RESUMO
The primary treatment for retroperitoneal sarcomas is surgery. This requires a carefully planned, typically multivisceral, resection. A few complex scenarios that may arise include vascular involvement, pancreatic involvement, or herniation of the tumor into another compartment outside of the retroperitoneum. These scenarios must be anticipated before surgery to optimize preoperative preparation, minimize postoperative morbidity and mortality, and improve oncologic outcomes. Our aim is to highlight these clinically challenging anatomic presentations that can be encountered in patients with retroperitoneal sarcomas.
Assuntos
Neoplasias Retroperitoneais , Sarcoma , Neoplasias de Tecidos Moles , Humanos , Sarcoma/patologia , Pâncreas/cirurgia , Abdome , Neoplasias Retroperitoneais/cirurgia , Estudos RetrospectivosRESUMO
Leptomeningeal metastasis is extremely rare in patients with ovarian cancer, but should be considered in patients presenting with neurologic deficits such as cauda equine syndrome. Given its poor prognosis and lack of data currently on management, additional studies are needed to optimize treatment regimens and improve outcomes.
RESUMO
BACKGROUND: Atypical teratoid/rhabdoid tumors (AT/RTs) are highly malignant neoplasms that rarely occur in adults. Due to the complex histology of AT/RTs, the differential diagnosis of these tumors is quite challenging and increasingly relies on demonstration of characteristic SMARCB1/INI1 inactivation in tumor cells. CASE DESCRIPTION: A 51-year-old man presented with diplopia, lethargy, and memory deficit owing to Parinaud syndrome and hydrocephalus. Magnetic resonance imaging revealed a T2-hyperintense and homogeneously enhancing tectal mass that extended to the pineal region. Initial biopsy suggested a World Health Organization grade II myxopapillary astrocytoma. However, subsequent definitive resection revealed an AT/RT, with loss of SMARCB1/INI1 observed through immunohistochemical staining as well as array cytogenetic analysis. Molecular profiling revealed additional mutations in RHPN2(L385I), MDM4(D396G), FLT3(V194M), and NPRL3(D53N). CONCLUSIONS: Pathologic diagnoses in the modern era increasingly integrate molecular data for confirmation as well as prognostication. We present a rare case of a tectal AT/RT in an adult patient and report several novel mutations previously unrecognized in this tumor subtype, in addition to canonical SMARCB1/INI1 loss. Further investigation of these novel variants may improve understanding of the pathogenesis underlying AT/RTs.
Assuntos
Neoplasias Infratentoriais/diagnóstico , Tumor Rabdoide/diagnóstico , Teratoma/diagnóstico , Biópsia , Encéfalo/patologia , Encéfalo/cirurgia , Quimiorradioterapia Adjuvante , Proteínas Cromossômicas não Histona/genética , Terapia Combinada , Análise Mutacional de DNA , Proteínas de Ligação a DNA/genética , Diagnóstico Diferencial , Inativação Gênica , Marcadores Genéticos/genética , Humanos , Neoplasias Infratentoriais/genética , Neoplasias Infratentoriais/patologia , Neoplasias Infratentoriais/radioterapia , Neoplasias Infratentoriais/cirurgia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Exame Neurológico , Neoplasias Hipofisárias/diagnóstico , Neoplasias Hipofisárias/genética , Neoplasias Hipofisárias/patologia , Neoplasias Hipofisárias/cirurgia , Tumor Rabdoide/genética , Tumor Rabdoide/patologia , Tumor Rabdoide/radioterapia , Tumor Rabdoide/cirurgia , Proteína SMARCB1 , Teratoma/genética , Teratoma/patologia , Teratoma/radioterapia , Teratoma/cirurgia , Fatores de Transcrição/genéticaRESUMO
BACKGROUND: Pineal parenchymal tumors of intermediate differentiation (PPTIDs) are rare lesions. The differential diagnosis and management strategy for PPTIDs can be challenging because of the variable prognostic and pathologic characteristics of these tumors. METHODS: A 24-year-old man presented with progressive headaches, gait abnormalities, and abulia. Magnetic resonance imaging revealed a large T1-hypointense, T2-isointense, contrast-enhancing, partially cystic mass of the pineal and tectal region. Near-total resection was achieved in a 2-stage operation followed by focal and craniospinal irradiation and adjuvant chemotherapy. RESULTS: Immunohistochemical analysis including use of pineal lineage marker confirmed a diagnosis of PPTID. Targeted exome sequencing showed mutations in TSC1(L388P) and IKZF3(F206C), whereas high-resolution array cytogenetics revealed losses in chromosomes 2, 3, 4, 8, 10, 11, 17, and 20, leading to single-copy loss of PTEN and TP53. CONCLUSIONS: Pineal parenchymal tumors reflect a broad spectrum of malignancy potential and prognoses, which mandate better understanding of the disease mechanism for rational therapeutic strategies. We present a case of PPTID and report several mutations and chromosomal abnormalities previously unrecognized in this tumor subtype. Review of the literature highlights a need for surgical resection followed by adjuvant chemoradiation. Further investigation of these novel variants may improve understanding of the pathogenesis underlying pineal parenchymal tumors.
