STAT6: A review of a signaling pathway implicated in various diseases with a special emphasis in its usefulness in pathology.

Signal Transducer and Activator of Transcription 6 (STAT6), belonging to a family of seven similar members is primarily stimulated by interleukin(IL)-4 and IL-13, and acts as a T helper type 2 (Th2)-inducing factor. Thus, it is implicated in the pathophysiology of various allergic conditions, such as asthma, atopic dermatitis, eosinophilic esophagitis and food allergies, but also in tumor microenvironment regulation. Furthermore, certain forms of lymphomas, notably the Hodgkin lymphoma group, the primary mediastinal and primary central nervous system lymphoma, as well as some follicular and T cell lymphomas are associated with dysregulation of the STAT6 pathway. STAT6 immunohistochemical expression also serves as a surrogate marker in the diagnosis of solitary fibrous tumor, despite not directly responsible for the tumorigenic effect. These pathophysiological implications of the STAT6 pathway, its diagnostic or prognostic role in pathology, as well its immunohistochemical detection with different antibodies will be discussed in this review.

Intracranial solitary fibrous tumor: Report of two cases.

RATIONALE: Intracranial solitary fibrous tumor (ISFT) is a rare spindle cell tumor derived from dendritic mesenchymal cells expressing CD34 antigens, which are widely distributed in human connective tissues. PATIENT CONCERNS: In two case reports, we describe a 61-year-old woman and a 42-year-old man who present with intracranial malignant SFTs. Computed tomography or magnetic resonance imaging of head revealed that the largest size is about 3.3 × 3.0 cm in left occipital part and 4.0 × 3.0 cm in right skull base. DIAGNOSIS: Postoperative pathological results demonstrated that all of two cases are SFT. Case one: Immunohistochemical examination demonstrated a strong immunoreaction for cluster of differentiation (CD)34, B-cell lymphoma 2 (Bcl-2) and Vimentin (Vim). Case two: The tumor was distinctively positive for Bcl-2, but not for CD34 and Vim. INTERVENTIONS: One of the two patients recurred 6 years after the first tumor resection. After the recurrence, two gamma knife treatments were given, and another operation was performed about five years later. In one case, only tumor resection was performed. OUTCOMES: Case one: The postoperative neurological status was substantially improved and regular follow-up examinations for 6 months postsurgery have shown that the patient is currently disease-free. Case two: The patient achieved a good outcome, with no epilepsy or other neurological symptoms experienced on a regular 6-month follow-up. The patient is currently disease free. LESSONS: Imaging findings can be used to assist the diagnosis. The diagnostic method is pathology, and total surgical resection is the most effective treatment. The main treatment methods were total resection, supplemented by radiotherapy and chemotherapy if necessary.

CD34 + tumours of the orbit including solitary fibrous tumours: a six-case series.

BACKGROUND: To report six cases of CD34+ fibroblastic mesenchymal tumours, which are uncommon neoplasms in the orbit. CASE PRESENTATION: Six patients presenting with proptosis and palpable mass who were later diagnosed with fibrous solitary tumours, fibrous histocytoma or haemangiopericytoma in the orbit were included. All patients received radiologic examinations and surgical excision for histopathology and immunohistochemistry examinations. Five patients had no recurrence after a minimum follow-up of 12 months. One patient (case 6) experienced recurrence twice, and had debulking surgeries each time. At present, the patient still has remnant tumour in the orbit, but no growth has been detected during the past two years. The tumour size will be closely monitored. CONCLUSIONS: Even though fibroblastic tumours are rarely found in the orbit, they can present as a palpable mass with proptosis. Complete surgical excision is important for long-term prognosis, and immunohistochemical study is helpful for confirming pathologic diagnosis.

Variable Solitary Fibrous Tumor Locations: CT and MR Imaging Features.

