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Article ; Online: Evolving classification of rhabdomyosarcoma.

Agaram, Narasimhan P

2021 Volume 80, Issue 1, Page(s) 98–108

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 ... ...

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.
MeSH term(s)	Biomarkers, Tumor/genetics ; Forkhead Box Protein O1/genetics ; Humans ; MyoD Protein/genetics ; Rhabdomyosarcoma/classification ; Rhabdomyosarcoma/genetics ; Rhabdomyosarcoma/pathology ; Soft Tissue Neoplasms/classification ; Soft Tissue Neoplasms/genetics ; Soft Tissue Neoplasms/pathology
Chemical Substances	Biomarkers, Tumor ; Forkhead Box Protein O1 ; MyoD Protein ; MyoD1 myogenic differentiation protein
Language	English
Publishing date	2021-12-24
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	131914-0
ISSN	1365-2559 ; 0309-0167
ISSN (online)	1365-2559
ISSN	0309-0167
DOI	10.1111/his.14449
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Article ; Online: Cellular Cutaneous Epithelioid Hemangioma Harboring the Rare GATA6::FOXO1 Gene Fusion.

Tepp, Jonathan A / Agaram, Narasimhan P / Chang, Jason C / Linos, Konstantinos

The American Journal of dermatopathology

2024 Volume 46, Issue 4, Page(s) 223–227

Abstract: Abstract: Epithelioid hemangioma (EH) is a benign vascular tumor displaying diverse histomorphologies. Among these, one EH subtype comprises cellular sheets of atypical epithelioid cells, posing potential challenges in distinguishing it from malignant ... ...

Abstract	Abstract: Epithelioid hemangioma (EH) is a benign vascular tumor displaying diverse histomorphologies. Among these, one EH subtype comprises cellular sheets of atypical epithelioid cells, posing potential challenges in distinguishing it from malignant vascular lesions. In this case report, we present a cutaneous cellular EH that carries the rare GATA6::FOXO1 gene fusion, a recent discovery. Our aim is to provide an updated insight into the evolving knowledge of EHs while delving into the histologic and molecular characteristics of the primary differential diagnoses.
MeSH term(s)	Humans ; Angiolymphoid Hyperplasia with Eosinophilia/pathology ; Hemangioma/pathology ; Vascular Neoplasms ; Gene Fusion ; Diagnosis, Differential ; Hemangioendothelioma, Epithelioid/genetics ; Forkhead Box Protein O1/genetics ; GATA6 Transcription Factor/genetics
Chemical Substances	FOXO1 protein, human ; Forkhead Box Protein O1 ; GATA6 protein, human ; GATA6 Transcription Factor
Language	English
Publishing date	2024-03-08
Publishing country	United States
Document type	Case Reports ; Journal Article
ZDB-ID	448469-1
ISSN	1533-0311 ; 0193-1091
ISSN (online)	1533-0311
ISSN	0193-1091
DOI	10.1097/DAD.0000000000002647
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Article ; Online: Update on Myogenic Sarcomas.

Agaram, Narasimhan P

Surgical pathology clinics

2018 Volume 12, Issue 1, Page(s) 51–62

Abstract: Myogenic sarcomas include soft tissue sarcomas that show skeletal muscle differentiation (rhabdomyosarcoma) and those with smooth muscle differentiation (leiomyosarcoma). Rhabdomyosarcomas are more common in the pediatric age group and leiomyosarcomas ... ...