Assuntos
Transformação Celular Neoplásica/patologia , Pinealoma/genética , Pinealoma/patologia , Pinealoma/terapia , Adulto , Quimioterapia Adjuvante , Deleção Cromossômica , Terapia Combinada , Irradiação Craniana , Análise Mutacional de DNA , Exoma , Marcadores Genéticos , Humanos , Imageamento por Ressonância Magnética , Masculino , PTEN Fosfo-Hidrolase/genética , Glândula Pineal/patologia , Glândula Pineal/cirurgia , Pinealoma/diagnóstico , Prognóstico , Proteína Supressora de Tumor p53/genéticaRESUMO
Astroblastomas are rare primary brain tumors, diagnosed based on histologic features. Not currently assigned a WHO grade, they typically display indolent behavior, with occasional variants taking a more aggressive course. We characterized the immunohistochemical characteristics, copy number (high-resolution array comparative genomic hybridization, OncoCopy) and mutational profile (targeted next-generation exome sequencing, OncoPanel) of a cohort of seven biopsies from four patients to identify recurrent genomic events that may help distinguish astroblastomas from other more common high-grade gliomas. We found that tumor histology was variable across patients and between primary and recurrent tumor samples. No common molecular features were identified among the four tumors. Mutations commonly observed in astrocytic tumors (IDH1/2, TP53, ATRX, and PTEN) or ependymoma were not identified. However one case with rapid clinical progression displayed mutations more commonly associated with GBM (NF1(N1054H/K63)*, PIK3CA(R38H) and ERG(A403T)). Conversely, another case, originally classified as glioblastoma with nine-year survival before recurrence, lacked a GBM mutational profile. Other mutations frequently seen in lower grade gliomas (BCOR, BCORL1, ERBB3, MYB, ATM) were also present in several tumors. Copy number changes were variable across tumors. Our findings indicate that astroblastomas have variable growth patterns and morphologic features, posing significant challenges to accurate classification in the absence of diagnostically specific copy number alterations and molecular features. Their histopathologic overlap with glioblastoma will likely confound the observation of long-term GBM "survivors". Further genomic profiling is needed to determine whether these tumors represent a distinct entity and to guide management strategies.
Assuntos
Neoplasias Encefálicas/genética , Estudo de Associação Genômica Ampla/métodos , Recidiva Local de Neoplasia/genética , Neoplasias Neuroepiteliomatosas/genética , Adulto , Neoplasias Encefálicas/patologia , Hibridização Genômica Comparativa , Análise Mutacional de DNA , Feminino , Dosagem de Genes , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Neoplasias Neuroepiteliomatosas/patologia , Análise de Sequência de DNARESUMO
Pituitary spindle cell oncocytoma (SCO) is an uncommon primary pituitary neoplasm that presents with mass effect on adjacent neurovascular structures, similar to non-hormone-producing pituitary adenomas. To determine the molecular etiology of SCO, we performed exome sequencing on four SCO cases, with matched normal controls, to assess somatic mutations and copy number alterations. Our analysis revealed a low mutation rate and a copy-neutral profile, consistent with the low-grade nature of this tumor. However, we identified a co-occurring somatic HRAS (p.Q61R) activating point mutation and MEN1 frameshift mutation (p.L117fs) present in a primary and recurrent tumor from one patient. Other SCOs demonstrated mutations in SND1 and FAT1, which are associated with MAPK pathway activation. Immunohistochemistry across the SCO cohort demonstrated robust MAPK activity in all cases (n=4), as evidenced by strong phospho-ERK staining, while phospho-AKT levels suggested only basal levels of PI3K pathway activation. Taken together, this identifies the MAPK signaling pathway as a novel therapeutic target for spindle cell oncocytoma, which may offer a powerful adjunct for aggressive tumors refractory to surgical resection.
