Infantile fibrosarcoma and congenital mesoblastic nephroma are tumors of infancy traditionally associated with the ETV6-NTRK3 gene fusion. However, a number of case reports have identified variant fusions in these tumors. In order to assess the frequency of variant NTRK3 fusions, and in particular whether the recently identified EML4-NTRK3 fusion is recurrent, 63 archival cases of infantile fibrosarcoma, congenital mesoblastic nephroma, mammary analog secretory carcinoma and secretory breast carcinoma (tumor types that are known to carry recurrent ETV6-NTRK3 fusions) were tested with NTRK3 break-apart FISH, EML4-NTRK3 dual fusion FISH, and targeted RNA sequencing. The EML4-NTRK3 fusion was identified in two cases of infantile fibrosarcoma (one of which was previously described), and in one case of congenital mesoblastic nephroma, demonstrating that the EML4-NTRK3 fusion is a recurrent genetic event in these related tumors. The growing spectrum of gene fusions associated with infantile fibrosarcoma and congenital mesoblastic nephroma along with the recent availability of targeted therapies directed toward inhibition of NTRK signaling argue for alternate testing strategies beyond ETV6 break-apart FISH. The use of either NTRK3 FISH or next-generation sequencing will expand the number of cases in which an oncogenic fusion is identified and facilitate optimal diagnosis and treatment for patients.
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.
We describe a novel gene fusion, EWSR1-CREM, identified in 3 cases of clear cell carcinoma (CCC) using anchored multiplex polymerase chain reaction, a next-generation sequencing-based technique. CCC is a low-grade salivary tumor recently characterized to have EWSR1-ATF1 fusions in the majority of cases. Three cases of malignant tumor presenting in the base of tongue, lung, and nasopharynx were studied. All cases shared a clear cell morphology with hyalinized stroma, presence of mucin and p63 positivity and were initially diagnosed as mucoepidermoid carcinoma but were negative for evidence of any of the expected gene fusions. Anchored multiplex polymerase chain reaction demonstrated a EWSR1-CREM fusion in all 3 cases to confirm a diagnosis of CCC. This finding is biologically justified as CREM and ATF1 both belong to the CREB family of transcription factors. EWSR1-CREM fusions have not been previously reported in CCC and have only rarely been reported in other tumors. We show that the ability to discover novel gene variants with next-generation sequencing-based assays has clinical utility in the pathologic classification of fusion gene-associated tumors.
Supplemental Digital Content is available in the text.
Inflammatory myofibroblastic tumor (IMT) is a myofibroblastic/fibroblastic neoplasm of intermediate malignant potential. It is frequently characterized by genetic fusion of ALK with a variety of partner genes, which results in the activated ALK signaling pathway that can be targeted with kinase inhibitors. IMTs can occur in the gynecologic tract, with the uterus (corpus and cervix) being the most frequent site. Recent studies suggest that IMTs in the gynecologic tract are underrecognized, and a low-threshold for performing ALK immunohistochemistry has been proposed. The aim of this study was to evaluate the specificity of ALK immunohistochemistry for IMTs among uterine mesenchymal and mixed epithelial/mesenchymal tumors. We performed ALK immunohistochemistry on 14 molecularly confirmed uterine IMTs and 260 other uterine pure mesenchymal and mixed epithelial/mesenchymal tumors. Cases showing any positive cytoplasmic and/or membranous staining of the tumor cells were considered to be ALK positive. All 14 IMTs were confirmed to harbor ALK genetic fusion by RNA sequencing, and ALK immunostaining in the form of granular cytoplasmic positivity with paranuclear accentuation was observed in all 14 cases. ALK was negative (complete absence of staining) in all the other pure mesenchymal tumors and in all mixed epithelial/mesenchymal tumors examined. Our findings show that ALK is a highly specific diagnostic immunohistochemical marker for ALK fusion in uterine mesenchymal tumors. In the work-up of uterine mesenchymal tumors, particularly smooth muscle tumors showing myxoid stromal changes, a diagnosis of IMT should be strongly considered if ALK positivity is observed.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.