Abstract	Myogenic sarcomas include soft tissue sarcomas that show skeletal muscle differentiation (rhabdomyosarcoma) and those with smooth muscle differentiation (leiomyosarcoma). Rhabdomyosarcomas are more common in the pediatric age group and leiomyosarcomas occur more often in the adult population. Based on the clinico-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. In this update on myogenic sarcomas, each entity is discussed with special emphasis on recent updates in genetic findings and the diagnostic approach to these tumors.
MeSH term(s)	Biomarkers, Tumor/genetics ; Cell Differentiation ; Diagnosis, Differential ; Humans ; Immunohistochemistry ; Mutation/genetics ; MyoD Protein/genetics ; Myosarcoma/classification ; Myosarcoma/diagnosis ; Myosarcoma/genetics ; Myosarcoma/pathology ; Prognosis ; Soft Tissue Neoplasms/classification ; Soft Tissue Neoplasms/diagnosis ; Soft Tissue Neoplasms/genetics ; Soft Tissue Neoplasms/pathology
Chemical Substances	Biomarkers, Tumor ; MyoD Protein ; MyoD1 myogenic differentiation protein
Language	English
Publishing date	2018-12-20
Publishing country	United States
Document type	Journal Article ; Review
ISSN	1875-9157
ISSN (online)	1875-9157
DOI	10.1016/j.path.2018.10.003
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Article ; Online: GLI1 Co-Amplification in Well-differentiated/Dedifferentiated Liposarcomas: Clinicopathologic and Molecular Analysis of 92 Cases.

Sharma, Aarti E / Dickson, Mark / Singer, Samuel / Hameed, Meera R / Agaram, Narasimhan P

Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc

2024 , Page(s) 100494

Abstract: Background: GLI1 (12q13.3) amplification is identified in a subset of mesenchymal neoplasms with a distinct nested round cell/epithelioid phenotype. MDM2 and CDK4 genes are situated along the oncogenic 12q13-15 segment, amplification of which defines ... ...

Abstract	Background: GLI1 (12q13.3) amplification is identified in a subset of mesenchymal neoplasms with a distinct nested round cell/epithelioid phenotype. MDM2 and CDK4 genes are situated along the oncogenic 12q13-15 segment, amplification of which defines well-differentiated (WDLPS)/dedifferentiated liposarcoma (DDLPS). The 12q amplicon can occasionally include GLI1 - a gene in close proximity to CDK4. We hereby describe the first cohort of GLI1/MDM2/CDK4 co-amplified WD/DDLPS. Materials and methods: The departmental database was queried retrospectively for all cases of WD/DDLPS having undergone next generation (IMPACT) sequencing with confirmed MDM2, CDK4, and GLI1 co-amplification. Clinicopathologic data was obtained from review of the medical chart and available histologic material. Results: 486 WD/DDLPS underwent DNA sequencing, 92 (19%) of which harbored amplification of the GLI1 locus in addition to MDM2 and CDK4. These included primary tumors (n=60), local recurrences (n=29), and metastases (n=3). Primary tumors were most frequently retroperitoneal (47/60,78%) mediastinal (4/60,7%), and paratesticular (3/60, 5%). Average age was 63 years with a male: female ratio of 3:2. The cohort was comprised by DDLPS (86/92 [93%], 6 of which were comprised by WDLPS with early dedifferentiation) , and WDLPS without any longitudinal evidence of dedifferentiation (6/92, 7%%). A fifth (13/86,17%) of DDLPS cases showed no evidence of a well-differentiated component in any of the primary, recurrent, or metastatic specimens. Dedifferentiated areas mostly showed high-grade undifferentiated pleomorphic sarcoma-like (26/86, 30%),) and high-grade myxofibrosarcoma-like (13/86, 16%)) morphology. A disproportionately increased incidence of meningothelial whorls with/without osseous metaplasia was observed as the predominant pattern in 16/86 (19%), and GLI1-altered morphology as described was identified in a total of 10/86 (12%) tumors. JUN (1p32.1), also implicated in the pathogenesis of WD/DDLPS, was co-amplified with all three of MDM2, CDK4, and GLI1 in 7/91 (8%) cases. Additional loci along chromosomal arms 1p and 6q, including TNFAIP3, LATS1 and ESR1, were also amplified in a subset of cases. Conclusions: In this large-scale cohort of GLI1 co-amplified WD/DDLPS, we elucidate uniquely recurrent features including meningothelial whorls and GLI-altered morphology in dedifferentiated areas. Assessment of tumor location (retroperitoneal or mediastinal), identification of a well-differentiated liposarcoma component, and co-amplification of other spatially discrete genomic segments (1p, 6q) might aid in distinction from tumors with true driver GLI1 alterations.
Language	English
Publishing date	2024-04-13
Publishing country	United States
Document type	Journal Article
ZDB-ID	645073-8
ISSN	1530-0285 ; 0893-3952
ISSN (online)	1530-0285
ISSN	0893-3952
DOI	10.1016/j.modpat.2024.100494
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Article ; Online: Toward Deploying a Deep Learning Model for Diagnosis of Rhabdomyosarcoma.

