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1
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Padilla EP, Voelz K, Kille T. A Unique Presentation of Multicentric Myofibromatosis in the Masseter Muscle of a Pediatric Patient. EAR, NOSE & THROAT JOURNAL 2025; 104:153S-157S. [PMID: 36085035 DOI: 10.1177/01455613221125933] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
A 12-year-old female with a history of multicentric infantile myofibromatosis (IM) presented with a tender, enlarging cheek mass and trismus. Imaging identified an intramasseteric tumor. Given the unknown etiology of the tumor and her bothersome symptoms, the mass was excised using a transoral approach with concurrent facial nerve monitoring. Her pathology report confirmed the diagnosis of a myofibromatosis lesion embedded within the masseter muscle. While IM can often present with lesions in the head and neck region, the intramasseteric location is rare and presents unique considerations for surgical approach. Myofibromatosis lesions typically occur before two years of age, although there are some rare documented cases of multicentric myofibromatosis lesions presenting at older ages. Furthermore, this patient's family history of similar lesions suggests a familial variant, which may have implications for disease behavior and need for further work-up, monitoring, and management. Overall, this was an unusual presentation of IM given the patient's age, prevalent family history, and the location of the mass. This case report adds to the literature and discusses the clinical differential of a pediatric cheek mass, the surgical considerations for an intramasseteric tumor, and the natural history of infantile myofibromatosis.
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Affiliation(s)
- Elena P Padilla
- Department of Surgery, Division of Otolaryngology, Head & Neck Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Katie Voelz
- Department of Pediatrics, Division of Hematology/Oncology & Bone Marrow Transplant, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Tony Kille
- Department of Surgery, Division of Otolaryngology, Head & Neck Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
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2
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Alston ELJ, Thangaiah JJ, Rowsey R, Hofich CD, Gliem T, Bakker AC, Sabbagh M, Church AJ, Papke DJ, Folpe AL, Al-Ibraheemi A. Pediatric-type Myoid Neoplasms of Somatic Soft Tissue: A Clinicopathological and Molecular Genetic Study of 78 Tumors, Highlighting Indolent Clinical Behavior and Frequent SRF Gene Rearrangements. Mod Pathol 2025; 38:100722. [PMID: 39864664 DOI: 10.1016/j.modpat.2025.100722] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2024] [Revised: 12/26/2024] [Accepted: 01/20/2025] [Indexed: 01/28/2025]
Abstract
Soft tissue tumors with smooth muscle differentiation are rare in pediatric patients. Despite often showing morphologic features sufficient for classification as "leiomyosarcoma" in adults (eg, high cellularity and mitotic activity), clinical follow-up has shown only indolent behavior. The pathological features of recently reported SRF-rearranged "cellular myofibromas/myopericytomas," typically occurring in children, overlap with those of true smooth muscle tumors. We studied a large series of pediatric tumors with morphologic and immunohistochemical evidence of smooth muscle differentiation, with the goals of better understanding their natural history and molecular genetic features. Seventy-eight tumors were identified in 45 males and 33 females, with a median age of 10 years. Clinical follow-up (50 patients; median, 45.5 months) disclosed local recurrence in 7 patients (15%). No metastases or deaths because of disease occurred. Group 1 (73/78) tumors consisted of cellular fascicles of mildly to at most moderately atypical, bland, ovoid to spindled cells with distinctly eosinophilic cytoplasm, appreciable mitotic activity (median, 5/50 high-power fields), and no necrosis. Group 2 tumors (5/78) showed greater cellularity, significant nuclear pleomorphism, and brisk mitotic activity (median, 59/50 high-power fields). Subsets of group 1 tumors harbored SRF rearrangements (16/47), and all group 2 tumors showed TP53 biallelic inactivation (5/5). SRF fusion partners included CITED1, NCOA2, C3orf62, RELA, ARGFXP1, ARNTI2, ICA1L, and unknown (n = 1). We conclude that the prognosis for pediatric tumors with smooth muscle differentiation that fall into group 1 is excellent. SRF rearrangements are present in a significant minority of tumors, typically showing features of smooth muscle rather than myopericytic differentiation. A smaller subset with more worrisome morphologic features harbor biallelic inactivation of TP53. To emphasize their unique features, we propose the term "pediatric-type myoid neoplasms of somatic soft tissue" rather than simply "leiomyoma" or "leiomyosarcoma" for group 1 tumors, and the designation of leiomyosarcoma in children should be limited to group 2 tumors.
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Affiliation(s)
- Erin L J Alston
- Department of Pathology, Boston Children's Hospital, Boston, Massachusetts; Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts
| | | | - Ross Rowsey
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Christopher D Hofich
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Troy Gliem
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Andrea C Bakker
- Department of Pathology, Boston Children's Hospital, Boston, Massachusetts
| | - Mark Sabbagh
- Department of Pathology, Boston Children's Hospital, Boston, Massachusetts
| | - Alanna J Church
- Department of Pathology, Boston Children's Hospital, Boston, Massachusetts
| | - David J Papke
- Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts
| | - Andrew L Folpe
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Alyaa Al-Ibraheemi
- Department of Pathology, Boston Children's Hospital, Boston, Massachusetts.
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3
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Chen S, Kelsey AM, Rudzinski ER. Rhabdomyosarcoma in children and young adults. Virchows Arch 2025; 486:101-116. [PMID: 39694930 DOI: 10.1007/s00428-024-03961-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Revised: 09/20/2024] [Accepted: 10/23/2024] [Indexed: 12/20/2024]
Abstract
Rhabdomyosarcoma (RMS) is the most common soft tissue malignancy in childhood, accounting for 3% of all pediatric malignancies and 50% of all pediatric soft tissue sarcomas. In adolescents and young adults (AYA) however, RMS comprises only 6.5% of all soft tissue sarcomas. Historically, diagnosis and treatment of RMS was based on histologic recognition of the alveolar subtype, which was associated with a worse prognosis. Within the past 20 years, the biologic characteristics of RMS have become clearer, with canonical fusion drivers, PAX3/7::FOXO1, characterizing the alveolar subtype (ARMS) and in turn associated with poor outcome, while chromosomal gains/losses in addition to RAS pathway alterations characterize the embryonal subtype (ERMS). Accordingly, detection of a FOXO1 gene fusion has become a commonplace diagnostic and prognostic tool allowing tumors to be treated based on presence or absence of a FOXO1 gene fusion. However, these cytogenetic and molecular alterations represent only a portion of the molecular landscape found in RMS, and other alterations are found with increasing frequency in various subsets of RMS. Clinical trials basing risk stratification on the presence or absence of the canonical PAX3/7::FOXO1 fusions have had success in identifying the poor responders. Due to poor outcomes, the presence of MYOD1 and TP53 alterations which are common in spindle cell sclerosing RMS (SSRMS) and RMS with anaplasia have also been integrated into trial risk stratification. Therefore, complete histologic and immunophenotypic characterization remain important to better recognize and study these rare subsets of RMS. This article will discuss the challenges of RMS classification including how to combine morphologic, immunophenotypic and molecular data to arrive at an integrated diagnosis. The use of newer techniques such as liquid biopsy and methylation profiling, will also continue to shape the classification of RMS and may further refine risk stratification and prognosis.
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Affiliation(s)
- Sonja Chen
- Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH, USA.
| | - Anna M Kelsey
- Diagnostic Paediatric Histopathology Service, Royal Manchester Children's Hospital, Oxford Road, Manchester, M13 9WL, England
| | - Erin R Rudzinski
- Department of Pathology and Laboratory Medicine, Indiana University, 350 W 11st St, Indianapolis, IN, 46202, USA
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Reyes MRT, Martins KH, Posantes GEM, Zelaya FJMC, Renderos SGG, León JE. Myofibroma with Atypical Features can Mimic Low-Grade Myofibroblastic Sarcoma: Two Paediatric Cases. Indian J Otolaryngol Head Neck Surg 2024; 76:4753-4756. [PMID: 39376390 PMCID: PMC11455742 DOI: 10.1007/s12070-024-04828-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Accepted: 06/17/2024] [Indexed: 10/09/2024] Open
Abstract
Myofibroma is a rare benign mesenchymal tumor that frequently affects the pediatric population with a predilection for the head and neck region. About 10% of myofibroma cases, presenting atypical features, can be misinterpreted as low-grade myofibroblastic sarcoma (LGMS), with therapeutic and prognostic impact. Here, we report two pediatric cases of benign myofibroblastic tumors, one of them showing typical characteristics of myofibroma, the other was an atypical myofibroma, which initially mimicked low-grade myofibroblastic sarcoma. Atypical myofibromas, despite its distinctive characteristics, follow a benign course, similar with typical myofibroma. It is necessary to distinguish atypical myofibroma from low-grade myofibroblastic sarcoma and avoid unnecessary invasive therapy.
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Affiliation(s)
- Magdalena Raquel Torres Reyes
- Department of Pediatric Dentistry, Ribeirão Preto Dental School, University of São Paulo (USP), Ribeirão Preto, Brazil
| | - Karina Helen Martins
- Department of Pediatric Dentistry, Ribeirão Preto Dental School, University of São Paulo (USP), Ribeirão Preto, Brazil
| | | | | | | | - Jorge Esquiche León
- Oral Pathology, Department of Stomatology, Public Oral Health, and Forensic Dentistry, Ribeirão Preto Dental School (FORP/USP), University of São Paulo, Av Do Café, S/n Campus USP, Ribeirão Preto, São Paulo, CEP: 14040-904 Brazil
- Department of Pathology and Forensic Medicine, Ribeirão Preto Medical School (FMRP/USP), University of São Paulo, Ribeirão Preto, Brazil
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Ajabnoor R. Different Shades of Desmoid-Type Fibromatosis (DTF): Detection of Noval Mutations in the Clinicopathologic Analysis of 32 Cases. Diagnostics (Basel) 2024; 14:2161. [PMID: 39410565 PMCID: PMC11476057 DOI: 10.3390/diagnostics14192161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2024] [Revised: 08/30/2024] [Accepted: 09/13/2024] [Indexed: 10/20/2024] Open
Abstract
BACKGROUND Desmoid-type fibromatosis (DTF) is a locally aggressive myofibroblastic/fibroblastic neoplasm with a high risk of local recurrence. It has a variety of histologic features that might confuse diagnosis, especially when detected during core needle biopsy. The Wnt/β-catenin pathway is strongly linked to the pathogenesis of DT fibromatosis. METHOD This study examined 33 desmoid-type fibromatoses (DTFs) from 32 patients, analyzing its clinical characteristics, histologic patterns, occurrence rates, relationship with clinical outcomes, immunohistochemical and molecular findings. RESULTS The DTFs exhibit a range of 1 to 7 histologic patterns per tumor, including conventional, hypercellular, myxoid, hyalinized/hypocellular, staghorn/hemangiopericytomatous blood vessels pattern, nodular fasciitis-like, and keloid-like morphology. No substantial association was found between the existence of different histologic patterns and the clinical outcome. All thirty-three (100%) samples of DTF had a variable percentage of cells that were nuclear positive for β-catenin. An NGS analysis detected novel non-CTNNB1 mutations in two DTFs, including BCL10, MPL, and RBM10 gene mutations. CONCLUSIONS This study reveals a diverse morphology of DTFs that could result in misdiagnosis. Therefore, surgical pathologists must comprehend this thoroughly. Also, the importance of the newly identified non-CTNNB1 gene mutations is still unclear. More research and analyses are needed to completely grasp the clinical implications of these mutations.
