Immunohistochemical selection of biomarkers for tumor-targeted image-guided surgery of myxofibrosarcoma

Abstract

Myxofibrosarcoma(MFS) is the most common soft tissue sarcoma(STS) in elderly patients. Surgical resection remains the main treatment modality but tumor borders can be difficult to delineate with conventional clinical methods. Incomplete resections are a common problem and local recurrence remains a clinical issue. A technique that has shown great potential in improving surgical treatment of solid tumors is tumor targeted imaging and image-guided surgery with near-infrared fluorescence. To facilitate this technique, it is essential to identify a biomarker that is highly and homogenously expressed on tumor cells, while being absent on healthy non-malignant tissue. The purpose of this study was to identify suitable molecular targets for tumor-targeted imaging of myxofibrosarcoma. Ten potential molecular targets for tumor targeted imaging were investigated with immunohistochemical analysis in myxofibrosarcoma tissue (n = 34). Results were quantified according to the immunoreactive score(IRS). Moderate expression rates were found for uPAR, PDGFRa and EMA/MUC1. High expression rates of VEGF and TEM1 were seen. Strong expression was most common for TEM1 (88.2%). These results confirms that TEM1 is a suitable target for tumor-targeted imaging of myxofibrosarcoma. Keywords Image-guided surgery; Immunohistochemistry; Molecular imaging; Myxofibrosarcoma; Soft tissue sarcoma; Tumor endothelial marker 1(TEM1), Vascular endothelial growth factor (VEGF).Myxofibrosarcoma (MFS) is a histological subtype of soft tissue sarcoma (STS) formerly classified as a myxoidtype malignant fibrous histiocytoma. It has been reclassified and defined as a distinct pathological entity in the World Health Organization (WHO) criteria set in 2002 1,2 . Myxofibrosarcoma is a relatively common sarcoma in the elderly that mainly arises in the extremities 3 . Primary MFS most often presents as a subcutaneous painless, slow growing nodule, but completely infiltrative growth patterns along fascial planes without formation of an evident tumor mass have also been described 4 . The low-grade lesions have a relatively low metastatic potential but show a significant propensity for local recurrences 5-8 . These recurrences show higher-grade histology in up to 50% of all cases compared to the primary tumor 3 . Subsequently, high and intermediate grade disease exhibits a greater metastatic potential, mainly metastasizing to the lungs and lymph nodes 7,9 . Current guidelines recommend wide surgical resection combined with pre or post-operative radiotherapy as the preferred treatment 10 . Despite this strategy, positive margins after surgery occur in up to 20% of cases and reported local relapse rates range from 15 to 65% [5][6][7][8]11 .Currently clinicians rely on conventional imaging modalities such as CT and MRI to determine the location and extent of tumor burden prior to surgery. Translating these conventional imaging modalities to the surgical theatre remains challenging, forcing the surgeon to depend mainly on tactile and visual cues during the procedure. P...

Candidate Biomarkers for Specific Intraoperative Near-Infrared Imaging of Soft Tissue Sarcomas: A Systematic Review

“…The presence of the biomarker in STS samples, regardless of the percentage of positive tumor cells, was determined on both tumor and stromal cells for TEM1. In STS, 77% (range 55–100%, n = 768) of the samples showed presence of TEM1 on average, reported in 4 different articles [ 26 , 27 , 28 , 29 ]. Staining was performed in 17 subtypes of STS ( Appendix C ).…”

“…In MFS it was demonstrated that TEM1 was present in all 34 investigated samples, with a diffuse pattern of expression [ 27 ]. Staining was negative or very limited in normal adjacent tissue such as muscular fascia and peripheral nerve bundles.…”

“…However, it still needs to be modified into a NIRF imaging tracer. A high-affinity human single-chain variable fragment (scFv)-Fc fusion protein (78Fc) targeting TEM1 has been engineered and conjugated with the near-infrared fluorochrome VivoTag-S750, which proved to be an efficient tracer in preclinical osteosarcoma and lung cancer models [ 25 , 27 , 124 , 127 ].…”

“…EGFR expression in STS was described in 36 scientific papers [ 27 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 ]. The presence of EGFR on STS tissue was observed in an average of 53% of the samples (range 0–100%, n = 1918).…”

“…Based on the literature search, PDGFRα was present in 64% of STS samples on average (range 0–100%, n = 1536) in 21 different articles [ 27 , 34 , 36 , 38 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 51 , 82 , 86 , 87 , 88 , 89 , 90 , 91 , 92 ]. Expression was evaluated in 22 different subtypes of STS ( Appendix C ).…”