Abstract
Soft tissue sarcomas are a heterogeneous group of tumors with many different subtypes. In 2014 an estimated 12,020 newly diagnosed cases and 4,740 soft tissue sarcoma related deaths can be expected in the United States. Many soft tissue sarcomas are associated with poor prognosis and therapeutic options are often limited. The evolution of precision medicine has not yet fully reached the clinical treatment of sarcomas since therapeutically tractable genetic changes have not been comprehensively studied so far. We analyzed a total of 484 adult-type malignant mesenchymal tumors by MET fluorescence in situ hybridization and MET and hepatocyte growth factor immunohistochemistry. Eleven different entities were included, among them the most common and clinically relevant subtypes and tumors with specific translocations or complex genetic changes. MET protein expression was observed in 2.6% of the cases, all of which were either undifferentiated pleomorphic sarcomas or angiosarcomas, showing positivity rates of 14% and 17%, respectively. 6% of the tumors showed hepatocyte growth factor overexpression, mainly seen in undifferentiated pleomorphic sarcomas and angiosarcomas, but also in clear cell sarcomas, malignant peripheral nerve sheath tumors, leiomyosarcomas and gastrointestinal stromal tumors. MET and hepatocyte growth factor overexpression were significantly correlated and may suggest an autocrine activation in these tumors. MET FISH amplification and copy number gain were present in 4% of the tumors (15/413). Two samples, both undifferentiated pleomorphic sarcomas, fulfilled the criteria for high level amplification of MET, one undifferentiated pleomorphic sarcoma reached an intermediate level copy number gain, and 12 samples of different subtypes were categorized as low level copy number gains for MET. Our findings indicate that angiosarcomas and undifferentiated pleomorphic sarcomas rather than other frequent adult-type sarcomas should be enrolled in screening programs for clinical trials with MET inhibitors. The screening methods should include both in situ hybridization and immunohistochemistry.
Highlights
Soft tissue sarcomas represent a heterogeneous tumor group which consists of over 50 different histologic subtypes [1]
Eleven different mesenchymal tumor entities with high clinical relevance were selected for this study: atypical lipomatous tumors/well differentiated liposarcomas (ALT; n = 43), dedifferentiated liposarcomas (DDLS; n = 70), myxoid liposarcomas (MLS; n = 30), pleomorphic liposarcomas (PLS; n = 10), leiomyosarcomas (LMS; n = 69), angiosarcomas (ASA; n = 41), synovial sarcomas (SS; n = 15), malignant peripheral nerve sheath tumors (MPNST; n = 24), undifferentiated pleomorphic high grade sarcomas (UPS; n = 36), clear cell sarcomas (CCS; n = 13), and gastrointestinal stromal tumors (GIST; n = 133)
These entities were selected i) to include the most frequent sarcoma subtypes (e.g., ALT, DDLS and LMS), ii) to compare tumors with known underlying genetic alterations with neoplasms which are characterized by complex genetic changes (e.g., undifferentiated pleomorphic sarcomas (UPS), MPNST), and iii) to include as well entities for which previous data indicate that MET alterations might play a role
Summary
Soft tissue sarcomas represent a heterogeneous tumor group which consists of over 50 different histologic subtypes [1]. Soft tissue sarcomas are often diagnosed at advanced stage, because symptoms may be absent for a long time. Standard treatment for localized tumors is surgery. Chemotherapy is currently used as standard treatment [4]. These treatments often have adverse effects or are ineffective, e.g., for retroperitoneal sarcomas the 5-year local control rate is only 40–71% and the 5-year survival rate is low with 51–60% [5]. Sarcomas of the extremities have a high local recurrence rate of 30–50% and half the patients die from their disease [6]
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