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Affiliation(s)
- Rana Ajabnoor
- Department of Pathology, Faculty of Medicine, King Abdulaziz University and King Abdulaziz University Hospital, Jeddah 22252, Saudi Arabia
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6
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Arcovito G, Crucitta S, Del Re M, Caporalini C, Palomba A, Nozzoli F, Franchi A. Recurrent USP6 rearrangement in a subset of atypical myofibroblastic tumours of the soft tissues: low-grade myofibroblastic sarcoma or atypical/malignant nodular fasciitis? Histopathology 2024; 85:244-253. [PMID: 38651320 DOI: 10.1111/his.15196] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2024] [Revised: 03/24/2024] [Accepted: 04/06/2024] [Indexed: 04/25/2024]
Abstract
AIMS Low-grade myofibroblastic sarcoma (LGMS) is a rarely metastasizing myofibroblastic tumour mostly affecting extremities and the head and neck of adults. Histologically, it shows long infiltrative fascicles of spindle cells with moderate nuclear atypia. By immunohistochemistry, it stains positive for smooth muscle actin (SMA) and sometimes for desmin. To date, no recurrent genetic abnormalities have been described. Ubiquitin-specific peptidase 6 (USP6) gene rearrangement is typically found in some benign bone and soft-tissue tumours including nodular fasciitis (NF), among others. Nevertheless, rare cases of USP6-rearranged tumours resembling NF with atypical features have been reported. METHODS AND RESULTS One index case of LGMS of the deltoid in a 56-year-old man presented the THBS2::USP6 translocation by RNA sequencing (Archer FusionPlex Sarcoma v2 panel). Further screening of 11 cases of LGMS using fluorescent in situ hybridization (FISH) analysis with a USP6 break-apart probe identified two additional cases. These cases were investigated with RNA-sequencing, and a RRBP1::USP6 translocation was detected in one. The other case was not assessable because of low-quality RNA. Noteworthy, rearranged LGMSs presented distinctive features including variable multinodular/plexiform architecture, prominent vasculature with occasional wall thickening, scattered osteoclast-like multinucleated giant cells, and peripheral lymphoid aggregates. CONCLUSION Our findings support the notion that among soft-tissue neoplasms with fibroblastic/myofibroblastic phenotype, USP6 rearrangement is not limited to benign tumours, and warrants further investigation of genetic changes in myofibroblastic sarcomas.
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Affiliation(s)
- Giorgia Arcovito
- Section of Pathology, Department of Translational Research, University of Pisa, Pisa, Italy
| | - Stefania Crucitta
- Unit of Clinical Pharmacology and Pharmacogenetics, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Marzia Del Re
- Unit of Clinical Pharmacology and Pharmacogenetics, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | | | - Annarita Palomba
- Unit of Histopathology and Molecular Diagnostic, Azienda Ospedaliera Universitaria Careggi, Florence, Italy
| | - Filippo Nozzoli
- Department of Health Sciences, University of Florence, Florence, Italy
| | - Alessandro Franchi
- Section of Pathology, Department of Translational Research, University of Pisa, Pisa, Italy
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7
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Lyvannak S, Sereyleak B, Khauv P, Jarzembowski J, Camitta B. Pyrites: A Supra-orbital Mass. J Pediatr Hematol Oncol 2024; 46:279-280. [PMID: 38912834 DOI: 10.1097/mph.0000000000002880] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Accepted: 04/15/2024] [Indexed: 06/25/2024]
Affiliation(s)
- Sam Lyvannak
- Angkor Hospital for Children, Siem Reap, Cambodia
| | | | - Phara Khauv
- Angkor Hospital for Children, Siem Reap, Cambodia
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8
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Kato K, Yamashita K, Dobashi A, Togashi Y, Baba S, Ae K, Matsumoto S, Takeuchi K. Novel THBS1::IGF1R fusion in myopericytic tumour. Histopathology 2024; 85:197-201. [PMID: 38576274 DOI: 10.1111/his.15186] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Revised: 03/13/2024] [Accepted: 03/17/2024] [Indexed: 04/06/2024]
Affiliation(s)
- Kenichiro Kato
- Department of Pathology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
- Department of Pathology, Kyorin University Faculty of Medicine, Tokyo, Japan
| | - Kyoko Yamashita
- Department of Pathology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
- Division of Pathology, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Akito Dobashi
- Department of Pathology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
- Division of Pathology, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan
- Pathology Project for Molecular Targets, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Yuki Togashi
- Department of Pathology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
- Division of Pathology, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan
- Pathology Project for Molecular Targets, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Satoko Baba
- Department of Pathology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
- Division of Pathology, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan
- Pathology Project for Molecular Targets, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Keisuke Ae
- Department of Orthopedic Oncology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Seiichi Matsumoto
- Department of Orthopedic Oncology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Kengo Takeuchi
- Department of Pathology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
- Division of Pathology, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan
- Pathology Project for Molecular Targets, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan
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9
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Warmke LM, Collier CD, Niziolek PJ, Davis JL, Zou YS, Michal M, Bell RC, Policarpio-Nicolas MLC, Cheng YW, Duckworth L, Dermawan JK, Fritchie KJ, Dehner CA. Novel CRTC1::MRTFB(MKL2) Gene Fusion Detected in Myxoid Mesenchymal Neoplasms With Myogenic Differentiation Involving Bone and Soft Tissues. Mod Pathol 2024; 37:100518. [PMID: 38763420 DOI: 10.1016/j.modpat.2024.100518] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Revised: 04/23/2024] [Accepted: 05/11/2024] [Indexed: 05/21/2024]
Abstract
Appropriate classification of fusion-driven bone and soft tissue neoplasms continues to evolve, often relying on the careful integration of morphologic findings with immunohistochemical, molecular, and clinical data. Herein, we present 3 cases of a morphologically distinct myxoid mesenchymal neoplasm with myogenic differentiation and novel CRTC1::MRTFB (formerly MKL2) gene fusion. Three tumors occurred in 1 male and 2 female patients with a median age of 72 years (range: 28-78). Tumors involved the left iliac bone, the right thigh, and the left perianal region with a median size of 4.0 cm (4.0-7.6 cm). Although 1 tumor presented as an incidental finding, the other 2 tumors were noted, given their persistent growth. At the time of the last follow-up, 1 patient was alive with unresected disease at 6 months, 1 patient was alive without evidence of disease at 12 months after surgery, and 1 patient died of disease 24 months after diagnosis. On histologic sections, the tumors showed multinodular growth and were composed of variably cellular spindle to round-shaped cells with distinct brightly eosinophilic cytoplasm embedded within a myxoid stroma. One tumor showed overt smooth muscle differentiation. Cytologic atypia and mitotic activity ranged from minimal (2 cases) to high (1 case). By immunohistochemistry, the neoplastic cells expressed focal smooth muscle actin, h-caldesmon, and desmin in all tested cases. Skeletal muscle markers were negative. Next-generation sequencing detected nearly identical CRTC1::MRTFB gene fusions in all cases. We suggest that myxoid mesenchymal tumors with myogenic differentiation harboring a CRTC1::MRTFB fusion may represent a previously unrecognized, distinctive entity that involves soft tissue and bone. Continued identification of these novel myxoid neoplasms with myogenic differentiation will be important in determining appropriate classification, understanding biologic potential, and creating treatment paradigms.
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Affiliation(s)
- Laura M Warmke
- Department of Pathology, Indiana University School of Medicine, Indianapolis, Indiana
| | - Christopher D Collier
- Department of Orthopedic Surgery, Indiana University School of Medicine, Indianapolis, Indiana
| | - Paul J Niziolek
- Department of Radiology and Imaging Sciences, Musculoskeletal Imaging, Indiana University School of Medicine, Indianapolis, Indiana
| | - Jessica L Davis
- Department of Pathology, Indiana University School of Medicine, Indianapolis, Indiana
| | - Ying S Zou
- Department of Pathology, The Johns Hopkins Hospital, Baltimore, Maryland
| | | | - Robert C Bell
- Department of Pathology, Michigan University, Ann Arbor, Michigan
| | | | - Yu-Wei Cheng
- Department of Pathology and Laboratory Medicine, Cleveland Clinic, Cleveland, Ohio
| | - Lauren Duckworth
- Department of Pathology and Laboratory Medicine, Cleveland Clinic, Cleveland, Ohio
| | - Josephine K Dermawan
- Department of Pathology and Laboratory Medicine, Cleveland Clinic, Cleveland, Ohio
| | - Karen J Fritchie
- Department of Pathology and Laboratory Medicine, Cleveland Clinic, Cleveland, Ohio
| | - Carina A Dehner
- Department of Pathology, Indiana University School of Medicine, Indianapolis, Indiana.
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10
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Slack JC, Church AJ. Molecular Alterations in Pediatric Solid Tumors. Clin Lab Med 2024; 44:277-304. [PMID: 38821645 DOI: 10.1016/j.cll.2023.08.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/02/2024]
Abstract
Pediatric tumors can be divided into hematologic malignancies, central nervous system tumors, and extracranial solid tumors of bone, soft tissue, or other organ systems. Molecular alterations that impact diagnosis, prognosis, treatment, and familial cancer risk have been described in many pediatric solid tumors. In addition to providing a concise summary of clinically relevant molecular alterations in extracranial pediatric solid tumors, this review discusses conventional and next-generation sequencing-based molecular techniques, relevant tumor predisposition syndromes, and the increasing integration of molecular data into the practice of diagnostic pathology for children with solid tumors.
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Affiliation(s)
- Jonathan C Slack
- Pathology & Laboratory Medicine Institute (Robert J. Tomsich), Cleveland Clinic, Cleveland, OH, USA
| | - Alanna J Church
- Department of Pathology, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
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11
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Velagala S, Heiden E, Lisse S, Wu H, Prior D, Chen G, Christison-Lagay E, Provini L, Antaya RJ, Spencer-Manzon M, Johnston LC. A Unique Presentation of Nodular Masses in Infancy. Neoreviews 2024; 25:e370-e374. [PMID: 38821908 DOI: 10.1542/neo.25-6-e370] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Accepted: 02/21/2024] [Indexed: 06/02/2024]
Affiliation(s)
| | - Erica Heiden
- Department of Pediatrics, Yale University School of Medicine, New Haven, CT
| | - Sean Lisse
- Department of Radiology, Yale University School of Medicine, New Haven, CT
| | - Hao Wu
- Department of Pathology, Yale University School of Medicine, New Haven, CT
| | - Daniel Prior
- Department of Pediatrics, Yale University School of Medicine, New Haven, CT
| | - Gloria Chen
- Yale University School of Medicine, New Haven, CT
| | - Emily Christison-Lagay
- Division of Pediatric Surgery, Department of Surgery, Yale University School of Medicine, New Haven, CT
| | - Lauren Provini
- Department of Dermatology, Yale University School of Medicine, New Haven, CT
| | - Richard J Antaya
- Department of Pediatrics, Yale University School of Medicine, New Haven, CT
- Department of Dermatology, Yale University School of Medicine, New Haven, CT
| | - Michele Spencer-Manzon
- Department of Pediatrics, Yale University School of Medicine, New Haven, CT
- Department of Genetics, Yale University School of Medicine, New Haven, CT
| | - Lindsay C Johnston
- Department of Pediatrics, Yale University School of Medicine, New Haven, CT
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12
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Wachtel M, Surdez D, Grünewald TGP, Schäfer BW. Functional Classification of Fusion Proteins in Sarcoma. Cancers (Basel) 2024; 16:1355. [PMID: 38611033 PMCID: PMC11010897 DOI: 10.3390/cancers16071355] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Revised: 03/25/2024] [Accepted: 03/27/2024] [Indexed: 04/14/2024] Open
Abstract
Sarcomas comprise a heterogeneous group of malignant tumors of mesenchymal origin. More than 80 entities are associated with different mesenchymal lineages. Sarcomas with fibroblastic, muscle, bone, vascular, adipocytic, and other characteristics are distinguished. Nearly half of all entities contain specific chromosomal translocations that give rise to fusion proteins. These are mostly pathognomonic, and their detection by various molecular techniques supports histopathologic classification. Moreover, the fusion proteins act as oncogenic drivers, and their blockade represents a promising therapeutic approach. This review summarizes the current knowledge on fusion proteins in sarcoma. We categorize the different fusion proteins into functional classes, including kinases, epigenetic regulators, and transcription factors, and describe their mechanisms of action. Interestingly, while fusion proteins acting as transcription factors are found in all mesenchymal lineages, the others have a more restricted pattern. Most kinase-driven sarcomas belong to the fibroblastic/myofibroblastic lineage. Fusion proteins with an epigenetic function are mainly associated with sarcomas of unclear differentiation, suggesting that epigenetic dysregulation leads to a major change in cell identity. Comparison of mechanisms of action reveals recurrent functional modes, including antagonism of Polycomb activity by fusion proteins with epigenetic activity and recruitment of histone acetyltransferases by fusion transcription factors of the myogenic lineage. Finally, based on their biology, we describe potential approaches to block the activity of fusion proteins for therapeutic intervention. Overall, our work highlights differences as well as similarities in the biology of fusion proteins from different sarcomas and provides the basis for a functional classification.
