Inflammatory myofibroblastic tumor (IMT) can occur in a number of anatomic sites, including the uterus. Like its soft tissue counterpart, uterine IMT frequently expresses ALK and harbors ALK genetic rearrangements. The aim of this study is to fully characterize the genetic fusions that occur in uterine IMT. We studied 11 uterine IMTs with typical histology and 8 uterine myxoid smooth muscle tumors (5 leiomyomas, 1 smooth muscle tumor of uncertain malignant potential, and 2 leiomyosarcomas) in which the differential of IMT was considered, using a RNA-sequencing–based fusion assay to detect genetic fusions involving ALK, ROS1, RET, NTRK1/3, and other genes. ALK was expressed in 10 of 11 IMTs and 1 tumor initially categorized as a myxoid leiomyoma (granular cytoplasmic staining with paranuclear accentuation). Fusion transcripts involving ALK were identified in 9 of 10 ALK immunopositive IMTs, with 3 harboring IGFBP5-ALK, 3 harboring THBS1-ALK, 2 harboring FN1-ALK, and 1 harboring TIMP3-ALK. Among the smooth muscle tumors, IGFBP5-ALK fusion transcript was identified in only 1 ALK immunopositive case. Further review revealed that although a diagnosis of IMT was considered for the ALK immunopositive myxoid leiomyoma, this diagnosis was not initially rendered only because fluorescence in situ hybridization analysis was interpreted as negative for ALK genetic rearrangement; this case is best reclassified as an IMT. Notably, all the ALK fusions identified in our study included the transmembrane domain-encoding exon 19 of ALK. Our findings confirm the high frequency of ALK fusions in uterine IMT, with an enrichment of novel 5′ ALK fusion partners (IGFBP5, THBS1, and TIMP3) and exon 19-containing ALK fusion. Given that IGFBP5 and FN1 are both situated on the same chromosome as ALK, fluorescence in situ hybridization analysis for ALK rearrangement may not be reliable and a negative result should not exclude a diagnosis of uterine IMT if the histologic features and ALK immunostaining findings are supportive.
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*ArcherDX Inc., Boulder, CO
†Department of Histopathology, King Edward Memorial Hospital, Perth, WA
§Sullivan Nicolaides Pathology, Brisbane, Qld, Australia
‡Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB
#Department of Pathology, British Columbia Cancer Agency and Vancouver General Hospital, Vancouver, BC, Canada
∥Department of Pathology, Royal Devon and Exeter Hospital, Exeter
**Department of Pathology, Belfast Health and Social Care Trust, Belfast, UK
¶Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan
J.D.H. and C.J.R.S. contributed equally.
Partially supported by research funds from Royal Alexandra Hospital Foundation and Alberta Cancer Foundation.
Conflicts of Interest and Source of Funding: J.D.H., B.A.K., and B.P.C. are salaried employees and shareholders of ArcherDX Inc. The remaining authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article.
Correspondence: Cheng-Han Lee, MD, PhD, Department of Pathology, British Columbia Cancer Agency, Room 3225 600 W 10th Ave, Vancouver, BC, Canada V5Z 4E6 (e-mail: firstname.lastname@example.org).