9 results on '"Agaram, Narasimhan"'
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2. Evolving classification of rhabdomyosarcoma.
- Author
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Agaram NP
- Subjects
- Forkhead Box Protein O1 genetics, Humans, MyoD Protein genetics, Rhabdomyosarcoma classification, Rhabdomyosarcoma genetics, Soft Tissue Neoplasms classification, Soft Tissue Neoplasms genetics, Biomarkers, Tumor genetics, Rhabdomyosarcoma pathology, Soft Tissue Neoplasms pathology
- Abstract
Rhabdomyosarcomas comprise the single largest category of soft tissue sarcomas in children and adolescents in the United States, occurring in 4.5 million people aged below 20 years. Based on the clinicopathological features and genetic abnormalities identified, rhabdomyosarcomas are classified into embryonal, alveolar, spindle cell/sclerosing and pleomorphic subtypes. Each subtype shows distinctive morphology and has characteristic genetic abnormalities. This review discusses the evolution of the classification of rhabdomyosarcoma to the present day, together with a discussion of key histomorphological and genetic features of each subtype and the diagnostic approach to these tumours., (© 2021 John Wiley & Sons Ltd.)
- Published
- 2022
- Full Text
- View/download PDF
3. Head and neck rhabdomyosarcoma with TFCP2 fusions and ALK overexpression: a clinicopathological and molecular analysis of 11 cases.
- Author
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Xu B, Suurmeijer AJH, Agaram NP, Zhang L, and Antonescu CR
- Subjects
- Adolescent, Adult, Age Factors, Aged, Biomarkers, Tumor analysis, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, Female, Genetic Predisposition to Disease, Humans, In Situ Hybridization, Fluorescence, Male, Middle Aged, Myogenin genetics, Myogenin metabolism, Prognosis, RNA-Binding Protein EWS genetics, RNA-Binding Protein EWS metabolism, RNA-Binding Protein FUS genetics, RNA-Binding Protein FUS metabolism, Soft Tissue Neoplasms genetics, Soft Tissue Neoplasms pathology, Transcription Factors genetics, Transcription Factors metabolism, Young Adult, Anaplastic Lymphoma Kinase metabolism, Head and Neck Neoplasms genetics, Head and Neck Neoplasms pathology, Oncogene Proteins, Fusion genetics, Oncogene Proteins, Fusion metabolism, Rhabdomyosarcoma genetics, Rhabdomyosarcoma pathology
- Abstract
Aims: Primary intraosseous rhabdomyosarcoma (RMS) is a rare entity defined by EWSR1/FUS-TFCP2 or, less commonly, MEIS1-NCOA2 fusions. The lesions often show a hybrid spindle and epithelioid phenotype, frequently coexpress myogenic markers, ALK, and cytokeratin, and show a striking propensity for the pelvic and craniofacial bones. The aim of this study was to investigate the clinicopathological and molecular features of 11 head and neck RMSs (HNRMSs) characterised by the genetic alterations described in intraosseous RMS., Methods and Results: The molecular abnormalities were analysed with fluorescence in-situ hybridisation and/or targeted RNA/DNA sequencing. Seven cases had FUS-TFCP2 fusions, four had EWSR1-TFCP2 fusions, and none had MEIS1-NCOA2 fusions. All except one case were intraosseous, affecting the mandible (n = 4), maxilla (n = 3), and skull (n = 3). One case occurred in the superficial soft tissue of the neck. The median age was 29 years (range, 16-74 years), with an equal sex distribution. All tumours showed mixed epithelioid and spindle morphology. Immunohistochemical coexpression of desmin, myogenin, MyoD1, ALK, and cytokeratin was seen in most cases. An intragenic ALK deletion was seen in 43% of cases. Regional and distant spread were seen in three and four patients, respectively. Two patients died of their disease., Conclusions: We herein present the largest series of HNRMSs with TFCP2 fusions to date. The findings show a strong predilection for the skeleton in young adults, although we also report an extraosseous case. The tumours are characterised by a distinctive spindle and epithelioid phenotype and a peculiar immunoprofile, with coexpression of myogenic markers, epithelial markers, and ALK. They are associated with a poor prognosis, including regional or distant spread and disease-related death., (© 2021 John Wiley & Sons Ltd.)