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Affiliation(s)
- Marco Wachtel
- Department of Oncology and Children’s Research Center, University Children’s Hospital, Steinwiesstrasse 75, CH-8032 Zurich, Switzerland
| | - Didier Surdez
- Balgrist University Hospital, Faculty of Medicine, University of Zurich (UZH), CH-8008 Zurich, Switzerland
| | - Thomas G. P. Grünewald
- Division of Translational Pediatric Sarcoma Research, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), 69120 Heidelberg, Germany
- Hopp-Children’s Cancer Center (KiTZ), 69120 Heidelberg, Germany
- National Center for Tumor Diseases (NCT), NCT Heidelberg, a Partnership between DKFZ and Heidelberg University Hospital, 69120 Heidelberg, Germany
- Institute of Pathology, Heidelberg University Hospital, 69120 Heidelberg, Germany
| | - Beat W. Schäfer
- Department of Oncology and Children’s Research Center, University Children’s Hospital, Steinwiesstrasse 75, CH-8032 Zurich, Switzerland
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13
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Zhou Y, Sun YW, Liu XY, Shen DH. Misdiagnosis of synovial sarcoma - cellular myofibroma with SRF-RELA gene fusion: A case report. World J Clin Cases 2024; 12:1326-1332. [PMID: 38524524 PMCID: PMC10955539 DOI: 10.12998/wjcc.v12.i7.1326] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2023] [Revised: 01/06/2024] [Accepted: 01/25/2024] [Indexed: 02/29/2024] Open
Abstract
BACKGROUND Cellular myofibroma is a rare subtype of myofibroma that was first described in 2017. Its diagnosis is often challenging because of its relative rarity, lack of known genetic abnormalities, and expression of muscle markers that can be confused with sarcomas that have myogenic differentiation. Currently, scholars have limited knowledge of this disease, and published cases are few. Further accumulation of diagnostic and treatment experiences is required. CASE SUMMARY A 16-year-old girl experienced left upper limb swelling for 3 years. She sought medical attention at a local hospital 10 months ago, where magnetic resonance imaging revealed a 5-cm soft tissue mass. Needle biopsy performed at a local hospital resulted in the diagnosis of a spindle cell soft tissue sarcoma. The patient was referred to our hospital for limb salvage surgery with endoprosthetic replacement. She was initially diagnosed with a synovial sarcoma. Consequently, clinical management with chemotherapy was continued for the malignant sarcoma. Our pathology department also performed fluorescence in situ hybridization for result validation, which returned negative for SS18 gene breaks, indicating that it was not a synovial sarcoma. Next-generation sequencing was used to identify the SRF-RELA rearrangement. The final pathological diagnosis was a cellular/myofibroblastic neoplasm with an SRF-RELA gene fusion. The patient had initially received two courses of chemotherapy; however, chemotherapy was discontinued after the final diagnosis. CONCLUSION This case was misdiagnosed because of its rare occurrence, benign biological behavior, and pathological similarity to soft tissue sarcoma.
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Affiliation(s)
- Ying Zhou
- Department of Pathology, Peking University People’s Hospital, Beijing 100044, China
| | - Yi-Wen Sun
- Department of Pathology, Peking University People’s Hospital, Beijing 100044, China
| | - Xiao-Yang Liu
- Department of Pathology, Peking University People’s Hospital, Beijing 100044, China
| | - Dan-Hua Shen
- Department of Pathology, Peking University People’s Hospital, Beijing 100044, China
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14
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Buckley J, Schmidt RJ, Ostrow D, Maglinte D, Bootwalla M, Ruble D, Govindarajan A, Ji J, Kovach AE, Orgel E, Raca G, Navid F, Mascarenhas L, Pawel B, Robison N, Gai X, Biegel JA. An Exome Capture-Based RNA-Sequencing Assay for Genome-Wide Identification and Prioritization of Clinically Important Fusions in Pediatric Tumors. J Mol Diagn 2024; 26:127-139. [PMID: 38008288 DOI: 10.1016/j.jmoldx.2023.11.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Revised: 08/14/2023] [Accepted: 11/07/2023] [Indexed: 11/28/2023] Open
Abstract
This study reports the development of an exome capture-based RNA-sequencing assay to detect recurring and novel fusions in hematologic, solid, and central nervous system tumors. The assay used Twist Comprehensive Exome capture with either fresh or formalin-fixed samples and a bioinformatic platform that provides fusion detection, prioritization, and downstream curation. A minimum of 50 million uniquely mapped reads, a consensus read alignment/fusion calling approach using four callers (Arriba, FusionCatcher, STAR-Fusion, and Dragen), and custom software were used to integrate, annotate, and rank the candidate fusion calls. In an evaluation of 50 samples, the number of calls varied substantially by caller, from a mean of 24.8 with STAR-Fusion to 259.6 with FusionCatcher; only 1.1% of calls were made by all four callers. Therefore a filtering and ranking algorithm was developed based on multiple criteria, including number of supporting reads, calling consensus, genes involved, and cross-reference against databases of known cancer-associated or likely false-positive fusions. This approach was highly effective in pinpointing known clinically relevant fusions, ranking them first in 47 of 50 samples (94%). Detection of pathogenic gene fusions in three diagnostically challenging cases highlights the importance of a genome-wide and nontargeted method for fusion detection in pediatric cancer.
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Affiliation(s)
- Jonathan Buckley
- Center for Personalized Medicine, Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, California; Keck School of Medicine of University of Southern California, Los Angeles, California
| | - Ryan J Schmidt
- Center for Personalized Medicine, Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, California; Keck School of Medicine of University of Southern California, Los Angeles, California
| | - Dejerianne Ostrow
- Center for Personalized Medicine, Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, California
| | - Dennis Maglinte
- Center for Personalized Medicine, Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, California
| | - Moiz Bootwalla
- Center for Personalized Medicine, Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, California
| | - David Ruble
- Center for Personalized Medicine, Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, California
| | - Ananthanarayanan Govindarajan
- Center for Personalized Medicine, Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, California
| | - Jianling Ji
- Center for Personalized Medicine, Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, California; Keck School of Medicine of University of Southern California, Los Angeles, California
| | - Alexandra E Kovach
- Keck School of Medicine of University of Southern California, Los Angeles, California; Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, California
| | - Etan Orgel
- Keck School of Medicine of University of Southern California, Los Angeles, California; Division of Hematology and Oncology, Department of Pediatrics, Children's Hospital Los Angeles, Los Angeles, California
| | - Gordana Raca
- Center for Personalized Medicine, Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, California; Keck School of Medicine of University of Southern California, Los Angeles, California
| | - Fariba Navid
- Keck School of Medicine of University of Southern California, Los Angeles, California; Division of Hematology and Oncology, Department of Pediatrics, Children's Hospital Los Angeles, Los Angeles, California
| | - Leo Mascarenhas
- Keck School of Medicine of University of Southern California, Los Angeles, California; Division of Hematology and Oncology, Department of Pediatrics, Children's Hospital Los Angeles, Los Angeles, California
| | - Bruce Pawel
- Keck School of Medicine of University of Southern California, Los Angeles, California; Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, California
| | - Nathan Robison
- Division of Hematology and Oncology, Department of Pediatrics, Children's Hospital Los Angeles, Los Angeles, California
| | - Xiaowu Gai
- Center for Personalized Medicine, Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, California; Keck School of Medicine of University of Southern California, Los Angeles, California
| | - Jaclyn A Biegel
- Center for Personalized Medicine, Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, California; Keck School of Medicine of University of Southern California, Los Angeles, California.
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15
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Suurmeijer AJH, Dickson BC, Antonescu CR. Complementary value of molecular analysis to expert review in refining classification of uncommon soft tissue tumors. Genes Chromosomes Cancer 2024; 63:e23196. [PMID: 37702439 PMCID: PMC11293799 DOI: 10.1002/gcc.23196] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Revised: 08/06/2023] [Accepted: 08/14/2023] [Indexed: 09/14/2023] Open
Abstract
The classification of many soft tissue tumors remains subjective due their rarity, significant overlap in microscopic features and often a non-specific immunohistochemical (IHC) profile. The application of molecular genetic tools, which leverage the underlying molecular pathogenesis of these neoplasms, have considerably improved the diagnostic abilities of pathologists and refined classification based on objective molecular markers. In this study, we describe the results of an international collaboration conducted over a 3-year period, assessing the added diagnostic value of applying molecular genetics to sarcoma expert pathologic review in a selected series of 84 uncommon, mostly unclassifiable mesenchymal tumors, 74 of which originated in soft tissues and 10 in bone. The case mix (71% historical, 29% contemporary) included mostly unusual and challenging soft tissue tumors, which remained unclassified even with the benefit of expert review and routine ancillary methods, including broad IHC panels and a limited number of commercially available fluorescence in situ hybridization (FISH) probes. All cases were further tested by FISH using a wide range of custom bacterial artificial chromosome probes covering most of known fusions in sarcomas, whereas targeted RNA sequencing was performed in 13 cases negative by FISH, for potential discovery of novel fusion genes. Tumor-defining molecular alterations were found in 48/84 tumors (57%). In 27 (32%) cases the tumor diagnosis was refined or revised by the additional molecular work-up, including five cases (6%), in which the updated diagnosis had clinical implications. Sarcoma classification is rapidly evolving due to an increased molecular characterization of these neoplasms, so unsurprisingly 17% of the tumors in this series harbored abnormalities only very recently described as defining novel molecularly defined soft tissue tumor subsets.
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Affiliation(s)
- Albert J H Suurmeijer
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Brendan C Dickson
- Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Cristina R Antonescu
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA
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16
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Difilippo V, Saba KH, Styring E, Magnusson L, Nilsson J, Nathrath M, Baumhoer D, Nord KH. Osteosarcomas With Few Chromosomal Alterations or Adult Onset Are Genetically Heterogeneous. J Transl Med 2024; 104:100283. [PMID: 37931683 DOI: 10.1016/j.labinv.2023.100283] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Revised: 10/30/2023] [Accepted: 11/01/2023] [Indexed: 11/08/2023] Open
Abstract
Osteosarcoma is the most common primary bone malignancy, often detected in children and adolescents and commonly associated with TP53 alterations along with a high number of chromosomal rearrangements. However, osteosarcoma can affect patients of any age, and some tumors display less genetic complexity. Besides TP53 variants, data on key driving mutations are lacking for many osteosarcomas, particularly those affecting adults. To detect osteosarcoma-specific alterations, we screened transcriptomic and genomic sequencing and copy number data from 150 bone tumors originally diagnosed as osteosarcomas. To increase the precision in gene fusion detection, we developed a bioinformatic tool denoted as NAFuse, which extracts gene fusions that are verified at both the genomic and transcriptomic levels. Apart from the already reported genetic subgroups of osteosarcoma with TP53 structural variants, or MDM2 and/or CDK4 amplification, we did not identify any recurrent genetic driver that signifies the remaining cases. Among the plethora of mutations identified, we found genetic alterations characteristic of, or similar to, those of other bone and soft tissue tumors in 8 cases. These mutations were found in tumors with relatively few other genetic alterations or in adults. Due to the lack of clinical context and available tissue, we can question the diagnosis only on a genetic basis. However, our findings support the notion that osteosarcomas with few chromosomal alterations or adult onset seem genetically distinct from conventional osteosarcomas of children and adolescents.
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Affiliation(s)
- Valeria Difilippo
- Department of Laboratory Medicine, Division of Clinical Genetics, Lund University, Lund, Sweden
| | - Karim H Saba
- Department of Laboratory Medicine, Division of Clinical Genetics, Lund University, Lund, Sweden
| | - Emelie Styring
- Department of Orthopedics, Lund University, Skåne University Hospital, Lund, Sweden
| | - Linda Magnusson
- Department of Laboratory Medicine, Division of Clinical Genetics, Lund University, Lund, Sweden
| | - Jenny Nilsson
- Department of Laboratory Medicine, Division of Clinical Genetics, Lund University, Lund, Sweden
| | - Michaela Nathrath
- Children's Cancer Research Centre and Department of Pediatrics, Klinikum rechts der Isar, Technische Universität München, Munich, Germany; Department of Pediatric Oncology, Klinikum Kassel, Kassel, Germany
| | - Daniel Baumhoer
- Bone Tumour Reference Centre at the Institute of Pathology, University Hospital and University of Basel, Basel, Switzerland
| | - Karolin H Nord
- Department of Laboratory Medicine, Division of Clinical Genetics, Lund University, Lund, Sweden.