Ho, David Joon / Agaram, Narasimhan P / Frankel, Arthur O / Lathara, Melvin / Catchpoole, Daniel / Keller, Charles / Hameed, Meera R

Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc

2024 Volume 37, Issue 3, Page(s) 100421

MeSH term(s)	Humans ; Deep Learning ; Rhabdomyosarcoma/diagnosis ; Rhabdomyosarcoma/pathology ; Diagnosis, Differential
Language	English
Publishing date	2024-02-08
Publishing country	United States
Document type	Letter
ZDB-ID	645073-8
ISSN	1530-0285 ; 0893-3952
ISSN (online)	1530-0285
ISSN	0893-3952
DOI	10.1016/j.modpat.2024.100421
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Article ; Online: Test yourself: Recurrent right groin lump.

Kwok, Henry Chi Kit / Brady, Mary Susan / Agaram, Narasimhan P / Hwang, Sinchun

Skeletal radiology

2021 Volume 51, Issue 5, Page(s) 1099–1101

MeSH term(s)	Groin/diagnostic imaging ; Humans
Language	English
Publishing date	2021-11-26
Publishing country	Germany
Document type	Editorial
ZDB-ID	527592-1
ISSN	1432-2161 ; 0364-2348
ISSN (online)	1432-2161
ISSN	0364-2348
DOI	10.1007/s00256-021-03964-9
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Zs.A 1304: Show issues

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Article ; Online: Test yourself: recurrent right groin lump.

Kwok, Henry Chi Kit / Brady, Mary Susan / Agaram, Narasimhan P / Hwang, Sinchun

Skeletal radiology

2021 Volume 51, Issue 5, Page(s) 1081–1083

MeSH term(s)	Groin/diagnostic imaging ; Humans
Language	English
Publishing date	2021-11-25
Publishing country	Germany
Document type	Editorial
ZDB-ID	527592-1
ISSN	1432-2161 ; 0364-2348
ISSN (online)	1432-2161
ISSN	0364-2348
DOI	10.1007/s00256-021-03963-w
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Article ; Online: Malignant peripheral nerve sheath tumor in children: A clinicopathologic and molecular study with parallels to the adult counterpart.

Agaram, Narasimhan P / Wexler, Leonard H / Chi, Ping / Antonescu, Cristina R

Genes, chromosomes & cancer

2022 Volume 62, Issue 3, Page(s) 131–138

Abstract: Malignant peripheral nerve sheath tumors (MPNST) are aggressive neoplasms, arising either sporadically, in the setting of neurofibromatosis type I (NF1) or post radiation. Most MPNST occur in adults and their pathogenesis is driven by the loss of ... ...

