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Epithelioid hemangioendotheliomas with TFE3 gene translocations are compossible with CAMTA1 gene rearrangements.

ABSTRACT: Epithelioid hemangioendotheliomas (EHEs) are vascular tumors of intermediate malignancy that can undergo high-grade malignant transformations. EHEs have been characterized by tumor-specific WW domain-containing transcription regulator 1(WWTR1)-calmodulin-binding transcription activator 1 (CAMTA1) translocations, and recently, a novel Yes-associated protein 1 (YAP1)-transcription factor E3 (TFE3) gene fusion was identified in EHEs. In this study, we examined the expression levels of TFE3 and CAMTA1 via immunohistochemical staining and identified chromosomal alterations using fluorescence in situ hybridization (FISH) assays and RT-PCR tests. Although all of the EHEs were CAMTA1-positive in immunohistochemical staining, only five out of 18 EHEs (27.78%) positively expressed nuclear TFE3. The five TFE3-positive EHEs exhibited TFE3 gene break-apart in FISH assays. YAP1-TFE3 gene fusions were confirmed by RT-PCR. Interestingly, we observed CAMTA1 gene break-apart in all of the five TFE3-positive EHEs via FISH assays, and four out of the five TFE3-positive EHEs exhibited WWTR1-CAMTA1 gene fusions via RT-PCR. These results indicate that these two chromosomal alterations are not mutually exclusive but compossible in EHEs. Finally, primary tumor sites in TFE3-positive EHEs consistently contained single masses (P = 0.0359) with larger sizes (P = 0.0550) compared to TFE3-negative EHEs. Similar to previous reports, we observed well-formed vessels more frequently in TFE3-positive EHEs than in TFE3-negative EHEs (P = 0.0441). In addition, TFE3-positive EHEs tended to more frequently demonstrate high-grade nuclear atypia (P = 0.0654) and hypercellularity (P=0.0987) than TFE3-negative EHEs. Thus, we have now established two clinically distinct subgroups of EHEs: TFE3-positive and TFE3-negative EHEs.

SUBMITTER: Lee SJ

PROVIDER: S-EPMC4884933 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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Epithelioid hemangioendotheliomas with TFE3 gene translocations are compossible with CAMTA1 gene rearrangements.

Lee Seok Joo SJ Yang Woo Ick WI Chung Woo-Suk WS Kim Sang Kyum SK

Oncotarget 20160201 7

Epithelioid hemangioendotheliomas (EHEs) are vascular tumors of intermediate malignancy that can undergo high-grade malignant transformations. EHEs have been characterized by tumor-specific WW domain-containing transcription regulator 1(WWTR1)-calmodulin-binding transcription activator 1 (CAMTA1) translocations, and recently, a novel Yes-associated protein 1 (YAP1)-transcription factor E3 (TFE3) gene fusion was identified in EHEs. In this study, we examined the expression levels of TFE3 and CAMT ...[more]

PMID: 26840265

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Project description:Sclerosing epithelioid fibrosarcoma (SEF) is an aggressive soft tissue sarcoma, characterized by a distinctive epithelioid phenotype in a densely sclerotic collagenous stroma, that shows frequent MUC4 immunoreactivity and recurrent gene fusions, often involving EWSR1 gene. A pathogenetic link with low-grade fibromyxoid sarcoma (LGFMS) has been suggested, due to cases with hybrid morphology as well as overlapping genetic signature. However, a small subset of SEF is negative for MUC4 and lacks the canonical EWSR1/FUS gene rearrangements. Triggered by the identification of recurrent YAP1-KMT2A gene fusions by RNA sequencing in 3 index cases of MUC4-negative, EWSR1/FUS fusion-negative SEF, we further investigated a cohort of 14 similar SEF cases (MUC4-negative, EWSR1/FUS fusion-negative) by fluorescence in situ hybridization (FISH), reverse transcription-polymerase chain reaction, and/or DNA-based massively parallel sequencing (MSK-IMPACT) for abnormalities in these genes. Three additional SEFs with KMT2A gene rearrangements and one additional case with YAP1 gene rearrangements were identified by FISH. In addition, one case with YAP1-KMT2A and one with KMT2A-YAP1 fusion were detected by reverse transcription-polymerase chain reaction and MSK-IMPACT, respectively. As a control group, 24 fibromyxoid spindle cell tumors, diagnosed or suspected as fusion-negative LGFMS, were also tested for YAP1 and KMT2A abnormalities by FISH, but none were positive. The YAP1/KMT2A-rearranged SEF group affected patients ranging from 10 to 86 years old (average and median: 45) of both sexes (4 females, 5 males). The tumors involved somatic soft tissues with a wide distribution, including extremities, trunk, neck, and dura. Histologically, the tumors showed variable cellularity, with monotonous ovoid to epithelioid tumor cells and hyalinized collagenous background typical of SEF. More than half of the cases showed infiltrative borders, within fat or skeletal muscle. No LGFMS component was identified. All tumors were negative for MUC4 and had an otherwise nonspecific immunophenotype. Of the 6 cases with available follow-up information, 2 had local recurrences, and 2 developed soft tissue and/or bone metastases, including 1 of them died of the disease.

Project description:Epithelioid hemangioma (EH) is a unique benign vasoformative tumor composed of epithelioid endothelial cells. Although a small subset of EHs with atypical features harbor ZFP36-FOSB fusions, no additional genetic abnormalities have been found to date in the remaining cases. On the basis of a novel FOS-LMNA gene fusion identified by RNA sequencing in an index case of a skeletal EH with typical morphology, we sought to investigate the prevalence of FOS rearrangement in a large cohort of EHs. Thus 57 additional EH cases lacking FOSB rearrangements were studied for FOS gene abnormalities by fluorescence in situ hybridization, and results were correlated with morphologic appearance and clinical presentation. The EHs were subclassified as typical (n=25), cellular (n=21), and angiolymphoid hyperplasia with eosinophilia (ALHE) (n=12) variants. The ALHE was defined as an EH with a vascular "blow-out" pattern associated with a variable degree of inflammation. There were 17 (29%) cases bearing FOS gene rearrangements among 58 cases tested, including 12 male and 5 female patients, with a mean age of 42 years. Most FOS-rearranged EHs occurred in the bone (10) and soft tissue (6), whereas only 1 case was cutaneous. The predominant anatomic site was the extremity (12), followed by trunk (3), head and neck (1), and penis (1). The incidence of FOS rearrangement was significantly higher in bone (59%, P=0.006) and lower in head and neck (5%, P=0.009). Twelve of the FOS-rearranged cases were cellular EH (P=0.001) associated with moderate mitotic activity (2 to 5/10 HPF) and milder inflammatory background. All 12 ALHE cases lacked FOS gene abnormalities, suggesting different pathogenesis. In conclusion, FOS rearrangement was present in a third of EHs across different locations and histologic variants; however, it was more prevalent in cellular EH and intraosseous lesions, compared with those in skin, soft tissue, and head and neck. This genetic abnormality can be useful in challenging cases, to distinguish cellular EHs from malignant epithelioid vascular tumors. These results also suggest that dysregulation of the FOS family of transcription factors through chromosomal translocation is as a key event in the tumorigenesis of EH except for the ALHE variant.

Dataset Information

Epithelioid hemangioendotheliomas with TFE3 gene translocations are compossible with CAMTA1 gene rearrangements.

Publications

Epithelioid hemangioendotheliomas with TFE3 gene translocations are compossible with CAMTA1 gene rearrangements.

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