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17
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Crowell C, Schollenberg E, Tran TH, Wilson D, Bezuhly M, Mata-Mbemba D, Antonescu CR, Erker C. An SRF-rearranged malignant cellular myoid neoplasm with a novel SRF-MKL2 fusion. Pediatr Blood Cancer 2023; 70:e30675. [PMID: 37715727 DOI: 10.1002/pbc.30675] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Accepted: 09/03/2023] [Indexed: 09/18/2023]
Affiliation(s)
- Cameron Crowell
- IWK Health Centre, Halifax, Nova Scotia, Canada
- Dalhousie University, Halifax, Nova Scotia, Canada
| | - Erica Schollenberg
- IWK Health Centre, Halifax, Nova Scotia, Canada
- Dalhousie University, Halifax, Nova Scotia, Canada
| | - Thai Hoa Tran
- Charles-Bruneau Cancer Centre, CHU Saint-Justine, Montreal, Québec, Canada
- Université de Montreal, Montreal, Québec, Canada
| | - David Wilson
- IWK Health Centre, Halifax, Nova Scotia, Canada
- Dalhousie University, Halifax, Nova Scotia, Canada
| | - Michael Bezuhly
- IWK Health Centre, Halifax, Nova Scotia, Canada
- Dalhousie University, Halifax, Nova Scotia, Canada
| | - Daddy Mata-Mbemba
- IWK Health Centre, Halifax, Nova Scotia, Canada
- Dalhousie University, Halifax, Nova Scotia, Canada
| | | | - Craig Erker
- IWK Health Centre, Halifax, Nova Scotia, Canada
- Dalhousie University, Halifax, Nova Scotia, Canada
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18
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Gier H, Chung C, Prasad V, Bjorklund K, Fernandez Faith E. Enlarging ulcerated nodule on the hand of a child. Pediatr Dermatol 2023; 40:1136-1138. [PMID: 37253660 DOI: 10.1111/pde.15367] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Accepted: 05/13/2023] [Indexed: 06/01/2023]
Affiliation(s)
- Hannah Gier
- Heritage College of Osteopathic Medicine, Ohio University, Columbus, Ohio, USA
| | - Catherine Chung
- Department of Dermatology, The Ohio State University, Columbus, Ohio, USA
- Department of Pathology, The Ohio State University, Columbus, Ohio, USA
- Laboratory Medicine and Anatomic Pathology, Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Vinay Prasad
- Laboratory Medicine and Anatomic Pathology, Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Kim Bjorklund
- Department of Plastic and Reconstructive Surgery, Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Esteban Fernandez Faith
- Division of Dermatology, Department of Pediatrics, Nationwide Children's Hospital, Columbus, Ohio, USA
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19
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Liu Y, Housley Smith M, Patel PB, Bilodeau EA. Pediatric Gnathic Bony and Mesenchymal Tumors. Pediatr Dev Pathol 2023; 26:621-641. [PMID: 37232383 DOI: 10.1177/10935266231170744] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/27/2023]
Abstract
Evaluation of bone pathology within the head and neck region, particularly the gnathic bonesis is complex, demonstrating unique pathologic processes. In part, this variation is due to odontogenesis and the embryological cells that may be involved, which can contribute to disease development and histologic variability. As with any boney pathosis, the key is to have clinical correlation, particularly with radiographic imaging prior to establishing a definitive diagnosis. This review will cover those entities that have a predilection for the pediatric population, and while it is not all inclusive, it should serve as a foundation for the pathologist who is evaluating bony lesions involving the craniofacial skeleton.
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Affiliation(s)
- Yingci Liu
- Rutgers School of Dental Medicine, Newark, NJ, USA
| | | | - Paras B Patel
- Center for Oral Pathology, Dallas, TX, USA
- Oral and Maxillofacial Pathology ProPath, Dallas, TX, USA
| | - Elizabeth Ann Bilodeau
- Oral & Maxillofacial Pathology, Director, UDHS Oral Pathology Laboratory, University of Pittsburgh School of Dental Medicine, Pittsburgh, PA, USA
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20
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Papa B, Nguyen MA, Kumar A, Song L, Dorwal P, Cheah AL. Cellular myofibromas with SRF fusions: clinicopathological and molecular study of 3 cases of a rare entity and a potential mimic of sarcoma. Hum Pathol 2023; 138:41-48. [PMID: 37245628 DOI: 10.1016/j.humpath.2023.05.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 05/15/2023] [Accepted: 05/23/2023] [Indexed: 05/30/2023]
Abstract
Cellular myofibromas/myopericytomas harboring recurring SRF fusions are recently characterized as rare and diagnostically challenging entities, which can mimic myogenic sarcomas. These tumors belong to the pericytic/perivascular myoid tumor family, which comprises a group of genetically heterogenous and sometimes morphologically overlapping entities. In this series, we describe 3 cases of SRF-rearranged cellular myofibromas/perivascular myoid tumors with a smooth muscle-like phenotype in children. The children ranged from 7 to 16 years of age, and all presented with a painless mass in the extremities, 2 of which were deep-seated. Histologically, the tumors demonstrated a smooth muscle-like morphology and immunophenotype with mild atypia and low-level mitotic activity. Prominent dense collagen deposition and coarse calcification was observed in 2 tumors. RNA sequencing revealed SRF fusions in all cases, with each tumor showing a different 3' partner gene, RELA, NFKBIE, and NCOA3. Of these, NCOA3 has not been reported previously, and this expands the molecular spectrum by identifying a novel fusion partner for SRF. Given that histological features can be worrisome for a myogenic sarcoma, wider awareness of this emerging tumor is valuable to avoid potential misclassification.
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Affiliation(s)
- Brigitte Papa
- Department of Anatomical Pathology, Monash Health, Clayton, VIC 3168, Australia
| | - Minh Anh Nguyen
- Douglass Hanly Moir Pathology, Macquarie Park, NSW 2113, Australia
| | - Amit Kumar
- Diagnostic Genomics, Monash Health, Clayton, VIC 3168, Australia
| | - Liyan Song
- Diagnostic Genomics, Monash Health, Clayton, VIC 3168, Australia
| | - Pranav Dorwal
- Department of Anatomical Pathology, Monash Health, Clayton, VIC 3168, Australia; Diagnostic Genomics, Monash Health, Clayton, VIC 3168, Australia; School of Clinical Sciences, Monash University, Clayton, VIC 3800, Australia.
| | - Alison L Cheah
- Douglass Hanly Moir Pathology, Macquarie Park, NSW 2113, Australia; School of Medicine, The University of Notre Dame Australia, Darlinghurst, NSW 2010, Australia
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21
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Georgantzoglou N, Linos K. An update on selected cutaneous (myo) fibroblastic mesenchymal tumors. Semin Diagn Pathol 2023; 40:295-305. [PMID: 37150655 PMCID: PMC10602371 DOI: 10.1053/j.semdp.2023.04.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Revised: 04/24/2023] [Accepted: 04/24/2023] [Indexed: 05/09/2023]
Abstract
Cutaneous (myo)fibroblastic tumors constitute a group of tumors with overlapping clinicopathological features and variable biologic behavior. In the present review we focus on the histomorphology, immunohistochemical profile and molecular background of the following entities: dermatofibrosarcoma protuberans (DFSP), CD34-positive fibroblastic tumor (SCD34FT), myxoinflammatory sarcoma (MIFS), low-grade myofibroblastic sarcoma, solitary fibrous tumor and nodular fasciitis. Although some of these entities typically arise in deep-seated locations, they may occasionally present as cutaneous/superficial tumors and might be challenging to recognize. This review covers in depth the latest advances in molecular diagnostics and immunohistochemical markers that have significantly facilitated the correct classification and diagnosis of these neoplasms.
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Affiliation(s)
- Natalia Georgantzoglou
- Department of Pathology & Laboratory Medicine, Dartmouth Hitchcock Medical Center, Lebanon, NH, United States
| | - Konstantinos Linos
- Department of Pathology & Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, United States.
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22
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Yasir M, Park J, Han ET, Park WS, Han JH, Kwon YS, Lee HJ, Hassan M, Kloczkowski A, Chun W. Investigation of Flavonoid Scaffolds as DAX1 Inhibitors against Ewing Sarcoma through Pharmacoinformatic and Dynamic Simulation Studies. Int J Mol Sci 2023; 24:9332. [PMID: 37298283 PMCID: PMC10253386 DOI: 10.3390/ijms24119332] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Revised: 05/24/2023] [Accepted: 05/24/2023] [Indexed: 06/12/2023] Open
Abstract
Dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1 (DAX1) is an orphan nuclear receptor encoded by the NR0B1 gene. The functional study showed that DAX1 is a physiologically significant target for EWS/FLI1-mediated oncogenesis, particularly Ewing Sarcoma (ES). In this study, a three-dimensional DAX1 structure was modeled by employing a homology modeling approach. Furthermore, the network analysis of genes involved in Ewing Sarcoma was also carried out to evaluate the association of DAX1 and other genes with ES. Moreover, a molecular docking study was carried out to check the binding profile of screened flavonoid compounds against DAX1. Therefore, 132 flavonoids were docked in the predicted active binding pocket of DAX1. Moreover, the pharmacogenomics analysis was performed for the top ten docked compounds to evaluate the ES-related gene clusters. As a result, the five best flavonoid-docked complexes were selected and further evaluated by Molecular Dynamics (MD) simulation studies at 100 ns. The MD simulation trajectories were evaluated by generating RMSD, hydrogen bond plot analysis, and interaction energy graphs. Our results demonstrate that flavonoids showed interactive profiles in the active region of DAX1 and can be used as potential therapeutic agents against DAX1-mediated augmentation of ES after in-vitro and in-vivo evaluations.
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Affiliation(s)
- Muhammad Yasir
- Department of Pharmacology, Kangwon National University School of Medicine, Chuncheon 24341, Republic of Korea; (M.Y.); (J.P.); (H.-J.L.)
| | - Jinyoung Park
- Department of Pharmacology, Kangwon National University School of Medicine, Chuncheon 24341, Republic of Korea; (M.Y.); (J.P.); (H.-J.L.)
| | - Eun-Taek Han
- Department of Medical Environmental Biology and Tropical Medicine, Kangwon National University School of Medicine, Chuncheon 24341, Republic of Korea; (E.-T.H.); (J.-H.H.)
| | - Won Sun Park
- Department of Physiology, Kangwon National University School of Medicine, Chuncheon 24341, Republic of Korea;
| | - Jin-Hee Han
- Department of Medical Environmental Biology and Tropical Medicine, Kangwon National University School of Medicine, Chuncheon 24341, Republic of Korea; (E.-T.H.); (J.-H.H.)
| | - Yong-Soo Kwon
- College of Pharmacy, Kangwon National University School of Medicine, Chuncheon 24341, Republic of Korea;
| | - Hee-Jae Lee
- Department of Pharmacology, Kangwon National University School of Medicine, Chuncheon 24341, Republic of Korea; (M.Y.); (J.P.); (H.-J.L.)
| | - Mubashir Hassan
- The Steve and Cindy Rasmussen Institute for Genomic Medicine at Nationwide Children’s Hospital, Columbus, OH 43205, USA; (M.H.); (A.K.)
| | - Andrzej Kloczkowski
- The Steve and Cindy Rasmussen Institute for Genomic Medicine at Nationwide Children’s Hospital, Columbus, OH 43205, USA; (M.H.); (A.K.)
| | - Wanjoo Chun
- Department of Pharmacology, Kangwon National University School of Medicine, Chuncheon 24341, Republic of Korea; (M.Y.); (J.P.); (H.-J.L.)
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23
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Fischer GM, Papke DJ. Gene fusions in superficial mesenchymal neoplasms: Emerging entities and useful diagnostic adjuncts. Semin Diagn Pathol 2023:S0740-2570(23)00046-1. [PMID: 37156707 DOI: 10.1053/j.semdp.2023.04.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Accepted: 04/24/2023] [Indexed: 05/10/2023]
Abstract
Cutaneous mesenchymal neoplasms are diagnostically challenging because of their overlapping morphology, and, often, the limited tissue in skin biopsy specimens. Molecular and cytogenetic techniques have identified characteristic gene fusions in many of these tumor types, findings that have expanded our understanding of disease pathogenesis and motivated development of useful ancillary diagnostic tools. Here, we provide an update of new findings in tumor types that can occur in the skin and superficial subcutis, including dermatofibrosarcoma protuberans, benign fibrous histiocytoma, epithelioid fibrous histiocytoma, angiomatoid fibrous histiocytoma, glomus tumor, myopericytoma/myofibroma, non-neural granular cell tumor, CIC-rearranged sarcoma, hybrid schwannoma/perineurioma, and clear cell sarcoma. We also discuss recently described and emerging tumor types that can occur in superficial locations and that harbor gene fusions, including nested glomoid neoplasm with GLI1 alterations, clear cell tumor with melanocytic differentiation and ACTIN::MITF translocation, melanocytic tumor with CRTC1::TRIM11 fusion, EWSR1::SMAD3-rearranged fibroblastic tumor, PLAG1-rearranged fibroblastic tumor, and superficial ALK-rearranged myxoid spindle cell neoplasm. When possible, we discuss how fusion events mediate the pathogenesis of these tumor types, and we also discuss the related diagnostic and therapeutic implications of these events.
