dichotomized mitotic index cut-off of 4/1000 tumor cells, we found that while mitotic index was significantly associated with outcome in IDH-wild type tumors (log-rank p < 0.0001, HR = 4.41, 95 % CI = 2.55-7.63), it was not associated with outcome in IDH-mutant tumors (log-rank p = 0.5157, HR = 1.10, 95 % CI = 0.80-1.51), and could demonstrate a statistical interaction (p < 0.0001) between IDH mutation and mitotic index (i.e., suggesting that the effect of mitotic index on patient outcome is dependent on IDH mutation status). Patient age, an established prognostic factor in diffuse glioma, was significantly associated with outcome only in the IDH-wild type subset, and consistent with prior data, 1p/19q co-deletion conferred improved outcome in the IDH-mutant cohort. These findings suggest that stratification of grade II-III gliomas into subsets defined by the presence or absence of IDH mutation leads to subgroups with distinct prognostic characteristics. Further evaluation of grading criteria and prognostic markers is warranted within IDH-mutant versus IDH-wild type diffuse grade II-III gliomas as independent entities.
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Neoplasias Encefálicas/genética , Glioma/genética , Isocitrato Deshidrogenasa/genética , Índice Mitótico , Mutación/genética , Adolescente , Adulto , Anciano , Neoplasias Encefálicas/diagnóstico , Deleción Cromosómica , Cromosomas Humanos Par 1/genética , Femenino , Glioma/diagnóstico , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Análisis de Supervivencia , Adulto JovenRESUMEN
The WHO 2007 classification of tumors of the CNS distinguishes between diffuse astrocytoma WHO grade II (A II(WHO2007)) and anaplastic astrocytoma WHO grade III (AA III(WHO2007)). Patients with A II(WHO2007) are significantly younger and survive significantly longer than those with AA III(WHO2007). So far, classification and grading relies on morphological grounds only and does not yet take into account IDH status, a molecular marker of prognostic relevance. We here demonstrate that WHO 2007 grading performs poorly in predicting prognosis when applied to astrocytoma carrying IDH mutations. Three independent series including a total of 1360 adult diffuse astrocytic gliomas with IDH mutation containing 683 A II(IDHmut), 562 AA III(IDHmut) and 115 GBM(IDHmut) have been examined for age distribution and survival. In all three series patients with A II(IDHmut )and AA III(IDHmut) were of identical age at presentation of disease (36-37 years) and the difference in survival between grades was much less (10.9 years for A II(IDHmut), 9.3 years for AA III(IDHmut)) than that reported for A II(WHO2007) versus AA III(WHO2007). Our analyses imply that the differences in age and survival between A II(WHO2007) and AA III(WHO2007) predominantly depend on the fraction of IDH-non-mutant astrocytomas in the cohort. This data poses a substantial challenge for the current practice of astrocytoma grading and risk stratification and is likely to have far-reaching consequences on the management of patients with IDH-mutant astrocytoma.
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Astrocitoma/genética , Astrocitoma/mortalidad , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidad , Isocitrato Deshidrogenasa/genética , Mutación/genética , Adolescente , Adulto , Distribución por Edad , Astrocitoma/clasificación , Neoplasias Encefálicas/clasificación , Cromosomas Humanos Par 1 , Femenino , Humanos , Masculino , Persona de Mediana Edad , Análisis de Supervivencia , Organización Mundial de la Salud , Adulto JovenRESUMEN
Gliosarcoma is classified by the World Health Organization as a variant of glioblastoma. These tumors exhibit biphasic histologic and immunophenotypic features, reflecting both glial and mesenchymal differentiation. Gliosarcomas can be further classified into primary (de novo) tumors, and secondary gliosarcomas, which are diagnosed at recurrence after a diagnosis of glioblastoma. Using a retrospective review, patients seen at MD Anderson Cancer Center between 2004 and 2014 with a pathology-confirmed diagnosis of gliosarcoma were identified. 34 patients with a diagnosis of gliosarcoma seen at the time of initial diagnosis or at recurrence were identified (24 primary gliosarcomas (PGS), 10 secondary gliosarcomas (SGS)). Molecular analysis performed on fourteen patients revealed a high incidence of TP53 mutations and, rarely, EGFR and IDH mutations. Median overall survival (OS) for all patients was 17.5 months from the diagnosis of gliosarcoma, with a progression free survival (PFS) of 6.4 months. Comparing PGS with SGS, the median OS was 24.7 and 8.95 months, respectively (from the time of sarcomatous transformation in the case of SGS). The median OS in SGS patients from the initial diagnosis of GB was 25 months, with a PFS of 10.7 months. Molecular analysis revealed a higher than expected rate of TP53 mutations in GS patients and, typical of primary glioblastoma, IDH mutations were uncommon. Though our data shows improved outcomes for both PGS and SGS when compared to the literature, this is most likely a reflection of selection bias of patients treated on clinical trials at a quaternary center.