The aim of the study is to describe the radiological imaging features of different solitary fibrous tumors (SFTs) locations and present histopathological correlations. From 2007 to 2013, 20 cases of histologically confirmed that SFTs were retrospectively analyzed with computed tomography (CT; 9/20), magnetic resonance imaging (MRI; 5/20), or both CT and MRI (6/20). All 20 SFTs were well defined, lobular, soft-tissue masses, and 60% were located outside of the pleura. One pleural case invaded to the 10th thoracic vertebra and had lung metastases. Images revealed 11 heterogeneous lesions that exceeded 3.0 ± 0.203 cm along the greatest axis with patchy necrotic foci, and 9 homogeneous lesions <3.0 ± 0.203. Microscopically, all SFTs were proliferative spindle cells with varying degrees of fibrosis and interspersed vessel branching. Cells were strongly immunopositive for CD34. Here we review variable imaging findings of SFTs, which can be within the pleura as well as within other serosal tissues such as the meninges and postperitoneum. SFTs > 3.0 ± 0.203 cm along the greatest axis appeared to be mixed patterns, whereas SFTs < 3.0 ± 0.203 cm had isodense appearances. SFTs cells were CD34 immunopositive and surgery was a first-line treatment choice.

The pericyte antigen RGS5 in perivascular soft tissue tumors.

Perivascular soft tissue tumors are relatively uncommon neoplasms of unclear lineage of differentiation, although most are presumed to originate from or differentiate to pericytes or a modified perivascular cell. Among these, glomus tumor, myopericytoma, and angioleiomyoma share a spectrum of histologic findings and a perivascular growth pattern. In contrast, solitary fibrous tumor was once hypothesized to have pericytic differentiation--although little bona fide evidence of pericytic differentiation exists. Likewise the perivascular epithelioid cell tumor (PEComa) family shares a perivascular growth pattern, but with distinctive dual myoid-melanocytic differentiation. RGS5, regulator of G-protein signaling 5, is a novel pericyte antigen with increasing use in animal models. Here, we describe the immunohistochemical expression patterns of RGS5 across perivascular soft tissue tumors, including glomus tumor (n = 6), malignant glomus tumor (n = 4), myopericytoma (n = 3), angioleiomyoma (n = 9), myofibroma (n = 4), solitary fibrous tumor (n = 10), and PEComa (n = 19). Immunohistochemical staining and semi-quantification was performed, and compared to αSMA (smooth muscle actin) expression. Results showed that glomus tumor (including malignant glomus tumor), myopericytoma, and angioleiomyoma shared a similar diffuse immunoreactivity for RGS5 and αSMA across all tumors examined. In contrast, myofibroma, solitary fibrous tumor and PEComa showed predominantly focal to absent RGS5 immunoreactivity. These findings further support a common pericytic lineage of differentiation in glomus tumors, myopericytoma and angioleiomyoma. The pericyte marker RGS5 may be of future clinical utility for the evaluation of pericytic differentiation in soft tissue tumors.

FDG PET/CT and MR imaging of CD34-negative soft-tissue solitary fibrous tumor with NAB2-STAT6 fusion gene.

Extrapleural solitary fibrous tumor (SFT) is an uncommon mesenchymal neoplasm of intermediate biological potential. Herein, we describe the radiological, histological, immunohistochemical and molecular genetic features of an SFT arising in the left thigh of a 55-year-old woman. Magnetic resonance imaging exhibited a well-defined mass with intermediate signal intensity on T1-weighted sequences and heterogeneous high signal intensity on T2-weighted sequences. Contrast-enhanced T1-weighted sequences showed strong homogeneous enhancement of the mass. A prominent vascular pedicle was visible. Integrated positron-emission tomography (PET)/computed tomographic (CT) scan demonstrated a moderate 18F-fluorodeoxyglucose (FDG) uptake (maximum standardized uptake value, 4.45) in the mass. Following an open biopsy, wide excision of the tumor was performed. Histologically, the tumor was composed of a proliferation of spindle cells in a fibrous stroma with focal hyalinization. Thin-walled branching hemangiopericytoma-like vessels were observed. Immunohistochemically, the tumor cells were diffusely positive for signal transducer and activator of transcription 6 (STAT6) but negative for CD34. The MIB-1 labeling index was less than 5%. Subsequent reverse transcriptase-polymerase chain reaction analysis identified a nerve growth factor inducible-A binding protein 2-STAT6 gene fusion. Our case supports the utility of STAT6 immunohistochemistry as an adjunct in the diagnosis of soft-tissue SFT with loss of CD34 positivity. To the best of our knowledge, this is the first report showing the FDG PET/CT findings of soft-tissue SFT.

Adaptive immune contexture at the tumour site and downmodulation of circulating myeloid-derived suppressor cells in the response of solitary fibrous tumour patients to anti-angiogenic therapy.