Assuntos
Adenoma Oxífilo/genética , Sistema de Sinalização das MAP Quinases/fisiologia , Neoplasias Hipofisárias/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Adenoma Oxífilo/metabolismo , Idoso , Análise Mutacional de DNA , Humanos , Pessoa de Meia-Idade , Mutação , Neoplasias Hipofisárias/metabolismoRESUMO
Brain metastases represent the greatest clinical challenge in treating HER2-positive breast cancer. We report the development of orthotopic patient-derived xenografts (PDXs) of HER2-expressing breast cancer brain metastases (BCBM), and their use for the identification of targeted combination therapies. Combined inhibition of PI3K and mTOR resulted in durable tumor regressions in three of five PDXs, and therapeutic response was correlated with a reduction in the phosphorylation of 4EBP1, an mTORC1 effector. The two nonresponding PDXs showed hypermutated genomes with enrichment of mutations in DNA-repair genes, which suggests an association of genomic instability with therapeutic resistance. These findings suggest that a biomarker-driven clinical trial of PI3K inhibitor in combination with an mTOR inhibitor should be conducted for patients with HER2-positive BCBM.
Assuntos
Aminopiridinas/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias da Mama/tratamento farmacológico , Everolimo/farmacologia , Morfolinas/farmacologia , Complexos Multiproteicos/antagonistas & inibidores , Inibidores de Fosfoinositídeo-3 Quinase , Serina-Treonina Quinases TOR/antagonistas & inibidores , Proteínas Adaptadoras de Transdução de Sinal , Animais , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/secundário , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proteínas de Transporte/efeitos dos fármacos , Proteínas de Transporte/metabolismo , Caspase 3/efeitos dos fármacos , Caspase 3/metabolismo , Proteínas de Ciclo Celular , Reparo do DNA/genética , Resistencia a Medicamentos Antineoplásicos/genética , Quimioterapia Combinada , Fatores de Iniciação em Eucariotos , Feminino , Perfilação da Expressão Gênica , Instabilidade Genômica , Humanos , Imuno-Histoquímica , Antígeno Ki-67/efeitos dos fármacos , Antígeno Ki-67/metabolismo , Imageamento por Ressonância Magnética , Alvo Mecanístico do Complexo 1 de Rapamicina , Camundongos , Camundongos SCID , Terapia de Alvo Molecular , Transplante de Neoplasias , Fosfoproteínas/efeitos dos fármacos , Fosfoproteínas/metabolismo , Fosforilação , Receptor ErbB-2/metabolismo , Indução de Remissão , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Angiocentric gliomas are pediatric low-grade gliomas (PLGGs) without known recurrent genetic drivers. We performed genomic analysis of new and published data from 249 PLGGs, including 19 angiocentric gliomas. We identified MYB-QKI fusions as a specific and single candidate driver event in angiocentric gliomas. In vitro and in vivo functional studies show that MYB-QKI rearrangements promote tumorigenesis through three mechanisms: MYB activation by truncation, enhancer translocation driving aberrant MYB-QKI expression and hemizygous loss of the tumor suppressor QKI. To our knowledge, this represents the first example of a single driver rearrangement simultaneously transforming cells via three genetic and epigenetic mechanisms in a tumor.