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Affiliation(s)
- Grant M Fischer
- Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States of America
| | - David J Papke
- Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States of America.
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24
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Iwamura R, Komatsu K, Kusano M, Kubo C, Inaba Y, Shiba E, Nawata A, Tajiri R, Matsuyama A, Matoba H, Koga K, Takeda M, Itami H, Hisaoka M. PDGFRB and NOTCH3 Mutations are Detectable in a Wider Range of Pericytic Tumors, Including Myopericytomas, Angioleiomyomas, Glomus Tumors, and Their Combined Tumors. Mod Pathol 2023; 36:100070. [PMID: 36788105 DOI: 10.1016/j.modpat.2022.100070] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Revised: 11/07/2022] [Accepted: 12/11/2022] [Indexed: 01/11/2023]
Abstract
Pericytic tumors are subclassified as myopericytomas, myofibromas, angioleiomyomas, and glomus tumors according to the current World Health Organization classification. These pericytic tumors form a continuous morphologic spectrum, including those with combined morphology. However, to our knowledge, no widely accepted criteria for classifying tumors with combined morphology are available. Recent studies have identified platelet-derived growth factor receptor-beta (PDGFRB) gene mutations in a subset of myofibromas, myopericytomas, and myopericytomatoses but not in angioleiomyomas. NOTCH receptor 3 (NOTCH3) mutations have been reported in a subset of infantile myofibromatosis. To assess their potential role in classifying pericytic tumors, we investigated PDGFRB and NOTCH3 mutations in 41 pericytic tumors of variable morphology, including some combined forms. Our results show these mutations to be present in a variety of pericytic tumors, such as myopericytomas (PDGFRB, 3/11; NOTCH3, 4/11), myopericytomatoses (1/2; 1/2), myofibromas (3/6; 0/6), angioleiomyomas (2/13; 3/13), and glomus tumors (5/9; 1/9). Point mutations were identified in 3 tumors in PDGFRB exon 12 (Y562C, S574F, and G576S), 12 tumors in PDGFRB exon 14 (M655I, H657L, and N666K), and 9 tumors in NOTCH3 exon 25 (A1480S/T, D1481N, G1482S, T1490A, E1491K, G1494S, and V1512A). All PDGFRB mutations and NOTCH3 G1482S, T1490A, and G1494S mutations were classified as "deleterious/damaging" by ≥4 of 6 pathogenicity prediction tools in silico. Five-mutation-positive tumors, including 1 myopericytoma-angioleiomyoma, 2 myopericytomatoses-myofibroma, 1 myofibroma-myopericytoma and 1 angioleiomyoma-myopericytoma, were of combined morphology. Therefore, we found PDGFRB and NOTCH3 mutations to be detectable in a much wider variety of pericytic tumors than previously reported and confirmed myopericytomas, myofibromas, angioleiomyomas, and glomus tumors as members harboring PDGFRB or NOTCH3 mutations. Our results thus suggest that PDGFRB or NOTCH3 mutations are not useful for subclassifying members of the pericytic tumor family.
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Affiliation(s)
- Ryuji Iwamura
- Department of Pathology and Oncology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
| | - Kazuki Komatsu
- Department of Pathology and Oncology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Midori Kusano
- Department of Pathology and Oncology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Chisachi Kubo
- Department of Pathology and Oncology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Yuna Inaba
- Department of Pathology and Oncology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Eisuke Shiba
- Department of Pathology and Oncology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Aya Nawata
- Department of Pathology and Oncology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Ryosuke Tajiri
- Department of Pathology and Oncology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan; Department of Obstetrics and Gynecology, School of Medicine University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Atsuji Matsuyama
- Division of Laboratory Medicine and Pathology, Fukuoka Wajiro Hospital, Fukuoka, Japan
| | - Hisanori Matoba
- Department of Molecular Pathology, Shinshu University Graduate School of Medicine, Matsumoto, Japan
| | - Kaori Koga
- Department of Pathology, Fukuoka University School of Medicine, Fukuoka, Japan
| | - Maiko Takeda
- Department of Diagnostic Pathology, Nara Medical University, Kashihara, Japan
| | - Hiroe Itami
- Department of Diagnostic Pathology, Nara Medical University, Kashihara, Japan; Department of Pathology, Kobe City Medical Center General Hospital, Kobe, Japan
| | - Masanori Hisaoka
- Department of Pathology and Oncology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
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25
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Giraldo-Roldán D, Fernandes DT, Louredo BVR, Penafort PVM, Roza ALOC, Santos-Silva AR, Vargas PA. An ulcerative nodule on the dorsal tongue in an 8-year-old boy. Oral Surg Oral Med Oral Pathol Oral Radiol 2023:S2212-4403(23)00031-7. [PMID: 36935231 DOI: 10.1016/j.oooo.2023.02.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Revised: 02/01/2023] [Accepted: 02/02/2023] [Indexed: 02/13/2023]
Affiliation(s)
- Daniela Giraldo-Roldán
- Department of Oral Diagnosis, Piracicaba Dental School, University of Campinas, Piracicaba, São Paulo, Brazil
| | - Diego Tetzner Fernandes
- Department of Head and Neck Surgery, Santa Casa de Misericórdia de Limeira, Limeira, São Paulo, Brazil
| | | | | | | | - Alan Roger Santos-Silva
- Department of Oral Diagnosis, Piracicaba Dental School, University of Campinas, Piracicaba, São Paulo, Brazil
| | - Pablo Agustin Vargas
- Department of Oral Diagnosis, Piracicaba Dental School, University of Campinas, Piracicaba, São Paulo, Brazil; Department of Oral and Maxillofacial Pathology, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa.
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26
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Sumida S, Toki SI, Mori T, Satomi K, Takao S, Nobusawa S, Kakimoto T, Nakagawa S, Ryo E, Matsushita Y, Ichimura K, Nishisho T, Bando Y, Yoshida A. ZFTA::RELA fusion in a distinct liposarcoma morphologically overlapping with chondroid lipoma. Genes Chromosomes Cancer 2023; 62:101-106. [PMID: 36201637 DOI: 10.1002/gcc.23098] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 09/06/2022] [Accepted: 09/06/2022] [Indexed: 12/13/2022] Open
Abstract
Chondroid lipoma is a rare benign adipose tumor characterized by a recurrent ZFTA::MRTFB fusion. Herein, we report an unusual liposarcoma that partly exhibited overlapping features with those of chondroid lipoma and harbored a ZFTA::RELA fusion. A 59-year-old man presented with a shoulder mass that had existed for approximately 8 years and with increasing pain due to a pelvic mass. The 5.8-cm resected shoulder tumor partly consisted of nests and strands of variably lipogenic epithelioid cells within a hyalinized or focally chondromyxoid stroma, indistinguishable from chondroid lipoma. The histological pattern gradually transitioned to highly cellular, stroma-poor, diffuse sheets of cells with greater nuclear atypia and mitotic activity. Vascular invasion and necrosis were present. The metastatic pelvic tumor revealed a similar histology. Despite multimodal treatment, the patient developed multiple bone metastases and succumbed to the disease 14 months after presentation. Targeted RNA sequencing identified an in-frame ZFTA (exon 3)::RELA (exon 2) fusion, which was confirmed by reverse transcription-polymerase chain reaction, Sanger sequencing, and break-apart fluorescent in situ hybridization assays. The tumor showed a different histology from that of ependymoma, no brain involvement, and no match with any sarcoma types or ZFTA::RELA-positive ependymomas according to DNA methylation analysis. p65 and L1CAM were diffusely expressed, and a CDKN2A/B deletion was present. This is the first report of an extra-central nervous system tumor with a ZFTA::RELA fusion. The tumor partly displayed an overlapping histology with that of chondroid lipoma, suggesting that it may represent a hitherto undescribed malignant chondroid lipoma with an alternative ZFTA fusion.
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Affiliation(s)
- Satoshi Sumida
- Division of Pathology, Tokushima University Hospital, Tokushima, Japan
| | - Shun-Ichi Toki
- Department of Orthopedics, Institute of Biomedical Sciences, Tokushima University, Tokushima, Japan
| | - Taisuke Mori
- Department of Diagnostic Pathology, National Cancer Center Hospital, Tokyo, Japan.,Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo, Japan
| | - Kaishi Satomi
- Department of Diagnostic Pathology, National Cancer Center Hospital, Tokyo, Japan.,Department of Pathology, Kyorin University School of Medicine, Tokyo, Japan
| | - Shoichiro Takao
- Department of Diagnostic Radiology, Graduate School of Health Sciences, Tokushima University, Tokushima, Japan
| | | | - Takumi Kakimoto
- Division of Pathology, Tokushima University Hospital, Tokushima, Japan
| | - Shinya Nakagawa
- Department of Orthopedics, Institute of Biomedical Sciences, Tokushima University, Tokushima, Japan
| | - Eijitsu Ryo
- Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo, Japan
| | - Yuko Matsushita
- Department of Brain Disease Translational Research, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Koichi Ichimura
- Department of Brain Disease Translational Research, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Toshihiko Nishisho
- Department of Orthopedics, Institute of Biomedical Sciences, Tokushima University, Tokushima, Japan
| | - Yoshimi Bando
- Division of Pathology, Tokushima University Hospital, Tokushima, Japan
| | - Akihiko Yoshida
- Department of Diagnostic Pathology, National Cancer Center Hospital, Tokyo, Japan.,Rare Cancer Center, National Cancer Center Hospital, Tokyo, Japan
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27
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Slack JC, Hollowell ML, Khouri KS, Church AJ, Ganske IM, Delano S, Al-Ibraheemi A. Expanding the Spectrum of Perioral Myogenic Tumors in Pediatric Patients: An SRF::NCOA2 Fused Perivascular Tumor of the Philtrum. Pediatr Dev Pathol 2023; 26:65-71. [PMID: 36457254 DOI: 10.1177/10935266221138896] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/05/2022]
Abstract
BACKGROUND Perivascular tumors, which include myopericytoma and myofibroma, are rare benign soft tissue neoplasms composed of perivascular smooth muscle cells. Most demonstrate characteristic morphology and are readily diagnosed. However, a recently identified hypercellular subset shows atypical histologic features and harbor unique SRF gene fusions. These cellular perivascular tumors can mimic other more common sarcomas with myogenic differentiation. METHODS Clinical, radiological, morphological, immunohistochemical, and molecular findings were reviewed. RESULTS A slow-growing, fluctuant mass was noted within the philtrum at 16 months. Ultrasonography revealed a well-circumscribed cystic hypoechoic lesion. A small (1.0 cm), tan, well-circumscribed soft-tissue mass was excised after continued growth. Histologically, the encapsulated tumor was hypercellular and composed of spindle cells with predominantly-storiform architecture, focal perivascular condensation, dilated branching thin-walled vessels, increased mitoses, and a smooth muscle immunophenotype. An SRF::NCOA2 fusion was identified. CONCLUSION We report the first case of an SRF-rearranged cellular myopericytoma in the perioral region in a young child. This case expands the differential diagnosis of perioral soft tissue tumors with myogenic differentiation. We highlight key clinical, pathological, and molecular features. As we illustrate, these rare tumors pose a considerable diagnostic challenge, and risk misdiagnosis as sarcoma, most notably spindle cell rhabdomyosarcoma.
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Affiliation(s)
- Jonathan C Slack
- Department of Pathology, Boston Children's Hospital/Harvard Medical School, Boston, MA, USA
| | - Monica L Hollowell
- Department of Pathology, Boston Children's Hospital/Harvard Medical School, Boston, MA, USA
| | - Kimberly S Khouri
- Department of Plastic and Oral Surgery, Boston Children's Hospital/Harvard Medical School, Boston, MA, USA
| | - Alanna J Church
- Department of Pathology, Boston Children's Hospital/Harvard Medical School, Boston, MA, USA
| | - Ingrid M Ganske
- Department of Plastic and Oral Surgery, Boston Children's Hospital/Harvard Medical School, Boston, MA, USA
| | - Sophia Delano
- Department of Pediatrics (Dermatology Program), Boston Children's Hospital/Harvard Medical School, Boston, MA, USA
| | - Alyaa Al-Ibraheemi
- Department of Pathology, Boston Children's Hospital/Harvard Medical School, Boston, MA, USA
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28
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Jabbari S, Salari B, He M, Dehner LP. Infantile Fibrosarcoma and Other Spindle Cell Neoplasms of Infancy. A Review of Morphologically Overlapping yet Molecularly Distinctive Entities. Fetal Pediatr Pathol 2022; 41:996-1014. [PMID: 35044292 DOI: 10.1080/15513815.2021.2024631] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
BACKGROUND Regardless of age at presentation, many soft tissue neoplasms have overlapping histopathologic and immunophenotypic features to serve as a diagnostic challenge. CASE REPORT We reported a case of a spindle cell neoplasm in an infant, which was initially considered a vascular anomaly clinically and an eventual biopsy revealed marked inflammation with a spindle cell component that was resolved as an infantile fibrosarcoma with an ETV6 break-apart. CONCLUSION The context of this case lead to a further consideration of various other spindle cell neoplasms arising predominantly in the soft tissues during the infancy period as defined by the first two years of age. Though sharing similar morphologic features, these tumors can be categorized into several molecular genetic groups, which have provided both diagnostic and pathogenetic insights as well as treatment options in some cases.