- Published
- 2021
- Full Text
- View/download PDF
4. Expanding the Spectrum of Intraosseous Rhabdomyosarcoma: Correlation Between 2 Distinct Gene Fusions and Phenotype.
- Author
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Agaram NP, Zhang L, Sung YS, Cavalcanti MS, Torrence D, Wexler L, Francis G, Sommerville S, Swanson D, Dickson BC, Suurmeijer AJH, Williamson R, and Antonescu CR
- Subjects
- Adult, Bone Neoplasms pathology, DNA-Binding Proteins genetics, Female, Genetic Predisposition to Disease, Humans, In Situ Hybridization, Fluorescence, Male, Myeloid Ecotropic Viral Integration Site 1 Protein genetics, Nuclear Receptor Coactivator 2 genetics, Phenotype, RNA-Binding Protein EWS genetics, RNA-Binding Protein FUS genetics, Rhabdomyosarcoma pathology, Sequence Analysis, RNA, Transcription Factors genetics, Young Adult, Biomarkers, Tumor genetics, Bone Neoplasms genetics, Gene Fusion, Gene Rearrangement, Rhabdomyosarcoma genetics
- Abstract
Primary intraosseous rhabdomyosarcomas (RMSs) are extremely rare. Recently 2 studies reported 4 cases of primary intraosseous RMS with EWSR1/FUS-TFCP2 gene fusions, associated with somewhat conflicting histologic features, ranging from spindle to epithelioid. In this study we sought to further investigate the pathologic and molecular abnormalities of a larger group of intraosseous RMSs by a combined approach using targeted RNA sequencing analysis and fluorescence in situ hybridization (FISH). We identified 7 cases, 3 males and 4 females, all in young adults, age range 20 to 39 years (median, 27 y). Three cases involved the pelvis, 2 involved the femur and 1 each involved the maxilla and the skull. Molecular studies identified recurrent gene fusions in all 7 cases tested, including: a novel MEIS1-NCOA2 fusion in 2 cases, EWSR1-TFCP2 in 3 cases, and FUS-TFCP2 gene fusions in 1 case. One case showed a FUS gene rearrangement, without a TFCP2 gene abnormality by FISH. The MEIS1-NCOA2-positive cases were characterized by a more primitive and fascicular spindle cell appearance, while the EWSR1/FUS rearranged tumors had a hybrid spindle and epithelioid phenotype, with more abundant eosinophilic cytoplasm and mild nuclear pleomorphism. Immunohistochemically, all tumors were positive for desmin and myogenin (focal). In addition, 4 tumors with TFCP2-associated gene fusions also coexpressed ALK and cytokeratin. In conclusion, our results suggest a high incidence of gene fusions in primary RMSs of bone, with 2 molecular subsets emerging, defined by either MEIS1-NCOA2 or EWSR1/FUS-TFCP2 fusions, showing distinct morphology and immunophenotype. Additional studies with larger numbers of cases and longer follow-up data are required to definitively evaluate the biological behavior of these tumors and to establish their relationship to other spindle cell RMS genetic groups.
- Published
- 2019
- Full Text
- View/download PDF
5. MYOD1-mutant spindle cell and sclerosing rhabdomyosarcoma: an aggressive subtype irrespective of age. A reappraisal for molecular classification and risk stratification.
- Author
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Agaram NP, LaQuaglia MP, Alaggio R, Zhang L, Fujisawa Y, Ladanyi M, Wexler LH, and Antonescu CR
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Child, Child, Preschool, Female, Humans, Male, Middle Aged, Mutation, Young Adult, MyoD Protein genetics, Rhabdomyosarcoma classification, Rhabdomyosarcoma genetics, Rhabdomyosarcoma pathology
- Abstract
Sclerosing and spindle cell rhabdomyosarcoma is a rare histologic subtype, designated in the latest WHO classification as a stand-alone pathologic entity. Three genomic groups have been defined: an infantile subset of spindle cell rhabdomyosarcoma harboring VGLL2-related gene fusions, a MYOD1-mutant subset commonly associated with sclerosing morphology, and a subset lacking recurrent genetic abnormalities. In this study, we focus on MYOD1-mutant rhabdomyosarcoma to further define their clinicopathologic characteristics and behavior in a larger patient cohort. We investigated 30 cases of MYOD1-mutant rhabdomyosarcoma (12 previously reported and 18 newly diagnosed) with an age range of 2-94 years, including 15 children. All cases showed morphology within the spectrum of spindle cell/sclerosing rhabdomyosarcoma (8 cases showing pure sclerosing morphology, 8 cases showing pure spindle cell morphology and 14 cases showing a hybrid phenotype of spindle, sclerosing and primitive undifferentiated areas). All tumors harbored either homozygous or heterozygous MYOD1 (p.L122R) exon 1 mutations. In 10 (33%) cases, a co-existent PIK3CA mutation was identified. Hot-spot mutations in NRAS and HRAS were each identified in a single case, respectively. Follow-up was available on 22 (73%) patients with a median duration of 28 months. Local recurrence was seen in 12 (55%) and distant recurrence in 12 (55%) cases, despite multimodality chemoradiation therapy. At last follow-up, 15 (68%) patients died of the disease, one patient was alive with disease and five had no evidence of disease. The prognosis was equally poor in pediatric and adult patients. In conclusion, MYOD1 mutation defines an aggressive rhabdomyosarcoma subset, with poor outcome and response to therapy, irrespective of age. Given that this distinct molecular subtype is characterized by an aggressive biologic behavior compared to other genetic subtypes of spindle and sclerosing rhabdomyosarcoma, the MYOD1 genotype should be used as a molecular marker in both subclassification and prognostication of rhabdomyosarcoma.
