Analysis of Clinical and Molecular Factors Impacting Oncologic Outcomes in Undifferentiated Pleomorphic Sarcoma

Abstract

Background Undifferentiated pleomorphic sarcomas (UPS) present a diagnostic and therapeutic challenge. Identification of prognostic molecular markers is required for the discovery of novel treatment approaches. The aim of this study was to correlate clinicopathologic variables, expression of tyrosine kinase receptors, and markers of cell cycle progression and survival with oncologic outcomes. Methods A tissue microarray containing 208 primary UPS samples was analyzed by immunohistochemistry for protein markers and in situ hybridization for microRNA. Staining results were correlated with clinicopathologic features and oncologic outcomes. Univariate and multivariate analyses were conducted to assess associations between expression of protein markers, mi-RNA and outcome. Results At a median follow-up of 3.9 years (9 years for survivors), 5-year disease-specific survival (DSS) was 63%. Clinical variables associated with improved DSS included age < 61 years, tumor size < 10 cm, margin-negative resection and sporadic-tumor status. At the protein level, loss of cyclin D1 (p=0.06), pEGFR (p=0.023), pIGF-1R (p=0.022), and PTEN (p<0.001) and overexpression of AXL (p=0.015) were associated with reduced DSS on univariate analysis. Ki67, PCNA and pEGFR were more highly expressed in sporadic UPS than radiation-associated (RA-UPS) while RA-UPS samples expressed higher levels of both phosphorylated and total IGF-1R. Discussion Cyclin D1, AXL and PTEN are associated with cancer-specific outcomes and warrant further investigation in UPS. The differences in protein expression in sporadic versus RA-UPS may indicate that the activated molecular signaling nodes may be different for each specific histology and could also explain the aggressive phenotype seen in RA-UPS when compared to the sporadic lesions.

MAGE-A3 Is a Clinically Relevant Target in Undifferentiated Pleomorphic Sarcoma/Myxofibrosarcoma

“…This underlies the need for identification and testing of other immunotherapy methods and targets that may be effective in UPS. Promising markers and therapeutic targets have been identified in UPS and MFS using primary cultures [24,25], and correlation of oncologic outcome and clinicopathologic variables as well as expression of various markers has been also studied [26]. In addition, a small study of 17 patients treated with neoadjuvant radiation therapy prior to resection, immune cell infiltrates and PD-L1 expression were observed to increase with radiation treatment [21].…”

Undifferentiated Pleomorphic Sarcoma of Liver: Case Report and Review of the Literature

“…No sex predisposition has been described [ 8 ]. Some cases are associated with radiation exposure with other cases not having a strong etiologic link [ 5 , 9 ]. Symptoms are usually nonspecific including weight loss, anorexia, fever, jaundice, malaise, right upper quadrant pain, and palpable abdominal mass [ 8 ].…”

“…Meanwhile, a number of recurrent chromosomal regions of gain and loss have been identified in soft tissue UPS [ 24 ]. Some of them were reportedly associated with better patient survival [ 9 , 24 ]. Another study [ 25 ] showed that polysomic chromosomes appeared more characteristically in UPS; however, in their study sarcoma-specific chromosomal breaks and oncogene amplifications were rarely identified.…”

The PTEN Tumor Suppressor Gene in Soft Tissue Sarcoma

“…Immunohistochemical evaluation of the pAkt in UPS also showed an increased expression of this protein [30]. The high pAkt levels were associated with a poorer disease-specific survival (DSS) outcome, independent of other clinical variables (histological grade, site and depth of the tumor, positive/negative margins, gender and age of patients) and molecular factors (expression of phosphorylated FKHR, phosphorylated ERK1/2, Hepatocyte Growth Factor and C-Met) [30,119,120]. The PTEN gene deletion in UPS is 4% and in MFH is 8% [14] (Figure 2C), suggesting a PTEN-independent activation of the Akt/mTOR pathway [120].…”

“…The high pAkt levels were associated with a poorer disease-specific survival (DSS) outcome, independent of other clinical variables (histological grade, site and depth of the tumor, positive/negative margins, gender and age of patients) and molecular factors (expression of phosphorylated FKHR, phosphorylated ERK1/2, Hepatocyte Growth Factor and C-Met) [30,119,120]. The PTEN gene deletion in UPS is 4% and in MFH is 8% [14] (Figure 2C), suggesting a PTEN-independent activation of the Akt/mTOR pathway [120]. For example, it cannot be excluded that the oncogenic activation of this pathway can occur through an inappropriate or unregulated activation of the upstream RTKs or by cross-talk of other pathways with members of the Akt/mTOR pathway.…”