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Affiliation(s)
- Shiva Jabbari
- Lauren V. Ackerman Laboratory of Surgical Pathology, Washington University Medical Center, St. Louis, MO, USA
| | - Behzad Salari
- Lauren V. Ackerman Laboratory of Surgical Pathology, Washington University Medical Center, St. Louis, MO, USA
| | - Mai He
- Lauren V. Ackerman Laboratory of Surgical Pathology, Washington University Medical Center, St. Louis, MO, USA.,St. Louis Children's Hospitals, Washington University Medical Center, St. Louis, MO, USA
| | - Louis P Dehner
- Lauren V. Ackerman Laboratory of Surgical Pathology, Washington University Medical Center, St. Louis, MO, USA.,St. Louis Children's Hospitals, Washington University Medical Center, St. Louis, MO, USA
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29
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SRF Rearrangements in Soft Tissue Tumors with Muscle Differentiation. Biomolecules 2022; 12:biom12111678. [DOI: 10.3390/biom12111678] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 11/07/2022] [Accepted: 11/08/2022] [Indexed: 11/16/2022] Open
Abstract
The Serum Response Factor (SRF) is a transcription factor that regulates the expression of a wide set of genes involved in cell proliferation, migration, cytoskeletal organization and myogenesis. Accumulating evidence suggests that SRF may play a role in carcinogenesis and tumor progression in various neoplasms, where it is often involved in different fusion events. Here we investigated SRF rearrangements in soft tissue tumors, along with a gene expression profile analysis to gain insight into the oncogenic mechanism driven by SRF fusion. Whole transcriptome analysis of cell lines transiently overexpressing the SRF::E2F1 chimeric transcript uncovered the specific gene expression profile driven by the aberrant gene fusion, including overexpression of SRF-dependent target genes and of signatures related to myogenic commitment, inflammation and immune activation. This result was confirmed by the analysis of two cases of myoepitheliomas harboring SRF::E2F1 fusion with respect to EWSR1-fusion positive tumors. The recognition of the specific gene signature driven by SRF rearrangement in soft tissue tumors could aid the molecular classification of this rare tumor entity and support therapeutic decisions.
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30
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Tan MWP, Wei Tay AY, Tang PY, Chew KY, Nicholas Yeo EM. Myopericytoma: A Review of Twenty-Three Cases Over Twelve Years and a Case Report of a Rare Neoplasm. Am J Dermatopathol 2022; 44:623-631. [PMID: 35980090 DOI: 10.1097/dad.0000000000002130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
Myopericytoma is a rare soft tissue tumor with a predilection for the distal extremities. It is commonly found in the skin and subcutaneous tissues and usually takes a benign course. Current knowledge is limited to isolated case series and reports; hence, this study aims to report our tertiary institution's experience with this uncommon entity. A review of our institution's pathology records for cases of myopericytoma was performed. From January 2009 to September 2020, 23 cases of myopericytoma were identified and their clinicopathologic features were reported. A unique case of myopericytoma of the ankle from the series was also highlighted as a case report. Among the 22 cutaneous cases, 18 were in the extremities and 4 in the head and neck. One patient had an intracranial lesion. Most patients developed asymptomatic nodules (72.2%), but 1 patient had a locally aggressive tumor on presentation. None recurred despite marginal excision in some patients (80.0%). In conclusion, pathologists and surgeons who encounter this rare neoplasm can reassure patients of its benign tendency.
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Affiliation(s)
- Marcus Wei Ping Tan
- Medical Officer, Department of Orthopaedic Surgery, Singapore General Hospital, Singapore, , Singapore
| | - Adriel You Wei Tay
- Resident, Department of Orthopaedic Surgery, Singapore General Hospital, Singapore, Singapore
| | - Po Yin Tang
- Consultant, Department of Anatomical Pathology, Singapore General Hospital, Singapore, Singapore
| | - Khong Yik Chew
- Consultant, Department of Plastic, Reconstructive & Aesthetic Surgery, Singapore General Hospital, Singapore, Singapore ; and
| | - Eng Meng Nicholas Yeo
- Consultant, Department of Plastic, Reconstructive & Aesthetic Surgery, Singapore General Hospital, Singapore, Singapore
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31
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Li Y, Huang D, Bi R, Yao Q, Ge L, Yu L, Zhou X, Yang W. Uterine tumors with myogenic differentiation harboring
SRF
::
RELA
fusions. Histopathology 2022; 81:477-485. [DOI: 10.1111/his.14724] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Revised: 07/14/2022] [Accepted: 07/16/2022] [Indexed: 11/28/2022]
Affiliation(s)
- Yimin Li
- Department of Pathology Fudan University Shanghai Cancer Center Shanghai People’s Republic of China
- Department of Oncology, Shanghai Medical College Fudan University Shanghai People’s Republic of China
| | - Dan Huang
- Department of Pathology Fudan University Shanghai Cancer Center Shanghai People’s Republic of China
- Department of Oncology, Shanghai Medical College Fudan University Shanghai People’s Republic of China
| | - Rui Bi
- Department of Pathology Fudan University Shanghai Cancer Center Shanghai People’s Republic of China
- Department of Oncology, Shanghai Medical College Fudan University Shanghai People’s Republic of China
| | - Qianlan Yao
- Department of Pathology Fudan University Shanghai Cancer Center Shanghai People’s Republic of China
- Department of Oncology, Shanghai Medical College Fudan University Shanghai People’s Republic of China
| | - Ling Ge
- Department of Pathology Fudan University Shanghai Cancer Center Shanghai People’s Republic of China
- Department of Oncology, Shanghai Medical College Fudan University Shanghai People’s Republic of China
- Department of Pathology, The Third Hospital of Xiamen Xiamen People’s Republic of China
| | - Lin Yu
- Department of Pathology Fudan University Shanghai Cancer Center Shanghai People’s Republic of China
- Department of Oncology, Shanghai Medical College Fudan University Shanghai People’s Republic of China
| | - Xiaoyan Zhou
- Department of Pathology Fudan University Shanghai Cancer Center Shanghai People’s Republic of China
- Department of Oncology, Shanghai Medical College Fudan University Shanghai People’s Republic of China
| | - Wentao Yang
- Department of Pathology Fudan University Shanghai Cancer Center Shanghai People’s Republic of China
- Department of Oncology, Shanghai Medical College Fudan University Shanghai People’s Republic of China
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32
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Shastri M, Gupta N, Dey P, Srinivasan R, Radotra BD. Cytomorphological Spectrum of Solitary Fibrous Tumor: Revisited. Cytopathology 2022; 33:688-695. [PMID: 35778919 DOI: 10.1111/cyt.13163] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Revised: 06/09/2022] [Accepted: 06/28/2022] [Indexed: 11/29/2022]
Abstract
BACKGROUND Solitary fibrous tumor (SFT) is a tumor of mesenchymal origin. Its diagnosis on cytology is challenging, owing to variation in cellularity, sparsely distributed cellular and stromal components and inapparent vasculature. The cytomorphologic findings have been rarely described in literature with a few case reports and occasional case series. We present the cytomorphologic features of SFT with special emphasis on immunochemical findings. MATERIALS AND METHODS We present cytological data from eight cases of histopathologically proven SFTs. The cytomorphologic features, immunochemical markers and differential diagnostic entities on fine needle aspiration cytology (FNAC) arediscussed. RESULTS FNA was performed at different anatomical sites. Cytology smears showed variable cellularity with tumor cells arranged in loose clusters and as singly scattered cells. Interlacing fascicles with palisading of cells was noted. The cells were predominantly spindle to elongated, having moderate cytoplasm with elongated wavy nuclei. These nuclei had fine to coarse chromatin, with inconspicuous to prominent nucleoli. There was prominent metachromatically staining, amorphous to fibrillary, collagenous to myxoid matrix materialassociated with tumor cells. Other findings included intranuclear pseudo-inclusions, multinucleated giant cells and atypical mitoses. Cytological diagnosis offered varied from 'spindle cell neoplasm' to 'spindle cell sarcoma' or 'suggestive of sarcoma'.Immunocytochemistry (ICC) done on cell block sections showed positivity for STAT6, CD34 and Bcl-2. CONCLUSION Cytological diagnosis of SFT can be challenging. A prudent search for characteristic cytomorphological features is of diagnostic help. The cytomorphology should be interpreted with caution with appropriate ICC panel including STAT6 and CD34.
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Affiliation(s)
- Malvika Shastri
- Department of Cytology and Gynaecological Pathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Nalini Gupta
- Department of Cytology and Gynaecological Pathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Pranab Dey
- Department of Cytology and Gynaecological Pathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Radhika Srinivasan
- Department of Cytology and Gynaecological Pathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Bishan Dass Radotra
- Department of Histopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
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33
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Multicentric infantile myofibromatosis with extensive involvement limited to bone. Skeletal Radiol 2022; 51:1503-1510. [PMID: 34865192 DOI: 10.1007/s00256-021-03968-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2021] [Revised: 11/23/2021] [Accepted: 11/29/2021] [Indexed: 02/02/2023]
Abstract
Infantile myofibromatosis (IM) is the most common benign fibrous tumor of infancy, characterized by the development of single or multiple nodules in the skin, soft tissues, bone, and/or viscera. Multicentric forms are less frequent and can affect different tissues simultaneously and their prognosis depends on their extension and visceral involvement. Rarely, these forms are limited to the skeleton, in which case the absence of extraosseous lesions makes it difficult to suspect this entity. We present the case of an infant with multiple radiolucent lesions involving the skull, ribs, spine, and long bones, discovered in a radiological study performed after a minor trauma. A broad differential diagnosis was considered based on the osteolytic and polyostotic nature of the lesions on imaging studies. This report details and illustrates the typical radiological findings in bony involvement of IM, which suggest this disorder over other diagnostic options.
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34
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Jo VY, Demicco EG. Update from the 5th Edition of the World Health Organization Classification of Head and Neck Tumors: Soft Tissue Tumors. Head Neck Pathol 2022; 16:87-100. [PMID: 35312984 PMCID: PMC9018918 DOI: 10.1007/s12105-022-01425-w] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Accepted: 02/03/2022] [Indexed: 01/27/2023]
Abstract
The fifth (5th) edition of the World Health Organization (WHO) Classification of Head and Neck Tumors introduces a new chapter dedicated to soft tissue neoplasms commonly affecting the head and neck. While the diversity, rarity, and wide anatomic range of soft tissue tumors precludes a discussion of all entities that may be found in the head and neck, the addition of this new chapter to the head and neck "blue book" aims to provide a more comprehensive and uniform reference text, including updated diagnostic criteria, of mesenchymal tumor types frequently (or exclusively) arising at head and neck sites. Since publication of the previous edition in 2017, there have been numerous advances in our understanding of the pathogenesis of many soft tissue tumors which have facilitated refinements in tumor classification, identification of novel entities, development of diagnostic markers, and improved prognostication. This review will provide a focused discussion of the soft tissue tumors included in the 5th edition WHO Head and Neck classification, with an emphasis on updates.
