STAT6 is amplified in a subset of dedifferentiated liposarcoma

Abstract

A recurrent intrachromosomal rearrangement on chromosome 12q in solitary fibrous tumor leads to the formation of a NAB2-STAT6 fusion oncogene. As a result, nuclear expression of the cytoplasmic transcription factor STAT6 is found in solitary fibrous tumor and serves as a useful diagnostic marker. STAT6 is located in 12q13, a region containing well-characterized oncogenes that are commonly amplified in dedifferentiated liposarcoma; we have previously reported that STAT6 is expressed in a subset of dedifferentiated liposarcoma. The aim of this study was to determine the frequency of STAT6 expression in dedifferentiated liposarcoma and the underlying genetic mechanism. STAT6 protein expression was analyzed by immunohistochemistry in a well-characterized series of 35 previously unpublished cases of dedifferentiated liposarcoma, all with nuclear MDM2 and/or CDK4 expression by immunohistochemistry and/or cytogenetic features of dedifferentiated liposarcoma. FISH for STAT6 was performed in all cases with STAT6 expression, and a subset of control cases without STAT6 expression. In total 4/35 cases (11%) showed STAT6 expression (three with multifocal staining of moderate to strong intensity and one with weak focal staining). FISH demonstrated amplification of STAT6 in all cases positive for STAT6 by immunohistochemistry; in contrast, FISH performed on four STAT6-negative dedifferentiated liposarcomas demonstrated no STAT6 amplification (P ¼ 0.0286). Of the four STAT6 amplified cases, three patients were male and one was female, ranging in age from 51 to 76 years. Tumors were located in the mediastinum (n ¼ 2), paratesticular soft tissue (n ¼ 1), and perirenal soft tissue (n ¼ 1). Three patients received pre-operative chemotherapy þ / À radiation therapy. In conclusion, STAT6 is amplified in a subset of dedifferentiated liposarcoma, resulting in STAT6 protein expression that can be detected by immunohistochemistry and may be a potential pitfall in the differential diagnosis of dedifferentiated liposarcoma and solitary fibrous tumor. These findings suggest a role for STAT6-mediated transcriptional activity in some cases of dedifferentiated liposarcoma and highlight the genomic complexity and heterogeneity of dedifferentiated liposarcoma.

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

“…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.…”

Immunohistochemistry as a surrogate to molecular diagnosis in pancreatic tumors

“…A potential pitfall is weak nuclear and cytoplasmic staining in a subset of retroperitoneal dedifferentiated liposarcomas, which likely represents amplification of the 12q13 region, where STAT6 is included within the MDM2 and CDK4 amplicon. 25 In these cases, overexpression of MDM2 and/or CDK4 would favor a diagnosis of dedifferentiated liposarcoma.…”

An Update on the Application of Newly Described Immunohistochemical Markers in Soft Tissue Pathology

“…64 Perhaps the greatest potential pitfall in the use of STAT6 for evaluating spindle cell lesions, particularly those in an intra-abdominal/retroperitoneal location, is the presence of STAT6 expression in approximately 7% to 15% of dedifferentiated liposarcomas, which likely represents amplification of the 12q13 region in this tumor type, where STAT6 is located close to MDM2 and CDK4. 60,62,193 The staining pattern in dedifferentiated liposarcoma is variable and may be focal or diffuse, weak or medium to strong in intensity, unlike the generally strong diffuse pattern seen in solitary fibrous tumor. In addition, unlike the predominantly nuclear pattern of staining seen in solitary fibrous tumor, both cytoplasmic and nuclear expression is common in dedifferentiated liposarcoma.…”

“…60 Other studies have since confirmed the high sensitivity and specificity of STAT6 for the diagnosis of SFT, with staining seen in a subset of dedifferentiated liposarcomas, and rarely in other tumor types. [60][61][62][63]193 The antibodies used differed in some of these studies, accounting for the additional cytoplasmic staining described by some authors; however, nuclear expression is expected in SFT. [61][62][63] Interestingly, a very recent study has shown a correlation between specific fusion types and morphology, with tumors with NAB2ex4-STAT6ex2/3 fusion genes corresponding to classic SFTs that arise most often in the pleura of older patients, show diffuse fibrosis, and typically have a benign clinical course.…”

“…In addition, unlike the predominantly nuclear pattern of staining seen in solitary fibrous tumor, both cytoplasmic and nuclear expression is common in dedifferentiated liposarcoma. 193 Diffuse expression of MDM2 and CDK4 helps favor a diagnosis of dedifferentiated liposarcoma, and if doubt persists, FISH for MDM2 amplification may also be useful. Because STAT6 and NAB2 are located close together on the long arm of chromosome 12, FISH to demonstrate rearrangement of the genes is technically challenging and not diagnostically useful.…”