Nuclear expression of STAT6 distinguishes solitary fibrous tumor from histologic mimics

Abstract

Solitary fibrous tumor (SFT) is composed of spindled to ovoid cells in a patternless architecture with prominent stromal collagen and hemangiopericytoma-like vessels. Some tumors show hypercellularity, nuclear atypia, and significant mitotic activity; the latter feature in particular often portends an aggressive clinical course. SFT can sometimes be difficult to distinguish from other benign mesenchymal tumors and sarcomas. The most characteristic (albeit nonspecific) immunohistochemical finding in SFT is CD34 expression. A NAB2-STAT6 gene fusion, resulting in a chimeric protein in which a repressor domain of NGFI-A binding protein 2 (EGR1 binding protein 2) (NAB2) is replaced with a carboxy-terminal transactivation domain from signal transducer and activator of transcription 6, interleukin-4 induced (STAT6), was recently identified as a consistent finding in SFT. However, as these genes are located in close proximity on 12q13, this fusion can only rarely be detected by conventional chromosomal banding or fluorescence in situ hybridization analysis. Nuclear expression of the carboxy terminal part of STAT6 is a consistent finding in SFT of the meninges (so-called 'meningeal hemangiopericytoma'). We investigated STAT6 expression by immunohistochemistry in SFTs and other soft tissue tumors arising outside the central nervous system to validate the diagnostic utility of this novel marker. Whole-tissue sections of 231 tumors were evaluated, including 60 cases of SFT as well as other benign and malignant mesenchymal neoplasms and sarcomatoid mesotheliomas. Fifty-nine of 60 SFT cases (98%) showed nuclear expression of STAT6, which was usually diffuse and intense. All other tumor types were negative for STAT6, except for three dedifferentiated liposarcomas and one deep fibrous histiocytoma, which showed weak staining. In conclusion, STAT6 is a highly sensitive and almost perfectly specific immunohistochemical marker for SFT and can be helpful to distinguish this tumor type from histologic mimics.

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

“…1-6) as having usual, 8 as having malignant (nos. [7][8][9][10][11][12][13][14], and 10 as having dedifferentiated solitary fibrous tumors (nos. [15][16][17][18][19][20][21][22][23][24].…”

“…8 STAT6 immunohistochemistry. All of the 7 usual and 11 malignant tumors showed strong and diffuse STAT6 immunostaining restricted to the nucleus, a hallmark of solitary fibrous tumors 6,10,11 (Figure 1a), whereas immunohistochemistry profile was more heterogeneous in the dedifferentiated tumors: only two (nos. 17 and 18) showed typical STAT6 immunostaining, six samples from five patients (nos.…”

“…6,7 The discovery of the NAB2/STAT6 fusion made it possible to diagnose solitary fibrous tumor molecularly using reverse-transcription polymerase chain reaction; moreover, the overexpression and phosphorylation-independent nuclear translocation of the STAT6 C-terminus can be readily identified by means of STAT6 immunohistochemistry, a sensitive, specific and more widely available means of accurate diagnosis. 6,10,11 However, although the presence of the NAB2/STAT6 rearrangement is pathognomonic for solitary fibrous tumors, it does not provide any known insights into the biological basis of the spectrum, prognosis or progression of the tumors. Furthermore, to the best of our knowledge, a solitary fibrous tumor diagnosis has been molecularly confirmed by reverse-transcription polymerase chain reaction in only two dedifferentiated cases.…”

NAB2–STAT6 fusion types account for clinicopathological variations in solitary fibrous tumors

“…3,9 However, the variations in the cellular components, mitotic activity, and stromal matrix constitute a broad clinicopathological spectrum of solitary fibrous tumors, which not only poses difficulties in predicting clinical aggressiveness but also brings about histological subtypes challenging in distinguishing from other benign or malignant mesenchymal neoplasms. 3,9,10 In the past, solitary fibrous tumors were diagnosed by combined assessment of clinicopathological context and immunohistochemical markers with imperfect sensitivity and specificity, such as CD34, which is not expressed in 5-10% of histologically characteristic solitary fibrous tumors. 3,6,9,10 In the era of advocating minimally invasive needle biopsy for deep-seated mesenchymal neoplasms, it is highly desirable to have novel robust biomarker(s) or molecular testing to aid in the diagnosis of difficult cases.…”

“…3,9,10 In the past, solitary fibrous tumors were diagnosed by combined assessment of clinicopathological context and immunohistochemical markers with imperfect sensitivity and specificity, such as CD34, which is not expressed in 5-10% of histologically characteristic solitary fibrous tumors. 3,6,9,10 In the era of advocating minimally invasive needle biopsy for deep-seated mesenchymal neoplasms, it is highly desirable to have novel robust biomarker(s) or molecular testing to aid in the diagnosis of difficult cases.…”