Abstract	Malignant peripheral nerve sheath tumors (MPNST) are aggressive neoplasms, arising either sporadically, in the setting of neurofibromatosis type I (NF1) or post radiation. Most MPNST occur in adults and their pathogenesis is driven by the loss of function mutations in the PRC2 complex, regardless of their clinical presentation. In contrast, pediatric MPNST are rare and their pathogenesis has not been elucidated. In this study, we investigate a large cohort of 64 MPNSTs arising in children and young adults (younger than the age of 20 years) to better define their clinicopathologic and molecular features. Sixteen (25%) cases were investigated by MSK-IMPACT, a targeted NGS panel of 505 cancer genes. Most patients (80%) were aged 11-20 years. A history of NF1 was established in half of the cases. Mean tumor size was 8.5 cm. The most common locations included the extremities (34%) and abdomen/pelvis (27%). Histologically, 89% of high-grade MPNST showed conventional features, while the remaining three cases showed a predominant epithelioid phenotype. Heterologous differentiation occurred in 25% of high grade cases, with half showing rhabdomyoblastic differentiation. Tumors arose in a background of a plexiform neurofibroma (16%), neurofibroma (13%), and schwannoma in two cases (3%). Immunohistochemically, H3K27me3 expression was lost in 82% of conventional high-grade MPNST analyzed, while loss of SMARCB1 expression was seen in one epithelioid MPNST. Genomically, all cases showed more than one genetic abnormality, with 53% showing mutations in EED / SUZ12 genes, and 47% of cases harboring alterations in NF1 and CDKN2A/CDKN2B genes. At the last follow-up, 30% patients died of disease, 28% were alive with disease and 42% had no evidence of disease. NF1 status did not correlate with overall survival. In conclusion, half of pediatric and young adult MPNST were NF1-related and showed loss of function alterations in PRC2 complex, NF1, and CDKN2A, similar to the adult counterpart. Thus, H3K27me3 loss of expression may be used in the diagnosis of high grade MPNSTs in children. Moreover, a small subset of pediatric MPNST have an epithelioid morphology with different pathogenesis.
MeSH term(s)	Humans ; Child ; Neurofibrosarcoma/genetics ; Histones/genetics ; Neurofibromatosis 1/genetics ; Neurilemmoma/genetics ; Neurilemmoma/diagnosis ; Neurilemmoma/pathology ; Mutation ; Nerve Sheath Neoplasms/genetics
Chemical Substances	Histones
Language	English
Publishing date	2022-11-30
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1018988-9
ISSN	1098-2264 ; 1045-2257
ISSN (online)	1098-2264
ISSN	1045-2257
DOI	10.1002/gcc.23106
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Article ; Online: Head and Neck Mesenchymal Tumors with Kinase Fusions: A Report of 15 Cases With Emphasis on Wide Anatomic Distribution and Diverse Histologic Appearance.

Xu, Bin / Suurmeijer, Albert J H / Agaram, Narasimhan P / Antonescu, Cristina R

The American journal of surgical pathology

2022 Volume 47, Issue 2, Page(s) 248–258

Abstract: Mesenchymal tumors harboring various kinase fusions were recently recognized as emerging entities mainly in the soft tissues. We herein investigate the clinicopathologic and molecular characteristics of head and neck mesenchymal tumors harboring kinase ... ...

Abstract	Mesenchymal tumors harboring various kinase fusions were recently recognized as emerging entities mainly in the soft tissues. We herein investigate the clinicopathologic and molecular characteristics of head and neck mesenchymal tumors harboring kinase fusions. The study cohort included 15 patients with a median age of 13 years (ranging from congenital to 63 y). The kinase genes involved in descending order were NTRK1 (n=6), NTRK3 (n=5), BRAF (n=2), and 1 each with MET, and RET. The anatomic locations were broad involving all tissue planes, including skin (n=4), intraosseous (n=4), major salivary glands (n=2), sinonasal tract (n=2), soft tissue of face or neck (n=2), and oral cavity (n=1). The histologic spectrum ranged from benign to high grade, in descending order including tumors resembling malignant peripheral nerve sheath tumor (MPNST)-like, fibrosarcoma (infantile or adult-type), lipofibromatosis-like neural tumor (LPFNT), inflammatory myofibroblastic tumor-like, and a novel phenotype resembling myxoma. Perivascular hyalinization/stromal keloid-like collagen bands and staghorn vasculature were common features in MPNST-like and LPFNT-like tumors. Two tumors (1 each with NTRK1 or BRAF rearrangement) were classified as high grade. By immunohistochemistry, S100 and CD34 positivity was noted in 71% and 60%, frequently in MPNST-like and LPFNT-like phenotypes. Pan-TRK was a sensitive marker for NTRK-translocated tumors but was negative in tumor with other kinase fusions. One patient with a high-grade tumor developed distant metastasis. Molecular testing for various kinase fusions should be considered for S100+/CD34+ spindle cell neoplasms with perivascular hyalinization and staghorn vessels, as pan-TRK positivity is seen only in NTRK fusions.
MeSH term(s)	Humans ; Neurofibrosarcoma ; Proto-Oncogene Proteins B-raf ; Fibrosarcoma/genetics ; Receptor, trkA/genetics ; Receptor, trkC/genetics ; Head and Neck Neoplasms/genetics ; Biomarkers, Tumor/genetics
Chemical Substances	Proto-Oncogene Proteins B-raf (EC 2.7.11.1) ; Receptor, trkA (EC 2.7.10.1) ; Receptor, trkC (EC 2.7.10.1) ; Biomarkers, Tumor
Language	English
Publishing date	2022-10-21
Publishing country	United States
Document type	Case Reports ; Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	752964-8
ISSN	1532-0979 ; 0147-5185
ISSN (online)	1532-0979
ISSN	0147-5185
DOI	10.1097/PAS.0000000000001982
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Article ; Online: Untying the Gordian knot of composite hemangioendothelioma: Discovery of novel fusions.

