Primary Pulmonary Myxoid Sarcoma With EWSR1-CREB1 Fusion

Abstract

We present clinicopathologic data on 10 pulmonary myxoid sarcomas, which are defined by distinctive histomorphologic features and characterized by a recurrent fusion gene, that appear to represent a distinct tumor entity at this site. The patients [7 female, 3 male; aged 27 to 67 y (mean, 45 y)] presented with local or systemic symptoms (n=5), symptoms from cerebral metastasis (1), or incidentally (2). Follow-up of 6 patients showed that 1 with brain metastasis died shortly after primary tumor resection, 1 developed a renal metastasis but is alive and well, and 4 are disease free after 1 to 15 years. All tumors involved pulmonary parenchyma, with a predominant endobronchial component in 8 and ranged from 1.5 to 4 cm. Microscopically, they were lobulated and composed of cords of polygonal, spindle, or stellate cells within myxoid stroma, morphologically reminiscent of extraskeletal myxoid chondrosarcoma. Four cases showed no or minimal atypia, 6 showed focal pleomorphism, and 5 had necrosis. Mitotic indices varied, with most tumors not exceeding 5/10 high-power fields. Tumors were immunoreactive for only vimentin and weakly focal for epithelial membrane antigen. Of 9 tumors, 7 were shown to harbor a specific EWSR1-CREB1 fusion by reverse transcription-polymerase chain reaction and direct sequencing, with 7 of 10 showing EWSR1 rearrangement by fluorescence in situ hybridization. This gene fusion has been described previously in 2 histologically and behaviorally different sarcomas: clear cell sarcoma-like tumors of the gastrointestinal tract and angiomatoid fibrous histiocytomas; however, this is a novel finding in tumors with the morphology we describe and that occur in the pulmonary region.

Angiomatoid Fibrous Histiocytoma: The Current Status of Pathology and Genetics

“…64 While most have behaved relatively indolently, cases have been shown to metastasize to distant sites (kidney and brain), with brain metastasis leading to death. 64 Primary pulmonary myxoid sarcomas are lobulated tumors composed of clusters and cords of largely bland spindle or ovoid cells, often with a reticular pattern within prominent myxoid stroma, which is Alcian blue positive and sensitive to treatment with hyaluronidase.…”

“…64 While most have behaved relatively indolently, cases have been shown to metastasize to distant sites (kidney and brain), with brain metastasis leading to death. 64 Primary pulmonary myxoid sarcomas are lobulated tumors composed of clusters and cords of largely bland spindle or ovoid cells, often with a reticular pattern within prominent myxoid stroma, which is Alcian blue positive and sensitive to treatment with hyaluronidase. 64,65 Primary pulmonary myxoid sarcomas bear a striking histologic resemblance to extraskeletal myxoid chondrosarcoma but lack the characteristic translocations of extraskeletal myxoid chondrosarcoma that fuse NR4A3 on chromosome 9q22 to a variety of partner genes.…”

“…64 Primary pulmonary myxoid sarcomas are lobulated tumors composed of clusters and cords of largely bland spindle or ovoid cells, often with a reticular pattern within prominent myxoid stroma, which is Alcian blue positive and sensitive to treatment with hyaluronidase. 64,65 Primary pulmonary myxoid sarcomas bear a striking histologic resemblance to extraskeletal myxoid chondrosarcoma but lack the characteristic translocations of extraskeletal myxoid chondrosarcoma that fuse NR4A3 on chromosome 9q22 to a variety of partner genes. [66][67][68][69][70][71][72][73] Primary pulmonary myxoid sarcomas generally express only vimentin but are occasionally weakly and focally immunoreactive for epithelial membrane antigen.…”

Clear Cell Sarcoma-like Tumor of the Gastrointestinal Tract: Clinical Outcome and Pathologic Features of a Molecularly Characterized Tertiary Center Case Series

“…There are few clinical data regarding this sarcoma type, but reported metastatic sites include the liver, lymph nodes and other intra-abdominal sites (2). This entity was first described in 2003 by Zambrano et al (3), who described six cases of a biologically-aggressive neoplasm affecting sites exclusively within the gastrointestinal tract which showed similarities to soft tissue clear cell sarcoma (CCS), also referred to as clear cell sarcoma of soft parts or conventional-type clear cell sarcoma, which typically affects extremity deep soft tissue sites, particularly around the foot and ankle (4,5).…”

“…EWSR1 rearrangements have been described in many clinically and histologically different sarcomas, including desmoplastic small round cell tumor, Ewing sarcoma, extraskeletal myxoid chondrosarcoma, myxoid liposarcoma, angiomatoid fibrous histiocytoma and primary pulmonary myxoid sarcoma (4)(5)(6). The most frequent translocation in soft tissue CCS is t(12:22)(q13;q12) resulting in the fusion of EWSR1 and ATF1 genes (7), while another translocation t(2;22)(q32.3;q12), results in EWSR1-CREB1 fusion.…”