Dataset Information

Clinical Characteristics and Outcomes for Solitary Fibrous Tumor (SFT): A Single Center Experience.

ABSTRACT: Solitary fibrous tumor (SFT) is a mesenchymal neoplasm of fibrous origin. The 2013 WHO classification of soft tissue tumors defines malignant forms as hypercellular, mitotically active (>4 mitosis/10 high-power fields), with cytological atypia, tumor necrosis, and/or infiltrative margins. With an IRB-approved protocol, we investigated patient records and clinicopathologic data from our Sarcoma Database to describe the clinical characteristics of both benign and malignant SFT. All pathology specimens were reviewed by two pathologists. Descriptive statistics and univariate/multivariate survival analysis were performed. Patient records and Social Security Death Index were used to evaluate vital status. Of 82 patients, 47 (57%) were women and 73 (89%) were Caucasian. Median age was 62 years (range, 20 to 89). Thirty-two (39%) patients succumbed to the disease. Primary tumor site was lung/pleura in 28 (34%), abdomen/pelvis in 23 (28%), extremity in 13 (16%), and head/neck in 9 (11%) patients. Pathology was described as benign in 42 (51%) and malignant in 40 (49%) patients. Compared to benign SFT, malignant histology is associated with larger tumor size, higher mitotic counts, metastatic disease at diagnosis, and greater use of chemotherapy and radiation therapy. Gender, age, and tumor site were not significantly different between benign and malignant subtypes. By univariate analysis, only benign vs. malignant variant and complete resection positively impacted overall survival (P = 0.02 and P<0.0001, respectively). In the multivariable analysis of overall survival, receiving chemotherapy or not receiving surgery were two variables significantly associated with higher failure rate in overall survival: patients with chemotherapy vs. no chemotherapy (P = 0.003, HR = 4.55, with 95% CI: 1.68-12.34) and patients without surgery vs. with surgery (P = 0.005, HR = 25.49, with 95% CI: 2.62-247.57). Clear survival differences exist between benign and malignant SFT. While surgery appears to be the best treatment option for benign and malignant SFT, better systemic therapies are needed to improve outcomes of patients with metastatic, malignant SFT.

SUBMITTER: DeVito N

PROVIDER: S-EPMC4607370 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Clinical Characteristics and Outcomes for Solitary Fibrous Tumor (SFT): A Single Center Experience.

DeVito Nicholas N Henderson Evita E Han Gang G Reed Damon D Bui Marilyn M MM Lavey Robert R Robinson Lary L Zager Jonathan S JS Gonzalez Ricardo J RJ Sondak Vernon K VK Letson G Douglas GD Conley Anthony A

PloS one 20151015 10

Solitary fibrous tumor (SFT) is a mesenchymal neoplasm of fibrous origin. The 2013 WHO classification of soft tissue tumors defines malignant forms as hypercellular, mitotically active (>4 mitosis/10 high-power fields), with cytological atypia, tumor necrosis, and/or infiltrative margins. With an IRB-approved protocol, we investigated patient records and clinicopathologic data from our Sarcoma Database to describe the clinical characteristics of both benign and malignant SFT. All pathology speci ...[more]

PMID: 26469269

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Project description:Solitary fibrous tumors (SFTs) are NAB2-STAT6 fusion-associated neoplasms. There are several subtypes of NAB2-STAT6 fusions, but their clinical significances are still unclear. Moreover, the mechanisms of malignant progression are also poorly understood. In this study, using 91 SFT cases, we examined whether fusion variants are associated with clinicopathological parameters and also investigated the molecular mechanism of malignant transformation using whole-exome sequencing. We detected variant 1b (NAB2ex4-STAT6ex2) in 51/91 (56%) cases and variants 2a/2b (NAB2ex6-STAT6ex16/17) in 17/91 (19%) cases. The NAB2-STAT6 fusion variant types were significantly associated with their primary site (P < 0.001). In addition, a TERT promoter mutation was detected in 7/73 (10%) cases, and it showed a significant association with malignant SFTs (P = 0.003). To identify molecular changes during malignant progression, we selected an index patient to obtain parallel tissue samples from the primary and metastatic tumors. In the metastatic tissue, 10 unique molecular alterations, including those in TP53 and APAF1, were detected. In vitro functional experiments showed that APAF1 depletion increased the tumor potency of cells expressing NAB2-STAT6 fusion protein under treatment with staurosporine. We found that TP53 immunopositivity (P = 0.006) and loss of APAF1 immunoreactivity (P < 0.001) were significantly associated with malignant SFTs. Our study suggests that dysfunction of TP53 and APAF1 leads to impaired apoptotic function, and eventually contributes toward malignant SFT transformation. KEY MESSAGES: We firstly found that the TERT promoter mutation was strongly associated with malignant SFTs (P = 0.003) and the representative 1b (NAB2ex4-STAT6ex2) or 2a (NAB2ex6-STAT6ex16) fusion variants similarly contribute to tumorigenicity. We also found that TP53 immunopositivity (P = 0.006) and loss of APAF1 immunoreactivity (P < 0.001) were significantly associated with malignant SFTs. Our study suggests that dysfunction of TP53 and APAF1 leads to impaired apoptotic function, and eventually contributes toward malignant SFT transformation.

Project description:Solitary fibrous tumor is a mesenchymal neoplasm exhibiting a broad spectrum of biological behavior and harboring the NAB2-STAT6 fusion. Clinicopathologic parameters are currently used in risk-prediction models for solitary fibrous tumor, but the molecular determinants of malignancy in solitary fibrous tumors remain unknown. We proposed that the activation of telomere maintenance pathways confers a perpetual malignant phenotype to these tumors. Therefore, we investigated telomerase reverse transcriptase (TERT) reactivation induced by promoter mutations as a potential molecular mechanism for aggressive clinical behavior in solitary fibrous tumor. The retrospective study included tumor samples from 94 patients with solitary fibrous tumor (31 thoracic and 63 extra-thoracic). Follow-up information was available for 68 patients (median, 46 months). TERT promoter mutation analysis was performed by PCR and Sanger sequencing, and TERT mRNA expression was assessed by real-time quantitative reverse transcription PCR. Patients were stratified into clinicopathologic subgroups (high-risk (n=20), moderate-risk (n=28), and low-risk (n=46)) according to the risk-stratification model proposed by Demicco et al. TERT promoter mutations were identified in 26 of 94 (28%) solitary fibrous tumors: -124C>T in 23 tumors (88%), -124C>A in 1 tumor (4%), and -146C>T in 2 tumors (8%). Real-time quantitative reverse transcription PCR revealed that TERT mRNA expression was higher in all solitary fibrous tumors with the mutant TERT promoter than those with the wild-type TERT promoter. TERT promoter mutations were strongly associated with high-risk clinicopathologic characteristics and outcome. An adverse event (relapse, death) occurred in 16 of 68 (24%) patients, 12 with solitary fibrous tumors with TERT promoter mutations and 4 with the wild-type TERT promoter. TERT promoter mutations were strongly associated with older age (P=0.006), larger tumor size (P=0.000002), higher risk classifications (P=2.9 × 10-9), and a worse event-free survival (P=0.0082). Thus, TERT promoter mutations in solitary fibrous tumor influence gene expression and are associated with adverse patient outcome. Integrating TERT promoter mutational status with existing multivariable risk-prediction models might improve risk prediction in patients with solitary fibrous tumor.

Dataset Information

Clinical Characteristics and Outcomes for Solitary Fibrous Tumor (SFT): A Single Center Experience.

Publications

Clinical Characteristics and Outcomes for Solitary Fibrous Tumor (SFT): A Single Center Experience.

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