Asunto(s)
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidad , Gliosarcoma/genética , Gliosarcoma/mortalidad , Mutación/genética , Proteínas de Neoplasias/genética , Adulto , Anciano , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/terapia , Receptores ErbB/genética , Receptores ErbB/metabolismo , Femenino , Proteína Ácida Fibrilar de la Glía/metabolismo , Gliosarcoma/patología , Gliosarcoma/terapia , Humanos , Isocitrato Deshidrogenasa/genética , Antígeno Ki-67/metabolismo , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/metabolismo , Estudios Retrospectivos , Proteínas S100/metabolismo , Análisis de Supervivencia , Resultado del Tratamiento , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
Glioblastoma is the most common and most aggressive diffuse glioma, associated with short survival and uniformly fatal outcome, irrespective of treatment. It is characterized by morphological, genetic and gene-expression heterogeneity. The current standard of treatment is maximal surgical resection, followed by radiation, with concurrent and adjuvant chemotherapy. Due to the heterogeneity, most tumours develop resistance to treatment and shortly recur. Following recurrence, glioblastoma is quickly fatal in the majority of cases. Recent genetic molecular advances have contributed to a better understanding of glioblastoma pathophysiology and disease stratification. In this paper we review basic glioblastoma pathophysiology, with emphasis on clinically relevant genetic molecular alterations and potential targets for further drug development.
Asunto(s)
Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/genética , Neoplasias Encefálicas/tratamiento farmacológico , Descubrimiento de Drogas , Glioblastoma/tratamiento farmacológico , Medicina de Precisión , Animales , Neoplasias Encefálicas/clasificación , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Resistencia a Antineoplásicos , Predisposición Genética a la Enfermedad , Glioblastoma/clasificación , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/patología , Humanos , Terapia Molecular Dirigida , Selección de Paciente , Fenotipo , Transducción de Señal/efectos de los fármacosRESUMEN
We report a case of alveolar soft part sarcoma (ASPS) presenting as an isolated frontal lobe metastasis. The tumor demonstrated little or no immunoreactivity for a broad panel of antibodies yet strong, diffuse immunoreactivity with CD68. On electron microscopy, the characteristic rectangular to rhomboid crystalline inclusions of ASPS were not present. Electron-dense granules resembling peroxisomes were present, sometimes in association with elongated granular structures having a periodic, lattice-like arrangement. Metastatic ASPS was confirmed by demonstration of an ASPSCR1-TFE3 fusion and imaging studies that excluded metastatic Xp11.2 translocation renal cell carcinoma. The primary site was subsequently identified in the lower extremity.