BACKGROUND: Host immunity is emerging as a key player in the prognosis and response to treatment of cancer patients. However, the impact of the immune system and its modulation by therapies are unknown in rare soft tissue sarcomas such as solitary fibrous tumours (SFTs), whose management in the advanced forms includes anti-angiogenic therapy. Here, we studied the in situ and systemic immune status of advanced SFT patients and the effects of sunitinib malate (SM) in association with the clinical efficacy. METHODS: Immune contexture of SFTs was assessed by immunohistochemistry in lesions from untreated or SM-treated patients. Frequency of circulating myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs) and T-cell functions was assessed ex vivo in SFT patients prior and during anti-angiogenic therapy. Patients with long-term tumour control were included to correlate immune profiles and clinical responses. RESULTS: Anti-angiogenic naïve SFT lesions were heavily infiltrated by CD163(+)CD14(+)CD68(-) and CD163(+)CD14(-)CD68(-) myeloid cells but devoid of T cells. Conversely, post-SM tumours acquired a new subset of CD68(+)CD14(+) myeloid cells and displayed traits of an on-going adaptive immunity, strongly enriched in activated CD8(+) and CD4(+) T cells. These changes at the tumour site paralleled the alleviation of systemic immunosuppression and the drop in the frequency of circulating monocytic MDSCs (mMDSCs) and granulocytic MDSCs (gMDSCs). Rebound in the number of mMDSCs, but not of gMDSCs occurred at disease progression, and a reduced percentages of mMDSCs, comparable to those found in healthy donors (HDs), endured only in the SM-responsive patients. CONCLUSIONS: The immune contexture of SFT patients is heavily involved in anti-angiogenic therapy and it could be exploited to achieve more durable disease control through immune-based combination strategies.

Orbital solitary fibrous tumor: encompassing terminology for hemangiopericytoma, giant cell angiofibroma, and fibrous histiocytoma of the orbit: reappraisal of 41 cases.

Hemangiopericytomas and solitary fibrous tumors are uncommon neoplasms found in many locations, including the orbit. Both mesenchymal neoplasms share several clinicopathologic features, thus prompting intense debate as to whether they are variants of the same entity or merit separate designations in the orbit. These 2 entities, with the addition of giant cell angiofibroma of orbit, are of benign- to uncertain-behavior, CD34-positive, collagen-rich, specialized fibroblastic tumors, which may have overlapping or histologically identical features. In addition, so-called fibrous histiocytoma of orbit, a previous designation, has overlapping morphologic features with these tumors. To date, a large series of these collagen-rich fibroblastic tumors of the orbit has not been fully explored. Forty-one fibroblastic orbital tumors, originally diagnosed as hemangiopericytomas (n = 16), fibrous histiocytomas (n = 9), mixed tumors (hemangiopericytomas/fibrous histiocytoma) (n = 14), and giant cell angiofibromas of orbit (n = 2) between 1970 and 2009, were retrieved from our consultation files, the Ophthalmic Registry, at the Armed Forces Institute of Pathology. Slides and clinical records were reviewed, analyzed, and compared. Immunochemistry was performed for CD34, CD99, Bcl-2, Ki-67, and p53. Upon histologic review, all cases were reclassified as solitary fibrous tumor (41/41). The patients included 23 (56%) males, 17 (41%) females, and 1 unknown, with a mean age at presentation of 40.7 years (range, 16-70 years). The sites of involvement were the right orbit in 18 (44%) cases and the left in 16 (39%) cases. Tumors ranged in size from 0.4 to 5.0 cm (mean, 2.2 cm). Seventeen (41%) patients presented with an orbital mass, 8 (20%) with proptosis, 2 (5%) with painful mass, and 2 (5%) with painless mass. Duration of symptoms ranged from 3 to 96 months, with a mean of 23 months (median, 9 months). Microscopically, all lesions showed considerable similarity, varying in degree of cellularity, stromal collagen, and the presence of giant cells. Overlapping features with soft tissue giant cell fibroblastoma were observed. Immunochemistry revealed positivity for CD34 in all cases (100%), p53 in 85%, CD99 in 67.5%, and Bcl-2 in 47.5%. Although Ki-67 labeling was seen in all cases, it ranged from less than 1% in 54.3% of cases to 5% to 10% in 20% of cases. Taken together, the findings of this study suggest that orbital hemangiopericytoma and some cases previously designated as fibrous histiocytoma, giant cell angiofibroma of orbit, and solitary fibrous tumor have overlapping morphologic and immunohistochemical features and should be designated as solitary fibrous tumor. Adipocytes and unusual multivacuolated adipocytic cells may be present in these tumors, as well stromal myxoid change; and even stromal intramembranous ossification can be observed. There are overlapping features of orbital solitary fibrous tumor with another CD34-positive specialized fibroblastic tumor of soft tissue, giant cell fibroblastoma. Morphologic criteria for uncertain behavior to low-grade malignant ocular solitary fibrous tumors can be made by cytologic atypia and increased mitotic activity, but overall outcome for malignant solitary fibrous tumors of the eye should be further explored.

