STAT6 Immunohistochemistry Is Helpful in the Diagnosis of Solitary Fibrous Tumors

Abstract

Solitary fibrous tumor (SFT) is an uncommon fibroblastic neoplasm. Although histologic characteristics and frequent CD34 expression allow for an accurate diagnosis in the majority of SFT cases, a wide histologic spectrum and an occasional unexpected immunophenotype may pose diagnostic challenges. Molecular analyses have discovered that almost all SFTs harbor an NAB2-STAT6 fusion gene, which is considered specific to this tumor type. Recent studies have suggested that STAT6 immunohistochemistry is a reliable surrogate for detection of the fusion gene. Our aim was to validate these findings by examining a large number of SFT cases and a broad array of 30 different types of non-SFT tumors. A total of 49 SFTs with a range of histologic characteristics and 159 benign or malignant tumors that can mimic SFTs were retrieved and stained for STAT6. All 49 SFTs (100%) showed STAT6 expression that was restricted in the nucleus, mostly in a diffuse and strong manner, irrespective of the tumor sites and histologic patterns. The staining was uniform in most cases but was heterogenous in about 20% of the cases in which zonal staining attenuation was observed, likely reflecting variability in fixation or tissue ischemia. In contrast, only 4 non-SFT tumors (2.5%) exhibited weak nuclear STAT6 expression, whereas the remaining 155 cases showed no staining or often weak reactivity in both the cytoplasm and the nucleus. Therefore, nuclear STAT6 immunoreactivity is a highly sensitive and specific marker of SFTs and can be helpful when diagnosis is inconclusive by conventional methods.

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

“…11,13,18,19 Given the nuclear entry of STAT6 driven by the NAB2-STAT6 gene fusion, several studies have reported the roles of STAT6 nuclear expression both in authenticating CD34-negative solitary fibrous tumors and in distinguishing solitary fibrous tumors from histological mimics featuring staghorn vasculature and/or CD34 reactivity. 10,20,21 In this study, STAT6 exhibited distinctive nuclear labeling in seven of eight CD34-negative solitary fibrous tumors with typical histology, indicating its better sensitivity. In addition, we experienced a peculiar CD34-positive tumor with a rich, but potentially misleading, vascular network of lobules of capillaries and dilated staghorn vessels, which closely mimicked a soft-tissue angiofibroma but turned out to be a solitary fibrous tumor with diffuse STAT6 nuclear expression.…”

“…2,[11][12][13]18 As the resultant NAB2-STAT6 fusion protein drives the nuclear entry of STAT6, 11 several groups exploited this biological character of STAT6 nuclear expression to facilitate the discrimination between solitary fibrous tumors and histological mimics, without resorting to RT-PCR. 10,20,21 However, Doyle et al 22 have notified that STAT6 nuclear expression is driven by gene amplification and coamplified with CDK4 and MDM2 in a minor subset of dedifferentiated liposarcomas, a treacherous caveat liable to result in misdiagnosis of solitary fibrous tumors, given occasional presence of solitary fibrous tumorlike histology in dedifferentiated liposarcomas. 23,24 Aiming at better characterization of the relevance of STAT6 nuclear entry and NAB2-STAT6 fusion variants, we have comparatively analyzed the STAT6 immunoexpression and NAB2-STAT6 exon composition types and correlated the findings with clinicopathological features of a large cohort of recently accessioned thoracic, extrathoracic, and meningeal solitary fibrous tumors.…”

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.…”