Dataset Information

Ectomesenchymal Chondromyxoid Tumor: A Neoplasm Characterized by Recurrent RREB1-MKL2 Fusions.

ABSTRACT: Ectomesenchymal chondromyxoid tumor is a rare and benign neoplasm with a predilection for the anterior dorsal tongue. Despite morphologic heterogeneity, most cases are characterized by a proliferation of bland spindle cells with a distinctive reticular growth pattern and myxoid stroma. The immunophenotype of these neoplasms is likewise variable; most cases express glial fibrillary acid protein and S100 protein, with inconsistent reports of keratin and myoid marker expression. The molecular pathogenesis is poorly understood; however, a subset of cases has been reported to harbor EWSR1 gene rearrangement. Following identification of an RREB1-MKL2 fusion gene by RNA Sequencing in an index patient, a retrospective review of additional cases of ectomesenchymal chondromyxoid tumors was performed to better characterize the clinical, immunohistochemical, and molecular attributes of this neoplasm. A total of 21 cases were included in this series. A marked predisposition for the dorsal tongue was confirmed. Most cases conformed to prior morphologic descriptions; however, hypercellularity, hyalinized stroma, and necrosis were rare attributes not previously emphasized. The neoplastic cells frequently coexpressed glial fibrillary acid protein, S100 protein, keratin, smooth muscle actin, and/or desmin; a single case was found to contain significant myogenin expression. An RREB1-MKL2 fusion product was identified in 19 tumors (90%), a single tumor (5%) had an EWSR1-CREM fusion product, and the remaining case lacked any known fusion gene by RNA Sequencing. The latter 2 cases subtly differed morphologically from many in the cohort. This series illustrates that recurrent RREB1-MKL2 fusions occur in most, perhaps all, cases of ectomesenchymal chondromyxoid tumor.

SUBMITTER: Dickson BC

PROVIDER: S-EPMC6133728 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Ectomesenchymal Chondromyxoid Tumor: A Neoplasm Characterized by Recurrent RREB1-MKL2 Fusions.

Dickson Brendan C BC Antonescu Cristina R CR Argyris Prokopios P PP Bilodeau Elizabeth A EA Bullock Martin J MJ Freedman Paul D PD Gnepp Douglas R DR Jordan Richard C RC Koutlas Ioannis G IG Lee Cheng-Han CH Leong Iona I Merzianu Mihai M Purgina Bibianna M BM Thompson Lester D R LDR Wehrli Bret B Wright John M JM Swanson David D Zhang Lei L Bishop Justin A JA

The American journal of surgical pathology 20181001 10

Ectomesenchymal chondromyxoid tumor is a rare and benign neoplasm with a predilection for the anterior dorsal tongue. Despite morphologic heterogeneity, most cases are characterized by a proliferation of bland spindle cells with a distinctive reticular growth pattern and myxoid stroma. The immunophenotype of these neoplasms is likewise variable; most cases express glial fibrillary acid protein and S100 protein, with inconsistent reports of keratin and myoid marker expression. The molecular patho ...[more]

PMID: 29912715

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Project description:An increasing number of epithelioid vascular lesions, in particular tumors from the benign and low-grade end of the spectrum, have been characterized by recurrent gene fusions. As a result, the detection of these molecular markers have improved the classification of diagnostically challenging cases. However, despite the significant progress, there are occasional lesions that do not fit in known histologic or molecular groups. Herein, we present five such unclassified epithelioid vascular lesions, which occurred in the bone and showed a distinct morphology composed of alternating vasoformative and solid growth and mild to moderate nuclear pleomorphism. The variegated morphologic appearance resembled that of composite hemangioendothelioma, being distinct from both epithelioid hemangioma and epithelioid hemangioendothelioma, and consistently showed cytologic atypia. Due to their unusual morphologic appearance and negative molecular work-up, targeted transcriptome sequencing was performed in two cases showing the presence of NFATC2 fusions with either EWSR1 or FUS genes. Three additional bone tumors with EWSR1 gene rearrangements were identified by FISH screening of a large cohort of 45 fusion-negative epithelioid vascular neoplasms, one fused to NFATC2 while two others to NFATC1. There were three females and two males, with a wide age range at presentation, mean of 44 years. The lesions occurred in the pelvis, maxillary sinus, and humerus. Two patients presented with polyostotic disease, both located in the pelvic bones. Two patients had available follow-up, one developed two local recurrences in the humerus over a 15-year period, while the other showed no recurrence 4 years subsequent to an en-bloc resection. Tumors were positive for CD31 and ERG, while negative for EMA, CK, synaptophysin, and chromogranin. FISH confirmed this abnormality in all cases, none of them being associated with gene amplifications. Further studies are needed to establish the pathogenetic relationship of this rare molecular subset with other epithelioid vascular tumors and to determine its clinical behavior.

Project description:Gene fusions resulting in oncogenic activation of various receptor tyrosine kinases, including NTRK1-3, ALK, and RET, have been increasingly recognized in soft tissue tumors (STTs), displaying a wide morphologic spectrum and therefore diagnostically challenging. A subset of STT with NTRK1 rearrangements were recently defined as lipofibromatosis-like neural tumors (LPFNTs), being characterized by mildly atypical spindle cells with a highly infiltrative growth in the subcutis and expression of S100 and CD34 immunostains. Other emerging morphologic phenotypes associated with kinase fusions include infantile/adult fibrosarcoma and malignant peripheral nerve sheath tumor-like patterns. In this study, a large cohort of 73 STT positive for various kinase fusions, including 44 previously published cases, was investigated for the presence of an LPFNT phenotype, to better define the incidence of this distinctive morphologic pattern and its relationship with various gene fusions. Surprisingly, half (36/73) of STT with kinase fusions showed at least a focal LPFNT component defined as >10%. Most of the tumors occurred in the subcutaneous tissues of the extremities (n = 25) and trunk (n = 9) of children or young adults (<30 years old) of both genders. Two-thirds (24/36) of these cases showed hybrid morphologies with alternating LPFNT and solid areas of monomorphic spindle to ovoid tumor cells with fascicular or haphazard arrangement, while one-third (12/36) had pure LPFNT morphology. Other common histologic findings included lymphocytic infiltrates, staghorn-like vessels, and perivascular or stromal hyalinization, especially in hybrid cases. Mitotic activity was generally low (<4/10 high power fields in 81% cases), being increased only in a minority of cases. Immunoreactivity for CD34 (92% in hybrid cases, 89% in pure cases) and S100 (89% in hybrid cases, 64% in pure cases) were commonly present. The gene rearrangements most commonly involved NTRK1 (75%), followed by RET (8%) and less commonly NTRK2, NTRK3, ROS1, ALK, and MET.

Dataset Information

Ectomesenchymal Chondromyxoid Tumor: A Neoplasm Characterized by Recurrent RREB1-MKL2 Fusions.

Publications

Ectomesenchymal Chondromyxoid Tumor: A Neoplasm Characterized by Recurrent RREB1-MKL2 Fusions.

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