Cutaneous CD34+ spindle cell neoplasms: Histopathologic features distinguish spindle cell lipoma, solitary fibrous tumor, and dermatofibrosarcoma protuberans.

Spindle cell lipoma (SCL), dermatofibrosarcoma protuberans (DFSP), and solitary fibrous tumors (SFT) are cutaneous CD34+ spindle cell tumors that may exhibit histopathologic and immunophenotypic overlap. We sought ways to reliably distinguish among these lesions even in small or superficial biopsies. Ten morphologic characteristics were analyzed in a group of 5 SCLs, 6 cutaneous SFTs, and 12 DFSPs. SFT and DFSP exhibited extensive histopathologic overlap in small or partial biopsies. However, adnexal entrapment, defined as diffuse proliferation of tumor cells around pilosebaceous and eccrine structures with minimal disruption or expansion of the dermis, was a feature seen in 10 of the 12 DFSPs and in none of the SFTs or SCLs. Even when only superficial portions of a lesion were present, this feature was identifiable. Spindle cell lipomas posed little diagnostic difficulty, in part because excisional biopsies were performed in all cases of SCL. The number of samples included in the study is relatively small, in part due to the rarity of cutaneous solitary fibrous tumors. We conclude that careful attention to these histopathologic features enables reliable distinction among these tumors.

Lines of cell differentiation in solitary fibrous tumor: an ultrastructural and immunohistochemical study of 10 cases.

BACKGROUND: Solitary fibrous tumor (SFT) is a rare ubiquitous mesenchymal neoplasm of probable fibroblastic type with a prominent hemangiopericytoma-like vascular pattern. Since their initial description as arising from the pleura, SFTs have been reported in many extraserosal sites. It is now accepted that this neoplasm is derived from mesenchymal cells but its histogenesis is still not known. METHODS: The authors gathered clinical data on 10 patients with SFT. Tissue microarrays were constructed to perform inmunohistochemical tests and we reviewed hematoxilin-eosin-stained slides. Electron-microscopically collected samples were fixed with formalin or Karnovsky reactive and embedded in epoxy resin. RESULTS: The histopathological review showed varying degrees of cell density and mitotic activity, which correlated with clinical behavior. Immunohistochemically most tumors stained positively for vimentin, CD99, and CD34. Ultrastructural study showed some degree of myofibroblastic differentiation in all cases and focal smooth muscle features. In addition, 9 cases showed perivascular undifferentiated cells. CONCLUSION: SFT is an uncommon neoplasm with different histological patterns and clinical behavior. The authors hypothesize that the perivascular undifferentiated cells that most cases showed might correspond to a quiescent stage of adult stem mesenchymal cell and could be the target of the molecular aberrations implied in its pathogenesis.

Solitary fibrous tumor of the liver expressing CD34 and vimentin: a case report.

A case of a successfully treated solitary fibrous tumor (SFT) of the liver is reported. An 82-year-old female presented with left upper abdominal discomfort, a firm mass on palpation, and imaging studies revealed a large tumor, 15 cm in diameter, arising from the left lobe of the liver. A formal left hepatectomy was performed. Microscopic evaluation showed spindle and fibroblast-like cells within the collagenous stroma. Immunohistochemistry disclosed diffuse CD34 and positive vimentin, supporting the diagnosis of a benign SFT. The patient remained well 21 months after surgery. SFT of the liver is a very rare neoplasm of mesenchymal origin. In most cases it is a benign lesion, although some may have malignant histological features and recur locally or metastasize. With less than 30 reported cases in the literature, little can be said regarding its natural history or the benefits of adjuvant radiochemotherapy. Complete surgical resection remains the cornerstone of its treatment.