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Frequent FOS Gene Rearrangements in Epithelioid Hemangioma: A Molecular Study of 58 Cases With Morphologic Reappraisal.

ABSTRACT: 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.

SUBMITTER: Huang SC

PROVIDER: S-EPMC4567921 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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Frequent FOS Gene Rearrangements in Epithelioid Hemangioma: A Molecular Study of 58 Cases With Morphologic Reappraisal.

Huang Shih-Chiang SC Zhang Lei L Sung Yun-Shao YS Chen Chun-Liang CL Krausz Thomas T Dickson Brendan C BC Kao Yu-Chien YC Agaram Narasimhan P NP Fletcher Christopher D M CD Antonescu Cristina R CR

The American journal of surgical pathology 20151001 10

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 ...[more]

PMID: 26135557

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Project description:The genetic hallmark of epithelioid hemangioma (EH) is the presence of recurrent gene fusions involving FOS and FOSB transcription factors, which occur in one-third of the cases. Certain clinical, pathologic, and genotypic correlations have been described, with FOS-related fusions being more often detected in skeletal and cellular variants of EH, while FOSB gene rearrangements are more commonly associated with atypical histologic features and penile location. These fusions are infrequently detected in the cutaneous or head and neck EH. Overall, two-thirds of EH lack these canonical fusions and remain difficult to classify, especially when associated with atypical features and/or clinical presentations. Triggered by an index case of an intravascular soft tissue EH with a novel GATA6-FOXO1 gene fusion by targeted RNA sequencing (Archer® FusionPlex® Sarcoma Panel), we have investigated 27 additional EH cases negative for FOS and FOSB gene rearrangements for this novel abnormality to determine its recurrent potential, and its association with clinical and pathologic features. Four additional EH cases were found to display GATA6-FOXO1 fusions (18%). There were three females and two males, with a mean age of 32 years old. Three lesions occurred in the head and neck (dura, nasopharyngeal, and cheek), one in the back and one in the leg. Two of these lesions were cutaneous and one was intravascular in the subcutis of the leg. Microscopically, the tumors showed a variegated morphology, with alternating vasoformative and solid components, extravasated red blood cells and mild to moderate cytologic atypia. None showed brisk mitotic activity or necrosis. Tumors were negative for FOS and FOSB by immunohistochemistry. In conclusion, we report a new GATA6-FOXO1 fusion in a subset of EH, with a predilection for skin, and head and neck location. The relationship of this novel molecular subset with the more common FOS/FOSB fusion-positive EH remains to be determined.

Project description:ACTB-GLI1 fusions have been reported as the pathognomonic genetic abnormality defining an unusual subset of actin-positive, perivascular myoid tumors, known as "pericytoma with the t(7;12) translocation." In addition, GLI1 oncogenic activation through a related MALAT1-GLI1 gene fusion has been recently reported in 2 unrelated gastric tumors, namely plexiform fibromyxoma and gastroblastoma. Triggered by unexpected targeted RNA-sequencing results detecting GLI1-related fusions in a group of malignant neoplasms with round to epithelioid morphology, and frequently strong S100 protein immunoreactivity, we investigated their clinicopathologic features in relation to other known pathologic entities sharing similar genetics. On the basis of a combined approach of targeted RNA sequencing and fluorescence in situ hybridization screening, we identified 6 cases with GLI1 gene fusions, including 4 fused to ACTB, 1 with MALAT1 and 1 with PTCH1 gene. Patients had a mean age of 36 years at diagnosis (range, 16 to 79?y) and slight female predilection all except 1 tumor originated in the soft tissue. Microscopically, the tumors had a monomorphic epithelioid phenotype arranged in a distinctive nested or cord-like architecture, separated by thin septae and delicate capillary network. All except 2 cases were strongly positive for S100 protein, whereas being negative for SOX10, SMA, and EMA. Only 1 tumor showed focal cytokeratin positivity in rare cells. Although the tumors showed some resemblance to pericytic/glomus tumors or myoepithelial tumors, the immunoprofile was not supportive of either lineage. Moreover, in contrast to the benign course of so-called pericytoma with t(7;12), 3 patients in this series developed metastatic disease to either lymph nodes or lung. In fact the only patient with lung metastases showed a novel PTCH1-GLI1 gene fusion. It remains to be determined whether these tumors represent a clinically and immunohistologically distinct subset of pericytoma, or an altogether novel soft tissue sarcoma. Our findings open new opportunities for targeted therapy, as tumors with GLI1 oncogenic activation, and subsequent PTCH1 overexpression, might be sensitive to sonic hedgehog pathway inhibitors.

Dataset Information

Frequent FOS Gene Rearrangements in Epithelioid Hemangioma: A Molecular Study of 58 Cases With Morphologic Reappraisal.

Publications

Frequent FOS Gene Rearrangements in Epithelioid Hemangioma: A Molecular Study of 58 Cases With Morphologic Reappraisal.

Similar Datasets

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