Inflammatory Myofibroblastic Tumors Harbor Multiple Potentially Actionable Kinase Fusions

Lovly, Christine M.; Gupta, Abha; Lipson, Doron; Otto, Geoff; Brennan, Tina; Chung, Catherine T.; Borinstein, Scott C.; Ross, Jeffrey S.; Stephens, Philip J.; Miller, Vincent A.; Coffin, Cheryl M.

doi:10.1158/2159-8290.cd-14-0377

Cited by 375 publications

(471 citation statements)

References 18 publications

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“…This concept is potentially Fusion genes in phosphaturic mesenchymal tumors supported by a recently identified FN1-ALK oncoprotein, which contains the ALK transmembrane domain absent from other ALK fusion proteins. 17,18 Additionally, a novel FN1-FGF1 fusion gene was identified in three phosphaturic mesenchymal tumors, all originating from bone. If we assume that FN1-FGF1 and FN1-FGFR1 fusions are mutually exclusive, as suggested by the data from representative cases, then the estimated overall prevalence of FGF1 rearrangement and rearrangement of either gene in phosphaturic mesenchymal tumors is 6% (3/50) and 48% (24/50), respectively.…”

Section: Discussionmentioning

confidence: 99%

Characterization of FN1–FGFR1 and novel FN1–FGF1 fusion genes in a large series of phosphaturic mesenchymal tumors

et al. 2016

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Phosphaturic mesenchymal tumors typically cause paraneoplastic osteomalacia, chiefly as a result of FGF23 secretion. In a prior study, we identified FN1-FGFR1 fusion in 9 of 15 phosphaturic mesenchymal tumors. In this study, a total of 66 phosphaturic mesenchymal tumors and 7 tumors resembling phosphaturic mesenchymal tumor but without known phosphaturia were studied. A novel FN1-FGF1 fusion gene was identified in two cases without FN1-FGFR1 fusion by RNA sequencing and cross-validated with direct sequencing and western blot. Fluorescence in situ hybridization analyses revealed FN1-FGFR1 fusion in 16 of 39 (41%) phosphaturic mesenchymal tumors and identified an additional case with FN1-FGF1 fusion. The two fusion genes were mutually exclusive. Combined with previous data, the overall prevalence of FN1-FGFR1 and FN1-FGF1 fusions was 42% (21/50) and 6% (3/50), respectively. FGFR1 immunohistochemistry was positive in 82% (45/55) of phosphaturic mesenchymal tumors regardless of fusion status. By contrast, 121 cases of potential morphologic mimics (belonging to 13 tumor types) rarely expressed FGFR1, the main exceptions being solitary

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Section: Discussionmentioning

confidence: 99%

Characterization of FN1–FGFR1 and novel FN1–FGF1 fusion genes in a large series of phosphaturic mesenchymal tumors

et al. 2016

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“…The apparent relationship between ALK and CD30 expression in this and in other tumor types 16,17 is notable but poorly understood at this time. Very recently, ROS1 has been identified as an alternate kinase driver to ALK in a subset of lung adenocarcinomas and inflammatory myofibroblastic tumors, 18,19 and immunohistochemistry for ROS1 has been shown to correlate with ROS1 rearrangement. 20 We evaluated ROS1 expression in the four epithelioid fibrous histiocytoma cases that were negative for ALK expression; all were negative for ROS1, arguing against an underlying ROS1 rearrangement.…”

Section: Discussionmentioning

confidence: 99%

ALK rearrangement and overexpression in epithelioid fibrous histiocytoma

et al. 2015

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Epithelioid benign fibrous histiocytoma, also known as 'epithelioid cell histiocytoma,' has traditionally been considered a morphologic variant of cutaneous fibrous histiocytoma (dermatofibroma). In addition to its characteristic epithelioid cytomorphology, several phenotypic differences suggest that epithelioid fibrous histiocytoma may differ biologically from other variants. Recently, ALK rearrangement was described in two cases of epithelioid fibrous histiocytoma and separately in two cases reported as 'atypical' fibrous histiocytoma (with epithelioid features), with corresponding ALK expression detectable by immunohistochemistry. The goals of this study were to determine the frequency of ALK expression by immunohistochemistry in epithelioid fibrous histiocytoma, to determine its value for the diagnosis of epithelioid fibrous histiocytoma among variants and other histologic mimics, and to evaluate ALK gene rearrangement in epithelioid fibrous histiocytoma. ALK protein expression was evaluated in whole tissue sections from 33 epithelioid fibrous histiocytomas, 41 other cases of fibrous histiocytoma (11 conventional and 10 each cellular, atypical, and aneurysmal types), 10 cutaneous syncytial myoepitheliomas, and 5 atypical fibroxanthomas, using a mouse anti-ALK monoclonal antibody. Fluorescence in situ hybridization (FISH) was performed using break-apart probes. In total, 29/33 (88%) cases of epithelioid fibrous histiocytoma showed diffuse cytoplasmic ALK expression. Staining was moderate to strong in intensity in all cases except one, which showed diffuse weak expression. All other tumor types were negative for ALK expression. FISH demonstrated ALK rearrangement in all ALK-immunoreactive cases evaluated (n = 13), and not in one ALK expression-negative epithelioid fibrous histiocytoma successfully examined. In conclusion, the majority of epithelioid fibrous histiocytomas demonstrate ALK expression and ALK gene rearrangement. ALK expression is not seen in other variants of fibrous histiocytoma, providing a useful diagnostic tool to distinguish epithelioid fibrous histiocytoma from most histologic mimics. The expression of ALK suggests that epithelioid fibrous histiocytoma is a biologically distinct tumor type, unrelated to conventional fibrous histiocytoma and histologic variants. Modern Pathology (2015) 28, 904-912;

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“…Rearrangements involving the ALK locus on chromosome 2p23 have been demonstrated in approximately 50% of IMTs, based on immunohistochemical analysis. ALK-positive IMTs may have higher recurrence rates, while ALK-negative IMTs seem to occur in older patients and have higher metastatic rate (2,12). In our case, the tumor had two poor predictive factors, including the infiltrating characteristics at presentation and negativity for ALK; nevertheless, regression without surgical resection was observed.…”

Section: Discussionmentioning

confidence: 52%

Pelvic inflammatory myofibroblastic tumor mimicking a rectal cancer

Ramos¹

2015

Rev Esp Enferm Dig

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We report a case of a 50-year-old woman who presented to the emergency department with large bowel obstruction and anemia. The initial imaging study suggested an inoperable rectal tumor with involvement of surrounding structures. In this paper, we discuss the diagnostic work-up of this patient with a diagnosis of pelvic/ perirectal inflammatory myofibroblastic tumor (IMT). IMT is a rare tumor with intermediate malignant potential that frequently mimics clinical and imaging features of malignancy. Additionally, to the best of our knowledge, this is the first case of a pelvic IMT that regressed without surgical excision.

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Inflammatory Myofibroblastic Tumors Harbor Multiple Potentially Actionable Kinase Fusions

Cited by 375 publications

References 18 publications

Characterization of FN1–FGFR1 and novel FN1–FGF1 fusion genes in a large series of phosphaturic mesenchymal tumors

Characterization of FN1–FGFR1 and novel FN1–FGF1 fusion genes in a large series of phosphaturic mesenchymal tumors

ALK rearrangement and overexpression in epithelioid fibrous histiocytoma

Pelvic inflammatory myofibroblastic tumor mimicking a rectal cancer

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