Attia, Steven

Key Clinical Message Myxoinflammatory fibroblastic sarcoma is a rare sarcoma which typically presents in the extremities and is treated by definitive surgery. In recurrent disease, the reported utilization of radiotherapy is increasing, and more modern techniques such as intensity‐modulated radiotherapy may be improving long‐term outcomes.

Langerhan's cell sarcoma (LCS) is a rare neoplasm with a poor prognosis. To our knowledge, only sixty-six cases have been published. We discuss two patients who presented very differently with LCS, as well as a recently published review of all sixty-six cases. Our first case had a complicated history of metastatic, high-grade myxofibrosarcomas and presented with a single skin lesion of LCS which was treated with resection to a positive margin and adjuvant radiotherapy. The LCS recurred locoregionally and was again resected. The patient is alive two years after initial diagnosis. The second case presented with bone marrow and splenic involvement, leukocytosis, and thrombocytopenia. This patient had an excellent response to etoposide, prednisone, oncovorin, cyclophosphamide, and adriamycin, with normalization of the complete blood count, negative bone marrow biopsy at follow up, and splenectomy without viable neoplasm. This patient is alive without signs of disease at 16 months after initial diagnosis.

We report a response to pazopanib in a 69-year-old man with heavily pre-treated metastatic extraosseous Ewing sarcoma in addition to molecular profiling of his tumor. To our knowledge, this case is the earliest to demonstrate activity of an oral multi-targeted kinase inhibitor in Ewing sarcoma. This case provides rationale for adding a Ewing sarcoma arm to SARC024, a phase II study of regorafenib, another multi-targeted kinase inhibitor, in patients with liposarcoma, osteosarcoma and Ewing and Ewing-like sarcomas (NCT02048371). This national multi-institutional study is ongoing.

Perineal leiomyosarcoma is an extremely rare and aggressive cancer with a high metastatic potential and no defined standard treatment. There are only a few (six) reported cases in the literature. We report the case of a 67-year-old woman with a perineal leiomyosarcoma arising at the same site of a previously resected superficial angiomyxoma. Initially, she was treated for a presumptive recurrence of angiomyxoma. As she did not respond to medical therapy, she underwent repeat surgical excision. Pathology revealed a high grade leiomyosarcoma, histologically strikingly distinct from the initial diagnosis. She received adjuvant local radiation therapy, and remains without evidence of recurrent disease 36 months after completion of all therapy. This is the first reported case of a high grade perineal leiomyosarcoma originating at the same site as a resected benign superficial angiomyxoma. Our case emphasizes the necessity of a prompt histological diagnosis in cases of presumed recurrent perineal angiomyxoma.

Abstract Background: Extranodal follicular dendritic cell sarcoma (FDCS) is an exceedingly rare tumor type that is limited to few cases in the literature. Given the rarity of this tumor, there is a lack of genetic understanding of this disease resulting in a non-individualized plan of care for patients with this disease. Herein, we are the first to describe extensively molecularly the DNA and RNA of this tumor. Methods: Under an IRB approved protocol, the patient's tumor and whole blood was freshly frozen for molecular analysis. We performed Next Generation Sequencing (NGS) genomic profiling including exome capture, mate pair and mRNA sequencing on this tumor. Exome and mRNA data were processed through Mayo's Bioinformatics Core standard pipelines, GENOME GPS 1.2.1 and MAPRSeq v1.2.1. Mutations and indels were prioritized depending on whether or not they belonged to known cancer associated genes. Copy number variations (CNVs) in Exome and Mate Pair data was found through PatternCNV v 1.0.1 and fusion transcripts were found using SNOWSHOES-FTD and Tophat-Fusion 2.0.6. Results: At the genomic level large scale genomic rearrangements were detected, including chr19 and chr20 trisomy, chr15q and chr17q segmental duplications result in two intra-chromosomal fusion genes, and translocations leading to four inter-chromosomal fusion genes between chr15 and chr17. Of particular interest is a stop codon gain in the CLTC1 (chr22) gene, which is involved in the mitotic spindle organization which has been associated with meningiomas and breast tumorigenesis. The new stop codon is before the site required for the recruitment of the proteins to the spindle. The large scale genomic rearrangement described above is consistent with this defective spindle assembly hypothesis. Another intriguing mutation detected in the VEGFR1 (chr13) gene leads to a 45% mis-spliced transcript. VEGFR1 is thought to modulate VEGFR2 which plays an essential role in angiogenesis, by acting as a decoy receptor. Therefore the loss of function of VEGFR1 might lead to hyper-activity of VEGFR2 pathway and a potential therapeutic strategy is to directly inhibit the VEGFR2 pathway. Furthermore missense mutations in the ATM (chr11) and TP53 (chr17) genes were found. PARP inhibitors have been used with success for cancer with defects in the ATM gene. Finally a novel fusion transcript of HDGRFP3 (chr15) and SHC4 (chr15) was identified. Such fusion results in an overexpressed SHC4 gene which has been associated with metastatic melanomas. Conclusions: In summary, genomic profiling of a rare thyroid FDCS identified drug targetable genes as well as changes related to tumor etiology. Future work is necessary to determine the functional significance of these molecular findings and whether they will predict benefit to targeted therapies. Citation Format: Jaime I. Davila, Jason Starr, Steven Attia, Chen Wang, Xue Wang, Brian Necela, Casler John, David Menke, Vivek Sarangi, Gavin Oliver, Richard Joseph, John Copland, Alexander Parker, E. Aubrey Thompson, Robert Smallridge, Yan W. Asmann. Extensive genomic profiling of a rare extranodal-follicular dendritic cell sarcoma: Implications for future individualized therapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1894. doi:10.1158/1538-7445.AM2014-1894

Abstract Purpose: Endoglin/CD105 is a homodimeric transmembrane glycoprotein that is expressed on the proliferating endothelium of solid tumors. TRC105, the chimeric IgG1 antibody with high affinity binding for human CD105, has recently undergone human testing. This exploratory study sought to validate CD105 as a potential therapeutic target in sarcomas. Methods: We performed immunohistochemical staining for CD105 expression in 146 retrospectively identified paraffin embedded sarcoma patient samples in our tumor registry, utilizing an anti-CD105 antibody (clone 4G11, Novocastra). The diagnoses were verified and samples were examined for CD105 expression in the malignant vasculature as well as tumor cells. Results: The vast majority of specimen expressed CD105 in the tumor vasculature, 134 of 137 evaluable cases. CD105 expression in the cells of the varied sarcoma histologies themselves were as follows: 19/20 angiosarcomas, 6/7 Ewing sarcomas, 8/20 undifferentiated pleomorphic sarcomas, 6/20 uterine leiomyosarcomas (LMS), 4/20 osteosarcomas, 3/20 non-uterine LMS, 3/20 synovial sarcomas. None of the 19 evaluated chondrosarcoma cells expressed CD105. Thirteen of 19 angiosarcomas showed CD105 expression in >50% of tumor cells, 3 of 19 showed CD105 expression in 25-49% of the tumor cells and 3 of 19 showed CD105 expression in 5-24% of tumor cells. Conclusions: CD105 targeting appears to be a rational antiangiogenic therapeutic approach in sarcomas, with particular emphasis on angiosarcomas. A clinical trial utilizing TRC105 in soft tissue sarcomas is currently under development. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B237. Citation Format: Karen Fritchie, Steven Attia, Scott Okuno, Carola Arndt, Steven Robinson. CD105: A therapeutic target for sarcomas. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B237.