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Affiliation(s)
- Vickie Y Jo
- Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, Boston, MA, 02115, USA.
| | - Elizabeth G Demicco
- Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
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35
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Slim Z, Wong D, van Vliet C, Amanuel B, Sader C, Boeddinghaus R, Farah CS. A 33-year-old man with a rapidly growing lump on the dorsal tongue. Oral Surg Oral Med Oral Pathol Oral Radiol 2022; 134:505-512. [PMID: 35461797 DOI: 10.1016/j.oooo.2022.02.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2021] [Revised: 01/16/2022] [Accepted: 02/14/2022] [Indexed: 11/25/2022]
Affiliation(s)
- Zena Slim
- Western Diagnostic Pathology, Jandakot, Australia.
| | - Daniel Wong
- PathWest Laboratory Medicine WA, Nedlands, Australia
| | | | | | | | | | - Camile S Farah
- Hollywood Private Hospital and Australian Clinical Labs, Nedlands, Australia
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36
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Azam H, Pierro L, Reina M, Gallagher WM, Prencipe M. Emerging role for the Serum Response Factor (SRF) as a potential therapeutic target in cancer. Expert Opin Ther Targets 2022; 26:155-169. [PMID: 35114091 DOI: 10.1080/14728222.2022.2032652] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
INTRODUCTION The Serum Response Factor (SRF) is a transcription factor involved in three hallmarks of cancer: the promotion of cell proliferation, cell death resistance and invasion and metastasis induction. Many studies have demonstrated a leading role in the development and progression of multiple cancer types, thus highlighting the potential of SRF as a prognostic biomarker and therapeutic target, especially for cancers with poor prognosis. AREAS COVERED This review examines the role of SRF in several cancers in promoting cellular processes associated with cancer development and progression. SRF co-factors and signalling pathways are discussed as possible targets to inhibit SRF in a tissue and cancer-specific way. Small-molecule inhibitors of SRF, such as the CCGs series of compounds and lestaurtinib, which could be used as cancer therapeutics, are also discussed. EXPERT OPINION Targeting of SRF and its co-factors represents a promising therapeutic approach. Further understanding of the molecular mechanisms behind the action of SRF could provide a pipeline of novel molecular targets and therapeutic combinations for cancer. Basket clinical trials and the use of SRF immunohistochemistry as companion diagnostics will help testing of these new targets in patients.
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Affiliation(s)
- Haleema Azam
- Cancer Biology and Therapeutics Laboratory, UCD Conway Institute, University College Dublin, Belfield, D4, Dublin, Ireland.,UCD School of Biomolecular and Biomedical Science, University College Dublin, Belfield, D4, Dublin, Ireland
| | - Lisa Pierro
- Cancer Biology and Therapeutics Laboratory, UCD Conway Institute, University College Dublin, Belfield, D4, Dublin, Ireland.,UCD School of Biomolecular and Biomedical Science, University College Dublin, Belfield, D4, Dublin, Ireland
| | - Martina Reina
- Cancer Biology and Therapeutics Laboratory, UCD Conway Institute, University College Dublin, Belfield, D4, Dublin, Ireland.,UCD School of Biomolecular and Biomedical Science, University College Dublin, Belfield, D4, Dublin, Ireland
| | - William M Gallagher
- Cancer Biology and Therapeutics Laboratory, UCD Conway Institute, University College Dublin, Belfield, D4, Dublin, Ireland.,UCD School of Biomolecular and Biomedical Science, University College Dublin, Belfield, D4, Dublin, Ireland
| | - Maria Prencipe
- Cancer Biology and Therapeutics Laboratory, UCD Conway Institute, University College Dublin, Belfield, D4, Dublin, Ireland.,UCD School of Biomolecular and Biomedical Science, University College Dublin, Belfield, D4, Dublin, Ireland
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37
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Abstract
In this issue of Molecular Cell, Alerasool et al. (2022) present a proteome-scale functional screen to systematically uncover human proteins that can activate transcription.
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Affiliation(s)
- Filip Nemčko
- Research Institute of Molecular Pathology (IMP), Vienna BioCenter (VBC), Campus-Vienna-Biocenter 1, Vienna, Austria; Vienna BioCenter PhD Program, Doctoral School of the University of Vienna and Medical University of Vienna, Vienna, Austria
| | - Alexander Stark
- Research Institute of Molecular Pathology (IMP), Vienna BioCenter (VBC), Campus-Vienna-Biocenter 1, Vienna, Austria; Medical University of Vienna, Vienna BioCenter (VBC), Vienna, Austria.
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38
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Alerasool N, Leng H, Lin ZY, Gingras AC, Taipale M. Identification and functional characterization of transcriptional activators in human cells. Mol Cell 2022; 82:677-695.e7. [PMID: 35016035 DOI: 10.1016/j.molcel.2021.12.008] [Citation(s) in RCA: 68] [Impact Index Per Article: 22.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Revised: 11/04/2021] [Accepted: 12/09/2021] [Indexed: 12/13/2022]
Abstract
Transcription is orchestrated by thousands of transcription factors (TFs) and chromatin-associated proteins, but how these are causally connected to transcriptional activation is poorly understood. Here, we conduct an unbiased proteome-scale screen to systematically uncover human proteins that activate transcription in a natural chromatin context. By combining interaction proteomics and chemical inhibitors, we delineate the preference of these transcriptional activators for specific co-activators, highlighting how even closely related TFs can function via distinct cofactors. We also identify potent transactivation domains among the hits and use AlphaFold2 to predict and experimentally validate interaction interfaces of two activation domains with BRD4. Finally, we show that many novel activators are partners in fusion events in tumors and functionally characterize a myofibroma-associated fusion between SRF and C3orf62, a potent p300-dependent activator. Our work provides a functional catalog of potent transactivators in the human proteome and a platform for discovering transcriptional regulators at genome scale.
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Affiliation(s)
- Nader Alerasool
- Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON M5S 3E1, Canada
| | - He Leng
- Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON M5S 3E1, Canada
| | - Zhen-Yuan Lin
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Sinai Health System, Toronto, ON M5G 1X5, Canada
| | - Anne-Claude Gingras
- Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Sinai Health System, Toronto, ON M5G 1X5, Canada.
| | - Mikko Taipale
- Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON M5S 3E1, Canada.
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39
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Davis JL, Al‐Ibraheemi A, Rudzinski ER, Surrey LF. Mesenchymal neoplasms with NTRK and other kinase gene alterations. Histopathology 2021; 80:4-18. [DOI: 10.1111/his.14443] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2021] [Revised: 06/30/2021] [Accepted: 07/01/2021] [Indexed: 12/20/2022]
Affiliation(s)
- Jessica L Davis
- Department of Pathology Oregon Health & Science University Portland OregonUSA
| | - Alyaa Al‐Ibraheemi
- Department of Pathology Boston Children’s Hospital Boston MassachusettsUSA
| | - Erin R Rudzinski
- Department of Laboratories Seattle Children’s Hospital Seattle WashingtonUSA
| | - Lea F Surrey
- Department of Pathology and Laboratory Medicine The Children’s Hospital of Philadelphia Philadelphia Pennsylvania USA
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40
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Rodriguez JD, Selleck AM, Abdel Razek AAK, Huang BY. Update on MR Imaging of Soft Tissue Tumors of Head and Neck. Magn Reson Imaging Clin N Am 2021; 30:151-198. [PMID: 34802577 DOI: 10.1016/j.mric.2021.06.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
This article reviews soft tissue tumors of the head and neck following the 2020 revision of WHO Classification of Soft Tissue and Bone Tumours. Common soft tissue tumors in the head and neck and tumors are discussed, along with newly added entities to the classification system. Salient clinical and imaging features that may allow for improved diagnostic accuracy or to narrow the imaging differential diagnosis are covered. Advanced imaging techniques are discussed, with a focus on diffusion-weighted and dynamic contrast imaging and their potential to help characterize soft tissue tumors and aid in distinguishing malignant from benign tumors.
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Affiliation(s)
- Justin D Rodriguez
- Department of Radiology, Duke University, 2301 Erwin Rd, Durham, NC 27705, USA
| | - A Morgan Selleck
- Department of Otolaryngology/Head and Neck Surgery, University of North Carolina Hospitals, 170 Manning Drive, CB 7070, Physicians Office Building, Rm G190A, Chapel Hill, NC 27599, USA
| | | | - Benjamin Y Huang
- Department of Radiology, UNC School of Medicine, 101 Manning Drive, CB#7510, Chapel Hill, NC 27599, USA.
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41
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Shi Z, Zhao XM, Jiang JM, Li M, Xie LZ. Clinical and imaging features of desmoid tumors of the extremities. World J Clin Cases 2021; 9:8710-8717. [PMID: 34734049 PMCID: PMC8546812 DOI: 10.12998/wjcc.v9.i29.8710] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Revised: 07/14/2021] [Accepted: 08/13/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Desmoid fibroma is a rare soft tissue tumor originating from the aponeurosis, fascia, and muscle, and it is also known as aponeurotic fibroma, invasive fibroma, or ligamentous fibroma.
AIM To investigate the clinical and imaging features of desmoid tumors of the extremities.
METHODS Thirteen patients with desmoid fibroma of the extremities admitted to our hospital from October 2016 to March 2021 were included. All patients underwent computed tomography (CT), magnetic resonance imaging (MRI), and pathological examination of the lesion. Data on the diameter and distribution of the lesion, the relationship between the lesion morphology and surrounding structures, MRI and CT findings, and pathological features were statistically analyzed.
RESULTS The lesion diameter ranged from 1.7 to 8.9 cm, with an average of 5.35 ± 2.39 cm. All lesions were located in the deep muscular space, with the left and right forearm each accounting for 23.08% of cases. Among the 13 patients with desmoid fibroma of the extremities, the lesions were "patchy" in 1 case, irregular in 10, and quasi-round in 2. The boundary between the lesion and surrounding soft tissue was blurred in 10 cases, and the focus infiltrated along the tissue space and invaded the adjacent structures. Furthermore, the edge of the lesion showed "beard-like" infiltration in 2 cases; bone resorption and damage were found in 8, and bending of the bone was present in 2; the boundary of the focus was clear in 1. According to the MRI examination, the lesions were larger than 5 cm (61.54%), round or fusiform in shape (84.62%), had an unclear boundary (76.92%), showed uniform signal (69.23%), inhomogeneous enhancement (84.62%), and "root" or "claw" infiltration (69.23%). Neurovascular tract invasion was present in 30.77% of cases. CT examination showed that the desmoid tumors had slightly a lower density (69.23%), higher enhancement (61.54%), and unclear boundary (84.62%); a CT value < 50 Hu was present in 53.85% of lesions, and the enhancement was uneven in 53.85% of cases. Microscopically, fibroblasts and myofibroblasts were arranged in strands and bundles, without obvious atypia but with occasional karyotyping; cells were surrounded by collagen tissue. There were disparities in the proportion of collagen tissue in different regions, with abundant collagen tissue and few tumor cells in some areas, similar to the structure of aponeuroses or ligaments, and tumor cells invading the surrounding tissues.
CONCLUSION Desmoid tumors of the extremities have certain imaging features on CT and MRI. The two imaging techniques can be combined to improve the diagnostic accuracy, achieve a comprehensive diagnosis of the disease in the clinical practice, and reduce the risk of missed diagnosis or misdiagnosis. In addition, their use can ensure timely diagnosis and treatment.
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Affiliation(s)
- Zhuo Shi
- Department of Imaging Diagnosis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Xin-Ming Zhao
- Department of Imaging Diagnosis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Jiu-Ming Jiang
- Department of Imaging Diagnosis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Meng Li
- Department of Imaging Diagnosis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Li-Zhi Xie
- GE Healthcare China, Beijing 100176, China
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42
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Davis JL, Rudzinski ER. Pediatric and Infantile Fibroblastic/Myofibroblastic Tumors in the Molecular Era. Surg Pathol Clin 2021; 13:739-762. [PMID: 33183731 DOI: 10.1016/j.path.2020.08.009] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Pediatric fibroblastic/myofibroblastic tumors are rare but include a wide variety of benign to malignant tumors. Given their uncommon frequency, they may present as a diagnostic dilemma. This article is focused on using clinical and pathologic clues in conjunction with the increasingly relevant and available molecular techniques to classify, predict prognosis, and/or guide treatment in these tumors.
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Affiliation(s)
- Jessica L Davis
- Department of Pathology, Oregon Health & Science University, L-471, Portland, OR 97239, USA.
| | - Erin R Rudzinski
- Department of Laboratories, Seattle Children's Hospital, OC.8.720, Seattle, WA 98105, USA
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43
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Slack JC, Bründler MA, Nohr E, McIntyre JB, Kurek KC. Molecular Alterations in Pediatric Fibroblastic/Myofibroblastic Tumors: An Appraisal of a Next Generation Sequencing Assay in a Retrospective Single Centre Study. Pediatr Dev Pathol 2021; 24:405-421. [PMID: 33970051 DOI: 10.1177/10935266211015558] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
BACKGROUND Pediatric fibroblastic/myofibroblastic tumors (PFMTs) can be challenging to definitively classify. Large case series or diagnostic updates have not been recently published despite identification of molecular alterations that could improve diagnostic accuracy. Our review of the literature found that over two-thirds of the more than 30 types of PFMTs harbor recurrent molecular alterations. We performed an institutional review of PFMTs to highlight limitations of a predominantly morphological classification, and evaluated the utility of a next-generation sequencing assay to aid diagnosis. METHODS PFMTs identified over a period of 12 years were reviewed, categorized per the new WHO classification, and tested using the Oncomine Childhood Cancer Research Assay. RESULTS Eighty-seven specimens from 58 patients were reviewed; 50 were chosen for molecular analysis, 16 (32%) lacking definitive classification. We identified alterations, some novel, in 33% of assayed cases. Expected alterations were identified for most known diagnoses and mutations were identified in 6 of 16 tumors (38%) that were initially unclassified. CONCLUSION We confirmed a significant subset of PFMTs remain difficult to classify using current criteria, and that a combined DNA/RNA assay can identify alterations in many of these cases, improving diagnostic certainty and suggesting a clinical utility for challenging cases.
