Solitary fibrous tumors: loss of chimeric protein expression and genomic instability mark dedifferentiation

Abstract

Solitary fibrous tumors, which are characterized by their broad morphological spectrum and unpredictable behavior, are rare mesenchymal neoplasias that are currently divided into three main variants that have the NAB2-STAT6 gene fusion as their unifying molecular lesion: usual, malignant and dedifferentiated solitary fibrous tumors. The aims of this study were to validate molecular and immunohistochemical/biochemical approaches to diagnose the range of solitary fibrous tumors by focusing on the dedifferentiated variant, and to reveal the genetic events associated with dedifferentiation by integrating the findings of array comparative genomic hybridization. We studied 29 usual, malignant and dedifferentiated solitary fibrous tumors from 24 patients (including paired samples from five patients whose tumors progressed to the dedifferentiated form) by means of STAT6 immunohistochemistry and (when frozen material was available) reverse-transcriptase polymerase chain reaction and biochemistry. In addition, the array comparative genomic hybridization findings were used to profile 12 tumors from nine patients. The NAB2/STAT6 fusion was detected in all of the tumors, but immunohistochemistry and western blotting indicated that chimeric protein expression was atypical or absent in 9 out of 11 dedifferentiated tumors. The comparative genomic hybridization results revealed that the usual and malignant solitary fibrous tumors had a simple profile, whereas the genome of the dedifferentiated tumors was complex and unstable, and suggested that 13q and 17p deletions and TP53 mutations may be present in malignant lesions before the full expression of a dedifferentiated phenotype. Solitary fibrous tumor dedifferentiation is associated with the loss of chimeric oncoprotein expression, genomic instability, and cell decommitment and reprogramming. The assessment of dedifferentiated solitary fibrous tumors is based on the presence of the fusion transcripts and, in principle, negative STAT6 immunohistochemistry should not rule out a diagnosis of solitary fibrous tumor. Modern Pathology (2015Pathology ( ) 28, 1074Pathology ( -1083 doi:10.1038/modpathol.2015 published online 29 May 2015 Solitary fibrous tumors are rare mesenchymal tumors (incidence o 1 per million) that were originally described on the pleurae but have subsequently been recognized at virtually all body sites. 1 The current classification includes usual, malignant and the recently described dedifferentiated variants. [1][2][3] The morphobiological features distinguishing the malignant and usual variants are hypercellularity, cell pleomorphism, necrosis and a mitotic index of 44/10 high-power fields. However,

Update on Select Benign Mesenchymal and Meningothelial Sinonasal Tract Lesions

“…As expected, more cellular tumors were associated with high vascular endothelial growth factor and PDGFb, whereas metastatic tumors more frequently over expressed PDGFRa compared to localized tumors [52]. 13q and 17p deletions and p53 mutations (over expression), in combination with TERT promoter mutations seem to play a role in the high grade transformation of SFT [53,54].…”

Analysis of NAB2-STAT6 Gene Fusion in 17 Cases of Meningeal Solitary Fibrous Tumor/Hemangiopericytoma

“…11,12 Subsequently, some groups analyzed SFT genetically by whole-exome sequencing, transcriptome sequencing, long-range genome polymerase chain reaction (PCR), or reverse transcription polymerase chain reaction (RT-PCR) and showed the NAB2-STAT6 fusion. [13][14][15][16][17][18][19][20] However, the frequency of fusion and their variants differed in each study. Moreover, most studies were about nonmeningeal SFT, containing very few cases of meningeal SFT/HPC, and only 1 study focused on meningeal SFT/HPC.…”

“…Other factors such as the extent of surgery (gross total resection or not) and/or adjuvant therapy may also be involved in tumor recurrence. In addition, recent studies showed mutations in p53 18,19,23 or telomerase reverse transcriptase (TERT) promoter mutations 14,24 in SFT, which might play some role in recurrence and/or progression. More detailed molecular biological analyses based on gene profiles would be necessary for understanding the correlation between the function of fusion protein and clinicopathologic behaviors.…”

Telomerase promoter mutations and copy number alterations in solitary fibrous tumours

“…One lesion with malignant progression exhibited decreased immunoreactivity in areas of dedifferentiation as previously described by others (figure 1). 18 …”