- Published
- 2019
- Full Text
- View/download PDF
6. Recurrent MYOD1 mutations in pediatric and adult sclerosing and spindle cell rhabdomyosarcomas: evidence for a common pathogenesis.
- Author
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Agaram NP, Chen CL, Zhang L, LaQuaglia MP, Wexler L, and Antonescu CR
- Subjects
- Adolescent, Adult, Aged, Child, Child, Preschool, Class I Phosphatidylinositol 3-Kinases, Female, Humans, Male, Middle Aged, Mutation, Nuclear Receptor Coactivator 2 genetics, Phosphatidylinositol 3-Kinases genetics, Proto-Oncogene Proteins c-mdm2 genetics, Rhabdomyosarcoma pathology, Rhabdomyosarcoma, Embryonal genetics, Rhabdomyosarcoma, Embryonal pathology, Sclerosis, Young Adult, MyoD Protein genetics, Rhabdomyosarcoma genetics
- Abstract
Sclerosing and spindle cell rhabdomyosarcoma (RMS) are rare types of RMS recently reclassified as a stand-alone pathologic entity, separate from embryonal RMS (ERMS). Although sclerosing and spindle cell RMS share clinical and morphologic features, a pathogenetic link based on shared molecular alterations has not been established. Spindle cell RMS in children have been associated with a less aggressive clinical course compared to adults. Recently, recurrent MYOD1 mutations were described in 44% of adult spindle cell RMS, but no pediatric tumors or sclerosing RMS were studied for comparison. Thus, we investigated 16 RMS (5 sclerosing and 11 spindle cell) in children and adults for the presence of MYOD1 mutations by targeted Polymerase Chain Reaction (PCR). Remarkably, all 5 sclerosing RMS and 4 of 11 spindle cell RMS showed the MYOD1 p.L122R hot-spot mutation. Of the five pediatric tumors, 2/2 sclerosing RMS and 2/3 spindle cell RMS showed MYOD1 mutations. Three of nine MYOD1-mutant RMS showed coexistent PIK3CA mutations, while no MDM2 amplifications were identified. All four pediatric MYOD1-mutated RMS patients died of the disease at 12-35 months following diagnosis. In conclusion, spindle cell and sclerosing RMS show recurrent MYOD1 mutations, in keeping with a single pathologic entity, regardless of age at presentation. This group however, is distinct from the infantile RMS associated with NCOA2 fusions. Although our study suggests that pediatric MYOD1-mutant RMS follow an aggressive behavior with high mortality, further studies are required to confirm this finding., (© 2014 Wiley Periodicals, Inc.)
- Published
- 2014
- Full Text
- View/download PDF
7. Soft Tissue Tumors of the Mediastinum
- Author
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Agaram, Narasimhan P., Roden, Anja C., editor, and Moreira, Andre L., editor
- Published
- 2017
- Full Text
- View/download PDF
8. Evolving classification of rhabdomyosarcoma
- Author
-
Agaram, Narasimhan P.
- Subjects
Histology ,Forkhead Box Protein O1 ,Rhabdomyosarcoma ,Biomarkers, Tumor ,Humans ,Soft Tissue Neoplasms ,General Medicine ,Article ,MyoD Protein ,Pathology and Forensic Medicine - Abstract
Rhabdomyosarcomas comprise the single largest category of soft tissue sarcomas in children and adolescents in the United States, occurring in 4.5 million persons aged less than 20 years. Based on the clinic-pathologic features and genetic abnormalities identified, the rhabdomyosarcomas are classified into embryonal, alveolar, spindle cell / sclerosing and pleomorphic subtypes. Each subtype shows distinctive morphology and has characteristic genetic abnormalities. This review discusses the evolution of the classification of rhabdomyosarcoma to the present day, along with a discussion of key histomorpholgic and genetic features of each subtype and the diagnostic approach to these tumors.
- Published
- 2021
9. Frequent HRAS mutations in malignant ectomesenchymoma
- Author
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Huang, Shih Chiang, Alaggio, Rita, Sung, Yun Shao, Chen, Chun Liang, Zhang, Lei, Kao, Yu Chien, Agaram, Narasimhan P., Wexler, Leonard H., and Antonescu, Cristina R.
- Subjects
FBXW7 ,ectomesenchymoma ,HRAS ,PTPRD ,rhabdomyosarcoma ,Anatomy ,2734 ,Surgery - Published
- 2016
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