Linos, Konstantinos / Dermawan, Josephine K / Pulitzer, Melissa / Hameed, Meera / Agaram, Narasimhan P / Agaimy, Abbas / Antonescu, Cristina R

Genes, chromosomes & cancer

2023 Volume 63, Issue 1, Page(s) e23198

Abstract: Composite hemangioendothelioma is a rare, locally aggressive, and rarely metastasizing vascular neoplasm which affects both children and adults. Recently, a number of gene fusions including YAP1::MAML2, PTBP1::MAML2, and EPC1::PHC2 have been detected in ... ...

Abstract	Composite hemangioendothelioma is a rare, locally aggressive, and rarely metastasizing vascular neoplasm which affects both children and adults. Recently, a number of gene fusions including YAP1::MAML2, PTBP1::MAML2, and EPC1::PHC2 have been detected in a small subset of cases with or without neuroendocrine expression. Herein, we present four additional cases with novel in-frame fusions. The cohort comprises two females and two males with a wide age range at diagnosis (24-80 years). Two tumors were deep involving the right brachial plexus and mediastinum, while the remaining were superficial (right plantar foot and abdominal wall). The size ranged from 1.5 to 4.8 cm in greatest dimension. Morphologically, all tumors had an admixture of at least two architectural patterns including retiform hemangioendothelioma, hemangioma, epithelioid hemangioendothelioma, or angiosarcoma. The tumors were positive for endothelial markers CD31 (3/3), ERG (4/4), and D2-40 (1/4, focal), while SMA was expressed in 2/3 highlighting the surrounding pericytes. Synaptophysin showed immunoreactivity in 2/3 cases. One patient had a local recurrence after 40 months, while two patients had no evidence of disease 4 months post-resection. Targeted RNA sequencing detected novel in-frame fusions in each of the cases: HSPG2::FGFR1, YAP1::FOXR1, ACTB::MAML2, and ARID1B::MAML2. The two cases with neuroendocrine expression occurred as superficial lesions and harbored YAP1::FOXR1 and ARID1B::MAML2 fusions. Our study expands on the molecular spectrum of this enigmatic tumor, further enhancing our current understanding of the disease.
MeSH term(s)	Adult ; Male ; Child ; Female ; Humans ; Young Adult ; Middle Aged ; Aged ; Aged, 80 and over ; Hemangioendothelioma/pathology ; Hemangioendothelioma, Epithelioid/genetics ; Hemangioma ; Base Sequence ; Diagnosis, Differential ; Biomarkers, Tumor/genetics ; Biomarkers, Tumor/metabolism ; Heterogeneous-Nuclear Ribonucleoproteins ; Polypyrimidine Tract-Binding Protein
Chemical Substances	Biomarkers, Tumor ; PTBP1 protein, human ; Heterogeneous-Nuclear Ribonucleoproteins ; Polypyrimidine Tract-Binding Protein (139076-35-0)
Language	English
Publishing date	2023-09-02
Publishing country	United States
Document type	Journal Article
ZDB-ID	1018988-9
ISSN	1098-2264 ; 1045-2257
ISSN (online)	1098-2264
ISSN	1045-2257
DOI	10.1002/gcc.23198
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