Assuntos
Glioma/genética , Proteínas Oncogênicas v-myb/genética , Proteínas de Fusão Oncogênica/genética , Proteínas de Ligação a RNA/genética , Carcinogênese/genética , Linhagem Celular Tumoral , Criança , Hibridização Genômica Comparativa , Exoma/genética , Regulação Neoplásica da Expressão Gênica , Rearranjo Gênico , Glioma/patologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mutação , Proteínas Oncogênicas v-myb/biossíntese , Proteínas de Fusão Oncogênica/biossíntese , Proteínas de Ligação a RNA/biossínteseRESUMO
IMPORTANCE: Conclusive intraoperative pathologic confirmation of diffuse infiltrative glioma guides the decision to pursue definitive neurosurgical resection. Establishing the intraoperative diagnosis by histologic analysis can be difficult in low-cellularity infiltrative gliomas. Therefore, we developed a rapid and sensitive genotyping assay to detect somatic single-nucleotide variants in the telomerase reverse transcriptase (TERT) promoter and isocitrate dehydrogenase 1 (IDH1). OBSERVATIONS: This assay was applied to tissue samples from 190 patients with diffuse gliomas, including archived fixed and frozen specimens and tissue obtained intraoperatively. Results demonstrated 96% sensitivity (95% CI, 90%-99%) and 100% specificity (95% CI, 95%-100%) for World Health Organization grades II and III gliomas. In a series of live cases, glioma-defining mutations could be identified within 60 minutes, which could facilitate the diagnosis in an intraoperative timeframe. CONCLUSIONS AND RELEVANCE: The genotyping method described herein can establish the diagnosis of low-cellularity tumors like glioma and could be adapted to the point-of-care diagnosis of other lesions that are similarly defined by highly recurrent somatic mutations.
Assuntos
Biomarcadores Tumorais/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/cirurgia , Glioma/genética , Glioma/cirurgia , Isocitrato Desidrogenase/genética , Técnicas de Diagnóstico Molecular , Polimorfismo de Nucleotídeo Único , Telomerase/genética , Neoplasias Encefálicas/enzimologia , Neoplasias Encefálicas/patologia , Feminino , Secções Congeladas , Glioma/enzimologia , Glioma/patologia , Humanos , Imuno-Histoquímica , Período Intraoperatório , Imageamento por Ressonância Magnética , Masculino , Gradação de Tumores , Reação em Cadeia da Polimerase , Valor Preditivo dos Testes , Regiões Promotoras Genéticas , Fatores de Tempo , Fixação de TecidosRESUMO
BACKGROUND: Multidimensional genotyping of formalin-fixed paraffin-embedded (FFPE) samples has the potential to improve diagnostics and clinical trials for brain tumors, but prospective use in the clinical setting is not yet routine. We report our experience with implementing a multiplexed copy number and mutation-testing program in a diagnostic laboratory certified by the Clinical Laboratory Improvement Amendments. METHODS: We collected and analyzed clinical testing results from whole-genome array comparative genomic hybridization (OncoCopy) of 420 brain tumors, including 148 glioblastomas. Mass spectrometry-based mutation genotyping (OncoMap, 471 mutations) was performed on 86 glioblastomas. RESULTS: OncoCopy was successful in 99% of samples for which sufficient DNA was obtained (n = 415). All clinically relevant loci for glioblastomas were detected, including amplifications (EGFR, PDGFRA, MET) and deletions (EGFRvIII, PTEN, 1p/19q). Glioblastoma patients ≤40 years old had distinct profiles compared with patients >40 years. OncoMap testing reliably identified mutations in IDH1, TP53, and PTEN. Seventy-seven glioblastoma patients enrolled on trials, of whom 51% participated in targeted therapeutic trials where multiplex data informed eligibility or outcomes. Data integration identified patients with complete tumor suppressor inactivation, albeit rarely (5% of patients) due to lack of whole-gene coverage in OncoMap. CONCLUSIONS: Combined use of multiplexed copy number and mutation detection from FFPE samples in the clinical setting can efficiently replace singleton tests for clinical diagnosis and prognosis in most settings. Our results support incorporation of these assays into clinical trials as integral biomarkers and their potential to impact interpretation of results. Limited tumor suppressor variant capture by targeted genotyping highlights the need for whole-gene sequencing in glioblastoma.