ETV6-NTRK3 Is Expressed in a Subset of ALK-Negative Inflammatory Myofibroblastic Tumors

Abstract

Inflammatory myofibroblastic tumor (IMT) is a genetically heterogenous tumor of the viscera and soft tissues, with multiple molecular features having been demonstrated in this tumor type. About 50% of cases harbor an anaplastic lymphoma kinase (ALK) gene rearrangement, and recent studies have described novel fusions involving the ROS1 and PDGFRβ genes in a subset of ALK-negative cases. However, the molecular features of the remaining subset of cases are not yet defined. We report a case of a large, highly aggressive IMT of the lung in a 17-year-old girl. This case was molecularly characterized through whole-genome and transcriptome sequencing. Subsequently, we investigated a cohort of 15 ALK-negative IMTs of various anatomic sites. All cases were screened using fluorescence in situ hybridization (FISH) for rearrangement of the ETV6 locus and with reverse transcription polymerase chain reaction (RT-PCR) for the ETV6-NTRK3 fusion transcript. Whole-genome and transcriptome sequencing revealed an ETV6-NTRK3 fusion transcript in our index case. This was confirmed by FISH studies for ETV6 gene rearrangement, as well as by RT-PCR. In addition, 2 additional cases in our cohort demonstrated ETV6 rearrangement by FISH. The presence of ETV6-NTRK3 fusion transcript was demonstrated by RT-PCR in one of these additional cases. In summary, we demonstrate the expression of the ETV6-NTRK3 fusion oncogene in a small subset of IMTs, lending further support to the role of oncogenic tyrosine kinases in the pathophysiology of this tumor type. Our data also further expand the growing spectrum of tumor types expressing the ETV6-NTRK3 fusion.

Immunohistochemical correlates of recurrent genetic alterations in sarcomas

“…Almost all cases are characterized by a t(12;15) resulting in an ETV6‐NTRK3 gene fusion . The same event is also seen in cellular congenital mesoblastic nephroma; secretory carcinomas of the breast, salivary gland, and thyroid; and rare IMTs and gastrointestinal stromal tumors (GISTs) . Clinically and morphologically similar tumors to IFS with LMNA‐NTRK1 and BRAF fusions have also been described recently and may be part of the same tumor spectrum .…”

Pulmonary spindle cell carcinoma with unusual morphology

“…ALK gene rearrangement is a feature of IMT. [16] In this case, PSCC was misdiagnosed as IMT based on the result of the intraoperative frozen section, but the further immunohistochemistry and FISH findings confirmed it as a PSCC.…”

“…ALK gene rearrangement is a feature of IMT. [16] In this case, PSCC was misdiagnosed as IMT based on the result of the intraoperative frozen section, but the further immunohistochemistry and FISH findings confirmed it as a PSCC.Malignant solitary fibrous tumor: The diameter of a malignant solitary fibrous tumor is often >10 cm, and it often contains dense areas of tumor cells with obvious sarcomatoid and atypical features. The nuclei are pleomorphic with mitosis >4/10 HPF.…”

A Case of Congenital Infantile Fibrosarcoma of the Bowel Presenting as a Neonatal Intussusception

“…reported the local relapse rate was 56% and the metastatic relapse rate was 10%. ETV6‐NTRK3 gene fusion was recently found in not only CFS but also other tumors, especially ALK‐negative IMT . If RT‐PCR showed the ETV6‐NTRK3 gene fusion, it is necessary to differentiate CFS from IMT.…”