Expanding the Spectrum of Genetic Alterations in Pseudomyogenic Hemangioendothelioma With Recurrent Novel ACTB-FOSB Gene Fusions

Abstract

Pseudomyogenic hemangioendothelioma (PHE) is an uncommon, rarely metastasizing vascular neoplasm with predilection to affect young adults. The tumors often present as multiple nodules involving various tissue planes, including superficial and deep soft tissues as well as bone. Recurrent SERPINE1-FOSB gene fusions have been reported as the hallmark genetic abnormality in PHE, however, in our experience, a number of cases with typical histology lack this genetic abnormality. In this study, we identify a novel ACTB-FOSB gene fusion, which is as prevalent as the initial translocation reported. We selected 15 consecutive cases of PHE with typical morphologic features which had material for molecular testing. The cohort included 10 males and 5 females, ranging in age from 17 to 58 years (median age: 33 y; mean age: 35.3 y). Eight (53%) cases were located in the lower extremities (foot, calf, tibia, thigh), 5 (33%) were located in the trunk, abdomen or pelvis (abdominal wall-2, shoulder, back, ischium) and 2 (13%) were located in the upper extremity (humerus and hand). Ten (67%) cases had multifocal presentation and 5 (33%) presented as solitary lesions. Three (20%) cases were located only in the superficial dermis and subcutaneous tissues, 4 (27%) involved the superficial and deep soft tissue and 8 (53%) cases involved only the deep soft tissue and bone. Using fluorescence in situ hybridization and ARCHER fusionplex analysis we identified a novel ACTB-FOSB gene fusion in 7 cases, while the remaining 8 had the previously described SERPINE1-FOSB fusion. The clinicopathologic features and behavior of PHE associated with the ACTB-FOSB gene fusion were similar to those harboring the SERPINE1-FOSB; except that tumors with the ACTB variant were more often associated with solitary presentation. In conclusion, our results expand the spectrum of genetic alterations in PHE with a novel gene fusion identified in half of the cases. We speculate that some of the novel targeted therapies that have shown promise in SERPINE1-FOSB-positive PHE might also be beneficial in this molecular subset.

Figure 1:. Morphologic spectrum of PHE with ACTB-FOSB fusion.

(A, B) Case 4 (25/M, foot) showing bone involvement by a cellular neoplasm (A), showing a mixture of epithelioid and spindle cells (B); (C) Case 2 (54/F, shoulder) showing involvement of the dermis and subcutaneous tissue with spindle cell neoplasm in a fascicular pattern; (D) Case 5 (19/M, calf) showing infiltration of the skeletal muscle by tumor cells with abundant eosinophilic cytoplasm. (E-I) Case 1 (45/F, ischium) showing cellular spindle cell areas with increased mitoses (E) and other areas showing pleomorphic epithelioid cells (F); immunohistochemical stains positive for CD31 (G), ERG (H) and Cytokeratin (I).

Figure 2:. Morphologic spectrum of PHE with SERPINE1-FOSB fusion.

(A) Case 14 (25/M, calf) showing cells with abundant eosinophilic cytoplasm in a fibrotic stroma. (B, C) Case 12 (48/M, back) and Case 13 (58/M, abdominal wall) showing epithelioid cells with eosinophilic cytoplasm with accentuated membranes compactly arranged, suggestive of an epithelioid smooth muscle tumor. (D) Case 9 (33/M, tibia) showing spindle to epithelioid cells in a hyalinized stroma with prominent normal vasculature in the background.

Figure 3:. Morphologic features of ACTB-FOSB-positive epithelioid hemangioma.

(A-D) (A, B, 29/F, nasal cavity) Solid sheets of plump epithelioid cells with focal vasoformation (A) in a markedly hemorrhagic stroma; and cells with vacuolated cytoplasm (blister cells) (B). (C, D, 40/M, penis) plump spindle and epithelioid cells with focal vasoformation (C) and abundant extravasated RBCs; and cells with vacuolated cytoplasm (D), findings not seen in PHE cases with ACTB-FOSB fusion.

Figure 4:

(A) Schematic representation of the ACTB-FOSB fusion transcript identified by ARCHER fusionplex analysis, with fusion of ACTB exon 3 to FOSB exon 2 (case 2). (B-C) FISH analysis shows break-apart signals consistent with rearrangements of FOSB (B) and ACTB (C) genes (red, centromeric; green, telomeric; case 3).