Asunto(s)
Neoplasias Encefálicas/secundario , Neoplasias Encefálicas/ultraestructura , Diagnóstico Diferencial , Sarcoma de Parte Blanda Alveolar/diagnóstico , Sarcoma de Parte Blanda Alveolar/secundario , Sarcoma de Parte Blanda Alveolar/ultraestructura , Adolescente , Antígenos CD/metabolismo , Antígenos de Diferenciación Mielomonocítica/metabolismo , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/genética , Neoplasias Encefálicas/diagnóstico , Carcinoma de Células Renales/diagnóstico , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Péptidos y Proteínas de Señalización Intracelular , Pierna/patología , Masculino , Microscopía Electrónica de Transmisión , Proteínas de Fusión Oncogénica/genética , Proteínas Recombinantes de Fusión/genéticaRESUMEN
OPINION STATEMENT: Diffuse gliomas are the most common primary brain tumors, with glioblastoma (GBM) encompassing more than 50 % of all cases. Despite aggressive therapy, patients nearly always succumb to their disease and the survival for patients with GBM is approximately 1 year. During past years, numerous scientific contributions have reshaped the field of neuro-oncology and neuropathology. A series of molecular discoveries have shed light on new pathogenic mechanisms, as well as new prognostic and predictive biomarkers with clinical relevance. The current World Health Organization (WHO) classification system is solely based on morphologic criteria; however, there is accumulated evidence that tumors with similar histology have distinct molecular signatures with a clinically significant impact on treatment response and survival. Molecular markers and signatures could be incorporated into the glioma classification and grading system to mirror the clinical outcomes. Additionally, molecular markers could lead to a redefinition of currently controversial entities, such as mixed oligoastrocytomas. Newly discovered molecular alterations also have the potential to become targets for future drug development. Despite tremendous progress in the past decade, therapeutic progress for diffuse gliomas has been slow. A further understanding of glioma biology, in concert with well-designed clinical trials, is necessary to identify more putative molecular biomarkers and unravel the mysteries in the pathogenic mechanisms that trigger this menacing disease.
Asunto(s)
Biomarcadores de Tumor , Neoplasias Encefálicas , Toma de Decisiones , Glioma , Biomarcadores de Tumor/clasificación , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Neoplasias Encefálicas/clasificación , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Islas de CpG/genética , Metilasas de Modificación del ADN/genética , Enzimas Reparadoras del ADN/genética , Receptores ErbB/genética , Regulación Neoplásica de la Expresión Génica , Glioma/clasificación , Glioma/genética , Glioma/terapia , Humanos , Isocitrato Deshidrogenasa/genética , Mutación , Pronóstico , Proteínas Proto-Oncogénicas B-raf/genética , Proteína p53 Supresora de Tumor/genética , Proteínas Supresoras de Tumor/genéticaRESUMEN
Advanced age and contrast enhancement portend a poor prognosis in diffuse glioma (DG). Diffuse glioma may present as nonenhancing tumors that rapidly progress in weeks to months to a pattern of ring enhancement, characteristic of glioblastoma (GBM). Mutations involving isocitrate dehydrogenase 1 (IDH1) have recently emerged as important diagnostic and prognostic markers in DG. R132H is the most common mutation, expressed in more than 80% of DG and secondary GBM but in less than 10% of primary GBM. Adults older than 50 years with nonenhancing, rapidly progressing DG were identified. A comparison group comprised randomly selected, age-matched patients with nonenhancing, nonprogressing DG. Isocitrate dehydrogenase 1 status was evaluated using anti-IDH1-R132H antibodies (Dianova, Hamburg, Germany). The results were correlated with the clinical outcomes. We identified 4 patients who presented with nonenhancing DG that rapidly progressed to ring-enhancing lesions that were subsequently diagnosed on surgical resection as GBM. This group showed absent IDH1-R132H expression, which is characteristic of primary GBM. The comparison group of 5 patients presented with nonenhancing, nonprogressing DG, and all 5 tumors showed IDH1-R132H expression. In conclusion, negative IDH1-R132H mutation status in nonenhancing DG of older adults is a poor prognostic factor associated with rapid progression to ring-enhancing GBM. The shorter interval of progression and negative IDH1-R132H mutation status suggest a similar molecular pathway as seen in primary GBM.