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Affiliation(s)
- Jonathan C Slack
- Department of Pathology and Laboratory Medicine, Cumming School of Medicine, Calgary, Alberta, Canada
| | - Marie-Anne Bründler
- Department of Pathology and Laboratory Medicine, Cumming School of Medicine, Calgary, Alberta, Canada
- Department of Pediatrics, Cumming School of Medicine, Calgary, Alberta, Canada
| | - Erik Nohr
- Department of Pathology and Laboratory Medicine, Cumming School of Medicine, Calgary, Alberta, Canada
| | - John B McIntyre
- Precision Oncology Hub Laboratory, Tom Baker Cancer Centre, Department of Oncology, University of Calgary, Calgary, Alberta, Canada
| | - Kyle C Kurek
- Department of Pathology and Laboratory Medicine, Cumming School of Medicine, Calgary, Alberta, Canada
- Department of Genetics, Cumming School of Medicine, Calgary, Alberta, Canada
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44
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Abstract
Pediatric tumors can be divided into hematologic malignancies, central nervous system tumors, and extracranial solid tumors of bone, soft tissue, or other organ systems. Molecular alterations that impact diagnosis, prognosis, treatment, and familial cancer risk have been described in many pediatric solid tumors. In addition to providing a concise summary of clinically relevant molecular alterations in extracranial pediatric solid tumors, this review discusses conventional and next-generation sequencing-based molecular techniques, relevant tumor predisposition syndromes, and the increasing integration of molecular data into the practice of diagnostic pathology for children with solid tumors.
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Affiliation(s)
- Jonathan C Slack
- Department of Pathology, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA
| | - Alanna J Church
- Department of Pathology, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
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45
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Dachy G, Fraitag S, Boulouadnine B, Cordi S, Demoulin JB. Novel COL4A1-VEGFD gene fusion in myofibroma. J Cell Mol Med 2021; 25:4387-4394. [PMID: 33830670 PMCID: PMC8093964 DOI: 10.1111/jcmm.16502] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 03/15/2021] [Accepted: 03/18/2021] [Indexed: 12/18/2022] Open
Abstract
Myofibroma is a benign pericytic tumour affecting young children. The presence of multicentric myofibromas defines infantile myofibromatosis (IMF), which is a life‐threatening condition when associated with visceral involvement. The disease pathophysiology remains poorly characterized. In this study, we performed deep RNA sequencing on eight myofibroma samples, including two from patients with IMF. We identified five different in‐frame gene fusions in six patients, including three previously described fusion transcripts, SRF‐CITED1, SRF‐ICA1L and MTCH2‐FNBP4, and a fusion of unknown significance, FN1‐TIMP1. We found a novel COL4A1‐VEGFD gene fusion in two cases, one of which also carried a PDGFRB mutation. We observed a robust expression of VEGFD by immunofluorescence on the corresponding tumour sections. Finally, we showed that the COL4A1‐VEGFD chimeric protein was processed to mature VEGFD growth factor by proteases, such as the FURIN proprotein convertase. In conclusion, our results unravel a new recurrent gene fusion that leads to VEGFD production under the control of the COL4A1 gene promoter in myofibroma. This fusion is highly reminiscent of the COL1A1‐PDGFB oncogene associated with dermatofibrosarcoma protuberans. This work has implications for the diagnosis and, possibly, the treatment of a subset of myofibromas.
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Affiliation(s)
- Guillaume Dachy
- de Duve Institute, Université Catholique de Louvain, Brussels, Belgium
| | - Sylvie Fraitag
- Department of Pathology, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France
| | | | - Sabine Cordi
- de Duve Institute, Université Catholique de Louvain, Brussels, Belgium
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46
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Abstract
INTRODUCTION Myofibromatosis is a distinctive mesenchymal disorder occurring predominantly in childhood, which on microscopy shows peripheral light areas of spindle cells and central cellular areas of primitive oval to spindle cells arranged around hemagiopercytomatous vessels. PDFGRB mutations in the familial and multifocal sporadic forms and SRF-RELA fusions in the cellular variants have been identified. The index case is being presented to discuss the clinico-pathological features, differential diagnosis, and management of the lesion. CASE PRESENTATION An 11-year-old male presented with an infraorbital mass of 3 months duration. The mass was excised and microscopy revealed the morphological features of myofibroma with tram-track SMA immunopositivity. Nodular fasciitis and fibromatosis were the differentials considered. CONCLUSION The SRF-RELA gene fusion may represent a subset that in the future may be used to differentiate these myofibromas/myopericytomas from the ACTB-GLI fusion myopericytomas, and PDGFRB may be used to perhaps separate out familial myofibromas from other myofibromas.
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Affiliation(s)
- Kanika Rastogi
- Pathology, Chacha Nehru Bal Chikitsalaya, Geeta Colony, Delhi, India
| | - Lavleen Singh
- Department of Pathology, Chacha Nehru Bal Chikitsalaya, Delhi, India
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47
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Anderson WJ, Doyle LA. Updates from the 2020 World Health Organization Classification of Soft Tissue and Bone Tumours. Histopathology 2021; 78:644-657. [PMID: 33438273 DOI: 10.1111/his.14265] [Citation(s) in RCA: 127] [Impact Index Per Article: 31.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Revised: 09/23/2020] [Accepted: 09/24/2020] [Indexed: 12/16/2022]
Abstract
The fifth edition of the World Health Organization (WHO) classification of soft tissue and bone tumours was published in May 2020. This 'Blue Book', which is also available digitally for the first time, incorporates an array of new information on these tumours, amassed in the 7 years since the previous edition. Major advances in molecular characterisation have driven further refinements in classification and the development of ancillary diagnostic tests, and have improved our understanding of disease pathogenesis. Several new entities are also included. This review summarises the main changes introduced in the 2020 WHO classification for each subcategory of soft tissue and bone tumours.
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Affiliation(s)
- William J Anderson
- Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Leona A Doyle
- Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
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48
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SRF Fusions Other Than With RELA Expand the Molecular Definition of SRF-fused Perivascular Tumors. Am J Surg Pathol 2021; 44:1725-1735. [PMID: 33021523 DOI: 10.1097/pas.0000000000001546] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Pericytic tumors encompass several entities sharing morphologic and immunohistochemical features. A subset of perivascular myoid tumors associated with the SRF-RELA fusion gene was previously described. Herein, we report a series of 13 tumors belonging to this group, in which we have identified new fusion genes by RNA-sequencing, thus expanding the molecular spectrum of this entity. All patients except 1 were children and infants. The tumors, frequently located in the head (n=8), had a mean size of 38 mm (range 10 to 150 mm) and were mostly (n=9) well-circumscribed. Exploration of the follow-up data (ranging from 3 to 68 mo) confirmed the benign behavior of these tumors. These neoplasms presented a spectrum of morphologies, ranging from perivascular patterns to myoid appearance. Tumor cells presented mitotic figures but without marked atypia. Some of these tumors could mimic sarcoma. The immunohistochemical profiles confirmed a pericytic differentiation with the expression of the smooth muscle actin and the h-caldesmon, as well as the frequent positivity for pan-cytokeratin. The molecular analysis identified the expected SRF-RELA fusion gene, in addition to other genetic alterations, all involving SRF fused to CITED1, CITED2, NFKBIE, or NCOA2. The detection of SRF-NCOA2 fusions in spindle cell rhabdomyosarcoma of the infant has previously been described, representing a risk of misdiagnosis, although the cases reported herein did not express MyoD1. Finally, clustering analyses confirmed that this group of SRF-fused perivascular myoid tumors forms a distinct entity, different from other perivascular tumors, spindle cell rhabdomyosarcomas of the infant, and smooth muscle tumors.
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49
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Choi JH, Ro JY. The 2020 WHO Classification of Tumors of Soft Tissue: Selected Changes and New Entities. Adv Anat Pathol 2021; 28:44-58. [PMID: 32960834 DOI: 10.1097/pap.0000000000000284] [Citation(s) in RCA: 234] [Impact Index Per Article: 58.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Soft tissue tumors are a relatively rare and diagnostically challenging group of neoplasms that can have varying lines of differentiation. Accurate diagnosis is important for appropriate treatment and prognostication. In the 8 years since the publication of the 4th Edition of World Health Organization (WHO) classification of soft tissue tumors, significant advances have been made in our understanding of soft tissue tumor molecular biology and diagnostic criteria. The 5th Edition of the 2020 WHO classification of tumors of soft tissue and bone incorporated these changes. Classification of tumors, in general, but particularly in soft tissue tumors, is increasingly based on the molecular characteristics of tumor types. Understanding tumor molecular genetics improves diagnostic accuracy for tumors that have been difficult to classify on the basis of morphology alone, or that have overlapping morphologic features. In many large hospitals in the United States and Europe, molecular tests on soft tissue tumors are a routine part of diagnosis. Therefore, surgical pathologists should be familiar with newly emerging molecular genetic techniques in clinical settings. In the near future, molecular tests, particularly in soft tissue tumor diagnosis, will become as routine during diagnosis as immunohistochemistry is currently. This new edition provides an updated classification scheme and essential diagnostic criteria for soft tissue tumors. Newly recognized entities and subtypes of existing tumor types, several reclassified tumors, and newly defined molecular and genetic data have been incorporated. Herein, we summarize the updates in the WHO 5th Edition, focusing on major changes in each category of soft tissue tumor, and the newly described tumor entities and subtypes.
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Affiliation(s)
- Joon Hyuk Choi
- Department of Pathology, Yeungnam University College of Medicine, Daegu, South Korea
| | - Jae Y Ro
- Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Weill Medical College of Cornell University, Houston, TX
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50
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Habeeb O, Korty KE, Azzato EM, Astbury C, Farkas DH, Ko JS, Billings SD. EWSR1-SMAD3 rearranged fibroblastic tumor: Case series and review. J Cutan Pathol 2020; 48:255-262. [PMID: 32901982 DOI: 10.1111/cup.13870] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 08/23/2020] [Accepted: 08/31/2020] [Indexed: 11/29/2022]
Abstract
We report the largest series to date (N = 6) of EWSR1-SMAD3 rearranged fibroblastic tumor. Initially described in 2018, the tumor features a marked female predominance (F:M, 5:1, mean age 44-years, median age 45.5 years; range 27-57), with most cases (5/6, 83%) arising in acral locations (4 on foot/toe, 1 on hand). One case presented on the lower extremity. The lesions presented as nodules and were composed of short, variably cellular, intersecting fascicles of uniform spindled cells in a collagenous to myxoid stroma. In four cases, the tumor abutted the epidermis without a grenz zone. In one case, there was an abrupt transition to a central, acellular hyalinized area. Two other cases had admixed smaller collagenous areas, reminiscent of collagen rosettes. One had a concentric arrangement of tumor cells around blood vessels. Mitotic activity was low (<1/10 HPFs). All were positive for ERG by immunohistochemistry and negative for CD34 (6/6). An EWSR1-SMAD3 fusion was identified in three cases tested by next-generation sequencing (3/3). Rearrangement of EWSR1 by fluorescence in situ hybridization was showed in 1/1 case. Our series reaffirms prior findings and expands the known histopathologic spectrum of this emerging entity.
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Affiliation(s)
- Omar Habeeb
- Department of Anatomic Pathology, Middlemore Hospital, Counties Manukau District Health Board, Auckland, New Zealand
| | - Katelen E Korty
- Department of Pathology, Cleveland Clinic, Cleveland, Ohio, USA
| | | | | | - Daniel H Farkas
- Department of Pathology, Cleveland Clinic, Cleveland, Ohio, USA
| | - Jennifer S Ko
- Department of Pathology, Cleveland Clinic, Cleveland, Ohio, USA
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