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Bone and soft tissue tumors: clinicoradiologic-pathologic molecular-genetic correlation of novel fusion spindled, targetable-ovoid, giant-cell-rich, and round cell sarcomas

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Abstract

Background

New entities in the classification of bone and soft tissue tumors have been identified by use of advanced molecular-genetic techniques, including next-generation sequencing. Clinicoradiologic and pathologic correlation supports diagnostic classification.

Methods

Tumors from four morphologically grouped areas are selected to enhance diagnosis and awareness among the multidisciplinary team. These include select round cell tumors, spindle cell tumors, targetable tyrosine kinase/RAS::MAPK pathway-ovoid (epithelioid to spindled) tumors, and giant-cell-rich tumors of bone and soft tissue.

Results

Round cell tumors of bone and soft tissue include prototypical Ewing sarcoma, newer sarcomas with BCOR genetic alteration and CIC-rearranged, as well as updates on FUS/EWSR1::NFATc2, an EWSR1 non-ETS tumor that is solid with additional amplified hybridization signal pattern of EWSR1. This FUS/EWSR1::NFATc2 fusion has now been observed in seemingly benign to low-grade intraosseous vascular-rich and simple (unicameral) bone cyst tumors. Select spindle cell tumors of bone and soft tissue include rhabdomyosarcoma with FUS/EWSR1::TFCP2, an intraosseous high-grade spindle cell tumor without matrix. Targetable tyrosine-kinase or RAS::MAPK pathway-tumors of bone and soft tissue include NTRK, ALK, BRAF, RAF1, RET, FGFR1, ABL1, EGFR, PDGFB, and MET with variable ovoid myopericytic to spindled pleomorphic features and reproducible clinicopathologic and radiologic clues to their diagnosis. Giant-cell-rich tumors of bone, joint, and soft tissue are now respectively characterized by H3F3A mutation, CSF1 rearrangement (targetable), and HMGA2::NCOR2 fusion.

Conclusion

This article is an update for radiologists, oncologists, surgeons, and pathologists to recognize these novel ovoid, spindled, giant-cell-rich, and round cell tumors, for optimal diagnostic classification and multidisciplinary team patient care.

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Data Availability

The datasets generated during and/or analysed during the current review paper are available from cited accepted peer-reviewed journal articles and international presentations and from the corresponding author upon request.

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Acknowledgements

This section is to acknowledge and thank all of our interdisciplinary local and international colleagues. Thanks to colleagues Dr. Donald Flemming and MSK team for excellent daily interdisciplinary discussions. Thanks to Jessica D. Smith who excels in research and scientific writing/editing skills. Appreciation goes to those colleagues who contributed information and/or provided original, previously unpublished figures for this manuscript, including Dr. Daniel Baumhoer, Dr. Roman Guggenberger, Dr. Chantal Pauli, Dr. Sinchun Hwang, Dr. Meera Hameed, Dr. Paul O’Donnell, Dr. Fernanda Amary, Dr. Carol Morris, Dr. John Gross, Dr. Mark Murphey, Dr. Fiona Bonar, Dr. Adrienne Flanagan, and Dr. Mark Kransdorf.

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Authors and Affiliations

  1. Departments of Pathology, Orthopedics, Pediatrics, Penn State Health, Milton S. Hershey Medical Center, Penn State Children’s Hospital, Penn State College of Medicine, Hershey, PA, USA

    J. C. Fanburg-Smith

  2. Georgetown University, Washington, DC, USA

    J. D. Smith

  3. Department of Radiology, Penn State Health, Milton S. Hershey Medical Center, Penn State Children’s Hospital, Penn State College of Medicine, Hershey, PA, USA

    D. J. Flemming

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Key points

• Discuss clinicoradiologic features of the fine line between benign and malignant in vascular-rich and cystic round cell tumors EWSR1/FUS::NFATc2 (FET non-ETS Ewing) fusion.

• Awareness by the interdisciplinary team of new non-matrix/mineralizing high-grade spindled intraosseous rhabdomyosarcoma with EWSR1/FUS::TFCP2.

• Identify new RAS::MAPK pathway tyrosine-kinase fusion sarcomas involving NTRK, ALK, BRAF, RAF1, RET, FGFR1, ABL1, EGFR, and MET with options of targeted therapy, using clinicoradiologic and pathologic correlation.

• Update molecular classification of giant cell rich tumors of soft tissue, joint, and bone respectively involving H3F3A-mutation (K34W), CSF1 rearrangement, or HMGA2::NCOR2.

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Fanburg-Smith, J.C., Smith, J.D. & Flemming, D.J. Bone and soft tissue tumors: clinicoradiologic-pathologic molecular-genetic correlation of novel fusion spindled, targetable-ovoid, giant-cell-rich, and round cell sarcomas. Skeletal Radiol 52, 517–540 (2023). https://doi.org/10.1007/s00256-022-04244-w

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